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April 2007, Volume 20, Issue 2,pp.115-236 Editorial introductions vii Editorial introductions. Skin and soft tissue infections Edited by Roderick J. Hay 115 Fusarium infections of the skin. Rod J Hay Skin and soft tissue infections 118 Acute bacterial skin infections and cellulitis. Marion Gabillot-Carré; Jean-Claude Roujeau 124 Infection following soft tissue injury: its role in wound healing. Terence J Ryan 129 Infectious keratitis. Philip Aloysius Thomas; Pitchairaj Geraldine 142 New fungal nail infections. Matilde Iorizzo; Bianca Maria Piraccini; Antonella Tosti 146 Management of mycetoma: major challenge in tropical mycoses with limited international recognition. Abdalla AO Ahmed; Wendy WJ van de Sande; Ahmed Fahal; Irma Bakker-Woudenberg; Henri Verbrugh; Alex van Belkum 152 Transmission of human herpesvirus 8: an update. Francesca Pica; Antonio Volpi Respiratory infections 157 Molecular diagnostic methods in pneumonia. Yvonne R Chan; Alison Morris 165 Prognostic scoring systems: which one is best?. Charles Feldman 170 New guidelines for the management of adult community-acquired pneumonia. Kathryn Armitage; Mark Woodhead 177 How long should we treat community-acquired pneumonia?. Nikole M Scalera; Thomas M File Jr 182 Performance measures for pneumonia: are they valuable, and are process measures adequate?. Dale W Bratzler; Wato Nsa; Peter M Houck 190 Prevention measures for ventilator-associated pneumonia: a new focus on the endotracheal tube. Paula Ramirez; Miquel Ferrer; Antoni Torres 198 Therapy of nontuberculous mycobacterial disease. David E Griffith Editorial introductions Current Opinion in Infectious Diseases was launched in 1988. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of infectious diseases is divided into 12 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal’s Section Editors for this issue. tious Diseases; and the Royal College of Physicians Examination Committee. Professor Hay has authored over 400 scientific papers, books and reports on medical mycology and tropical dermatology, focusing on antifungal chemotherapy, cellular immunology and epidemiology. His present areas of research include a study of the antigenic and molecular structure of dimorphic fungi such as Penicillium marneffei, Histoplasma capsulatum and Paracoccidioides brasiliensis, an investigation of cellular immunity in dermatophytosis, and a study of virulence factors in Cryptococcus neoformans and Aspergillus fumigatus. Section Editors Michael S. Niederman Roderick James Hay Professor Hay was born in Cobham, Surrey, grew up in Devon, and now lives in Helen’s Bay, Co Down, N Ireland. He was educated at Oxford University and Guy’s Hospital Medical School, and has been a Lecturer/Senior Registrar at the London School of Hygiene and Tropical Medicine and at the St Johns Hospital for Diseases of the Skin. He has also been a Research Fellow at the Centers for Disease Control, Atlanta. Professor Hay is currently Head of the School of Medicine and Dentistry and a former Dean of the Faculty of Medicine and Health Sciences at Queens University Belfast. He is also Professor of Dermatology at Queens University, Visiting Professor in Tropical and Infectious Diseases at the London School of Hygiene and Tropical Medicine, and Chairman of the International Foundation of Dermatology. Professor Hay was President of the British Association of Dermatologists in 2001–2002, the British Society for Medical Mycology from 1997–2002, and the European Confederation of Medical Mycology from 1998–2002. He serves on a number of boards including: the Eastern Health and Social Services Board; the International Committee of Dermatology; the Northern Ireland Council for Postgraduate Medical and Dental Education; the Joint Royal Colleges Committee on Infec- Michael Niederman is Professor and Vice-Chairman of the Department of Medicine at the State University of New York at Stony Brook, and Chairman of the Department of Medicine at Winthrop-University Hospital in Mineola, New York. He obtained his medical degree from Boston University School of Medicine, and then completed his training in internal medicine at Northwestern University School of Medicine, before undertaking a pulmonary and critical care fellowship at Yale University School of Medicine. His interests lie in respiratory tract infections. These include mechanisms of airway colonization, the management of community- and hospital-acquired pneumonia, and the impact of antibiotic resistance on the management and outcomes of respiratory tract infections. Dr Niederman served as co-chairman of the committees that created the American Thoracic Society 1993 and 2001 guidelines for the treatment of community-acquired pneumonia, and the 1996 and 2005 committees that wrote guidelines for the treatment of nosocomial pneumonia. He is also Editor-in-Chief of Clinical Pulmonary Medicine, and has served on the editorial boards of The American Journal of Respiratory and Critical Care Medicine, Critical Care Medicine, and Chest. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. EDITORIAL REVIEW Fusarium infections of the skin Rod J. Hay School of Medicine and Dentistry, Queens University Belfast, Belfast, UK Correspondence to Professor Rod J. Hay, School of Medicine and Dentistry, Queens University Belfast, 73 University Road, Belfast BT7 1NN, UK Tel: +44 2890 973282/3; fax: +44 2890 971445; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:115–117 ß 2007 Lippincott Williams & Wilkins 0951-7375 Fungi of the genus Fusarium are nonpigmented organisms that are occasional pathogens of humans [1]. Their natural habitat is the natural environment, and they are important causes of contamination of soil and plant debris as well as causes of major economic diseases of grain crops, both in the field and in harvested grain stored under wet conditions. Their conidia are disseminated on air currents, and are most often found in the airborne flora in summer and autumn, particularly after rain [2,3]. Fusaria have long been recognised as important causes of mycotoxicoses such as toxic aleukia associated with ingestions of contaminated food, but they also cause poisoning in animals, such haemorrhagic and oestrogenic syndromes. The T2 toxin produced by fusaria is, for instance, an inhibitor of protein synthesis and it may also affect platelet aggregation. Another important group of toxins are the tricothecenes which affect immunity, but they are also toxic to the skin. It is not clear if these organisms’ pathological capabilities are enhanced by their production of a wide range of tissue toxins. Fusaria are, however, found to cause a number of important human diseases. These include disseminated fusariosis seen mainly in neutropenic subjects and increasingly described in association with severe neutropenic states associated with the management of leukaemia [4]. In Europe and the US the distribution of these infections varies; the infections are commoner for instance in Italy and France than elsewhere in Europe, although there is considerable variation in incidence between different hospital units. Fusarium species may cause localised deep infections [5], e.g. of the peritoneum following contamination of peritoneal dialysis catheters. In addition, these organisms also cause eumycetomas and corneal infections, mycotic keratitis, that may progress to endophthalmitis. Fusaria are sometimes found growing on leg ulcers, including diabetic ulcers, as well as the surface of burns, and cause deep invasion from these sites. In the skin there are a number of presentations of infection due to fungi of this genus. In all cases it is important to establish that they are truly acting as pathogens, e.g. by ensuring that there is evidence (such as microscopy) of tissue penetration. Skin disease caused by Fusarium species include onychomycosis, tinea pedis, localised abscesses or disseminated lesions following haematogenous dissemination The disseminated infections have a high mortality as patients are usually very severely neutropenic and responses to antifungals are variable, although successes have been recorded with amphotericin B (lipid associated) and voriconazole; some species are also sensitive in vitro to the newer triazole, posaconazole (see below). Sites infected included blood, liver and brain, in addition to skin lesions that are a common feature of disseminated infections [5,6]. While in some cases the route of infection is probably the respiratory tract, in others there is evidence of cellulitis affecting a digit (usually a toe) preceding the onset of clinical dissemination, suggesting that in these cases the skin was the source. In all such cases there is evidence of nail disease, which once again may serve as the source of infection. Clinical examination of nails, and if necessary laboratory confirmation of a possible infection as well as treatment, has been advised as a preventive measure in units treating severely neutropenic patients. The skin lesions associated with superficial infection by fusaria share a number of different attributes. For instance, in nail disease these organisms cause superficial white onychomycosis [7], proximal subungual onychomycosis [8], and distal and lateral subungual onychomycosis [9]. The more severe forms may progress to total dystrophic onychomycosis. In many cases the nail shows dense white discolouration, but melanonychia has been recorded due to F. solani [10]. In other words, fusaria cause the full repertoire of clinical forms of onychomycosis apart from endonyx infections. Fusarium infection may present with acute paronychia-like reaction with inflammatory change at the proximal nail fold [11]. This is often a primary infection, although fusaria are occasionally isolated from chronic paronychia. In tinea pedis it causes a macerated interdigital infection occasionally mixed with other fungi, yet often it appears to be the sole agent. [9,12]. This is most often seen in tropical environments where it is confused with tinea pedis due to dermatophytes, although there is usually erosive change more suggestive of a Gram-negative bacterial infection. There is debate as to whether this is secondary contamination rather than a true infection, although repeated isolations and the presence of hyphae suggest that it is a pathogen in its own right. In addition, Fusarium has also 115 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 116 Skin and soft tissue infections been found to cause a severe hyperkeratotic form of plantar infection [13]. Fusaria may also invade ulcerated areas of the skin including diabetic or arterial ulcers [14,15]. This is seen in the nonimmunocompromised patient. In patients with severe burns, fusaria, which are often confused initially with aspergilli, may invade burn wounds [16], and from there attack normal skin and lead to systemic invasion. It is important to recognise these fungi as causes of complicated burns infections in view of the potential fatal outcome. The rash of disseminated fusariosis is very typical, with widespread annular lesions often with a central dark or even haemorrhagic area [5]. Lesions are widely scattered on the trunk and limbs, and are usually large (1–2 cm in diameter). The means by which fusaria penetrate the skin is not known. There is no clear evidence as yet that they produce identifiable keratin-splitting enzymes, although they do produce proteases, including extracellular proteases with trypsin- or subtilisin-like properties [17]. Using a crude keratin assay, fusaria isolated from skin have been shown to break down keratin [18]. There is, however, another possibility as there is evidence from in-vitro studies of mycotoxins produced by fusaria, particularly the tricothecenes, and that these are potentially toxic to the epidermis and dermis [19]. In addition, they have specific effects on dendritic cells [20]. Hence, they may contribute to cell destruction as well as defective host defence. Fusaria isolated from mycotic keratitis have been shown to produce mycotoxins in culture [21]. At this stage, however, it has not been possible to prove the production of toxins in situ, although this remains a potential source of epidermal toxicity. Fusarium species recorded as causes of human disease include F. chlamydosporum, F. moniliforme, F. nivale, F. oxysporum, F. proliferatum, F. solani and F. verticillioides amongst others [1]. Although usually identified by culture, molecular techniques using polymerase chain reaction and primers provide an alternative and rapid means of identification, and have been applied to skin or nail infections [22]. Treatment of these infections is problematic. In the case of disseminated disease, successful treatments have been recorded with amphotericin B in high dosage, usually in the liposomal formulation, as well as voriconazole and posaconazole. The studies carried out to date with posaconazole have been based largely on anecdotal experience, but have shown 50% cure rates for Fusarium infections in patients with neutropenia [23]. Similarly, there are case reports of efficacy in complicated eye infection where keratitis and endophthalmitis are combined [24]. The same is true of voriconazole for which there is also case-based evidence of efficacy in endophthalmitis [25]. These drugs are not suitable for use in superficial skin infections or nail disease. Itraconazole has been recorded as being effective in some cases of nail disease caused by Fusarium spp. Topical terbinafine or azoles may work against tinea pedis caused by these fungi. Where these organisms invade skin ulcers their presence is potentially more serious and the use of an oral drug such as voriconazole is preferred. The source of Fusarium infections of the skin remains something a mystery. Although the organisms are common in the environment, it is not clear how they gain a foot-hold on the skin surface in addition to open wounds. There is, however, a growing literature on infections caused by these fungi in both the immunocompromised as well as the healthy patient. Systemic Fusarium infections have been recognised for a number of years as infections with a high mortality. It now appears that the species are increasingly involved in superficial infections of the skin as they are in the cornea. References 1 Moore CB, Denning DW. Deep hyalohyphomycosis. In: Merz WG, Hay RJ, editors. Medical mycology. Topley and Wilson’s microbiology and microbial infections, 10th edition. London: Hodder Arnold; 2005. pp. 739–762. 2 Raad I, Tarrand J, Hanna H, et al. Epidemiology, molecular mycology, and environmental sources of Fusarium infection in patients with cancer. Infect Cont Hosp Epidemiol 2002; 23:532–537. 3 Nir-Paz R, Strahilevitz J, Shapiro M, et al. Clinical and epidemiological aspects of infections caused by Fusarium species: a collaborative study from Israel. J Clin Microbiol 2004; 42:3456–3461. 4 Girmenia C, Pagano L, Corvatta L, et al. The epidemiology of fusariosis in patients with haematological diseases. Gimema Infection Programme. Br J Haematol 2000; 111:272–276. 5 Hennequin C, Lavarde V, Poirot JL, et al. Invasive Fusarium infections: a retrospective survey of 31 cases. The French ‘Groupe d’Etudes des Mycoses Opportunistes’ GEMO. J Med Vet Mycol 1997; 35:107–114. 6 Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years’ experience at a cancer center and implications for management. Blood 1997; 90:999–1008. 7 Piraccini BM, Tosti A. White superficial onychomycosis: epidemiological, clinical, and pathological study of 79 patients. Arch Dermatol 2004; 140:696–701. 8 Calado NB, Sousa F Jr, Gomes NO, et al. Fusarium nail and skin infection: a report of eight cases from Natal. Brazil Mycopathol 2006; 161: 27–31. 9 Romano C, Miracco C, Difonzo EM. Skin and nail infections due to Fusarium oxysporum in Tuscany, Italy. Mycoses 1998; 41:433–437. 10 Lee HJ, Koh BK, Moon JS, et al. A case of melanonychia caused by Fusarium solani. Br J Dermatol 2002; 147:607–608. 11 Gianni C, Cerri A, Crosti C. Unusual clinical features of fingernail infection by Fusarium oxysporum. Mycoses 1997; 40:455–459. 12 Romano C, Gianni C. Tinea pedis resulting from Fusarium spp. Int J Dermatol 2002; 41:360–362. 13 Pereiro M Jr, Labandeira J, Toribio J. Plantar hyperkeratosis due to Fusarium verticillioides in a patient with malignancy. Clin Exp Dermatol 1999; 24:175– 178. 14 Girardi M, Glusac EJ, Imaeda S. Subcutaneous Fusarium foot abscess in a renal transplant patient. Cutis 1999; 63:267–270. 15 Willemsen MJ, De Coninck AL, Coremans-Pelseneer JE, et al. Parasitic invasion of Fusarium oxysporum in an arterial ulcer in an otherwise healthy patient. Mykosen 1986; 29:248–252. 16 Latenser BA. Fusarium infections in burn patients: a case report and review of the literature. J Burn Care Rehabil 2003; 24:285–288. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Editorial review: Fusarium infections Hay 117 17 Di Pietro A, Huertas-Gonzalez MD, Gutierrez-Corona JF, et al. Molecular characterization of a subtilase from the vascular wilt fungus Fusarium oxysporum. Mol Plant-Microbe Interact 2001; 14:653–662. 22 Alexandrakis G, Jalali S, Gloor P. Diagnosis of Fusarium keratitis in an animal model using the polymerase chain reaction. Br J Ophthalmol 1998; 82:306– 311. 18 Oycka CA, Gugnani HC. Keratin degradation by Scytalidium species and Fusarium solani. Mycoses 1998; 41:73–76. 23 Raad II, Hachem RY, Herbrecht R, et al. Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions. Clin Infect Dis 2006; 42:1398–1403. 19 Bhavanishankar TN, Ramesh HP, Shantha T. Dermal toxicity of Fusarium toxins in combinations. Arch Toxicol 1988; 61:241–244. 20 Hymery N, Sibiril Y, Parent-Massin D. In vitro effects of trichothecenes on human dendritic cells. Toxicol In Vitro 2006; 20:899–909. 21 Naiker S, Odhav B. Mycotic keratitis: profile of Fusarium species and their mycotoxins. Mycoses 2004; 47:50–56. 24 Sponsel WE, Graybill JR, Nevarez HL, Dang D. Ocular and systemic posaconazole (SCH-56592) treatment of invasive Fusarium solani keratitis and endophthalmitis. Br J Ophthalmol 2002; 86:829–830. 25 Klont RR, Eggink CA, Rijs AJ, et al. Successful treatment of Fusarium keratitis with cornea transplantation and topical and systemic voriconazole. Clin Infect Dis 2005; 40:e110–e112. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Acute bacterial skin infections and cellulitis Marion Gabillot-Carré and Jean-Claude Roujeau Purpose of review Acute bacterial skin infections are very common, with various presentations and severity. This review focuses on deep skin infections. We separate acute nonnecrotizing infections of the hypodermis (erysipelas), forms with abscesses or exudates and necrotizing fasciitis. These three types actually differ in risk factors, bacteriology, treatment and prognosis. Recent findings Leg erysipelas/cellulitis occurs in more than one person/ 1000/year. It remains mainly due to streptococci. Foot intertrigo is an important risk factor. Necrotizing fasciitis is much rarer and usually occurs in patients with chronic diseases. Staphylococci, especially community-acquired methicillin-resistant strains in some areas, play a growing role in the intermediate form of cellulitis with abscesses and exudates. For erysipelas or noncomplicated cellulitis, antibiotic treatment at home, when feasible, is much less expensive and as effective as hospital treatment. Intermediate cases with collections and exudates often require surgical drainage. For necrotizing fasciitis early surgery remains essential in order to decrease the mortality rate. Summary Antibiotic treatment of deep skin infections must be active on streptococci; the choice of a larger spectrum of activity depends on clinical presentation, risk factors and the burden of methicillin-resistant staphylococci in the environment. Keywords acute bacterial skin infection, cellulitis, erysipelas, necrotizing fasciitis, skin and soft tissue infection Curr Opin Infect Dis 20:118–123. ß 2007 Lippincott Williams & Wilkins. Hopital Henri Mondor, Créteil, France Correspondence to Jean-Claude Roujeau, MD, Hopital Henri Mondor, 51 avenue Du Mal de Lattre de Tassigny, 94010 Créteil, France Tel: +33 0 1 49 81 25 12; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:118–123 Abbreviations CA IVIG MRSA community-associated intravenous immunoglobulin methicillin-resistant Staphylococcus aureus ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction The objective of this paper is to provide a critical review of recent publications on ‘skin and soft tissue infections’. Rather than a systematic review, it is the choice of what we consider of special interest from our biased point of view. We will discuss neither the problem of ‘diabetic foot’ nor opportunistic infections in immunocompromised patients as both raise specific questions in terms of clinical presentation, diagnosis and management. We will restrict our review to deep infections of the skin and try to avoid the common denomination of cellulitis, which we do not consider appropriate. ‘Soft tissues’ comprise muscles, fascia and the three layers of the skin: epidermis, dermis and the thickest hypodermis. Myositis or fasciitis clearly indicates which tissues are affected, but cellulitis does not. Most commonly, cellulitis indicates acute, nonnecrotizing inflammation of the dermis and hypodermis. That is not always related to infection. For example, Wells ‘cellulitis’ results from eosinophil infiltration of the dermis and hypodermis. ‘Cellulitis’ also occurs as a manifestation of Mediterranean fever or other inflammatory syndromes. When the inflammation results from infection the denomination should better be acute infectious nonnecrotizing hypodermatitis (which we consider a synonym for erysipelas). The denomination of ‘cellulitis’ is commonly used for both erysipelas and more severe forms that include tissue necrosis, collections or exudates, but do not involve the fascia. On the other hand, early necrotizing fasciitis may occasionally have little impact on the hypodermis and dermis with no patent inflammation of the skin. Whatever the denomination, it is of key importance to distinguish acute nonnecrotizing infections of the hypodermis, intermediate forms with abscesses or exudates (usual presentation of infections complicating diabetes or immunosuppression) and necrotizing fasciitis. These three types actually differ by clinical features, epidemiology, risk factors, bacteriology, treatment and prognosis. It is frequently admitted that the initial stages of the three types are undistinguishable. Very early severe forms can, however, be recognized by the rapid progression of local and systemic signs. Local signs include purple blisters, necrosis, pain out of proportion, marked edema, crepitus and anesthesia of some skin areas. Systemic toxicity is marked with hypotension, tachycardia, body temperature below 35 or above 408C and confusion. 118 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Acute bacterial skin infections Gabillot-Carré and Roujeau 119 Epidemiology and risk factors There are few data on incidence. Those concerning necrotizing fasciitis suggested a figure of about 1–4/106/ year in Canada [1]. A recent study in The Netherlands provided an incidence of about 2/1000/year when all forms of ‘cellulitis/erysipelas’ of the leg were taken together [2]. Even though performed in different countries with different methods, these studies evidence the frequent occurrence of ‘cellulitis’ in contrast to the rarity of necrotizing fasciitis. The Dutch study provided additional information: only 7% of the cases resulted in hospitalization, but these accounted for 83% of the total treatment costs. Not surprisingly the rate of hospital admission for ‘cellulitis/erysipelas’ increased sharply after 60 years of age to reach 1/1000/year in those aged above 75 [2]. we postulate that cellulitis with collections and exudates mostly share the risk factors of necrotizing fasciitis, principally diabetes mellitus. Several case reports had linked the occurrence or severity of necrotizing cellulitis to the use of nonsteroidal antiinflammatory drugs. A thorough review of available evidence (including large series, cohorts and case–control studies) concluded that such drugs do not increase the risk of occurrence or adversely affect the course of necrotizing fasciitis [8]. Furthermore, a controlled therapeutic trial showed a significant improvement of cellulitis by the association of nonsteroidal antiinflammatory drugs and antibiotics [9]. Diagnostic procedures Several epidemiological studies focused on risk factors. At least four case–control studies were devoted to erysipelas leading to hospitalization in recent years, and provided consistent results concerning both systemic and loco-regional risk factors [3–5,6]. Among systemic factors, only being overweight and having a history of prior cellulitis were constantly associated with increased risks. Diabetes was not a risk factor for erysipelas. Locoregional factors included chronic edema, lymphedema, surgery of regional nodes, saphenectomy, acute or chronic alteration of the cutaneous barrier and, especially, toe web intertrigo. Concerning toe web intertrigo, risk factors were higher for clinically patent intertrigo [3] than for cases where dermatophyte infection was proven by mycology [4]. Detection in the lesions of Gram-positive cocci was more frequent than that of dermatophytes [5]. Taken together, these results confirm that toe web intertrigo is a major portal of entry whether due or not to dermatophytes. Bacteriology examinations from needle aspiration, skin biopsy and blood culture are useless in erysipelas, because of the very low yield of positive results [10]. In patients with fissured interdigital toe spaces the responsible pathogens can be found locally in up to 50% of cases [5]. Most are streptococci. Bacterial sampling of portal of entry should be considered in populations where there is a high prevalence of methicillin-resistant Staphylococcus aureus (MRSA). The situation is totally different in necrotizing fasciitis or ‘cellulitis’ with collections or exudates. Needle aspiration and blood cultures are much more fruitful, and allow identification of one or several pathogens in more than two-thirds of cases [7]. This procedure should be considered for patients with diabetes mellitus, malignancy and unusual predisposing factors, such as immersion injury, animal bites, neutropenia and immunodeficiency [10,11]. Microbiology There is less data on risk factors for necrotizing fasciitis. Cohort studies [1,7] pointed principally to the high prevalence of comorbidities, especially diabetes mellitus and alcoholic liver diseases in adults, and varicella (chickenpox) in children. Based on these data it appears that risk factors for erysipelas and necrotizing fasciitis are different, as summarized in Table 1. From our clinical experience Table 1 Risk factors for erysipelas and necrotizing fasciitis [1,3–5,6,7] Erysipelas Necrotizing fasciitis Overweight Edema, lymphedema Prior leg surgery, especially saphenectomy History of erysipelas Leg ulcer Toe web intertrigo Diabetes Immunosuppression Alcoholism Chickenpox Arteritis Traumatism The majority of acute bacterial skin infections are caused by aerobic Gram-positive cocci, specifically S. aureus and streptococci. Several prior studies have shown that the largest proportion of erysipelas can be attributed to group A streptococci [10,12]. Nevertheless, many recent publications highlight the emergence of new pathogens and especially MRSA. Over the past few years, community-associated infections caused by MRSA (CA-MRSA) have become common in multiple areas in the US and worldwide, the majority involving skin and soft tissues. CA-MRSA infection outbreaks have occurred among intravenous drug users, prisoners, athletes, military trainees and men who have sex with men [13]. Between 2001 and 2004, the prevalence of MRSA among patients with skin and soft tissue infections increased from 29 to 64% in a Los Angeles institute [14]. In many US cities, MRSA is now the most common pathogen isolated in the emergency department from Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 120 Skin and soft tissue infections patients with skin and soft tissues infections [15]. CA-MRSA causes disease in young, otherwise healthy persons without the usual risk factors for nosocomial MRSA infections. In a football team, 11 out of 107 team members were diagnosed with CA-MRSA infections, the most common sign being a boil, and four were hospitalized [16]. Sharing personal toilet items and asymptomatic nasal carriage were significant risk factors [16,17]. Single-organism necrotizing fasciitis is also increasingly recognized as a manifestation of Klebsiella infections [7]. Single-organism necrotizing fasciitis due to Klebsiella spp. is strongly associated with predisposing conditions such as diabetes mellitus and has a propensity for metastatic dissemination resulting in multiple sites of infection. In a recent Taiwanese series, Klebsiella pneumoniae was the most common pathogen isolated (17/87 patients) [7,24]. In a prospective prevalence study involving 422 adult patients with skin and soft tissue infections who presented to a hospital emergency department, infections were classified as abscess in 81%, infected wound in 11% and ‘cellulitis with purulent exudates’ in 8%. Overall, MRSA was isolated in 59% of patients and specifically found in 47% of the cases of cellulitis with purulent exudates, whereas group A streptococci were rarely isolated [15]. Treatment – erysipelas/cellulitis In contrast to hospital-acquired strains, CA-MRSA is often susceptible to a wide variety of antimicrobials, including clindamycin, macrolides (variable), cotrimoxazole, tetracyclines and fluoroquinolones [15,18]. CA-MRSA strains bear the staphylococcal cassette chromosome mec type IV and the Panton-Valentine leukocidin genes. These strains have fewer resistance genes to non-b-lactam antimicrobial drugs than healthcare-associated MSRA strains [18,19]. By using pulsed-field gel electrophoresis for typing CA-MRSA strains it was found that they belonged to only two of the eight types distinguished at that time by the technique: USA300 and USA400 [20–22]. Several clinical and epidemiologic factors associated with CA-MRSA infection were identified, but did not appear useful in guiding the choice of empirical antibiotics: most patients without MRSA had at least one of these factors and almost half of those without any of these factors were found to have MRSA [15]. Necrotizing fasciitis is typically caused either by group A streptococci alone (type 2) or by a polymicrobial mixture (type 1) with aerobic and anaerobic organisms (group A streptococci, Enterobacteriales, anaerobes and S. aureus). S. aureus was not considered as a cause of necrotizing fasciitis as a single agent. Recently, 14 cases of necrotizing fasciitis associated with CA-MRSA were identified among 843 patients whose wound cultures grew MRSA [23]. In 12 patients (86%), wound cultures were monomicrobial for MRSA, but anaerobic wound cultures had been performed in only four of these 12 cases. It is noteworthy that these cases of ‘necrotizing fasciitis’ related to CA-MRSA had a better prognosis than expected. It is not clear whether they differed clinically from the cases reported as ‘cellulitis with purulent exudates’ in a more recent study [15]. Recent trends in the management of cellulitis concern ambulatory treatments, reduced duration of antibiotics and the role of new antistaphylococcal treatments. Alternative to hospitalization Most patients with erysipelas or cellulitis are not hospitalized [2]. The cost of hospital treatment was, however, shown to average 5300 Euros per patient in The Netherlands, and contributed 80% of all expenses for cellulitis and erysipelas, even though only 7% of patients were hospitalized. Milder forms can be controlled by oral antibiotics at home. According to the Infectious Diseases Society of America guidelines [10], hospitalization is required in the case of severe local symptoms and signs, hypotension and/or elevated creatinine level, low serum bicarbonate level, elevated creatine phosphokinase level, marked left shift polymorphonuclear neutrophils or elevated C-reactive protein. Severe forms often require intravenous antibiotics, traditionally delivered in hospitals in most countries. There is, however, a trend to avoid hospitalization by promoting intravenous treatments at home for economic reasons – home treatment being about half as costly as hospital treatment [25]. A prospective randomized controlled trial enrolled 200 patients randomized in the emergency department to receive intravenous antibiotics either in hospital or at home [26]. The two treatment groups did not differ significantly for the primary outcome of days to no advancement of cellulitis (mean 1.5 days). None of the other outcome measures differed significantly except for patients’ satisfaction, which was greater in home treatment. A limitation of the above study was that treatments dispensed at home or during hospitalization were not entirely equivalent, the choice of antibiotics and the decision when to switch from intravenous to oral antibiotics being left to attending doctors in the hospital or home. Eleven patients (12%) randomized to home treatment required secondary hospitalization. A similar rate of readmission was observed in a retrospective analysis evaluating the safety and efficacy of intravenous cephazolin (twice daily) as a first-line antibiotic for the treatment of cellulitis in an outpatient programme [27]. Among 124 patients Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Acute bacterial skin infections Gabillot-Carré and Roujeau 121 identified, 105 (84.7%) were treated successfully and 19 (15.3%) were readmitted. In this retrospective study, patients needed 6.24 days of intravenous therapy at home, which was similar to former data [28]. Noteworthy, only a third of patients requiring intravenous antibiotics for cellulitis were suitable for home treatment: from a total of 558 eligible patients, most required admission to hospital because of comorbidities, home situation and severity of their cellulitis [27]. In Corwin et al.’s [26] randomized study, patients allocated to community treatment received 2 g of cephazolin twice daily. A prior study [28] had suggested that a home treatment using once-daily cephazolin plus oral probenecid under nurse supervision was a safe option. Nevertheless, this dosage cannot yet be recommended [29]. Which antibiotics? Antibiotics active against streptococci must be the first choice in typical cases of erysipelas or cellulitis (amoxicillin). In cases with collection or penetrating trauma, an agent also effective against S. aureus should be preferred (dicloxacillin, cephalexin, clindamycin) [10]. In geographic areas with high rates of CA-MRSA it was suggested to use clindamycin or a combination of a blactam plus trimethoprim/sulfamethoxazole for nonpurulent cellulitis [15]. In case of using a fluoroquinolone, one with enhanced activity against Gram-positive bacteria should be used (levofloxacin, gatofloxacin, moxifloxacin), but emergence of resistance is possible. In case of severity or for patients unable to tolerate oral medications, the Infectious Diseases Society of America guidelines [10] recommend penicillinase-resistant penicillin such as nafcillin, a first-generation cephalosporin such as cefazolin, or, for patients with life-threatening penicillin allergies, clindamycin or vancomycin. Correlation between patient outcomes and the susceptibility of the pathogen to the prescribed antimicrobial agents is poor [15,30], suggesting that a majority of skin abscesses, even caused by MRSA, can be cured with adequate drainage alone. On the other hand, absence of collection drainage with antibiotic treatment may promote the emergence of resistance [31]. Antistaphylococcal penicillins or cephalosporins are commonly used to treat soft tissue infections. Intravenous vancomycin has been the first-line therapy against MRSA. In recent randomized clinical trials, newer agents with MRSA activity had efficacy similar (daptomycin and tigecycline) or slightly superior (linezolid) to that of vancomycin for the treatment of complicated skin and soft tissues infections associated with MRSA [32–34]. Treatment duration A randomized study suggested that the duration of treatment can be shortened [35]. Among 121 patients with ‘cellulitis’ treated for 5 days with oral levofloxacin once daily, 77 who were improved were randomized to a further 5 days of levofloxacin or placebo. In both groups residual signs of cellulitis were similarly improved at 10 days. This study has been quoted as indicating that a 5-day treatment is as effective as 10 days. The interpretation should be more prudent for at least two reasons. (1) At day 5, 34/121 patients were not randomized for reasons including insufficient improvement. (2) Levofloxacin has a prolonged effect and the 5-day regimen cannot be extrapolated to antibiotics with shorter half-lives, such as aminopenicillins. Short-course therapy should be reserved to patients with notable clinical improvement by day 5 of therapy and when follow-up is feasible. Prevention of recurrences Long-term administration of long-acting penicillin is commonly proposed as a prophylactic treatment of erysipelas recurrence. A recent retrospective cohort study analyzed the predictors of successful penicillin prophylactic therapy to prevent erysipelas recurrence in patients with upper limb lymphedema as a consequence of breast cancer treatment [36]. Forty-eight women were given long-acting prophylactic penicillin therapy (2.4 MU benzathin– penicillin G administered intramuscularly at 14-day intervals) to prevent recurrent erysipelas. The estimated rate of recurrence under prophylactic penicillin therapy was 26% at 1 year and 36% at 2 years. Even though uncontrolled, this study does not suggest a strong benefit from benzathin–penicillin G prophylaxis. Necrotizing fasciitis Surgery remains the most important part of necrotizing fasciitis management. When there is any doubt about the severity of the local signs, surgery should be considered anyhow in the presence of severe systemic symptoms. Iterative surgical intervention 24–36 h and daily after the first debridement is necessary in many cases. The rapidity of surgery may decrease the mortality rate. Patients who received emergency debridements less than 24 h after the onset of symptoms had a lower mortality rate than those who had delayed operations (26 vs. 45.9%, P ¼ 0.07) [7]. Concerning antibiotics in necrotizing fasciitis, we refer to the Infectious Diseases Society of America guidelines [10]. Treatment of polymicrobial necrotizing fasciitis must include agents effective against both aerobes and anaerobes such as a combination of ampicillin/sulbactam plus clindamycin plus ciprofloxacin. Necrotizing fasciitis and/or streptococcal toxic shock syndrome caused by Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 122 Skin and soft tissue infections group A streptococci should be treated with clindamycin and penicillin. Based on the observation that patients with severe group A streptococci had significantly lower serum levels of protective antibodies than noninvasive cases, administration of intravenous immunoglobulin (IVIG) was proposed to treat patients with streptococcal toxic shock syndrome and necrotizing fasciitis. Decreased mortality rates were reported in a multicenter randomized controlled trial of IVIG [37]. Too few patients were, however, included (10 IVIG recipients and 11 placebo recipients) to provide good evidence [38]. Additional studies on the efficacy of IVIG are necessary before a recommendation can be made regarding the use of IVIG for treatment of streptococcal toxic shock syndrome [10,38]. In necrotizing fasciitis, the mortality rate is high, approaching 50%–70% in patients with hypotension and organ failure [39]. In a large series from Taiwan, a multivariate logistic regression analysis revealed that risk of death was independently associated with more than one underlying condition, thrombocytopenia, anemia, delay of more than 24 h from symptom onset to surgery and age greater than 60 years [7]. Conclusion There is an obvious need for consensus definitions of erysipelas, cellulitis and necrotizing fasciitis, which do not share similar risk factors and bacteriology. Owing to the persistent confusion on denomination, it is not yet clear whether the increasing incidence of CA-MRSA soft tissue infections also includes necrotizing fasciitis. Concerning treatment of mild cases, the trends are towards shorter duration and home therapy. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 204). 1 Kaul R, McGeer A, Low DE, et al. Population-based surveillance for group A streptococcal necrotizing fasciitis: clinical features, prognosis indicators and microbiologic analysis of seventy-seven cases. Am J Med 1997; 103:18–24. Goettsch WG, Bouwes Bavinck JN, Herings RMC. Burden of illness of bacterial cellulitis and erysipelas of the leg in the Netherlands. J Eur Acad Dermatol Venereol 2006; 20:834–839. High incidence (179.6/100 000) in general practice. Only 7% of patients were hospitalized, accounting for 83% of treatment costs. 2 6 Mokni M, Dupuy A, Denguezli M, et al. Risk factors for erysipelas of the leg in Tunisia: a multicenter case-control study. Dermatology 2006; 212:108–112. Also in Tunisia, leg edema or lymphedema and cutaneous barrier disruption by traumatic wound, excoriated dermatosis or toe-web intertrigo are risk factors for erysipelas of the leg. 7 Liu YM, Chi CY, Ho MW, et al. Microbiology and factors affecting mortality in necrotizing fasciitis. J Microbiol Immunol Infect 2005; 38:430–435. 8 Aronoff DM, Bloch KC. Assessing the relationship between the use of nonsteroidal anti-inflammatory drugs and necrotizing fasciitis caused by group A streptococcus. Medicine 2003; 82:225–235. 9 Dall L, Peterson S, Simmons T, Dall A. Rapid resolution of cellulitis in patients managed with combination antibiotic and anti-inflammatory therapy. Cutis 2005; 75:177–180. 10 Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the management of skin and soft tissue infections. Clin Infect Dis 2005; 41: 1373–1406. 11 Kielhofner MA, Brown B, Dall L. Influence of underlying disease process on the utility of cellulitis needle aspirates. Arch Intern Med 1988; 148:2451– 2452. 12 Bernard P, Bedane C, Mounier M, et al. Streptococcal cause of erysipelas and cellulitis in adults. A microbiologic study using a direct immunofluorescence technique. Arch Dermatol 1989; 125:779–782. 13 Zinderman CE, Conner B, Malakooti MA, et al. Community-acquired methicillin-resistant Staphylococcus aureus among military recruits. Emerg Infect Dis 2004; 10:941–944. 14 Moran GJ, Amii RN, Abrahamian FM, Talan DA. Methicillin-resistant Staphylococcus aureus in community-acquired skin infections. Emerg Infect Dis 2005; 11:928–930. 15 Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006; 355:666–674. Multicenter study in 11 university affiliated emergency departments demonstrating the growing role of CA-MRSA in skin and soft tissue infections, including cellulitis with collection and exudates. 16 Nguyen DM, Mascola L, Brancoft E. Recurring methicillin-resistant Staphylococcus aureus infections in a football team. Emerg Infect Dis 2005; 11: 526–532. 17 Begier EM, Frenette K, Barrett NL, et al. A high-morbidity outbreak of methicillin-resistant Staphylococcus aureus among players on a college football team, facilitated by cosmetic body shaving and turf burns. Clin Infect Dis 2004; 39:1446–1453. 18 Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and healthcare-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003; 290:2976–2984. 19 Hiramatsu K, Okuma K, Ma XX, et al. New trends in Staphylococcus aureus infections: glycopetide resistance in hospital and methicillin resistance in the community. Curr Opin Infect Dis 2002; 15:407–413. 20 Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillin-resistant Staphylococcus aureus among professional football players. N Engl J Med 2005; 352:468–475. 21 McDougal LK, Steward CD, Killgore GE, et al. Pulsed-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol 2003; 41: 5113–5120. 22 Mishaan AM, Mason EO Jr, Martinez-Aguilar G, et al. Emergence of a predominant clone of community-acquired Staphylococcus aureus among children in Houston, Texas. Pediatr Infect Dis J 2005; 24:201–206. 23 Miller LG, Perdreau-Remington F, Rieg G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med 2005; 352:1445–1453. 24 Wong CH, Kurup A, Wang YS, et al. Four cases of necrotizing fasciitis caused by Klebsiella species. Eur J Clin Microbiol Infect Dis 2004; 23:403–407. 25 Grayson ML, Silvers J, Turnidge J. Home intravenous therapy. A safe and effective alternative to inpatient care. Med J Aust 1995; 162:249–253. 3 Dupuy A, Benchikhi H, Roujeau JC, et al. Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ 1999; 318:1591–1594. 26 Corwin P, Toop L, McGeoch G, et al. Randomized controlled trial of intravenous antibiotic treatment for cellulitis at home compared with hospital. BMJ 2005; 330:129. 4 Roujeau JC, Sigugeirsson B, Korting HC, et al. Chronic derematomycoses of the foot as risk factors for acute bacterial cellulitis of the leg: a case-control study. Dermatology 2004; 309:301–307. 27 Donald M, Marlow N, Swinburn E, Wu M. Emergency department management of home intravenous antibiotic therapy for cellulitis. Emerg Med J 2005; 22:715–717. 5 Bjornsdottir S, Gottfredsson M, Thorisdottir AS, et al. Risk factors for acute cellulitis of the lower limb: a prospective case-control study. Clin Infect Dis 2005; 41:1416–1422. 28 Grayson ML, McDonald M, Gibson K, et al. Once daily IV cephazolin plus oral probenecid is equivalent to once daily IV ceftriaxone plus oral placebo for the treatment of moderate to severe cellulitis. Clin Infect Dis 2002; 34:1440–1448. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Acute bacterial skin infections Gabillot-Carré and Roujeau 123 29 Cox VC, Zed PJ. Once-daily cefazolin and probenecid for skin and soft tissue infections. Ann Pharmacother 2004; 38:458–463. 30 Fridkin SK, Hageman JC, Morrison M, et al. Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med 2005; 352:1436–1444. 31 Lee MC, Rios AM, Aten MF, et al. Management and outcome of children with skin and soft tissue abscesses caused by community-acquired methicillinresistant Staphylococcus aureus. Pediatr Infect Dis J 2004; 23:123–127. 35 Matthew JH, Dooley DP, Skidmore PJ, et al. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004; 164:1669–1674. 36 Vignes S, Dupuy A. Recurrence of lymphoedema-associated cellulitis (erysi pelas) under prophylactic antibiotherapy: a retrospective cohort study. J Eur Acad Dermatol Venereol 2006; 20:818–822. A high level of recurrences in this series points to the need for formal studies of prophylaxis. 32 Carpenter CF, Chambers HF. Daptomycin: another novel agent for treating infections due to drug-resistant gram-positive pathogens. Clin Infect Dis 2004; 38:994–1000. 37 Darrenberg J, Ihendyane N, Sjölin J, et al. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2003; 37:333– 340. 33 Nathwani D. Tigecycline: clinical evidence and formulary positioning. Int J Antimicrob Agents 2005; 25:185–192. 38 Stevens DL. Dilemmas in the treatment of invasive Streptococcus pyogenes infections. Clin Infect Dis 2003; 37:341–343. 34 Weigelt J, Itani K, Stevens D, et al. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005; 49:2260–2266. 39 Chelsom J, Halstensen A, Haga T, Todd J. Necrotising fasciitis due to group A streptococci in western Norway: incidence and clinical features. Lancet 1994; 344:1111–1115. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infection following soft tissue injury: its role in wound healing Terence J. Ryan Purpose of review Wound infection has always been an unconquered problem temporarily improved with the discovery of antibiotics but now struggling with an epidemic of resistant organisms. Wound healing has become a popular sub-speciality for the doctor and allied health professional working in the laboratory or at the bedside. It is a field with many new journals and frequent congresses that publish elaborate proceedings. These have been examined for this review. Recent findings Measurement of infection remains elusive. A clear difference between contamination and infection is difficult to delineate. In the era of the HIV/AIDS epidemic attention is drawn to host factors, which when attended to are as effective in suppressing infection as antisepsis. The bacterial capacity to put on a protective coat known as biofilm is a newly investigated system. Summary Antisepsis and antibiotics continue to provide a wealth of studies and some new technology. The evidence base, as examined by Cochrane systematic reviews, suggests that our strategy for preventing and dealing with infection of wounds needs further refinement. Keywords antisepsis and antibiotics, biofilm, wound healing mechanisms, wound infection classification Introduction This review, in examining wound infection, addresses a costly and common problem which eludes satisfactory measurement. The topic needs a full understanding not only of the behaviour of bacteria but also of the complex host defences which continue to provide surprises and new openings for the battle against infection. Wounds heal through a sequence of events that include cessation of bleeding, inflammation, granulation tissue and remodelling. Inflammation is exacerbated by infection. The quality of the granulation tissue, which is a new organ bringing to the wound an adequate blood supply, can be impaired by bacteria. Scarring tends to be more disfiguring after wound infection. Skin barrier function and temperature control are once again topics of research and the newly discovered agents that are part of the epidermal defence add a new library of antimicrobial interference, which can be understood best in the context of research performed even more than 100 years ago. Also, however, as we understand how infective organisms can protect themselves by newly discovered mechanisms such as biofilm, we open up new perspectives to the attack on bacteria by older therapies including the use of maggots, hot fomentations, disruption by physical forces or bathing with herbals such as with the early morning cup of tea. Curr Opin Infect Dis 20:124–128. ß 2007 Lippincott Williams & Wilkins. Oxford International Wound Healing Foundation, Oxford, UK Correspondence to Terence J. Ryan, DM, FRCP, Emeritus Professor of Dermatology, Hill House, Abberbury Avenue, Iffley, Oxon, OX44EU, UK Tel: +44 1865 777 041; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:124–128 ß 2007 Lippincott Williams & Wilkins 0951-7375 The effect of infection is a balance between the virulence of the organism and the effectiveness of the host’s defences. Clinical symptoms are a guide [1,2]. Healing is the best sign that infection is not a problem. Predisposing factors contributing to soft tissue infection include the AIDS epidemic and the many drugs used to suppress immunity in transplantation. There is also the high prevalence of the diabetic foot ulcer and of lymphoedema, which a recent London survey [3] shows to be much more common (1.33 per 1000 population) than previously suspected. Cellulitis is an expensive problem commonly occurring in lymphoedema, often needing intravenous therapy with admission to well staffed hospitals for night administration. Following several articles about the cost of cellulitis to hospitals in the USA a study from the Netherlands [4] confirmed the difficulties and cost of management. Corwin et al. [5] advocate intravenous antibiotics at home as a safe procedure for only about one third of patients. Biomedicine is not the only system of medicine that has a view on this, and a contemporary research agenda in India draws attention to 124 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infection following soft tissue injury Ryan effective but ancient Ayurvedic systems of management at home, promoting lymph flow and restoring skin barrier function, that had an immediate effect in reducing the frequency of cellulitis in 199 patients treated in Kerala (S.R. Narahari et al., in preparation) [6]. The search for locally available sustainable low cost agents to manage wound infection turns up the most publications devoted to honey [7]. Its physical properties are copied by a paste made of sugar and water but the bee selects from plants many additional chemical agents that directly interfere with bacterial metabolism. 125 bacterial load in infected leg ulcers. It is a point made long ago in studies of tropical ulcers of the leg, and enhanced virulence caused by synergistic interaction between aerobic and anaerobic bacteria in polymicrobial populations is well documented. Rational prescribing of antibiotics requires identification of the organism to be eliminated and a persistent question of the field is how to take samples from wounds. Should it be by swab, or from wound exudates or by biopsy? Which part of the wound should be sampled and should it first be cleaned? Classification A wound classification system, of clean, contaminated, or dirty is far too vague to be useful. The persistent unanswered questions concern whether bacteria are merely present or whether they are doing harm [8]. Contamination is the presence of bacteria on the wound surface. Colonization is the presence of replicating bacteria attached to the wound surface but not causing injury to the host, versus infection which causes injury. The mere presence of bacteria does not matter. Staphylococcus aureus is present in the nares of 25–30% of healthy people. All body surfaces are covered by bacteria and low levels of nonpathogenic bacteria are even beneficial. Efforts to destroy them complicate the lives of the sick, unnecessarily, when bacteria are not doing any harm. We have learned much about the mutations of genes and horizontal transfer of resistance genes to other bacteria and worries persist about over-prescribing of antibiotics for every wound or for every teenager’s acne and by the veterinary field to promote more marketable dairy products or meat. Terms that justify prescribing antibiotics include critical colonization; a term used when bacteria are suspected of both delaying or stopping healing but there are few signs of infection. For three or more decades bacteria have been counted from wounds. Lookingbill et al. [9] in a study of 30 patients advocated that a figure of 100 000 per gram of tissue should be regarded as critical in delaying wound healing. The group A streptococci are harmful in smaller numbers than 100 000. Some bacteria work in synergy to do harm in smaller numbers, and especially if the host defences are weak. The organisms present in a wound change over time, being mostly Gram-positive initially but increasingly Gram-negative organisms are added during delayed healing. The role of anaerobic organisms requires more research, since they are always present but they are rarely looked for. Bowler and Davies [10] cultured 220 isolates from 44 infected leg ulcers and concluded that the role of microbial synergistic interactions in the pathogenesis of chronic wound infection may be of greater clinical importance than the isolated involvement of any specific potential pathogen. They drew attention to anaerobes representing 49% of the A recent very thorough examination of this question favoured Levine’s 1976 technique of rotating a swab over a 1 cm2 area taking 5 s, and with sufficient pressure to extract fluid. This study using a critical threshold of 37 000 organisms per swab provided a sensitivity of 90% and a specificity of 57% [11]. It remains impossible to distinguish contamination from infection using culture techniques. Relying on bacterial counts to assess severity is over-simplistic because in wounds there are many other factors equally able to delay healing. Biofilm Biofilm formation is an increasingly well recognized way that bacteria inform and protect themselves [12]. Bacteria create a protected colony of communicating organisms by secreting a polysaccharide extra-cellular matrix [13]. This protects them from attack, and water channels through the matrix allow distribution of nutrients and signalling products. Disrupting biofilm is achieved by electric current or by the secretions of the maggot, or for some biofilms by macrolides. Wounds that contain foreign materials are most likely to have biofilm firmly attached. Within the film bacteria are able to release and transport to other bacteria chemical signals including ways to become resistant to antibiotics. It is known as quorum signalling, andthere are agents that can inhibit the phenomenon. RNA III inhibiting peptide is one of these. It can inhibit infections by interfering with phosphorylation. Animal studies so far indicate effectiveness and safety [14]. Managing host factors The prescription debate is multifaceted and includes the advantages of topical versus systemic therapy. Even more important is the management of other causes of delay. Worldwide they are problems of lack of access to effective therapy [15], general ill health, or failure to bring to the wound an adequate blood supply: a fault of the surgeon, lack of apposition of wound edges, or space occupying material in the wound, and as yet unidentified factors that hopefully will become obvious as a result of more study. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 126 Skin and soft tissue infections The classical signs of inflammation, which are also a stage of wound healing, are suppressed by malnutrition, ill health such as anaemia, by many drugs such as steroids, and by immunosupression as in diabetes or HIV/AIDS. Infection may be suspected when there are additional signs of increasing inflammation such as redness, swelling, heat or pain, or new areas of breakdown, increased discharge, friable exuberant granulation tissue in several shades of red, foul odour and systemic illness. Erythema and pain may be absent in the ulcerated foot of diabetic neuropathy or the pressure ulcer in the paraplegic. Wound healing needs more, however, than clinical judgment. Unrestricted latent class analysis of observers asked their impression of infection showed great variability and low reliability [16]. Impaired wound healing in septic individuals in civilian or military trauma, especially in perforation of the bowel, is a common problem. Its effect is local impairment of collagen synthesis or impairment of the arrival of neutrophils and a failure of optimum keratinocyte repair. Using electrophoresis of a plasmid containing a keratinocyte growth factor, Lin et al. [20] achieved a 67% improvement in healing of a skin wound in a rat sepsis model. None of 30 animals died after wounding of the caecum by ligation. This technique localizes the growth factor to the abdominal skin wound and avoids the risk of undesirable effects remote from the wound target. The authors predict that such approaches may be helpful for future management of the wounded on the battlefield. Antibiotics In deciding which antibacterial agent to prescribe one must be aware of fashion: silver dressings are in favour and their use is massive. A recent Cochrane Systematic Review [21] found no studies of silver that met with the inclusion criteria and none that evaluated clinical effectiveness. Other Cochrane reviews found no benefit for preoperative showering or bathing in 10 000 patients. Another review found no reduction of surgical site infection from preoperative hair removal; but shaving caused more infection than clipping. ‘Insufficient evidence’ was the verdict of a Cochrane review of preoperative skin antiseptics for preventing surgical wound infections after clean surgery or, in another review, for the cleansing of pressure ulcers. In an era of antibiotic resistance, estimates have largely been based on prescribing studies for upper respiratory infections and only recently has the extent of prescribing of antibiotics for skin wounds been estimated by careful studies. One in seven of antibiotic prescriptions for the elderly was for skin wounds in a Scandinavian survey which stimulated a study of 184 852 persons in Wales [17] and especially of leg ulcers and foot problems in diabetic patients, revealing not only frequent prescribing for wounds but more prolonged than for other infections. Ineffective and inappropriate prescribing is a global problem and often is the result of inadequate assessment or wrong diagnosis. There is a strong association between the occurrence of chronic wounds and prescribing of antibiotics in primary healthcare. It is possibly the most prevalent contributor to antibiotic resistance. Some antibiotics may be working through a host response. Drugs such as tetracyclines or dapsone are used in several skin diseases not caused by infection and their role in acne or leprosy may be an effect on host factors. One consequence of the epidemic of antibiotic resistance is the increasing prescribing of antibiotics that are known to have life-threatening side effects: in the HIV/AIDS population, for example, prescribing of drugs when there is an enhanced risk of life threatening disorders such as toxic epidermal necrolysis. Careful titration of drugs with a watch on renal and liver responses can allow difficult drug resistant problems to achieve a successful outcome. Tascini et al. [18] describe the successful outcome of a colistin/rifampicin/imipenem mixture given systemically for 6 weeks for multi-resistant Pseudomonas aeruginosa diabetic foot infection and osteomyelitis. Not all agents placed on wounds are utilized because of an antiseptic role and it was therefore unanticipated that the local anaesthetic EMLA (eutectic mixture of local anaesthetics) would be found to have a powerful and rapid antibacterial effect [19]. In a review of wound healing and infection, Williams and Leaper [22] point out that bacteria have to overcome formidable defences in order to invade, multiply and cause damage, and that most organisms cannot succeed. They list defences such as the mucociliary escalator of the respiratory tract, the flushing action of tears, mucus in the gastrointestinal tract, chemical factors such as low pH, antimicrobials such as lysozyme and immunoglobulin A surfaces. Having reviewed at length the immune systems’ role and mechanisms for dealing with bacteria, they describe how an organism may wear an intact non-immunogenic capsule or a coat that mimics the host and is not recognized as foreign. The coat may be shed and invoke the attention of host cells, leaving the organism to do its work unmolested. In the past when antibiotic resistance was less prevalent, giving antibiotics routinely before operation was deemed the most effective way to reduce wound infection [23]. Antisepsis Increasing awareness of the prevalence and cost of wound infection has resulted in renewed emphasis on the low cost and effective remedy which is hand washing. So called social hand washing with soap and water and Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infection following soft tissue injury Ryan adequate drying is adequate for dressing of wounds and in theatre aqueous 4% chlorhexidine or 7.5% povidine iodine are said to reduce skin flora by 95% [22]. It has been observed, however, that inhibition of proteases by iodine rather than complete clearance of bacteria may be its major effect [24]. Alcohol wipes are lethal to bacteria exposed to them. More debatable is how much scrubbing is necessary and the vulnerability or poor barrier function of persons with skin diseases such as psoriasis that shed keratinocytes carrying bacteria. Gowns and caps are necessary to contain skin exfoliated products. It is aesthetic to wear gloves but they provide protection during a prolonged operation when the risk of skin puncture is 50%. Because of the HIV/AIDS epidemic double gloving is now advised. A topic of much debate is the use and effectiveness of antiseptics for ‘cleaning’ wounds. The original descriptions of Lister’s practice or the undoubted importance of Eusol or Dakins solution in reducing the prevalence of gangrene in the trench warfare of 1914–1918 cannot be questioned. The refined wound care of the contemporary wound healing team has to protect the living cells of the wound bed as well as to kill bacteria. It is certain that antiseptics kill living cells but some like chlorhexidine or povidine iodine are kinder to the healing wound. The chloride ion remains the most potent killer and contemporary research into hypochlorous acid [25] is aimed at finding ways to make it available to kill bacteria but to do no harm to the tissues, but the evidence base for antiseptic use remains dependent on a large library of unsatisfactory studies [26]. the need for supplements recognized as necessary by generations of wound observers. Vitamins A and C and iron and zinc supplements are essential for wound healing as proven in studies of a decade or so ago but still ignored. These studies are reviewed by Mulder et al. [31]. Conclusion Infected wounds are commonplace. They are contributing to the epidemic of bacterial resistance to a range of therapies. The solution requires more research into measurement of infection versus contamination. Although some of the new technology and exploration of phenomena such as biofilm are of great interest, some centuries-old procedures such as the washing of hands still head the list of desirable technologies. Attention to host defences even in the era of the devastating HIV/ AIDS epidemic also points to simple technologies such as good nutrition as a part solution to wound healing and wound infection. Acknowledgements The author acknowledges the help provided by lecture notes of the Southampton General Hospital microbiologist Adriana Basarab. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 205). 1 Gardner SE, Frantz RA, Doebbling BN. The validity of the clinical signs and symptoms used to identify localized chronic wound infection. Wound Rep Regen 2001; 9:178–186. 2 Gardner SE, Frantz RA, Troia C, et al. A tool to assess clinical signs and symptoms of localized infection in chronic wounds; development and reliability. Ostomy Wound Manage 2001; 47:40–47. 3 Moffatt CJ, Franks PJ, Doherty D, et al. Lymphoedema an underestimated problem. Q J Med 2003; 96:731–738. 4 Goettsch WG, Bouwes Bavinck JN, Herings RMC. Burden of illness of bacterial cellulitis and erysipelas of the leg in the Netherlands. J Europ Acad Dermatol Venereol 2006; 20:834–839. 5 Corwin P, Toop L, McGeoch G, et al. Randomized controlled trial of intravenous antibiotic treatment for cellulitis at home compared with hospital. Br Med J 2005; 330:129–132. 6 Narahari SR, Ryan TJ, Mahadevan KS, et al. Role of Indian systems of medicine in the morbidity reduction of filarial lymphoedema. Lymphology 2004; 37 (suppl):673–678. 7 Molan PC. The evidence supporting the use of honey dressing as a wound dressing. Int J Low Extrem Wounds 2006; 5:40–54. Debridement Debridement that removes the necrotic tissue in which bacteria thrive has also been much refined. Vacuum assisted closure is fashionable. It is a polyethylene ether foam dressing attached to a vacuum pump [27,28]. The topical negative pressure removes excess pus, and the wound fluid, which renders some antiseptics ineffective, and promotes granulation tissue, which is one of the best of antibacterial agents. It has been of proven value in a range of exceptionally difficult wounds. Less costly and now frequently prescribed in Europe is maggot therapy [29]. The secretions of the larvae seep out of the ‘tea bag’ in which they are placed and dissolve dead tissue. One study found ‘free range’ maggots more effective than when contained [30]. The cleaning up process is rapid and so far safe. Unlike the surgeon’s knife no damage is done to viable tissue and the oxygen demands in an ischaemic limb are not increased. Nutrition Neglect of nutrition is common. Although there is little of great value to be found in contemporary research into nutrition there is still a serious lack of attention to 127 Sibbald RG, Chapman P, Contrras-Ruiz J. The role of bacteria in pressure ulcers. In: Romanelli M, Cherry G, Colin D, Deflor T, editors. Science and practice of pressure ulcer management. London: Springer-Verlag; 2006. pp. 139–162. Sibbald has written more reviews on infection in wounds than anyone else in the last 3 years and this is comprehensive. 8 9 Lookingbill DP, Miller SH, Knowles RC. Bacteriology of chronic leg ulcers. Arch Dermatol 1976; 114:1765–1768. 10 Bowler PG, Davies BJ. The microbiology of infected and noninfected leg ulcers. Int J Dermatol 1999; 38:573–578. 11 Gardner SE, Frantz RA, Saltzman CL, et al. Diagnostic validity of three swab techniques for identifying chronic wound infection. Wound Rep Regen 2006; 14:548–557. 12 Cooper R, Okhiria O. Biofilms, wound infection and the issue of control. Wounds 2006; 2:48–57. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 128 Skin and soft tissue infections 13 Akiyama H, Huh WK, Yamasaki O, et al. Confocal laser scanning microscopic observation of glycocalyx production by Staphylococcus aureus in mouse skin:does S.aureus generally produce a biofilm on damaged skin? Br J Dermatol 2002; 147:879–885; 1360. 14 Giacometti A, Cirioni O, Gov Y, et al. RNA III inhibiting peptide inhibits in vivo biofilm formation by drug-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2003; 47:1979–1983. 22 Williams NA, Leaper DJ. Infection. In: Leaper DJ, Harding KG, editors. Wounds biology and management. Oxford: Oxford Medical Publications; 1998. pp. 71–87. 23 Bencini PL, Galimberti M, Signorini M, Crosti C. Antibiotic prophylaxis of wound infections in skin surgery. Arch Dermatol 1991; 127:1357–1360. 24 Khan MN, Naqvi AH. Antiseptics, iodine, povidone iodine and traumatic wound cleansing. J Tissue Viability 2006; 16:6–11. 15 Ryan TJ. Pressure ulcer prevention and management in the developing world: the developed world must provide leadership. In: Romanelli M, Cherry G, Colin D, Deflor T, editors. Science and practice of pressure ulcer management. London: Springer-Verlag; 2006. pp. 189–195. 25 Selkon JB, Cherry GW, Wilson JM, Hughes MA. Evaluation of hypochlorous acid washes in the treatment of chronic venous leg ulcers. J Wound Care 2006; 15:33–37. 16 Lorentzen HFL, Gottrup F. Clinical assessment of infection in nonhealing ulcers analyzed by latent class analysis. Wound Rep Regen 2006; 14:350– 353. 26 Smola H, Eming S, Smola-Hess S. A novel property of povidine-iodine: inhibition of excessive protease levels in chronic nonhealing wounds [abstract]. In: Abstracts of 16th Annual Meeting of the European Tissue Repair Society; 13–16 September 2006; Pisa. Pisa: Felici Editore; 2006. p. 40. 17 Howell-Jones RS, Price PE, Howard AJ, Thomas DW. Antibiotic prescribing for chronic wounds in primary care. Wound Rep Regen 2006; 14:387– 393. 18 Tascini C, Menichetti F, Gemignani G, et al. Clinical and micribiological efficacy of colistin therapy in combination with rifampin and imipenem in multi-resistant Pseudomonas aeruginosa diabetic foot infection with osteomyelitis. Int J Low Extrem Wounds 2006; 5:213–216. 19 Berg JO, Mössner BK, Skov MN, et al. Antibacterial properties of EMLA1 and Lidocaine inwound tissue biopsies for culturing. Wound Rep Regen 2005; 14:581–585. 20 Lin MP, Marti GP, Dieb R, et al. Delivery of plasmid DNA expression vector for keratinocyte growth factor-1 using electroporation to improve cutaneous wound healing in a septic rat model. Wound Rep Regen 2006; 14:618– 624. 21 The Cochrane Database of Systemic Reviews 2006. The Cochrane Collaboration. Chichester: John Wiley & Sons Ltd.; 2006. 27 Banwell P, Teot L, editors. Proceedings of the First International Topical Negative Pressure (TNP) Therapy Focus Group Meeting; London. London: TXP Communications; 2004. 28 Venturi ML, Attinger CE, Mesbahi AN, et al. Mechanisms and clinical applications of the vacuum-assisted closure (VAC) device; a review. Am J Clin Dermatol 2005; 6:185–194. 29 Courtney M, Church JCT, Ryan TJ. Larva therapy in wound management. J Roy Soc Med 2002; 93:72–74. 30 Steenvorde P, Doorn L Van and Oskam JCE. Maggot debridement therapy: free range or contained? [abstract]. In: Abstracts of 16th Annual Meeting of the European Tissue Repair Society; 13–16 September 2006; Pisa. Pisa: Felice Editore; 2006. p. 163. 31 Mulder GD, Brazinsky BA, Harding KG, Agren MS. Factors influencing wound healing in wounds: biology and management. Oxford: Oxford Medical Publications/Oxford University Press; 1998. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious keratitis Philip Aloysius Thomasa and Pitchairaj Geraldineb Purpose of review Infectious keratitis is a medical emergency. Improper management can lead to marked loss of vision. This review identifies recent trends in the study of infectious keratitis. Recent findings A multicountry outbreak of Fusarium keratitis emphasizes that contact lens wear is a major risk factor for infectious keratitis. Acanthamoeba and fungal keratitis are the most expensive forms of infectious keratitis to treat. Noninvasive methods and molecular techniques have improved diagnosis of infectious keratitis. Fortified topical antibiotics and fluoroquinolones are still the mainstay of bacterial keratitis therapy. Voriconazole and new routes of administration of conventional antifungals appear promising for fungal keratitis. Antivirals and amelioration of host inflammatory response are promising for viral keratitis; the host response is also crucial in pathogenesis of Pseudomonas aeruginosa keratitis. Trauma-induced bacterial and fungal keratitis and contact lens-associated keratitis are preventable entities. Summary Improved modalities of diagnosis and treatment have improved the outcome of infectious keratitis, but therapy of acanthamoebal, fungal and P. aeruginosa keratitis is still a challenge. Effective strategies must neutralize potential risk factors and counter host response overactivity without impairing killing of infecting microorganisms. Traumainduced bacterial and fungal keratitis can be prevented. Keywords corneal ulceration, keratitis aetiology, keratitis bacterial, keratitis fungal, keratitis viral, suppurative keratitis Curr Opin Infect Dis 20:129–141. ß 2007 Lippincott Williams & Wilkins. a Institute of Ophthalmology, Joseph Eye Hospital and bBharathidasan University, Tiruchirapalli, India Correspondence to Philip Aloysius Thomas, Institute of Ophthalmology, Joseph Eye Hospital, P.B. 138, Tiruchirapalli 620001, India Tel: +91 431 2460622; fax: +91 431 2414969; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:129–141 Abbreviations DFA LASIK MRSA NTM PCR PHMB PRK direct fluorescent antibody test laser in-situ keratomileusis methicillin-resistant S. aureus nontuberculous mycobacteria polymerase chain reaction polyhexamethylene biguanide photorefractive keratectomy ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction Infectious keratitis (microbial keratitis) is characterized by a defect of the corneal epithelium (hence the terms ‘infectious keratitis’ and ‘ulcerative keratitis’ are frequently used interchangeably) with inflammation of the underlying corneal stroma caused by replicating organisms including bacteria, viruses, fungi and protozoa [1]. The presentation is acute, with patients often in significant pain and distress. Infectious keratitis is a medical emergency; rapid initiation of aggressive treatment is needed to halt the disease process and limit the extent of corneal scarring and loss of vision. All clinicians who treat infectious diseases, and not just ophthalmologists, should recognize this sight-threatening condition. This review aims to highlight recent advances in our understanding of this problem. Epidemiology The actual prevalence of infectious keratitis is not known. The incidence of corneal ulceration per 100 000 population per year is estimated to vary from 6.3 in Hong Kong [2] and 11 in the USA [3] to 339 in Bhutan and 710 in Burma [4]; the incidence is six-fold higher in contact lens wearers [2]. Routine culture and virological investigations of such corneal ulcers may yield positive results in 55% [1] to 67% [5]; the remaining ‘sterile’ ulcers may occur due to nonmicrobial causes, or may be of infectious origin with negative culture and virological results due to various reasons (see below). Gender Infectious keratitis affects both males and females. A male preponderance [1,5,6] has been noted, although this may simply reflect the frequency of antecedent ocular trauma during outdoor work as a risk factor [1]. Age Age may influence the aetiological agent and outcome of therapy in infectious keratitis. When patients were categorized into three age-based groups, namely, paediatric (16 years), elderly (65 years) and control (17–64 years), fungal keratitis was found to occur significantly less frequently in the paediatric group than in other groups; polymicrobial infections were less frequent in controls (5%) than in other groups (20%); elderly patients presented with severe central ulcers with a significant risk of a poor visual outcome and non-traumatic predisposing factors (ocular surface disorders, prior ocular surgeries) approached trauma in importance [5]. In Australia, individuals with contact lens wear as a risk factor tended 129 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 130 Skin and soft tissue infections to be significantly younger (mean age 30 years) than those with other risk factors (mean age 40–47 years) [1]. The reasons for these age-based variations need to be elucidated. Occupation Agricultural work and outdoor occupations appear to predispose to infectious keratitis [6]. It is not clear whether certain occupations predispose to specific aetiologies of keratitis, for example agricultural work to fungal keratitis, although fungal keratitis was reported to occur frequently in onion harvesters in Taiwan [7]. Environmental factors The relative prevalence of filamentous fungal keratitis has been found to increase toward tropical latitudes, possibly due to the influence of wind, temperature and rainfall [8]. Similarly Curvularia keratitis along the Gulf of Mexico was found to cluster during the hotter, moister, summer months, possibly reflecting the increase in airborne Curvularia spores during these months [9]. Infectious keratitis due to other aetiological agents, however, does not exhibit such obvious geographical localization or relation to environmental factors. stroma and deeper part of the cornea are prone to become secondarily infected by bacteria and fungi and, to a lesser extent, by Acanthamoeba or other protozoa. This has been reported across different regions [1,5,8,14,15,16,17, 18] and age-groups [5]. One case–control study [21] noted antecedent ocular trauma in 35% of fungal and 52% of bacterial keratitis patients while another such study [22] observed that filamentous fungal keratitis was more frequently related to mechanical ocular trauma while bacterial keratitis (principally due to Pseudomonas aeruginosa) was less frequently related to trauma. Thus, it is unclear whether trauma per se, or specific traumatizing agents, predisposes to specific aetiologies in infectious keratitis. Wearing of contact lenses or orthokeratology lenses as a risk factor Contact lens wear is one of the most, if not the most, important risk factor for infectious keratitis in the developed world [1,2,3,23] and for Acanthamoeba keratitis in China and Turkey [14,24]. Increasingly, overnight wear of orthokeratology lenses, which are used for the temporary reduction of myopic refractive error, is being implicated as a risk factor for infectious keratitis in East Asia, where these lenses have become popular [11,12]. Risk factors for infectious keratitis Risk factors for infectious keratitis due to nonviral pathogens include trauma to the eye, overnight or extended wear of conventional contact lenses or orthokeratology lenses, chronic ocular surface disease (including atopic or vernal keratoconjunctivitis and blepharitis), prior ocular surgery, other ocular defects (lagophthalmos), systemic diseases (diabetes mellitus, leprosy, rheumatoid arthritis), use of topical corticosteroids or traditional eye medicines [1,2,3,5,6,7,8,10 –15,16,17,18 –20]. Around 10% of individuals with infectious keratitis may not exhibit any risk factor [1]. Risk factors for specific aetiologies of infectious keratitis Type and composition of lens as predisposing factors for contact lens-associated infectious keratitis One study noted the highest incidence of infectious keratitis in those who wore extended wear lenses, followed by users of daily wear lenses and by users of rigid lenses [2]. The composition of the lens worn may also be a risk factor, with higher numbers of Acanthamoeba trophozoites found to attach to first-generation lotrafilcon A silicone hydrogel lenses, compared with second-generation galyfilcon A lenses and conventional (etafilcon A) lenses [25]. Other factors predisposing to contact lens-associated infectious keratitis These have been described [13 –15,16,17,18 –20], but mostly in uncontrolled case series. Such descriptions may be misinterpreted, so that a risk factor is believed to be specific for infection by a specific microorganism. For example, in two recent series describing keratitis due to Moraxella [19] and that due to Haemophilus influenzae [20], multiple ocular risk factors were noted, the most frequent being prior ocular surgery and herpes simplex virus (HSV) keratitis. Thus, case–control studies are needed to elucidate risk factors unique to specific causes of infectious keratitis, but there have hitherto been few such investigations. When using conventional contact or orthokeratology lenses, inappropriate lens care procedures, patient noncompliance with practitioner instructions, overnight wear of lenses, smoking and persisting in lens wear despite discomfort, appear to be key risk factors; rinsing the lenses in tap water may predispose specifically to Acanthamoeba infection [2,11,12,14,15]. Contact lens wear may predispose to infectious keratitis because of prolonged hypoxia (experimentally found to augment internalization of P. aeruginosa in the cornea) [26], by causing minor breaks in the corneal epithelium (thereby exposing the underlying stroma to infection), or by other hitherto undefined mechanisms. Trauma as a risk factor An outbreak of contact lens-associated Fusarium keratitis Trauma to the eye can cause ulceration of the corneal epithelium; once the epithelium is breached, the corneal From mid-2005 to around July 2006, a rather unique, multicountry outbreak of contact lens-associated keratitis Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious keratitis Thomas and Geraldine 131 due to Fusarium species was witnessed, unique because hitherto filamentous fungi have been infrequently implicated in contact lens-associated keratitis [27]. The outbreak appears to have been first recognized in Hong Kong, but gained attention after reports from Singapore [28], where more than 60 patients were observed, and the USA [29,30,31,32,33], where more than 160 patients in 33 states were affected. Epidemiological and microbiological studies implicated the use of a specific brand of contact lens multipurpose solution, ReNu with Moisture Loc, in many patients. Fusarium was not recovered from the factory, warehouse or solution filtrate, however, or in any unopened bottles of this product, and the Fusarium strains isolated revealed high genetic diversity, suggesting that intrinsic contamination of the contact lens solution was not the direct cause of the infection [33]. The high polymer content of the solution, as well as patient noncompliance (particularly adding fresh solution to left-over solution in the containers), was hypothesized to have facilitated contamination of the solution by Fusarium derived from the local environments of the patients. This hypothesis, however, fails to consider the fact that there are numerous microbial species in the environment, and not just Fusarium. If contamination had been derived from the patients’ environments, one would have expected to see a greater diversity of contaminating organisms. Aetiological agents of trauma-associated infectious keratitis Regional variations in infecting organisms even within defined age groups can be discerned. In Australia, corneal scrapings from patients aged 15–64 years who had sustained ocular trauma yielded no growth of organisms (including Acanthamoeba) in 60%, and growth of Gram-positive bacteria (particularly coagulase-negative staphylococci, CoNS) in 31%, Gram-negative bacilli (GNB) in 5% and filamentous fungi in 3.2% [1]. In contrast, in India, corneal scrapings from essentially the same age-group of patients (many of whom had suffered ocular trauma) yielded no growth in 35%, and growth of filamentous fungi alone in 32.7%, bacteria alone (predominantly Streptococcus pneumoniae and P. aeruginosa) in 25% and Acanthamoeba in one patient [5], while in Malaysia, the commonest bacterial causes of keratitis were P. aeruginosa and Staphylococcus aureus [13]. Aetiological agents of lens-associated infectious keratitis Worldwide, aetiological agents of lens-associated infectious keratitis appear to be P. aeruginosa and Acanthamoeba in wearers of conventional and of orthokeratology lenses [11,12,14,15]. In Australia, Gram-negative organisms were isolated significantly more frequently in contact lens wearers than in trauma cases [1]. Ocular surgery as a risk factor With increasing recourse to refractive surgery such as laser in-situ keratomileusis (LASIK) and photorefractive keratectomy (PRK), it is natural that corneal surgery is a risk factor for infectious keratitis. LASIK has now become the surgery of choice for correction of errors of refraction between 8 and þ3 dioptres, due to various advantages. Although infectious keratitis during the early postoperative period is rare (<1 in 2919) [34], it is a dreaded enough complication to have warranted the publication of a white paper on its management [35]. Infectious keratitis may also rarely occur following PRK [36]. Risk factors associated with perforated corneal ulcers A case–control study in India found significant associations between 11 factors and the occurrence of corneal perforation in infectious keratitis [6]; of these, the lack of corneal vascularization, delay in starting initial treatment and failure to start fortified antibiotics retained significance on a logistic regression model. The authors themselves identified several limitations of their study. Aetiological agents of infectious keratitis The principal organisms isolated from various aetiologies of infectious keratitis are summarized in Table 1 [1,8,14,15,16,17,37,38,39 –45]. Aetiological agents of postsurgical infectious keratitis In post-LASIK infectious keratitis, nontuberculous mycobacteria (NTM), particularly Mycobacterium chelonae, are the most commonly cultured organisms [34,39,40], followed by staphylococci [including methicillin-resistant S. aureus (MRSA) [41], fungi such as Exophiala dermatitidis [42], streptococci, Nocardia [43] and GNB such as P. aeruginosa [44]]. Other aetiological agents In a study on infectious keratitis where attempts were made to detect viral pathogens, herpetic keratitis was diagnosed in 6.9% [1]. Microsporidial keratoconjunctivitis was found to account for 0.4% of suspected infectious keratitis in southern India [45]. Factors detrimental to isolation or detection of aetiological agents in infectious keratitis It may not be possible to detect a microorganism in around 35–60% of patients with suspected infectious keratitis, possibly because of scanty sample material, delay in performing investigations, prior use of antimicrobial agents or even the use of certain corneal stains such as rose bengal and lissamine green [46]. Prior use of topical antibiotics may only delay the time taken to grow organisms in culture without affecting culture-positivity rates [1,47]. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Gram-positive bacteria Diagnosis 1. Microscopy Clinical features Risk factors: Contact lens (CL) use and Ps. aeruginosa Burn/lagophthalmos and Acinetobacter Age > 50 years. and GNB (non-Pseudomonas) 1. Gram Ziehl–Neelsen, Kinyoun (c) NTM: ‘Cracked wind-shield’ type of appearance 1. Gram (b) Microsporidia: punctate epithelial lesions subepithelial scars (mimics atypical adenoviral keratoconjunctivitis) Acanthamoeba: Epithelial irregularities Single or multiple stromal infiltrates Ring-shaped configuration Severe pain and radial keratoneuritis Risk factors: Acanthamoeba - CL use - Contact with contaminated water - Trauma Microsporidia - Immunosuppression - CL wear Genera of microsporidia Acanthamoeba species Protozoa 1. Gram, Giemsa 1. (a) Acanthamoeba: potassium hydroxide (KOH), KOH, ink-KOH, ink-KOH LPCB lactophenol cotton blue (LPCB) Gram, Giemsa, acridine orange acridine orange, Gomori methenamine silver (GMS) GMS periodic acid Schiff (PAS) CFW calcofluor white (CFW) (b) Microsporidia KOHþCFW Gram; Giemsa Kinyoun’s 1% acid- fast (b) Candida: stromal keratitis resembles bacterial ulcer overlying epithelial defect discrete infiltrate slow progression occurs inferocentrally (a) Filamentous fungi: Dry elevated slough Stromal infiltrate with hyphate margins Satellite lesions Thick endothelial exudate Risk factors: Filamentous fungi: principally trauma Candida - Ocular surface disorders - Systemic diseases - CL use Gram-negative cocci: Neisseria gonorrhoeae Filamentous fungi: Fusarium Aspergillus Curvularia Fungi Yeast-like fungi: Candida albicans and Candida spp. Cryptococcus spp. Gram-negative bacilli (GNB): Pseudomonas aeruginosa Enterobacteriaceae Moraxella Haemophilus Gram-negative bacteria (a) GPC: GNB: Localised round or oval Rapid, inflammatory ulceration destructive course Greyish -white stromal infiltrates Dense stromal suppuration Distinct borders; minimal Hazy surrounding cornea surrounding stromal haze ‘Immune ring’ (b) Nocardia: Multiple small white infiltrates; resembles ‘wreath pattern’ May have fine filaments extending into surrounding cornea. Risk factors: Previous HSV keratitis and Streptococcus Trauma and S. aureus Age < 50 years. and S. aureus Gram-positive bacilli (GPB): Nontuberculous mycobacteria (NTM): Mycobacterium fortuitum/ Mycobacterium chelonae Filamentous GPB: Nocardia spp. Important Gram-positive cocci (GPC): corneal pathogens Coagulase-negative staphylococci (CONS) Streptococcus pneumoniae Staphylococcus aureus Feature Table 1 Salient features of infectious keratitis Vero cell culture Antigen detection techniques (c) Adenoviruses: Keratoconjunctivitis (b) VZV: Nummular keratitis (a) HSV: Superficial punctate keratitis Coarse epithelial punctate lesions Dendritric ulcer Geographical ulcer Necrotizing stromal keratitis Non-necrotizing (immune, disciform) stromal keratitis Varicella -zoster virus (VZV) Adenoviruses Herpes simplex virus (HSV) type 1 Viruses 132 Skin and soft tissue infections Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. (d) For Nocardia asteroides: ampicillin þ sulphonamides; cotrimoxazole; cefazolin; topical amikacin þ erythromycin (c) For Mycobacterium chelonae/ M. fortuitum: topical amikacin þ ciprofloxacin (c) For Pseudomonas ulcers: Ticarcillin/piperacillin (50 mg/ml) þ gentamicin (15 mg/ml) þ ceftazidime þ ciprofloxacin 0.3% (c) Recently topical and oral voriconazole (b) Oral antifungals (i) Ketoconazole: 200 mg twice daily (ii) Itraconazole: 200 mg once daily (iii) Fluconazole: 50–100 mg once daily (b) For Haemophilus influenzae, (b) For Candida: Klebsiella spp., (i) 1st line: 0.15% amphotericin B Proteus sp. & other enterobacteria: same as above (ii) 2nd line: fluconazole (b) For S. aureus, CoNS, Streptococcus: same as above Topical antifungals (a) for filamentous fungi: (i) 1st line: 5% natamycin (ii) 2nd line: 1% itraconazole, 2% econazole Media used for bacterial culture can be used for fungal culture if antibacterials are added. 2. Sabouraud glucose neopeptone agar and glucose neopeptone broth (supplemented with antibacterials) at 308C and 378C (a) Initial: cefazolin/cefuroxime þ gentamicin/ tobramycin Or fluoroquinolone monotherapy. (b) Liquid media at 378C Brain heart infusion broth Thioglycollate broth 2. (a) Solid media at 378C Sheep blood agar Cystine tryptone agar Brain heart infusion agar (a) Initial: cefazolin/cefuroxime þ gentamicin/ tobramycin Or fluoroquinolone monotherapy (c) For Mycobacterium Lowenstein-Jensen medium Middlebrook medium (b) Liquid media at 378C Brain heart infusion broth Thioglycollate broth 2. For GPC, GPB and Nocardia: (a) Solid media at 378C Sheep blood agar Cystine tryptone agar Brain heart infusion agar (b) Microsporidia: (i) debridement (ii) broad-spectrum antibiotic or PHMB or chlorhexidine (a) For Acanthamoeba: (i) Dibromopropamidine (ii) Hexamidine (iii) Chlorhexidine 0.02% (iv) Polyhexamethyl-biguanide (PHMB) 0.02% Recommended: Propamidine þ Chlorhexidine OR Propamidine þ PHMB (b) Microsporidia: Tissue culture 2. (a) Acanthamoeba (nonnutrient agar with Escherichia coli overlay) at 308C and 378C For nonnecrotizing stromal disease: Topical corticosteroids when lesion involves visual axis. Possibly oral acyclovir (debatable) For necrotizing stromal disease: Oral acyclovir and topical corticosteroids. (a) HSV keratitis: For epithelial disease: (i) Acyclovir 3% ointment 5 times a day (is able to penetrate intact corneal epithelium) (ii) Idoxuridine 0.1% drops now seldom used (toxicity) (iii) Debridement in dendritic ulcer Based on references [1,8,14,15,16,17,37,38,39 –45]). CFW, calcofluor white; CL, contact lens; CoNS, coagulase-negative staphylococci; GMS, Gomori methenamine silver; GNB, Gram-negative bacilli; GPB, Gram-positive bacilli; GPC, Gram-positive cocci; HSV, herpes simplex virus; KOH, potassium hydroxide; LPCB, lactophenol cotton blue; NTM, non-tuberculous mycobacteria; PAS, periodic acid Schiff; PHMB, polyhexamethyl biguanide; VZV, varicella-zoster virus. Treatment 2. Culture Infectious keratitis Thomas and Geraldine 133 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 134 Skin and soft tissue infections Co-infection by multiple aetiological agents Multiple similar or diverse pathogens may sometimes occur simultaneously or sequentially in an ocular infection. Specific investigations should be done to ensure that such polymicrobial infections are not missed, since the clinical evolution of the disease and the response to treatment may be affected. The reported incidence of polymicrobial keratitis varies from 5 to 22% [5,13,48], even when the same criteria are used to define an organism as a pathogen or contaminant. A recent study [48] established criteria to define a bacterial co-infection in fungal keratitis. Superinfection by the normal bacterial flora during early keratomycosis was believed to have led to polymicrobial keratitis. Candida isolates tended to be coinfected with staphylococci, the risk of polymicrobial infection being approximately three times greater than that with infection by filamentous fungi. Such synergism possibly contributes to the generally poor prognosis for fungal keratitis. Candida keratitis, however, actually tends to resolve better than does filamentous fungal keratitis [17], so the importance of bacterial co-infection in filamentous fungal keratitis in tropical regions requires further study. Aetiological agents of infectious keratitis and financial implications An interesting study tried to assess the financial burden of infectious keratitis [1]. Acanthamoeba keratitis was the most expensive to treat, followed by fungal and herpetic keratitis and lastly by culture-proven bacterial keratitis or culture-negative cases. to NTM is indolent in evolution and mimics herpetic, mycotic and Nocardia keratitis or even crystalline keratopathy [34,39]. Nonulcerative stromal keratitis, a complication of late congenital syphilis that typically begins during childhood or adolescence, may mimic viral interstitial keratitis [50]. Diagnosis In recent years, there have been notable advances in noninvasive techniques for diagnosis of infectious keratitis and in molecular techniques for diagnosis of viral and fungal keratitis. Noninvasive methods Noninvasive methods of diagnosis include confocal microscopy and impression cytology. Confocal microscopy The confocal microscope allows in-vivo examination of the cornea. First-generation confocal microscopes have yielded to the advanced tandem scanning confocal microscope and the Heidelberg retina tomograph II (HRT-II) with cornea module. These two confocal microscope models have been used for diagnosis of Acanthamoeba keratitis [14,15,51] by direct visualization of Acanthamoeba cysts in the corneal stroma, while HRT-II demonstrated inflammatory necrotic cells in the corneal stromal and anterior chamber cell reaction in bilateral infectious ulcers due to Streptococcus sanguis [10]. This facility is valuable in regions where cost is no constraint to the investigation of infectious keratitis. Clinical features Early signs and symptoms of infectious keratitis include redness, tearing, pain, sensitivity to light, discharge, decreased vision and a white corneal infiltrate. Certain signs have been described as being unique to specific presentations of infectious keratitis (Table 1). Again, the specificity of such findings requires simultaneous study of multiple presentations of infectious keratitis. Clinical features of fungal keratitis Serrated margins, raised slough and colour other than yellow were found to be independently associated with fungal keratitis in a logistic regression model [49]. The probability of fungal infection was 63% if one clinical feature was present, increasing to 83% if all three features were present. A drawback of this study was that clinical presentation was not stratified based on duration of symptoms nor were infecting bacteria or fungi arranged by genus. Clinical features of less frequent causes of infectious keratitis Microsporidial keratitis may mimic atypical or unusual adenoviral keratoconjunctivitis [45] while keratitis due Impression cytology Impression cytology can be used for diagnosis of ocular diseases, including infectious keratitis. A cellulose acetate filter is applied to the ocular surface to remove the most superficial layers of the ocular surface epithelium, the cells obtained then being subjected to histological, immunohistological or molecular analysis; deeper cells can also be accessed by repeated application over the same site [52]. Impression cytology has permitted the diagnosis of superficial infections due to HSV, varicella-zoster virus and adenoviruses [53], and of Acanthamoeba keratitis [54]. Conventional method of specimen collection To identify the aetiological agent in infectious keratitis, samples (usually scrapings) are obtained from the infected cornea; a biopsy or (in LASIK patients) material from the stromal bed after lifting the flap may sometimes be needed; material from the anterior chamber or a corneal endothelial plaque is an infrequent sample [17,37,39,40,45]. The material thus obtained is used for microscopic examination, using various stains, or inoculated onto appropriate culture media (Table 1). Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious keratitis Thomas and Geraldine 135 Diagnosis of viral keratitis This is done by cell culture using Vero cell lines, the direct fluorescent antibody test (DFA) or the polymerase chain reaction (PCR). In diagnosis of HSV keratitis, DFA was found to be more sensitive than PCR, which was in turn more sensitive than culture; DFA had better sensitivity and negative predictive values while PCR had better specificity and positive predictive values [55]. Demonstration of antibodies to HSV and varicella-zoster virus in samples from the anterior chamber may help to diagnose recurrent herpes keratitis in patients presenting with intraocular inflammation and neovascularization [56]. Recently, a fully automated molecular assay using an automated extraction system and a real-time PCR protocol successfully detected human adenoviral DNA in conjunctival smears, the results coinciding with those obtained using an immunofluorescent test kit [57]. Diagnosis of fungal keratitis A sensitive and rapid PCR-based method using singlestranded conformation polymorphism was recently described for diagnosis of fungal keratitis in four patients [58]. This approach may yield positive results when the conventional approach proves negative. Interestingly, in this study, a clinical diagnosis of fungal keratitis had been made in all four patients, and the PCR results only confirmed the diagnosis. Treatment Conventional lines of therapy for infectious keratitis are outlined in Table 1. The efficacy of povidone-iodine (betadine) in reducing the microbial load of corneal ulcers before patients were given antibiotics was recently assessed [59]. A single application of 5% betadine was not found to reduce the bacterial load of corneal ulcers more than just scraping and rinsing alone, possibly due to lack of penetration deep into the corneal stroma and the number of organisms present, as well as other factors. Acanthamoeba keratitis In Acanthamoeba keratitis, propamidine or hexamidine, in combination with polyhexamethylene biguanide (PHMB) or chlorhexidine, is the recommended line of treatment [14,15]. A combination of PHMB and hexamidine diisethionate exerted a synergistic effect and was more effective than PHMB, hexamidine diisethionate or miltefosine alone in a rat model of chronic Acanthamoeba polyphaga keratitis [60]. The advent of effective antiamoebic therapy has permitted a redefining of the goal of therapeutic penetrating keratoplasty in Acanthamoeba keratitis, from a mere salvaging of the affected cornea to restoration of useful vision after the infection has completely resolved. A study on a small series of patients showed that when penetrating keratoplasty was undertaken at least 3 months after discontinuation of antiamoebic therapy, with a negative preoperative confocal microscopy examination, there were no recurrences [61]. Here, the ‘waiting period’ of at least 3 months was identified as being crucial to success so that when the corneal limbus was affected, there was a longer waiting period. In some instances of very refractory infection, a combination of conjunctival flap surgery, corneal cryo treatment and penetrating keratoplasty may be needed [62]. Bacterial keratitis While treatment of P. aeruginosa keratitis requires special antibiotics, other forms of bacterial keratitis continue to be treated either by a combination of fortified topical antibiotics, using a cephalosporin and an aminoglycoside, or by fluoroquinolone monotherapy (Table 1). When combined therapy with cephalothin and gentamicin was used to treat patients with infectious keratitis, there was a clinical lack of response in 13% and treatment failure in 4%, whereas when ciprofloxacin monotherapy was used there were no treatment failures [63]. Treatment groups were nonrandomized, however, and the differential outcomes possibly reflected a desire to treat milder cases with monotherapy. The use of fluoroquinolone monotherapy (possibly in an inadequate frequency) and the delay or failure in starting fortified antibiotics were reported to be risk factors for perforation in patients with infectious keratitis [6]. There have also been concerns regarding the safety of fluoroquinolone use in keratitis. Fluoroquinolones, however, continue to be considered as useful alternatives, due to inherent problems in preparation and storage of fortified antibiotics [5,6,63]. Use of fluoroquinolones such as ofloxacin may be associated with corneal precipitates and poor wound healing due to impaired epithelialization [64]; fortunately these effects resolve when treatment is stopped. Fourth-generation fluoroquinolone therapy Gatifloxacin, was found to be superior to ciprofloxacin in treatment of bacterial keratitis, particularly that due to Gram-positive cocci [65], while gatifloxacin and moxifloxacin were found effective in M. chelonae keratitis, in varying combinations with amikacin, clarithromycin or other fluoroquinolones [39,40]. MRSA keratitis, however, was reported in a patient who was receiving gatifloxacin after LASIK, while P. aeruginosa keratitis developed in a patient receiving moxifloxacin after PRK; both cases resolved only after topical aminoglycoside therapy and surgical intervention [41]. Therefore, overuse of these advanced fluoroquinolones should be avoided to prevent development of widespread resistance. Therapy of keratitis due to nontuberculous mycobacteria, Moraxella and Haemophilus The course of post-LASIK infectious keratitis due to NTM is often protracted because of delayed diagnosis, Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 136 Skin and soft tissue infections the advent of resistance to monotherapy, the inadvertent use of corticosteroids, inadequate penetration of drugs into the cornea and slow response to therapy. More than 25% of patients with Moraxella keratitis were reported to have a poor visual outcome, which was attributed to both the nature of the infection and the predisposing factors [19]. Fortunately, H. influenzae keratitis appears to have a favourable outcome, with a good response to medical antibiotic therapy being noted in all 10 patients in a recently reported series of patients with this condition [20]. entire duration of hospitalization, and repeated cultures were done immediately before AMT. Viral keratitis While antivirals continue to be important in therapy of viral keratitis, there is increasing emphasis on methods to ameliorate the effects of an overactive host inflammatory response (Table 1). Treatment of herpes simplex virus epithelial keratitis The technique of subpalpebral lavage therapy was devised to provide continuous irrigation of the eye so as to improve scleral penetration by antibiotics, such as tobramycin (100 mg/ml) and levofloxacin (500 mg/100 ml) [66]. This technique also allows the cleaning of necrotic debris, causes a decrease in the free bacterial load, reduces likelihood of recurrences and is ideally suited for patients who may resist frequent nursing care. Acyclovir is currently the drug of choice [75]. In a small series of patients, topical ganciclovir gel 0.15%, given every 6 h, was helpful in the treatment of herpetic epithelial keratitis; when given twice daily, it was effective prophylaxis for patients with herpetic keratitis who were undergoing penetrating keratoplasty [76], while perioperative prophylaxis with oral valacyclovir and topical acyclovir ointment was found to prevent reactivation of latent HSV keratitis in a small series of patients who underwent LASIK [77]. These encouraging results require further confirmation in a larger series of patients, using controls. Defensins Treatment of herpes simplex virus stromal keratitis Defensins are small cationic peptides with broad in-vitro antimicrobial activity. They also offer potential as wound healing agents. Their efficacy in treating ocular microbial infections, however, may be affected by the presence of tears [67]. For nonnecrotizing (disciform) stromal keratitis, topical corticosteroids are predominantly applied. Topical corticosteroid use has many undesired side-effects and response to such therapy may be limited in some patients, hence other modalities of treatment have been tried. In a recent study [78], 10 of 12 patients with HSV nonnecrotizing stromal keratitis, who had failed to respond to 4 weeks of 1% topical prednisolone acetate therapy, were found to respond to 1 month of topical cyclosporine 0.05% twice daily; unfortunately, the keratitis recurred in four patients when therapy was discontinued. Oral acyclovir therapy, in conjunction with corticosteroids, might ameliorate the deep corneal inflammation of disciform keratitis. For necrotizing stromal keratitis, oral acyclovir is given to control the viral invasion and replication in corneal tissue, while topical corticosteroids are given twice daily to control inflammation. Recently, attempts have been made to apply protective cytokines topically, either as naked DNA or in plasmids, to mitigate the course of experimental herpes stromal keratitis [75]. Other methods of applying the DNA have also been tried [79]. Subpalpebral lavage therapy Fungal keratitis Filamentous fungal keratitis continues to be difficult to treat despite the use of topical and systemic antifungal agents and adjuvant surgery, such as corneal transplantation. Few prospective studies have evaluated the effectiveness of different therapeutic approaches for fungal keratitis [17]. Medical therapy of fungal keratitis Medical therapy has been boosted by the use of voriconazole, given topically or by other routes [68,69]. In addition, new ways of administering established drugs have been tried, for example intrastromal corneal injection of amphotericin B (5 mg per 0.1 ml) [70], subconjunctival fluconazole (0.5–1.0 ml of a 2% solution) [71,72], and topical fluconazole with oral ketoconazole [73]. It should be noted that the amphotericin B paper dealt with a single case, while in the fluconazole papers, there was insufficient detail regarding the severity of the keratitis in the patients. Amniotic membrane transplantation for fungal keratitis When amniotic membrane transplantation (AMT) was used to treat acute, culture-proven fungal keratitis in 23 eyes (23 patients), complete epithelialization was achieved in 75% of patients with active disease and in all patients with inactive disease. [74]; importantly, antifungal agents were administered throughout the Treatment of adenoviral keratitis Two new compounds, namely N-chlorotaurine [80] and a topical cobalt chelate, CTC-96 [81], were found to be effective against adenovirus in tissue culture and in Ad5/ NZW rabbit ocular model. Clinical trials with these compounds are awaited. Pathogenesis Infectious keratitis arises from an interplay between organism factors (e.g., invasiveness, toxins) and host Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious keratitis Thomas and Geraldine 137 Table 2 Recent advances in understanding pathogenesis/resistance in infectious keratitis References Putative virulence/resistance factor Important findings [83,84] IL-8 (not normally found in cornea; present in certain pathological conditions) [85] Toll-like receptors (TLRs) and common adapter protein MyD88 [86,87] IL-1; NFkB; [26] [88 ] Prolonged hypoxia (> 3 days) of cornea due to contact lens wear/eyelid suturing Nitric oxide causes bacterial killing/stasis [89] Matrix metalloproteinase (MMP)-9 [90] Toll-like receptor (TLR) 4 [91] Single immunoglobulin IL-1R-related molecule (SIGIRR) [92] 20-kDa polysaccharide (PS) antigen of Staphylococcus epidermidis (slime-producing strain) [93] Toll-like receptor (TLR)-2 [94] Vitronectin IL-8 production by corneal and conjunctival stromal cells caused chemoattraction of neutrophils leading to corneal ulceration and marked angiogenesis Activation of TLR2 and TLR4 caused chemokine secretion and neutrophil infiltration into corneal stroma, causing keratitis. This mechanism may be relevant to pathogenesis of Gram-positive and Gram-negative bacterial keratitis, respectively IL-1 stimulated (a) collagen degradation by cultured corneal fibroblasts (this effect is mediated by NF-kB) (b) synthesis or activation of matrix metalloproteinases. Sulfasalazine inhibited these effects. Physical effects of contact lens wear found to direct localization of lipid-raft associated P. aeruginosa internalization on corneal surface. Absence of IFNa and reduced nitric oxide synergistically increased proinflammatory cytokines, neutrophil number and bacterial load after corneal infection with P. aeruginosa MMP-9 found to regulate immune function in cornea by proteolysis, degrade collagen IV in corneal basement membrane and to upregulate chemotactic cytokines/chemokines IL-1 beta and MIP-2, thereby promoting corneal perforation in B6 mice with P. aeruginosa keratitis. In P. aeruginosa keratitis in mice, TLR4 deficiency caused increased neutrophil infiltration and proinflammatory cytokines, decreased induced nitric oxide synthase (iNOS) and beta-defensin-2 production, and impaired bacterial killing In P. aeruginosa keratitis in mice, inhibition of SIGIRR led to increased corneal opacity, stromal damage and bacterial load; significant upregulation of corneal mRNA levels of proinflammatory and type 1 cytokines; significant upregulation of protein levels for IL-1 beta and MIP-2 Active immunization with the antigen and passive immunization with anti20 kDa PS antibodies resulted in high levels of antibodies in serum and aqueous and significantly less corneal damage than in unimmunized rabbits Cultured corneal epithelial cells exposed to Staphylococcus aureus peptidoglycan produced proinflammatory cytokines, chemokines and antimicrobial peptide This extracellular matrix protein promoted and enhanced in-vitro infection of human corneal epithelium by adenovirus serotype 19 In primary HSV keratitis, NO was neuroprotective without antiviral effect. In recurrent HSV keratitis, inhibition of NO did not affect virus shedding or clinical disease. Therefore, NO may not have a significant role in evolution of recurrent HSV keratitis IL-6 played a key role in angiogenesis in HSV keratitis by stimulating production of vascular endothelial growth factor (VEGF). This effect was reversed by antibody to IL-6 HSV1 ICPO found in virus-free tears from rabbit eyes acutely infected with HSV1. Using ex vivo confocal microscopy to scan rabbit corneas infected with a HSV1-derived strain expressing ICPO, this protein was found expressed in corneal epithelial and stromal cells of acutely infected corneas. HSV 1 ICPO possibly excites the immune response in herpes stromal keratitis Protease patterns in Acanthamoeba polyphaga and Acanthamoeba castellanii found to be complex (17 bands ranging from 30 to 144 kDa). Aprotinin inhibited crude extract protease activity in cell culture. HSV mutant was able to produce keratitis even when anterograde axonal spread was not possible After gold particle-mediated gene transfer to mouse corneas 2 days before HSV1 infection, IL-10 and IL-4 were expressed in cornea, leading to reduced expression of IL-6 and milder clinical course of keratitis Trophozoites of A. castellanii bound strongly to cultured corneal epithelial cells in a mannose-inhibitable manner (cysts did not). Trophozoites of other Acanthamoeba strains that bound strongly to corneal cells and produced marked CPE robustly expressed MBP Oral immunization with rMBP ameliorated Acanthamoeba keratitis in a hamster model. This protection was associated with elevated levels of anti-MBP IgA in tear fluid of immunized animals. [95 ] Nitric oxide (NO) [96] IL-6 [97,98] Herpes simplex virus (HSV) type 1 immediate early protein ICPO [99] Protease activities of Acanthamoeba [100] Anterograde axonal spread of HSV1 [79] IL-10 and IL-4 [101] Mannose-binding protein (MBP) of Acanthamoeba [102] Recombinant mannose-binding protein (rMBP) of Acanthamoeba CL, contact lens; CPE, cytopathic effect; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; iNOS, induced nitric oxide synthase; MBP, mannose-binding protein; MIP-2, macrophage inflammatory protein-2; MMP, matrix metalloproteinase; NF, nuclear factor; PS, polysaccharide; rMBP, recombinant mannose-binding protein; SIGIRR, single Ig IL-1R-related molecule; TLR, Toll-like receptor; VEGF, vascular endothelial growth factor. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 138 Skin and soft tissue infections factors (e.g., polymorphonuclear leucocyte infiltration). Initially, much of the focus was on contribution of organism factors to pathogenesis of infectious keratitis; in recent years, there is increasing realization of the importance of host factors such as Toll-like receptors [82]. Recent advances in our understanding of the pathogenesis of, and resistance to, infectious keratitis are summarised in Table 2 [82,83,84,85,86,87,88,89,90,91, 92,93,94 –96,97,98,99,100,101,102]. Prevention There have been advances in prevention of traumaassociated and contact lens-associated infectious keratitis and in development of vaccines for some types of infectious keratitis. Prevention of trauma-associated infectious keratitis If posttraumatic infectious keratitis is initiated following infection of a breach in the corneal epithelium, then application of antimicrobials to the abraded cornea soon after trauma should reduce the incidence of infectious keratitis. Proof that this hypothesis is correct has been provided by two studies at the village level, one in Bhutan [103], and the other in Burma [104]; application of 1% chloramphenicol ointment or 1% chloramphenicol–clotrimazole ointment soon after detection of trauma-induced corneal abrasion effectively prevented bacterial and fungal keratitis respectively. These reports stressed the importance of committed grassroots workers (volunteer or otherwise), a fairly extensive rural health network and a campaign (either official or by word of mouth) to publicize the fact that individuals with abrasions could seek treatment with the health workers. Interestingly, neither of these papers dwelt on the importance of traditional healers in these defined populations, and whether it was necessary to solicit their cooperation. Prevention of contact lens-associated infectious keratitis General measures include proper storage, disinfection and cleaning of contact lenses and their cases; overnight contact lens wear should be avoided, and the contact lenses promptly removed at the onset of ocular irritation [27]. To prevent contact lens-associated Acanthamoeba keratitis, patients should be informed of the possible danger of wearing first-generation silicone hydrogel lenses when exposed to sources of the organisms while swimming or in showers and hot tubs, since such lenses are very sticky for Acanthamoeba trophozoites and may increase the chances of infection [25]; use of these lenses on a trial basis, or use of second-generation lenses could be advised. Infectious keratitis should not be treated with a corticosteroid in the absence of appropriate antimicrobial therapy since it may aggravate an unrecognized fungal keratitis. Prevention of infectious keratitis by using vaccines Vaccines for S. epidermidis and Acanthamoeba are at an experimental stage [92,102]. Much progress has been made, however, in developing vaccines to prevent HSV keratitis, and the routine use of such vaccines may become a reality one day [75,105]. Conclusion While infectious keratitis is a well recognized cause of visual loss in the developing world, the recent outbreak of contact lens-induced Fusarium keratitis has heightened the awareness of the international community about this problem. Hopefully, this will lead to increased recognition of potential risk factors predisposing to the condition, as well as improvements in diagnosis and therapy. An overactive host response is detrimental to the resolution of infectious keratitis, so methods need to be devised to check this overactivity without, however, impairing the elimination of pathogens. There should be increased emphasis on the prevention of infectious keratitis by prompt recognition of trauma-induced corneal abrasions, and by eliminating potential predisposing factors. Acknowledgements We wish to thank Drs C.M. Kalavathy, J. Kaliamurthy, Sunil Kumar and Selvakumar Subramanian and Mrs A. Geetha for their help in the preparation of this manuscript. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 205–206). 1 Keay L, Edwards K, Naduvilath T, et al. Microbial keratitis: predisposing factors and morbidity. Ophthalmology 2006; 113:109–116. This is a key addition to the literature on infectious keratitis, being the first paper reporting the financial implications of hospitalization for infectious keratitis and one of the few papers on infectious keratitis that reports on the entire spectrum of causative microorganisms (including herpesviruses). 2 Lam DS, Houang E, Fan DS, et al. Incidence and risk factors for microbial keratitis in Hong Kong: comparison with Europe and North America. Eye 2002; 16:608–618. 3 Erie JC, Nevitt MP, Hodge DO, Ballard DJ. Incidence of ulcerative keratitis in a defined population from 1950 through 1988. Arch Ophthalmol 1993; 111: 1665–1671. 4 World Health Organization. Guidelines for the management of corneal ulcer of primary, secondary, and tertiary care health facilities in the South-East Asia Region. SEA/Ophthal/126. New Delhi: WHO Regional Office for South-East Asia; 2004. pp. 1–36. 5 Parmar P, Salman A, Kalavathy CM, et al. Microbial keratitis at extremes of age. Cornea 2006; 25:153–158. This interesting study sought to assess the association of age with culturepositivity, aetiological agents, clinical outcome and other features of infectious keratitis. 6 Titiyal JS, Negi S, Anand A, et al. Risk factors for perforation in microbial corneal ulcers in north India. Br J Ophthalmol 2006; 90:686–689. This describes one of the few case–control studies on infectious keratitis. This study specifically looked for factors predisposing to an unsatisfactory outcome (corneal perforation); unique risk factors identified were illiteracy and excessive alcohol consumption. 7 Lin SH, Lin CP, Wang HZ, et al. Fungal corneal ulcers of onion harvesters in southern Taiwan. Occup Environ Med 1999; 56:423–425. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious keratitis Thomas and Geraldine 139 8 Leck AK, Thomas PA, Hagan M, et al. Aetiology of suppurative corneal ulcers in Ghana and south India, and epidemiology of fungal keratitis. Br J Ophthalmol 2002; 86:1211–1215. 9 Wilhelmus KR. Climatology of dematiaceous fungal keratitis. Am J Ophthal mol 2005; 140:1156–1157. This is a brief communication but important in emphasizing the influence of environmental factors on the frequency of occurrence of filamentous fungal keratitis; clustering of Curvularia keratitis was found when the temperature was 23.98C 38C and relative humidity averaged 73 13%. Yamamoto N, Yamamoto N, Jester JV, et al. Prolonged hypoxia induces lipid raft formation and increases Pseudomonas internalization in vivo after contact lens wear and lid closure. Eye Contact Lens 2006; 32:114–120. This paper suggests that hypoxia arising from prolonged contact lens wear may predispose to infectious keratitis. 26 27 Margolis TP, Whitcher JP. Fusarium: a new culprit in the contact lens case. JAMA 2006; 296:985–987. This commentary discusses the implications of the recent contact lens-associated outbreak of Fusarium keratitis. Khor W-B, Aung T, Saw S-M, et al. An outbreak of Fusarium keratitis associated with soft contact lens wear in Singapore. JAMA 2006; 295: 2867–2873. This describes the characteristics of patients in Singapore affected by the recent contact lens-associated outbreak of Fusarium keratitis. 10 Labbe A, Dupas B, Bensoussan L, Baudouin C. Bilateral infectious ulcers associated with atopic keratoconjunctivitis. Cornea 2006; 25:248–250. This is a case report but important in providing details of bilateral bacterial keratitis with an ocular disorder as the risk factor; a new-generation confocal microscope (Heidelberg retinal tomograph II with cornea module) contributed to the diagnosis. 28 11 Watt K, Swarbrick HA. Microbial keratitis in overnight orthokeratology: review of the first 50 cases. Eye Contact Lens 2005; 31:201–208. This is the first review of infectious keratitis associated with overnight wear of orthokeratology lenses; most patients were found to be from East Asia. 29 Centers for Disease Control and Prevention. Fusarium keratitis: multiple states. MMWR Morb Mortal Wkly Rep 2006; 55: 400–401. 30 Centers for Disease Control and Prevention. Update: Fusarium keratitis United States, 2005–2006. MMWR Morb Mortal Wkly Rep 2006; 55: 563–564. 12 Sun X, Zhao H, Deng S, et al. Infectious keratitis related to orthokeratology. Ophthalmic Physiol Opt 2006; 26:133–136. This is a case series of infectious keratitis in China where the risk factor was wearing of orthokeratology lenses. 13 Hooi SH, Hooi ST. Culture-proven bacterial keratitis in a Malaysian general hospital. Med J Malaysia 2005; 60:614–623. This is an interesting report on more than 100 patients with culture-proven bacterial keratitis in a general hospital in a tropical setting. 14 Sun X, Zhang Y, Li R, et al. Acanthamoeba keratitis: Clinical characteristics and management. Ophthalmology 2006; 113:412–416. This is a retrospective analysis of risk factors, presentation and management of 20 consecutive patients with Acanthamoeba keratitis in China. Parmar DN, Awad ST, Petroll WM, et al. Tandem scanning confocal corneal microscopy in the diagnosis of suspected Acanthamoeba keratitis. Ophthalmology 2006; 113:538–547. This is a retrospective analysis of risk factors (principally contact lens wear), diagnosis (principally by tandem scanning confocal microscopy) and management of 63 patients with Acanthamoeba keratitis in the USA. 15 Bernal MD, Acharya NR, Lietman TM, et al. Outbreak of Fusarium keratitis in soft contact lens wearers in San Francisco. Arch Ophthalmol 2006; 124:1051–1053. This describes the characteristics of patients in San Francisco affected by the recent contact lens-associated outbreak of Fusarium keratitis. 31 Alfonso EC, Cantu-Dibildox J, Munir WM, et al. Insurgence of Fusarium keratitis associated with contact lens wear. Arch Ophthalmol 2006; 124: 941–947. This describes the characteristics of patients in Florida affected by the recent contact lens-associated outbreak of Fusarium keratitis. 32 Chang DC, Grant GB, O’Donnell K, et al., for the Fusarium Keratitis Investigation Team. Multistate outbreak of Fusarium keratitis associated with use of a contact lens solution. JAMA 2006; 296:953–963. This is a brilliant exposition of the epidemiological aspects of the recent contact lens-associated outbreak of Fusarium keratitis in the United States. The conclusions made, however, may be open to debate. 33 34 16 Wang AG, Wu CC, Liu JH. Bacterial corneal ulcer: a multivariate study. Ophthalmologica 1998; 212:126–132. 17 Thomas PA. Current perspectives on ophthalmic mycoses. Clin Microbiol Rev 2003; 16:730–797. 35 18 Ritterband DC, Seedor JA, Shah MK, et al. Fungal keratitis at the New York Eye and Ear Infirmary. Cornea 2006; 25:264–267. In this retrospective analysis of fungal keratitis, seropositivity to human immunodeficiency virus was reported as the most important risk factor, a most unique finding. 36 Das S, Constantinou M, Daniell M, Taylor HR. Moraxella keratitis: predisposing factors and clinical review of 95 cases. Br J Ophthalmol 2006; 90:1236–1238. This case series of 95 patients contradicts the misplaced notion that Moraxella keratitis tends to occur in derelict individuals. 19 20 Yang K-S, Lin H-C, Ma DHK, et al. Ulcerative keratitis caused by Haemo philus influenzae. Cornea 2006; 25:701–704. A retrospective analysis of 10 patients with keratitis due to H. influenzae, one of the few bacteria that can penetrate an intact corneal epithelium. 21 Dunlop AA, Wright ED, Howlader SA, et al. Suppurative corneal ulceration in Bangladesh: a study of 142 cases, examining the microbiological diagnosis, clinical and epidemiological features of bacterial and fungal keratitis. Aust NZ J Ophthalmol 1994; 22:105–110. 22 Wong T-Y, Ng T-P, Fong K-S, Tan DTH. Risk factors and clinical outcome between fungal and bacterial keratitis. A comparative study. CLAO J 1997; 23:275–281. Schein OD, McNally JJ, Katz J, et al. The incidence of microbial keratitis among wearers of a 30-day silicone hydrogel extended-wear contact lens. Ophthalmology 2005; 112:2172–2179. This was another study to emphasize the importance of extended-wear contact lenses as a risk factor for infectious keratitis. 23 24 Demirci G, Ay GM, Karabas LV, et al. Acanthamoeba keratitis in a 5 year old boy without a history of contact lens usage. Cornea 2006; 25:356–358. This is a description of Acanthamoeba keratitis in a Turkish boy with no apparent risk factor for Acanthamoeba keratitis. Beattie TK, Tomlinson A, McFadyen AK. Attachment of Acanthamoeba to first- and second-generation silicone hydrogel contact lenses. Ophthalmology 2006; 113:117–125. This experimental study showed that the composition of a contact lens may predispose to Acanthamoeba keratitis. 25 Solomon R, Donnenfeld ED, Azar DT, et al. Infectious keratitis after laser in situ keratomileusis: results of an ASCRS survey. J Cataract Refract Surg 2003; 29:2001–2006. Donnenfeld ED, Kim T, Holland EJ, et al. ASCRS White Paper: Management of infectious keratitis after laser in situ keratomileusis. J Cataract Refract Surg 2006; 31:2008–2011. This is a straightforward description of management of infectious keratitis following LASIK. Wroblewski KJ, Pasternak JF, Bower KS, et al. Infectious keratitis after photorefractive keratectomy in the United States Army and Navy. Ophthalmology 2006; 113:520–525. Infectious keratitis is a rare occurrence after photorefractive keratectomy in personnel of the US Army and Navy. 37 Jones DB. Strategy for the initial management of suspected microbial keratitis. In: Barraquer JI, Binder PS, Buxton JN, et al., editors. Symposium on medical and surgical diseases of the cornea: Transactions of the New Orleans Academy of Ophthalmology. St Louis: CV Mosby; 1980. pp. 86– 119. 38 Seal DV, Bron AJ, Hay J. Ocular infection: investigation and treatment in practice. London: Martin Dunitz; 1998. 39 Umapathy T, Singh R, Dua HS, Donald F. Nontuberculous mycobacteria related infectious crystalline keratopathy. Br J Ophthalmol 2005; 89:1374–1375. This is a case report describing an unusual presentation of infectious keratitis. Hamam RN, Noureddin B, Salti HI, et al. Recalcitrant post-LASIK Mycobacterium chelonae keratitis eradicated after the use of fourth-generation fluoroquinolone. Ophthalmology 2006; 113:950–954. The authors describe the efficacy of fourth-generation fluoroquinolones for postLASIK keratitis. 40 Moshirfar M, Mirzaian G, Feiz V, Kang PC. Fourth-generation fluoroquinoloneresistant bacterial keratitis after refractive surgery. J Cataract Refract Surg 2006; 32:515–518. This provides a warning about the emergence of resistance to fourth-generation fluoroquinolones. 41 Patel SR, Hammersmith KM, Rapuano CJ, Cohen EJ. Exophiala dermatitidis keratitis after laser in situ keratomileusis. J Cataract Refract Surg 2006; 32:681–684. This describes an unusual pathogen in post-LASIK infectious keratitis. 42 Patel NR, Reidy JJ, Gonzalez-Fernandez F. Nocardia keratitis after laser in situ keratomileusis: clinicopathologic correlation. J Cataract Refract Surg 2005; 31:2012–2015. This describes another unusual pathogen in post-LASIK infectious keratitis. 43 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 140 Skin and soft tissue infections 44 Sharma N, Sinha R, Singhvi A, Tandon R. Pseudomonas keratitis after laser in situ keratomileusis. J Cataract Refract Surg 2006; 32:519–521. This is believed to be the first documented case of P. aeruginosa keratitis following LASIK. 60 Vasseneix C, Gargala G, Francois A, et al. A keratitis rat model for evaluation of anti-Acanthamoeba polyphaga agents. Cornea 2006; 25:597–602. This describes the first rat model of chronic amoebic keratitis, which mimics human Acanthamoeba keratitis in many respects. Joseph J, Sridhar MS, Murthy S, Sharma S. Clinical and microbiological profile of microsporidial keratoconjunctivitis in southern India. Ophthalmology 2006; 113:531–537. This paper describes the clinical presentation (mimics adenoviral keratoconjunctivitis), diagnosis using readily available stains and management of the largest documented (19 patients) case series of microsporidial keratoconjunctivitis; most of the patients were immunocompetent and did not wear contact lenses. 61 45 Seitzman GD, Cevallos V, Margolis TP. Rose bengal and lissamine green inhibit detection of herpes simplex virus by PCR. Am J Ophthalmol 2006; 141:756–758. Rose bengal, lissamine green and calcium alginate were found to inhibit PCR detection of several viruses and toxoplasma; this needs to be considered when using PCR for diagnosis of viral keratitis. 46 47 Marangon FB, Miller D, Alfonso EC. Impact of prior therapy on the recovery and frequency of corneal pathogens. Cornea 2004; 23:158–164. 48 Pate JC, Jones DB, Wilhelmus KR. Prevalence and spectrum of bacterial co infection during fungal keratitis. Br J Ophthalmol 2006; 90:289–292. This unique paper defines bacterial co-infection and describes criteria for assessing the relative importance of a bacterial isolate in a patient with culture-proven fungal keratitis; these criteria reflect the bacterial load in the wound but give relatively less weight to the virulence of the organism. Thomas PA, Leck AK, Myatt M. Characteristic clinical features as an aid to the diagnosis of suppurative keratitis caused by filamentous fungi. Br J Ophthalmol 2005; 89:1554–1558. This describes a partial diagnostic score to help in differentiating filamentous fungal from bacterial keratitis based on criteria such as serrated margins, raised slough and dry texture. 49 50 This with Wilhelmus KR, Jones DB. Adult-onset syphilitic stromal keratitis. Am J Ophthalmol 2006; 141:319–321. is a reminder that a syphilitic cause needs to be excluded when confronted a presentation of non-necrotizing stromal keratitis. Bourcier T, Dupas B, Borderie V, et al. Heidelberg retina tomograph II findings of Acanthamoeba keratitis. Ocul Immunol Inflamm 2005; 13: 487–492. This describes how Acanthamoeba keratitis can be diagnosed using this advanced version confocal microscope. 51 52 Singh R, Joseph A, Umapathy T, et al. Impression cytology of the ocular surface. Br J Ophthalmol 2005; 89:1655–1659. This reviews the use of impression cytology for diagnosis of various ocular disorders, including infectious keratitis. 53 Thiel MA, Bossart W, Bernauer W. Improved impression cytology techniques for the immunopathological diagnosis of superficial viral infections. Br J Ophthalmol 1997; 81:984–988. 54 Sawada Y, Yuan C, Huang AJ. Impression cytology in the diagnosis of acanthamoeba keratitis with surface involvement. Am J Ophthalmol 2004; 137:328. Abd El-Aal AM, El Sayed M, Mohammed E, et al. Evaluation of herpes simplex detection in corneal scrapings by three molecular methods. Curr Microbiol 2006; 52:379–382. This paper suggests that immunofluorescence be used for rapid primary screening, and viral culture and PCR to confirm the diagnosis, in suspected herpes simplex viral keratitis. 55 56 Robert P-Y, Liekfeld A, Metzner S. Specific antibody production in herpes keratitis: intraocular inflammation and corneal neovascularisation as predicting factors. Graefe’s Arch Clin Exp Ophthalmol 2006; 244: 210–215. Koidl C, Bozic M, Mossböck G, et al. Rapid diagnosis of adenoviral keratoconjunctivitis by a fully automated molecular assay. Ophthalmology 2005; 1521–1527. This describes a new molecular assay incorporating real-time PCR protocol and automated extraction of conjunctival smear samples. 57 Kumar M, Mishra NK, Shukla PK. Sensitive and rapid polymerase chain reaction-based diagnosis of mycotic keratitis through single-stranded conformation polymorphism. Am J Ophthalmol 2005; 140:851–857. A modified PCR technique was found superior to microscopy and culture in diagnosis of fungal keratitis but ultimately only confirmed the clinical suspicion of fungal keratitis in four patients. 58 Gregori NZ, Schiffman JC, Miller DM, Alfonso EC. Clinical trial of povidoneiodine (betadine) versus placebo in the pretreatment of corneal ulcers. Cornea 2006; 25:558–563. Povidone-iodine pretreatment of corneal ulcers before institution of specific antimicrobial therapy was not superior to placebo in improving the outcome of infectious keratitis. 59 Awwad ST, Parmar DN, Heilman M, et al. Results of penetrating keratoplasty for visual rehabilitation after Acanthamoeba keratitis. Am J Ophthalmol 2005; 1080–1084. The outcome of penetrating keratoplasty was improved (no recurrences) if there was an interval of at least 3 months between discontinuation of antiamoebic therapy and performing surgery. Mauger TF, Craig E. Combined Acanthamoeba and Stenotrophomonas maltophilia keratitis treated with a conjunctival flap followed by penetrating keratoplasty. Cornea 2006; 25:631–633. Polymicrobial infection was eradicated by a combination of conjunctival flap surgery, cryotherapy and keratoplasty. 62 Ly CN, Pham JN, Badenoch PR, et al. Bacteria commonly isolated from keratitis specimens retain antibiotic susceptibility to fluoroquinolones and gentamicin plus cephalothin. Clin Exp Ophthalmol 2006; 34:44– 50. This describes the continued relevance of fortified topical antibiotic therapy and of fluoroquinolone monotherapy for bacterial keratitis. 63 64 Mitra A, Tsesmetzoglou E, McElvanney A. Corneal deposits and topical ofloxacin: the effect of polypharmacy in the management of microbial keratitis. Eye 2006; Mar 17 [Epub ahead of print]. Parmar P, Salman A, Kalavathy CM, et al. Comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis. Am J Ophthalmol 2006; 141:282–286. This was the first paper describing efficacy of topical gatifloxacin therapy for bacterial keratitis, particularly that due to Gram-positive cocci. 65 66 Meallet MA. Subpalpebral lavage antibiotic treatment for severe infectious scleritis and keratitis. Cornea 2006; 25:159–163. Describes several advantages of a subpalpebral lavage technique for continuous perfusion of the eye with antibiotics; possible emergence of drug-resistant bacterial strains is not considered. McDermott AM, Rich D, Cullor J, et al. The in vitro activity of selected defensins against an isolate of Pseudomonas in the presence of human tears. Br J Ophthalmol 2006; 90:609–611. This elegant study showed that activity of defensins is affected by presence of human tears. This may have implications for other therapeutic modalities in the eye as well. 67 Sponsel W, Chen N, Dang D, et al. Topical voriconazole as a novel treatment for fungal keratitis. Antimicrob Agents Chemother 2006; 50: 262 –268. Topical voriconazole therapy was effective for experimental keratitis due to Paecilomyces lilacinus, which is, however, a less frequent cause of filamentous fungal keratitis than Fusarium or Aspergillus. 68 69 Ozbek Z, Kang S, Sivalingam J, et al. Voriconazole in the management of Alternaria keratitis. Cornea 2006; 25:242–244. This is a case report of the efficacy of voriconazole in therapy of keratitis due to Alternaria, another infrequent cause of filamentous fungal keratitis. Garcia-Valenzuela E, Song CD. Intracorneal injection of amphotericin B for recurrent fungal keratitis and endophthalmitis. Arch Ophthalmol 2005; 123:1721–1723. Combined intrastromal and intravitreal amphotericin B led to eradication of recurrent fungal keratitis in one patient. 70 71 Yilmaz S, Maden A. Severe fungal keratitis treated with subconjunctival fluconazole. Am J Ophthalmol 2005; 140:454–458. Subconjunctival fluconazole therapy was effective in treating 12 of 13 patients with fungal keratitis. Only six of the infections were culture-proven, however; eight of the infections were presumably with Candida, which is known to be susceptible to fluconazole. 72 Dev S, Rajaraman R, Raghavan A. Severe fungal keratitis treated with subconjunctival fluconazole. Am J Ophthalmol 2006; 141:783. Subconjunctival fluconazole therapy led to eradication of infection in 54% of patients with filamentous fungal keratitis; there was insufficient mention of the severity of keratitis in the patients. Sonego-Krone S, Sanchez-Di Martino D, Ayala-Lugo R, et al. Clinical results of topical fluconazole for the treatment of filamentous fungal keratitis. Graefe’s Arch Clin Exp Ophthalmol 2006; 244:782–787. Topical fluconazole, alone or in combination with oral ketoconazole, was effective in culture-proven filamentous fungal keratitis; there was insufficient detail about severity of the keratitis in the responders. 73 Chen H-C, Tan H-Y, Hsiao C-H, et al. Amniotic membrane transplantation for persistent corneal ulcers and perforations in acute fungal keratitis. Cornea 2006; 25:564–572. Amniotic membrane transplantation promoted epithelialization and prevented corneal perforation provided there was continued antifungal treatment. 74 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious keratitis Thomas and Geraldine 141 75 Kaye S, Choudhary A. Herpes simplex keratitis. Progress in Retinal and Eye Research 2006; 25:355–380. This is a very good review on herpes simplex viral keratitis that focuses on recent advances in management of the condition. 76 Tabbara KF. Treatment of herpetic keratitis. Ophthalmology 2005; 112:1640–1641. This is the first case series describing effective treatment and prophylaxis of herpetic keratitis by using ganciclovir gel 0.15%. de Rojas Silva MV, Diez-Feijoo E, Javaloy J, Sanchez-Salorio M. Prophylactic perioperative antiviral therapy for LASIK in patients with inactive herpetic keratitis. J Refract Surg 2006; 22:404–406. Oral valacyclovir and topical acyclovir were used to prevent LASIK-induced reactivation of herpetic keratitis in a small group of patients. 77 Rao SN. Treatment of herpes simplex virus stromal keratitis unresponsive to topical prednisolone 1% with topical cyclosporine 0.05%. Am J Ophthalmol 2006; 141:771–772. Topical cyclosporine was a safe and effective treatment for a series of patients with non-necrotizing herpes stromal keratitis who had not responded to corticosteroids. 78 Bauer D, Lu M, Wasmuth S, et al. Immunomodulation by topical particlemediated administration of cytokine plasmid DNA suppresses herpetic stromal keratitis without impairment of antiviral defense. Graefe’s Arch Clin Exp Ophthalmol 2006; 244:216–225. This interesting paper highlights probable future trends in therapy of herpetic stromal keratitis by delivering cytokine DNA directly to the affected cornea. 79 Romanowski EG, Yates KA, Teuchner B, et al. N-chlorotaurine is an effective antiviral agent against adenovirus in vitro and in the Ad5/NZW rabbit ocular model. Invest Ophthalmol Vis Sci 2006; 47:2021–2026. This describes a drug with potential future use for ocular adenoviral infections. 80 Epstein PS, Pashinsky YY, Gershon D, et al. Efficacy of topical cobalt chelate CTC-96 against adenovirus in a cell culture model and against adenovirus keratoconjunctivitis in a rabbit model. BMC Ophthalmology 2006; 6:22. This describes another drug with potential future use for ocular adenoviral infections. 81 Chang JH, McCluskey PJ, Wakefield D. Toll-like receptors in ocular immunity and the immunopathogenesis of inflammatory eye disease. Br J Ophthalmol 2006; 90:103–108. This is an outstanding review of the possible role of Toll-like receptors in ocular immunity and in pathogenesis of ocular conditions, including infectious keratitis; of particular interest is the explanation for responsiveness to ocular pathogens but relative inactivity in response to the normal conjunctival bacterial flora. 82 83 Xue ML, Zhu H, Willcox M, et al. The role of IL-1b in the regulation of IL-8 and IL-6 in human corneal epithelial cells during Pseudomonas aeruginosa colonization. Curr Eye Res 2001; 23:406–414. Oka M, Norose K, Matsushima K, et al. Overexpression of IL-8 in the cornea induces ulcer formation in the SCID mouse. Br J Ophthalmol 2006; 90:612– 615. Interleukin-8 causes chemoattraction of neutrophils in corneal ulceration, which may be relevant to pathogenesis of some forms of infectious keratitis. 84 85 Johnson AC, Heinzel FP, Diaconu E, et al. Activation of toll-like receptor (TLR)2. TLR4 and TLR9 in the mammalian cornea induces MyD88-dependent corneal inflammation. Invest Ophthalmol Vis Sci 2005; 46:589–595. 86 Hao JL, Nagano T, Nakamura M, et al. Galardin inhibits collagen degradation by rabbit keratocytes by inhibiting the activation of pro-matrix metalloproteinases. Exp Eye Res 1999; 68:565–572. 87 Lu Y, Fukuda K, Li Q, et al. Role of nuclear factor-kB in interleukin-1-induced collagen degradation by corneal fibroblasts. Exp Eye Res 2006; 83:560–568. Nuclear factor-KB was found to mediate interleukin 1-induced collagen degradation, so could serve as a target for therapies that aim to reduce collagen destruction in infectious keratitis. 88 McClellan SA, Lighvani S, Hazlett LD. IFN-gamma: regulation of nitric oxide in the P. aeruginosa-infected cornea. Ocul Immunol Inflamm 2006; 14:21–28. Synergistic interaction between IFN-gamma and nitric oxide may explain the resistance of BALB/c mice to P. aeruginosa keratitis, with positive implications for human infectious keratitis. Huang X, Hazlett LD, Du W, Barrett RP. SIGIRR promotes resistance against Pseudomonas aeruginosa keratitis by down-regulating type-1 immunity and IL-1R1 and TLR4 signaling. J Immunol 2006; 177:548–556. This experimental study explained another putative mechanism (single Ig IL-1Rrelated molecule) by which BALB/c mice are resistant to P. aeruginosa keratitis. 91 Georgakopoulos CD, Exarchou AM, Gartaganis SP, et al. Immunization with specific polysaccharide antigen reduces alterations in corneal proteoglycans during experimental slime-producing Staphylococcus epidermidis keratitis. Curr Eye Res 2006; 31:137–146. This paper raises the possibility of preventing infectious keratitis by active and passive immunization provided the relevant microbial antigens are identified. 92 93 Kumar A, Zhang J, Yu FS. Innate immune response of corneal epithelial cells to Staphylococcus aureus infection: role of peptidoglycan in stimulating proinflammatory cytokine secretion. Invest Ophthalmol Vis Sci 2004; 45:3513–3522. Xiao J, Nataraja K, Rajala MS, et al. Vitronectin: A possible determinant of adenovirus type 19 tropism for human corneal epithelium. Am J Ophthalmol 2005; 140:363–369. Just as this extracellular matrix protein promotes in-vitro adenoviral infection of human corneal epithelium, there may be other proteins which promote viral infection. 94 Keadle TL, Morris JL, Stuart PM. The effects of aminoguanidine on primary and recurrent ocular herpes simplex virus infection. Nitric Oxide 2005; 13: 247–253. Aminoguanidine (which inhibits inducible nitric oxide synthase) was not found to affect virus shedding or clinical disease in recurrent HSV keratitis. 95 Biswas PS, Banerjee K, Kinchington PR, Rouse BT. Involvement of IL-6 in the paracrine production of VEGF in ocular HSV-1 infection. Exp Eye Res 2006; 82:46–54. Interleukin-6 produced by HSV-infected cells found to stimulate corneal and inflammatory cells to produce VEGF, a potent angiogenic factor. 96 97 Naito J, Mott KR, Osorio N, et al. Herpes simplex virus type 1 immediate-early protein ICP0 diffuses out of infected rabbit corneas. J Gen Virol 2005; 86:2979–2988. Morishige N, Jester JV, Naito J, et al. Herpes simplex virus type 1 ICP0 localizes in the stromal layer of infected rabbit corneas and resides predominantly in the cytoplasm and/or perinuclear region of rabbit keratocytes. J Gen Virol 2006; 87:2817–2825. Eyes acutely infected with HSV were found to have this viral protein localized to corneal epithelial and stromal cells, which is a finding of great relevance to our understanding of pathogenesis of herpes stromal keratitis. 98 99 Serrano-Luna Jde J, Cervantes-Sandoval I, Calderon J, et al. Protease activities of Acanthamoeba polyphaga and Acanthamoeba castellanii. Can J Microbiol 2006; 52:16–23. 100 Polcicova K, Biswas PS, Banerjee K, et al. Herpes keratitis in the absence of anterograde transport of virus from sensory ganglia to the cornea. PNAS 2005; 102:11462–11467. An HSV USP mutant was constructed which did not exhibit anterograde axonal spread and yet was able to produce keratitis; this has important implications for our understanding of spread of HSV from sensory ganglia to the cornea. 101 Garate M, Marchant J, Cubillos I, et al. In vitro pathogenicity of Acanthamoeba is associated with the expression of the mannose-binding protein. Invest Ophthalmol Vis Sci 2006; 47:1056–1062. This important paper explains why Acanthamoeba cysts bind poorly to corneal cells, since there is little expression of the mannose-binding protein. 102 Garate M, Alizadeh H, Neelam S, et al. Oral immunization with Acanthamoeba mannose-binding protein ameliorates amoebic keratitis. Infect Immun 2006; Sep 18 [Epub ahead of print]. This paper raises the exciting possibility that acanthamoebic keratitis can be ameloriated, if not entirely prevented, by active immunization. 103 Getshen K, Srinivasan M, Upadhyay MP, et al. Corneal ulceration in South East Asia. I: A model for the prevention of bacterial ulcers at the village level in rural Bhutan. Br J Ophthalmol 2006; 90:276–278. This outstanding paper provides evidence that posttraumatic bacterial keratitis can be effectively prevented if antibiotic ointment is administered soon after trauma to treat the trauma-induced corneal abrasion. This is possibly the first such paper in its genre. McClellan SA, Huang X, Barrett RP, et al. Matrix metalloproteinase-9 amplifies the immune response to Pseudomonas aeruginosa corneal infection. Invest Ophthalmol Vis Sci 2006; 47:256–264. This outstanding experimental study explained the myriad mechanisms by which this metalloproteinase contributes to corneal destruction in P. aeruginosa keratitis. Metalloproteinase inhibitors may thus have a role in therapy of infectious keratitis. 104 Maung N, Thant CC, Srinivasan M, et al. Corneal ulceration in South-East Asia. II: A strategy for the prevention of fungal keratitis at the village level in Burma. Br J Ophthalmol 2006; 90:968–970. This is another outstanding paper to provide evidence that posttraumatic fungal keratitis can be effectively prevented if ointment containing an antibacterial and antifungal is administered soon after trauma to treat the trauma-induced corneal abrasion. Huang X, Du W, McClellan SA, et al. TLR4 is required for host resistance in Pseudomonas aeruginosa keratitis. Invest Ophthalmol Vis Sci 2006; 47:4910–4916. This outstanding experimental study explained the mechanisms by which deficiency of Toll-like receptor 4 promotes P. aeruginosa keratitis. This may have relevance for keratitis due to other ocular pathogens as well. 105 Pepose JS, Keadle TL, Morrison LA. Ocular herpes simplex: changing epidemiology, emerging disease patterns and the potential of vaccine prevention and therapy. Am J Ophthalmol 2006; 141:547–557. Development of vaccines against HSV is described in this complex review; that these vaccines should not exacerbate immune-mediated herpes stromal keratitis is stressed. 89 90 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. New fungal nail infections Matilde Iorizzo, Bianca Maria Piraccini and Antonella Tosti Purpose of review The number of people affected by onychomycosis continues to increase. The prevalence of different pathogens in different areas depends on several factors, such as climate, geography and migration. We reviewed the recent literature to identify new agents responsible for onychomycosis. Recent findings Recent studies performed in different countries are not only reporting molds and yeasts as contaminants, but are increasingly reporting them as pathogens. Infection by novel agents is also being reported, although the individual cases do not necessarily indicate that these are emerging agents. Summary Clinicians should bear in mind the increased number of case series reporting the role of molds and yeasts in onychomycosis, and should not treat the disease without first examining the mycology results. The question remains as to whether these agents are truly new fungi responsible for onychomycosis, or whether improvement of diagnostic techniques and increasing reference to such species in the literature has resulted in better identification of such agents. Keywords dermatophytes, fungi, nail, nondermatophytic molds, onychomycosis Curr Opin Infect Dis 20:142–145. ß 2007 Lippincott Williams & Wilkins. Department of Dermatology, University of Bologna, Bologna, Italy Correspondence to Matilde Iorizzo, MD, Department of Dermatology, University of Bologna, V. Massarenti 1, 40138, Bologna, Italy Tel: +39 051 341820; fax: +39 051 347847; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:142–145 ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction Onychomycosis is a common nail disease and describes the infection of the nail by fungi [1]. Different clinical patterns of infection depend on the way in which fungi colonize the nail [2,3]. Type of nail invasion depends on the responsible fungus and host susceptibility. Dermatophytes are the most common responsible agents, but onychomycosis can also be due to molds and yeasts. The prevalence of onychomycosis among the general population is still underestimated even though, thanks to the recent advances in diagnosis and risk factor identification, cases are increasingly being reported in the literature [4,5]. Moreover, dermatologists and general practitioners are now recognizing the importance of culture to identify the causative fungi and to plan the appropriate treatment. Despite the advances in treatment modalities, the number of people affected by this disorder continues to increase [6]. The condition remains difficult to treat and about 20% of onychomycosis of the toenail fails to respond to therapy. Current prospects Agents responsible for the majority of onychomycosis are listed in Table 1. The prevalence of different pathogens in different areas depends on factors such as climate, geography and migration. For instance, onychomycosis due to dermatophytes is common in all geographical areas (even if the percentage is higher in temperate western countries), while nail infection due to molds and yeasts is mainly seen in Mediterranean and tropical climates [6]. Laboratory examination is very important to confirm the diagnosis of onychomycosis because the clinical appearance caused by one species of fungus is usually indistinguishable from that caused by another. Species identification is important to better define the epidemiology of onychomycosis, to plan the appropriate treatment and to avoid relapses and recurrences [7,8]. Fungi can be difficult to isolate from nails because of their low number and viability. A negative mycological result does not rule out onychomycosis, as direct microscopy may be negative in up to 10% of cases and culture in up to 30% of cases. If initial investigations prove negative and the clinical features strongly suggest onychomycosis, it may be advisable to perform microscopic examination and culture more than once. Isolation of fungus from nails does not necessarily indicate onychomycosis, as saprophytic fungi may colonize the nail. 142 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. New fungal nail infections Iorizzo et al. 143 Table 1 Agents considered responsible for the majority of onychomycosis Common Uncommon Dermatophytes Trichophyton rubrum Trichophyton interdigitale Molds Scopulariopsis brevicaulis Fusarium oxysporum/solani Epidermophyton floccosum Microsporum canis/gypseum Trichophyton mentagrophytes/schoenleinii/soudanense/tonsurans/violaceum Acremonium spp. Aspergillus fumigatus/niger/flavus/terreus Onichocola Canadensis Scytalidium dimidiatum Penicillium spp. Candida albicans Candida parapsilosis Yeasts Correct collection of samples is important to avoid false negative results and to eliminate contaminants. Culture examination is always vital as microscopic examination is usually insufficient for identifying species and different fungi may require different therapies. A culture result is considered negative in the absence of growth after 4– 6 weeks. Different species of fungi are identified according to growth rate (molds grow faster than dermatophytes, i.e. 48 h versus 2– 6 weeks), and the macroscopic and microscopic appearance of the colonies. To better observe the microscopic appearance of the colony, a small superficial portion is selected by pressing tape over it. The nonadhesive side of the tape is then placed over a glass slide and stained with lactophenol cotton blue. A cover slip is placed over the glass slide and it is directly observed via microscopy. Histopathology of nail samples may be useful if other tests fail. The process can identify presence of hyphae and/or spores within the nail plate and/or in the subungual hyperkeratosis. The process can be performed on formalin fixed, paraffin embedded and periodic acid Schiff stained nail plate material (nail clippings). Species identification is however impossible, as histopathology provides no information about the vitality of the fungi. Molecular biology techniques based on detection of fungal DNA have also been tested but they are costintensive and require skilled operators. The abovementioned techniques in conjunction with the recently established criteria for confirming the etiological significance of nondermatophytes [9] are key to the correct identification of the agents responsible for onychomycosis. Yeasts have long been considered as natural or transient colonizers of the nail fold areas, especially in patients with chronic paronychia and onycholysis resulting from housework and certain occupations. Studies on molds in Italy report an increased prevalence of nail infection that should not be underestimated. In one study (1995–1998) [10], Scopulariopsis brevicaulis and Fusarium spp. were the two most frequently isolated molds, with a significant increase in the number of cases of Fusarium spp. during this period (Fusarium oxysporum having twice the prevalence of Fusarium solani). The other survey (1985–2000) showed Scopulariopsis brevicaulis and Aspergillus spp. as the two most frequently isolated molds, followed by Fusarium oxysporum, Alternaria spp., Acremonium spp. and Curvularia spp. The study evaluated all fungal nail infections, finding Candida albicans and Candida krusei to be the two most isolated yeasts [11]. The percentage of molds isolated from these two studies is around 13%. This high percentage can be explained by immigration and the use of mycologic methods more appropriate for mold growth. In a retrospective study (1990–2001) performed in Germany, Scopulariopsis brevicaulis and Candida parapsilosis have been, respectively, the mold and yeast most frequently isolated. Although the number of reported cases was very low, more rare agents have also been isolated, including Aspergillus ochraceus, Aspergillus nidulans, Chrysosporium pannorum among molds, and Candida guillermondii, Candida tropicalis, Candida glabrata and Trichosporon spp. among yeasts [12]. In Lebanon (2000–2004), the percentage of molds isolated from onychomycosis of the toenails was 4%; for yeasts the percentage was 18.9%. In fingernails, molds were 0.9% and yeasts were 81% [13]. Scopulariopsis brevicaulis and Aspergillus spp. were the two most frequently isolated molds; there was no detailed information about Candida species. New findings Recent studies performed in different countries are not only reporting molds and yeasts as contaminants, but are increasingly reporting them as pathogens. In Turkey, the percentage of molds isolated from onychomycosis was 9% and Aspergillus spp. was the most commonly isolated species (predominantly Aspergillus Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 144 Skin and soft tissue infections niger). Acremonium spp. and Fusarium spp. were also common. Ucocladium spp, Alternaria spp., Cladosporium spp, Paecilomyces spp. and Trichoderma spp. were also isolated [14]. In Taiwan, molds have been isolated in 8% of cases and yeasts in 31.5% (2002–2003). The distribution of pathogens varies with the involved sites, patients’ occupation and predisposing factors, such as diabetes [15]. As in Italy, Fusarium solani has been the most frequent isolated mold, followed by Aspergillus niger. Most of the Candida species isolated remained unidentified. The data from different countries are hardly comparable, however, due to different sample groups and survey duration. Scopulariopsis brevicaulis and Candida nonalbicans are the most common nondermatophytic agents responsible for onychomycosis, but Fusarium spp. and Aspergillus spp. also have to be taken into account. Clinicians should bear in mind the increasing number of case series reporting the role of molds and yeasts in onychomycosis, and should not treat the disease without first examining the mycology results. Molds, in fact, are often nonresponsive to conventional systemic antifungals and nail avulsion associated with topical antifungals is usually more effective than systemic treatment [10]. In the literature, there are also single case reports of onychomycosis from very rare molds or yeasts. As individual reports, these are important; however, the responsible agents are usually so rare that there is no need for physicians to be alarmed. Cases of infections by novel agents do not necessarily indicate that they are emerging agents. For example, during the period 2004–2006, Fusarium proliferatum, Aspergillus tamarii, Syncephalastrum racemosum and Ulocladium botrytis have been reported as single cases of infections in adults and children [16–19]. Fusarium proliferatum has been reported in two middleaged Japanese males; Aspergillus tamarii in a 3-year old male; Syncephalastrum racemosum in a 45-year old male; Ulocladium botrytis in a 45-year old male. The agents are usually contaminants or secondary pathogens, although in these reports they do appear responsible for the onychomycosis. Years ago, when molds were considered only coincidental findings in onychomycosis, it is likely that these rare agents were never reported. Conclusion Improvement of classic diagnostic techniques and development of new ones allow physicians to be more precise in the identification of pathogens causing nail infections. Physicians are aware that molds and yeasts are emerging agents and they pay more attention when making the diagnosis and in reporting their findings to the literature. The question remains as to whether these agents are truly new fungi responsible for onychomycosis, or whether improvement of diagnostic techniques and increasing (and alarmist) reference to such species in the literature has resulted in better identification of such agents. Assuming there are true new agents responsible for onychomycosis, the most important cause is likely to be migration. The identification of emerging agents is very important, not only for the epidemiology of the disease but also for physicians and pharmaceutical companies committed to the development of new treatment options. Such agents are considered resistant to treatment and should not be underestimated. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 205). 1 Effendy I, Lecha M, Feuilhade de Chauvin M, et al. Epidemiology and clinical classification of onychomycosis. J Eur Acad Dermatol Venereol 2005; 19 (Suppl 1):8–12. 2 Baran R, Hay R, Tosti A, Haneke E. A new classification of onychomycosis. Br J Dermatol 1998; 119:567–571. 3 Tosti A, Baran R, Piraccini BM, Fanti PA. Endonyx onychomycosis: a new modality of nail invasion by dermatophytic fungi. Acta Dermatovener 1999; 79:52–53. 4 Burzykowski T, Molenberghs G, Abeck D, et al. High prevalence of foot diseases in Europe: results of the Achilles project. Mycoses 2003; 46:496– 505. Tosti A, Hay R, Arenas-Guzman R. Patients at risk of onychomycosis – risk factor identification and active prevention. J Eur Acad Dermatol Venereol 2005; 19 (Suppl 1):13–16. Good review of the risk factors for onychomycosis. 5 6 Hay R. Literature review: onychomycosis. J Eur Acad Dermatol Venereol 2005; 19 (Suppl 1):1–7. The recent literature on onychomycosis is reviewed in this paper. 7 Feuilhade de Chauvin M. New diagnostic techniques. J Eur Acad Dermatol Venereol 2005; 19 (Suppl 1):20–24. Practical and useful review about the classic and alternative diagnostic techniques for onychomycosis. 8 Lilly KK, Koshnick RL, Grill JP, et al. Cost-effectiveness of diagnostic tests for toenail onychomycosis: a repeated-measure, single-blinded, cross-sectional evaluation of 7 diagnostic tests. J Am Acad Dermatol 2006; 55:620– 626. Summerbell RC, Cooper E, Bunn U, et al. Onychomycosis: a critical study of techniques and criteria for confirming the etiologic significance of nondermatophytes. Med Mycol 2005; 43:39–59. Very interesting study on criteria for confirming the etiologic significance of molds. 9 10 Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol 2000; 42:217–224. 11 Romano C, Gianni C, Difonzo EM. Retrospective study of onychomycosis in Italy: 1985–2000. Mycoses 2005; 48:42–44. 12 Mugge C, Haustein UF, Nenoff P. Causative agents of onychomycosis: a retrospective study [in German]. J Dtsch Dermatol Ges 2006; 4:218– 228. 13 El Sayed F, Ammoury A, Haybe RF, Dhaybi R. Onychomycosis in Lebanon: a mycological survey of 772 patients. Mycoses 2006; 49:216–219. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. New fungal nail infections Iorizzo et al. 145 14 Hilmioglu-Polat S, Metin DY, Inci R, et al. Non dermatophytic molds as agents of onychomycosis in Izmir, Turkey: a prospective study. Mycopathologia 2005; 160:125–128. 17 Kristensen L, Stenderup J, Otkjaer A. Onychomycosis due to Aspergillus tamarii in a 3-year old boy. Acta Derm Venereol 2005; 85: 261 –262. 15 Chi CC, Wang SH, Chou MC. The causative pathogens of onychomycosis in southern Taiwan. Mycoses 2005; 48:413–420. 18 Pavlovic MD, Bulajic N. Great toenail onychomycosis caused by Syncephalstrum racemosum. Dermatol Online J 2006; 12:7–10. 16 Hattori N, Shirai A, Sugiura Y, et al. Onychomycosis caused by Fusarium proliferatum. Br J Dermatol 2005; 153:647–649. 19 Romano C, Maritati E, Paccagnini E, Massai L. Onychomycosis due to Ulocladium botrytis. Mycoses 2004; 47:346–348. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Management of mycetoma: major challenge in tropical mycoses with limited international recognition Abdalla A.O. Ahmeda, Wendy W.J. van de Sandeb, Ahmed Fahalc, Irma Bakker-Woudenbergb, Henri Verbrughb and Alex van Belkumb Purpose of review The present review highlights an orphan infectious disease in alarming need of international recognition. While money is being invested to develop new broad-spectrum antimicrobial drugs to treat infection in general, improvement in the management of complicated infections such as mycetoma receives little support. Recent findings Many case presentations describe single-center experience in the management of mycetoma. Unfortunately, randomized and blinded clinical studies into the efficacy of antimicrobial treatment are desperately lacking. Response to medical treatment is usually better in actinomycetoma than eumycetoma. Eumycetoma is difficult to treat using current therapies. Surgery in combination with azole treatment is the recommended regimen for small eumycetoma lesions in the extremities. Bone involvement complicates clinical management, leaving surgical amputation as the only treatment option. Although clinical management has not received major attention recently, laboratory technology has improved in areas of molecular diagnosis and epidemiology. Summary Management of mycetoma and laboratory diagnosis of its etiological agents need to be improved and better implemented in endemic regions. Optimized therapeutic approaches and more detailed epidemiological data are urgently needed. It is vital to initiate multicenter collaborations on national and international levels to develop consensus clinical score sheets and state-of-theart treatment regimens for mycetoma patients. Keywords actinomycetoma, antimicrobial therapy, eumycetoma, management, mycetoma Curr Opin Infect Dis 20:146–151. ß 2007 Lippincott Williams & Wilkins. a King Saud University, Department of Pathology & Microbiology, Riyadh, Saudi Arabia, bErasmus MC, University Medical Center Rotterdam, Department of Medical Microbiology & Infectious Diseases, Rotterdam, The Netherlands and c Mycetoma Research Centre, University of Khartoum, Sudan Correspondence to Abdalla A.O. Ahmed, King Saud University, Department of Pathology & Microbiology, PO Box 2925, Riyadh 11461, Saudi Arabia Tel: +966 14671636; fax: +966 14672462; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:146–151 Abbreviation ELISA enzyme-linked immunosorbent assay ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction Mycetoma is a chronic granulomatous infection of cutaneous and subcutaneous tissues. The infection most likely starts after minor trauma such as thorn pricks, which may even further facilitate the inoculation of infectious materials from the environment. Mycetoma can be caused by bacteria (actinomycetoma) or fungi (eumycetoma) that inhabit soil and plants in endemic areas. The infection spreads slowly to involve deeper tissues and bone, resulting in deformity and disability. Fungi and bacteria causing mycetoma appear to survive within the host despite strong nonspecific innate immune responses, which lead to considerable inflammation [1]. Mycetoma is characterized by (large) soft tissue masses, sinuses and purulent discharge containing microbial sclerotia with different colors and morphology (Fig. 1). The latter may be of help in the taxonomic positioning and species identification of the causal organisms. In addition, a high prevalence of bacterial superinfection was noted in mycetoma patients, especially when open, active sinuses are observed. The common causes of these secondary infections are staphylococci and streptococci [2]. Mycetoma is diagnosed most frequently in patients originating from the tropics, with increased morbidity in poor people lacking access to essential healthcare facilities. As with other subcutaneous mycoses, mycetoma is difficult to treat and improper management is devastating, leading to poor social and economical prospects. No cases of spontaneous cure have been reported. Knowing the mycetoma type (actinomycetoma or eumycetoma) is vital for the initiation of correct medical management. Although actinomycetoma and eumycetoma usually present with distinct clinical features, their overall presentation may still be confusing. Adequate diagnostic microbiology laboratory testing must therefore be sought. The identification of many of these relatively rare species can be complicated by improper clinical specimens or a lack of experience or state-of-the-art diagnostic facilities 146 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Management of mycetoma Ahmed et al. 147 Figure 1 Mycetoma lesions involving different body sites requires long-term treatment, sometimes lasting 18– 24 months or more. Modern literature is rich in treatment case studies describing personal, single-center experiences in management of mycetoma. Unfortunately, there is a shortage of double-blind, placebo-controlled clinical studies into the efficacy of antifungal treatment. Consequently, there is no international consensus as to the nature of the optimal treatment regimen for mycetoma patients in general. In the case of actinomycetoma, chemotherapy alone results in high cure rates (60–90%); however, surgery may still be required in advanced cases including those refractory to antimicrobial treatment [7]. Many authors still agree that surgery is the most acceptable means of treating eumycetoma [7,8]. Surgery in mycetoma should be preferred when the disease process is still limited and localized. Diagnosis of mycetoma (a) Actinomycetoma due to Streptomyces somaliensis involving the axilla and the chest wall (Fahal A. Mycetoma: Clinicopathological Monograph. Khartoum: Khartoum University Press; 2006), (b) massive foot eumycetoma due to Madurella mycetomatis, and (c) eumycetoma involving the forefoot. [3,4]. Mycetoma is commonly seen in immunocompetent individuals, and there is no strong scientific evidence linking infection with defective cell-mediated immunity. Dissemination from the primary site, however, is a common feature among immunocompromised individuals [5]. Small lesions can be successfully eliminated by a combination of surgical and chemotherapeutical treatment. Long-term treatment, however, may lead to antifungal resistance, which may in turn complicate patient management. The response to chemotherapeutic treatment is very poor in advanced lesions, especially when bone tissue is involved [6]. Mycetoma therapy commonly In endemic areas, mycetoma must be considered in the differential diagnosis of all subcutaneous swellings. Clinical scores should be developed for a more thorough definition of the different disease presentations. Presently, however, clinical evaluation is not very reliable. It is therefore advisable to send clinical specimens, preferably those containing grains, for laboratory examination. Direct laboratory examination of crushed grains helps to determine whether the mycetoma is caused by bacteria or fungi. Histopathological techniques are useful for supporting the clinical diagnosis of mycetoma and in the differentiation of several bacterial causes of mycetoma. Correct identification of fungi causing mycetoma by histology only is difficult, however, if not impossible, and culture confirmation should always be pursued [9]. In contrast to eumycetoma, the immunopathology of actinomycetoma is much more extensively studied [10,11]. Even culture identification by itself is not easy and cannot be performed in medical microbiology laboratories with limited facilities. As a further complication, many black-grain producing fungi do not produce conidia or do so only after long incubation periods [9]. Many authors used immunoelectrophoresis, immunodiffusion and enzyme-linked immunosorbent assay (ELISA) for the extended diagnosis of mycetoma. The problem with such serological tests is the use of nonstandardized and poorly prepared crude antigens, which are prone to crossreactivity and false positive and false negative results [3]. Recently, the first genuine ELISA test for the detection of Madurella mycetomatis infection was presented [12]. This test involved the detection of antibodies against the first protein antigen of M. mycetomatis that was serologically identified, cloned, sequenced and produced as a recombinant protein. The translationally controlled tumor protein was found to be a predictor for the size of the lesion and the duration of the infection. In cured Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 148 Skin and soft tissue infections patients, the antibodies frequently became undetectable. The usefulness of this first assay should be evaluated in large serological screening tests in the endemic regions, preferably in a longitudinal study [12]. Molecular diagnosis of mycetoma Good clinical and microbiology services are necessary for proper specimen collection and processing. Even when isolation of causative agents is successful and pure cultures are obtained, identification of the etiological agents of mycetoma with standard bacteriological and mycological protocols can still be difficult. Most fungal agents show poor or delayed morphological differentiation, and biochemical identification requires complex procedures. To improve the quality of mycetoma diagnosis, molecular tests have been developed for several agents of blackgrain eumycetoma [13,14]. The availability of these molecular detection and identification tests will help microbiologists in species definition, which is necessary for proper management of patients. Ahmed et al. [13] developed M. mycetomatis-specific polymerase chain reaction-based tests based on the sequence of the internal transcribed spacer in the ribosomal gene complex, a region that has been successfully utilized by many investigators for the development of diagnostic DNA amplification assays. Postamplification restriction digestion facilitates correct species identification, and clearly differentiates M. mycetomatis from M. grisea [13]. Similar results were recently reported from France, where large numbers of black-grain eumycetoma agents were studied [14]. The molecular detection of mycetoma agents is not only useful for identification of clinical isolates, but also for studying the epidemiology of mycetoma agents [15,16] and generating precise therapeutic data. For M. mycetomatis, it appeared that the isolates obtained from larger lesions were genetically closely related and clustered separately upon amplified fragment length polymorphism analysis [17]. Interestingly, a molecular marker segregating isolates originating from similar geographical focus was also associated with a higher minimum inhibitory concentration (MIC) for amphotericin B [17]. Case studies Mycetoma infections where the causative agent cannot be identified easily are often subjected to both empirical antifungal and antimicrobial treatment [18]. In actinomycetoma, however, the nature of the etiologic agent should normally determine the choice of antimicrobial (combination) therapy. Most of the current treatment recommendations are based on various single-center clinical experiences, and seldom on independent clinical trial-based evidence. Streptomycin injection plus cotrimoxazole has been suggested as the best combination against Streptomyces somaliensis infection. Cotrimoxazole can be replaced with dapsone in cases of resistance [6]. In the case of Actinomadura species, streptomycin and dapsone can be used, while Nocardia cases are better treated with cotrimoxazole and dapsone. Serious cases caused by Nocardia are best treated with amikacin and cotrimoxazole [6]. A variety of treatment modules exist although these are, unfortunately, chosen in a relatively random manner. Actinomycetoma can usually be dealt with by antibiotic treatment alone. For instance, Kapoor and colleagues [19] reported an iatrogenic case of actinomycetoma due to Nocardia braziliensis, which was successfully treated with cotrimoxazole. Complete cure was achieved within 3 months and no recurrence was noted during 2-year follow-up. Successful treatment of cutaneous nocardiosis with cotrimoxazole was reported as well [20]. Actinomycetoma showing clinical improvement after (long-term) treatment with cotrimoxazole combined with amikacin is regularly reported [21]. Cotrimoxazole, however, may still fail in actinomycetoma caused by Nocardia veterana. Ultimately, the combination of clarithromycin, minocycline, imipenem/cilastatin and amikacin was shown to be effective in curing the lesion without further need for surgical intervention [22]. Imipenem alone or in combination with amikacin was also used for the treatment of actinomycetoma due to other Nocardia species [23]. In eumycetoma, medical treatment using antifungals is usually the first step on the road to cure. Treatment regimens can be complicated, as was recently illustrated in a unique case of disseminated subcutaneous Pseudallescheria boydii infection [5].The patient was atopic with a delayed hypersensitivity response and low numbers of suppressor T cells and natural killer cells. The patient was treated with a combination of itraconazole (400 mg/day) and surgical drainage and instillation of the subcutaneous nodules with 1 mg/ml amphotericin B suspension. The patient was also suffering from dermatophytosis in hair and nails, which was adequately covered by itraconazole. The patients responded well to medical treatment and all lesions disappeared within 4 months [5]. Eumycetoma may be treated with daily doses of oral ketoconazole. It is not clear whether this always requires additional surgical intervention. Eumycetoma frequently does need surgical intervention, however, as medical treatment alone is often not sufficient [24]. For instance, fluconazole and itraconazole treatment did not resolve Cladophialophora bantiana eumycetoma in a patient with systemic lupus erythematosus despite treatment by surgical debridement [25]. A small black-grain eumycetoma lesion in a Mexican patient with unknown etiology, however, was successfully treated with 200 mg itraconazole applied for a period of 6 months [26]. Success of chemotherapy appears to be strongly dependent on the stage of the infection and the agent causing it. In a case of eumycetoma due to Exophiala jeanselmei, itraconazole initially Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Management of mycetoma Ahmed et al. 149 presented with a clinical response, but it failed to achieve complete clinical resolution even when the infected tissue was surgically removed [27]. In another case of mycetoma in the scalp due to Microsporum canis, longterm treatment with itraconazole also failed, although such infections usually respond well to itraconazole treatment [28]. Voriconazole, the novel triazole, is bringing hope for mycetoma patients, even those with advanced lesions. It cured Scedosporium apiospermum mycetoma with bone involvement [29] and soft tissue mycetoma in immunocompromised patients [30]. Voriconazole was also used successfully in the management of M. mycetomatis eumycetoma without bone involvement [31]. Special remarks on the management of eumycetoma Eumycetoma is deemed to be relatively nonresponsive to antifungal treatment by many, and radical surgical amputation would appear to be the preferred intervention option, especially in areas with limited medical resources and where little other than surgery can be offered. Even with access to antifungal agents, however, eumycetoma still responds variably, ranging between complete clinical cure, limited improvement and no improvement whatsoever. Poor responses to different antifungal agents, even when given in combination and at high doses, are not uncommon. This is in contrary to in-vitro susceptibilities. Many reports have shown that M. mycetomatis has a low MIC to azoles, amphotericin B and the echinocandin anidulafungin. Overall, early diagnosis followed by surgical excision of small lesions and antifungal treatment before and after surgery usually results in the most successful outcome [32]. Local surgical excision alone is rarely successful, and in some cases might even enhance the lymphatic spread [6]. Ketoconazole and itraconazole show varying degrees of clinical efficacy. Hopes on effective medical treatment are increasing with the introduction of broad-spectrum triazoles such as voriconazole and posaconazole. In poor endemic regions in those developing countries where these agents are required most, however, their use may be limited by a lack of essential healthcare facilities, the absence of health insurance coverage, and the high cost of the azoles. In addition, solid antifungal efficacy data are desperately needed for the proper management of mycetoma. Only two recent papers are available for review. The first paper described a single-center open label efficacy and safety study of terbinafine in the treatment of eumycetoma. Twenty-five per cent of patients were cured and 55% showed clinical improvement. Although the study was limited by the small number of patients included (n ¼ 20), lack of randomization, missing control groups, lack of standardized cure or improvement criteria and possible investigator bias, the study is still considered as one of the rare ones done to evaluate the efficacy of antimycotic drugs used for treatment of mycetoma [33]. In the second study, the effect of posaconazole was evaluated on six eumycetoma cases caused by M. mycetomatis (n ¼ 2), M. grisea (n ¼ 3) and S. apiospermum (n ¼ 1). Five patients were successfully treated, and one did not show improvement [34]. A difficult decision in the case of mycetoma patients is when to stop treatment. The prevalence of the infection in poor patients living in remote areas renders continuation of treatment and regular follow-up rather difficult and usually even impossible. Some investigators tried to set some standards for clinical, serologic or radiologic cure, but so far there is no consensus on these standards. Many patients in whom medical treatment was stopped without a well-validated clinical score suffered from recurrence after initial improvement. There is no clear definition of cure in mycetoma and no test of cure enabling differentiation between infected and noninfected patients [7]. The translationally controlled tumor protein ELISA that was recently described [12] revealed a correlation between serological response and the severity or stage of eumycetoma. This requires further elaboration, preferably also using additional fungal antigens in the test system. In the end, such systems could be used for prospective detection of early stages of infection or relapse after therapy. Impact of animal models on mycetoma management Prevention and cure of mycetoma infections necessitates the use of animal models of infection. Some models have been presented for actinomycetoma; models for eumycetoma are more limited in numbers. In most cases, infections were studied in immunosuppressed animals [35,36]. The most reproducible current infection model for M. mycetomatis eumycetoma is the one described for BALB/c mice. Different routes of inoculation, various adjuvants, host immune status, and gender of the mice were evaluated. The infection rate was found to be inoculum-dependent with increasing infection rates with larger inocula. Adjuvants were essential and using autoclaved soil from an endemic region or Freund’s incomplete adjuvant was necessary for production of black grain. Establishment of infection in immunocompetent mice suggests that in people too, an intact immune system is unable to eliminate the infectious agents [37]. The role of adjuvant in establishing the infection is not clear, but it might be favoring the infection by modifying the host immune response. Scedosporium apiospermum (teleomorph Pseudallescheria boydii) and Scedosporium prolificans can infect immunocompetent individuals, causing eumycetoma or disseminated invasive infections in immunocompromised hosts. S. prolificans is resistant to virtually all commonly used antifungal agents, and Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 150 Skin and soft tissue infections therefore their infections are difficult if not impossible to treat. In an experimental murine model of S. prolificans scedosporiosis, the combination of amphotericin B and caspofungin increased mice survival when treatment started 1 day post inoculation. Combination therapy of amphotericin B and caspofungin, however, did not show synergy [38]. In contrast, infections due to S. apiospermum have been treated successfully with different azoles including ketoconazole and itraconazole. Voriconazole chemotherapy together with surgical debridement was used to successfully treat nodular skin lesions due to S. apiospermum in a kidney transplant patient [39]. the medical and societal burden associated with mycetoma is most severe. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 204–205). 1 De Hoog GS, Guarro J, Gene J, Figueras MJ. Atlas of clinical fungi. 2nd ed. Utrecht, Reus: Centraalbureau voor Schimmelcultures and Universitat Rovira i Virgili; 2000. 2 Ahmed AOA, Abugroun ESAM, Fahal AH, et al. Unexpected high prevalence of secondary bacterial infection in patients with mycetoma. J Clin Microbiol 1998; 36:850–851. 3 Ahmed AO, van Leeuwen W, Fahal A, et al. Mycetoma caused by Madurella mycetomatis: a neglected infectious burden. Lancet Infect Dis 2004; 4:566– 574. 4 De Hoog GS, Buiting A, Tan CS, et al. Diagnostic problems with imported cases of mycetoma in The Netherlands. Mycoses 1993; 36:81–87. Conclusion In general, chemotherapeutic medical treatment shows better response in actinomycetoma infection than in eumycetoma infection. Therapeutic success is mainly dependent on correct identification of the causative agent and clear clinical and laboratory monitoring to avoid resistance and relapse. Eumycetoma remains a serious fungal infection affecting poor people, resulting in inferior social and economical prospects, and its response to antifungal treatment is poor. Small lesions in the extremities can be surgically excised and recurrence rates can be minimized by antifungal therapy given perisurgically. In advanced lesions where bones are involved, treatment with azoles such as ketoconazole and itraconazole is rarely helpful. A better outcome is, however, expected with new triazoles such as voriconazole and posaconazole. Adequate antifungal susceptibility testing is a prerequisite control strategy that urgently needs to be developed. To provide better management of mycetoma, well-designed clinical studies are needed to evaluate the efficacy and safety of the different antifungal agents that are currently available and affordable for the people affected. Several important improvements have to be made over the coming years. First, a better definition of cases and the extent of infection need to be developed. Second, correct identification of causative agents needs to be pursued to at least the genus level. Third, susceptibility testing to correlate in-vitro with in-vivo responses is vital. Fourth, a consensus on clinical improvement or cure criteria needs to be reached among clinicians. Finally, the discovery of laboratory or radiology markers for the assessment of response and prediction of early recurrence is very important. In all, the clinical impact of mycetoma has essentially remained unchanged over the last decades. Clinicians can still only offer limited help, which is mostly restricted to amputation and supporting chemotherapy, for which the efficacy has not yet been unequivocally proven. Obviously, this needs international attention and enduring financial support for both clinical and fundamental research. Clinical care facilities and regional research centers should be established in endemic areas where Enshaieh SH, Darougheh A, Asilian A, et al. Disseminated subcutaneous nodules caused by Pseudallescheria boydii in an atopic patient. Int J Dermatol 2006; 45:289–291. This is an excellent paper showing that cell-mediated immunity is important in controlling the physiological spread of mycetoma lesions. The authors report on a disseminated eumycetoma infection in an atopic patient with a significantly delayed hypersensitivity response, and a strongly decreased number of suppressor T cells and natural killer cells. Dissemination of mycetoma through lymph or blood vessels is seen more often in actinomycetoma and immunocompromised patients. In immunocompetent patients, the host and the parasite are usually in balance and together with well-chosen medication, the extent of the lesions and tissue destruction can be kept under control. 5 6 Richardson MD, Warnock DW. Fungal infection: diagnosis and management. 3rd ed. Oxford: Blackwell Publishing; 2003. 7 Lupi O, Tyring SK, McGinnis MR. Tropical dermatology: fungal tropical diseases. J Am Acad Dermatol 2005; 53:931–951; quiz 952–954. 8 Lichon V, Khachemoune A. Mycetoma: a review. Am J Clin Dermatol 2006; 7:315–321. 9 Padhye AA, McGinnis MR. Fungi causing eumycotic mycetoma. In: Murray PR, Baron EJ, Pfaller MA, Tenover FC, Yolken RH, editors. Manual of clinical microbiology, 7th ed. Washington: American Society for Microbiology; 1999. pp. 1318–1326. 10 Salinas-Carmona MC, Ramos AI, Perez-Rivera I. Immunogenicity is unrelated to protective immunity when induced by soluble and particulate antigens from Nocardia brasiliensis in BALB/c mice. Microbes Infect 2006; 8:2531– 2538. 11 Salinas-Carmona MC, Perez-Rivera I. Humoral immunity through immunoglobulin M protects mice from an experimental actinomycetoma infection by Nocardia brasiliensis. Infect Immun 2004; 72:5597–5604. 12 Van de Sande WW, Janse DJ, Hira V, Goedhart H, et al. Translationally controlled tumor protein from Madurella mycetomatis, a marker for tumorous mycetoma progression. J Immunol 2006; 177:1997–2005. In this study, the authors present the first cloned Madurella mycetomatis antigen for which an experimental ELISA was developed. The antigen shares structural homology with a well-conserved human histamine-release factor in a range of eukaryotes. It was shown that the antigen was secreted during culture, whereas the antigen was well expressed in growing grains. Antibody levels in patients correlated with lesion size and disease duration. The authors also consider whether this antigen might be a suitable vaccine candidate molecule. 13 Ahmed AO, Mukhtar MM, Kools-Sijmons M, et al. Development of a speciesspecific PCR-restriction fragment length polymorphism analysis procedure for identification of Madurella mycetomatis. J Clin Microbiol 1999; 37:3175– 3178. 14 Desnos-Ollivier M, Bretagne S, Dromer F, et al. Molecular identification of black-grain mycetoma agents. J Clin Microbiol 2006; 44:3517–3523. The authors used the fungal internal transcribed spacer sequence for strain identification and assessing inter and intraspecies similarities. The internal transcribed spacer region within the ribosomal operon was proven to be a useful target for species identification and phylogenetic analyses. Molecular identification of fungi causing black-grain mycetoma may facilitate precise identification up to the species level, also for smaller nonspecialized laboratories in endemic areas. This type of diagnosis may generate better therapeutic and epidemiological data. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Management of mycetoma Ahmed et al. 151 15 Ahmed A, Adelmann D, Fahal A, et al. Environmental occurrence of Madurella mycetomatis, the major agent of human eumycetoma in Sudan. J Clin Microbiol 2002; 40:1031–1036. 16 Ahmed AO, Desplaces N, Leonard P, et al. Molecular detection and identification of agents of eumycetoma: detailed report of two cases. J Clin Microbiol 2003; 41:5813–5816. 28 Kramer SC, Ryan M, Bourbeau P, et al. Fontana-positive grains in mycetoma caused by Microsporum canis. Pediatr Dermatol 2006; 23:473–475. Case report describing a rare condition where Microsporum canis was able to cause true mycetoma with subcutaneous masses, sinuses and purulent discharge containing fungal grains. To our knowledge, this is the first report that demonstrates the ability of M. canis to produce melanin in vivo, which might contribute to the failure of itraconazole treatment. 17 Van de Sande WW, Gorkink R, Simons G, et al. Genotyping of Madurella mycetomatis by selective amplification of restriction fragments (amplified fragment length polymorphism) and subtype correlation with geographical origin and lesion size. J Clin Microbiol 2005; 43:4349–4356. 29 Porte L, Khatibi S, Hajj LE, et al. Scedosporium apiospermum mycetoma with bone involvement successfully treated with voriconazole. Trans R Soc Trop Med Hyg 2006; 100:891–894. 18 Gunduz K, Orguc S, Demireli P, et al. A case of mycetoma successfully treated with itraconazole and co-trimoxazole. Mycoses 2006; 49:436– 438. 30 Schaenman JM, Digiulio DB, Mirels LF, et al. Scedosporium apiospermum soft tissue infection successfully treated with voriconazole: potential pitfalls in the transition from intravenous to oral therapy. J Clin Microbiol 2005; 43:973–977. 19 Kapoor S, Khunger N, Jain RK, et al. Iatrogenic actinomycetoma of neck and back successfully treated with sulphonamides. Clin Exp Dermatol 2006 [Epub ahead of print]. 20 Stefano PC, Noriega AL, Kobrin AL, et al. Primary cutaneous nocardiosis in immunocompetent children. Eur J Dermatol 2006; 16:406–408. 21 De Palma L, Marinelli M, Pavan M, et al. A rare European case of Madura Foot due to actinomycetes. Joint Bone Spine 2006; 73:321–324. 22 Kashima M, Kano R, Mikami Y, et al. A successfully treated case of mycetoma due to Nocardia veterana. Br J Dermatol 2005; 152:1349–1352. 23 Fuentes A, Arenas R, Reyes M, et al. Actinomycetoma and Nocardia sp. Report of five cases treated with imipenem or imipenem plus amikacin. Gac Med Mex 2006; 142:247–252. 24 Daoud M, Ezzine Sebai N, Badri T, et al. Mycetoma: retrospective study of 13 cases in Tunisia. Acta Dermatovenerol Alp Panonica Adriat 2005; 14:153– 156. 25 Werlinger KD, Yen Moore A. Eumycotic mycetoma caused by Cladophialo phora bantiana in a patient with systemic lupus erythematosus. J Am Acad Dermatol 2005; 52 (5 Suppl 1):S114–S117. The authors report on a case of eumycetoma due to Cladophialophora bantiana most probably at 16 years after injury from tornado debris. Infectious materials inoculated upon that occasion remained dormant for a very long time and the eumycetoma nodules appeared at the same time as when systemic lupus erythematosus became apparent in this patient. What is especially interesting about this case is the role of a malfunctioning hyperimmune system in the pathology of mycetoma. 26 Lopez-Cepeda LD, Mora-Ruiz S, Padilla-Desgarennes Mdel C, RamosGaribay JA. Small eumycetic mycetoma due to black grain. Arch Dermatol 2005; 141:793–794. 27 Brownell I, Pomeranz M, Ma L. Eumycetoma. Dermatol Online J 2005; 11: 10. 31 Lacroix C, de Kerviler E, Morel P, et al. Madurella mycetomatis mycetoma treated successfully with oral voriconazole. Br J Dermatol 2005; 152:1067– 1068. 32 McGinnis MR. Mycetoma. Dermatol Clin 1996; 14:97–104. 33 N’Diaye B, Dieng MT, Perez A, et al. Clinical efficacy and safety of oral terbinafine in fungal mycetoma. Int J Dermatol 2006; 45:154–157. One of the few recent studies done to evaluate the efficacy of antimycotic treatment of fungal mycetoma. A better study design and recruitment of larger numbers of patients would, however, significantly increase the impact of such studies. 34 Negroni R, Tobon A, Bustamante B, et al. Posaconazole treatment of refrac tory eumycetoma and chromoblastomycosis. Rev Inst Med Trop Sao Paulo 2005; 47:339–346. Good example of an efficacy study targeted at one of the new extended-spectrum triazoles (posaconazole). Patients included in the study presented as eumycetoma and chromoblastomycosis cases refractory to standard therapy. The results were well presented and approaches such as the one discussed may bring future treatment hope for both patients and clinicians. 35 Gumaa SA, Abu-Samra MT. Experimental mycetoma infection in the goat. J Comp Pathol 1981; 91:341–346. 36 Mahgoub ES. Experimental infection of athymic nude New Zealand mice, nu nu strain with mycetoma agents. Sabouraudia 1978; 16:211–216. 37 Ahmed AO, van Vianen W, ten Kate MT, et al. A murine model of Madurella mycetomatis eumycetoma. FEMS Immunol Med Microbiol 2003; 37:29–36. 38 Bocanegra R, Najvar LK, Hernandez S, et al. Caspofungin and liposomal amphotericin B therapy of experimental murine scedosporiosis. Antimicrob Agents Chemother 2005; 49:5139–5141. 39 Farina C, Gotti E, Suter F, Goglio A. Scedosporium apiospermum soft-tissue infection: a case report and review of kidney transplant literature. Transplant Proc 2006; 38:1333–1335. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Transmission of human herpesvirus 8: an update Francesca Pica and Antonio Volpi Purpose of review Human herpesvirus 8 is associated with neoplastic diseases in the immunocompromised host, including Kaposi’s sarcoma, multicentric Castleman disease and primary effusion lymphoma. Acquisition and control of human herpesvirus 8 infection have not yet been fully elucidated. This review focuses on the most recent findings on human herpesvirus 8 transmission. Recent findings Horizontal transmission by saliva appears the most common route not only in families in endemic regions, but also among high-risk groups in Western countries. Vertical, sexual, and blood and transplant-related transmission, however, remain of significant concern worldwide. Novel approaches to standardize and optimize the assessment of human herpesvirus 8 infection have been reported. New insights on the host immune cell mechanisms devoted to the control of human herpesvirus 8 infection have also been presented. Summary The increasing knowledge about the routes of human herpesvirus 8 transmission, which appear now more similar to those of other more ubiquitous human herpesviruses (i.e. Epstein–Barr virus and cytomegalovirus), the growing efforts in improving laboratory diagnosis and the caution in the research of new biological associations are the major recent findings. They constitute a fundamental background for directing more appropriate future research and achieving more stringent evidence useful for the control of human herpesvirus 8 spread and for the management of human herpesvirus 8-related diseases. Keywords blood transfusion, human herpesvirus 8, transmission, transplantation, vertical Curr Opin Infect Dis 20:152–156. ß 2007 Lippincott Williams & Wilkins. Departments of Experimental Medicine and of Public Health, University of Rome ‘Tor Vergata’, Rome, Italy Correspondence to Antonio Volpi, MD, Department of Public Health, University of Rome ‘Tor Vergata’, Via Montpellier 1, 00133 Rome, Italy Tel: +39 6 72596876; fax: +39 6 72596873; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:152–156 Abbreviations BMT HHV HIV MSM PBMC bone marrow transplant human herpesvirus human immunodeficiency virus men who have sex with men peripheral blood mononuclear cells ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction Since the last review in this journal in 2004 [1], more than 600 papers on human herpesvirus (HHV)-8, of which more than 80 on transmission, have been published. Indubitably, saliva emerged as the main source of HHV-8 transmission, but additional studies suggesting the importance of sexual, blood transfusion, solid organ and bone marrow transplants and vertical routes have also been reported. Unfortunately, there are no clear gold standards for assessing HHV-8 antibodies and the performance characteristics of available tests not only differ considerably, but also do not always seem to correlate with the presence of viral DNA. In addition, in serial testing of patients the disappearance of antibodies, so-called seroreversion, is not uncommon, with serious consequences in seroprevalence studies. Vertical transmission Reactivation of herpesvirus infections occurs during pregnancy, but only little data about HHV-8 and pregnancy are available at the moment. HHV-8 is often found in cervicovaginal secretions of human immunodeficiency virus (HIV)-1/HHV-8-coinfected women and of HIVseronegative women in areas of high endemicity [2], suggesting that HHV-8 load in the female genital tract might influence vertical transmission. Initial studies on vertical transmission showed that HHV8 seroreactivity in newborns is mainly due to transplacental passage of maternal antibodies [3,4]. A rare case of Kaposi’s sarcoma in newborns was described, however, and HHV-8 DNA was also detected at birth in peripheral blood mononuclear cells (PBMCs) of a very low percentage of infants from Zambia [5,6]. These findings indicate that in-utero or intra-partum HHV-8 infection might, albeit rarely, occur in endemic countries. In a recent report [7], HHV-8 DNA was found in PBMCs from five out of 15 pregnant HIV-1/HHV-8-infected women. Viral reactivation in PBMCs was also accompanied by HHV-8 detection in the cervicovaginal secretions of five out of 15 pregnant women, rated at higher levels than those previously reported in nonpregnant HIV-1-infected women from the same geographic area and exceeding those in females from nonendemic areas [7]. HHV-8 was detected in cervicovaginal secretions mainly at delivery and viral loads were paralleled with an increase in genital HIV-1 shedding. HHV-8 152 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Transmission of human herpesvirus 8 Pica and Volpi infection did not affect intra-uterine growth and timing of delivery, in contrast to previous reports suggesting that HHV-8 seropositivity may negatively influence the outcome of pregnancies, by increasing abortion rate or determining low weight at birth [8,9]. In this study, the identification of the same ORFK1 subtype in a mother–child pair confirmed transmission of the maternal virus. The delivery was by cesarean section, however, and no HHV-8 sequences were found in the placental tissues, which both could argue against perinatal and in-utero transmission, and the authors conclude that HHV-8 reactivation might lead to oral shedding, facilitating perinatal transmission via infectious saliva [10]. Although limited to a relatively low number of pregnant women, this study demonstrates that, like other herpesviruses, HHV-8 may reactivate during pregnancy in HIV-1-infected women with an increased risk for HHV-8 perinatal transmission in this population. Childhood acquisition Acquisition of HHV-8 infection is common in children in low-income and crowded environments. What is still to be defined is the prevalent route of transmission, i.e. mother-to-child, child-to-child, child-to-mother. Probably all these routes play a role in HHV-8 transmission. The results of a recent study in which the HHV-8 K1 sequences were determined in Ugandan mother–child pairs to ascertain whether they shared the same viral strain are consistent with HHV-8 transmission by maternal and nonmaternal sources [11]. In three of six pairs the authors found complete nucleotide homology, in two the same subtype, but with different sequences, and in one a different subtype. The crosssectional design of the study prevented the authors from formally demonstrating mother-to-child HHV-8 transmission and they concluded that it is possible that the children in turn infect their mothers. In that country, children frequently shed HHV-8 in saliva [12], therefore they may be a significant source of HHV-8 infection, particularly to their younger siblings or playmates, but also to adult relatives or people caring for them. Such an epidemiology resembles that of cytomegalovirus, which was widely studied in day-care centers. Like HHV-8, cytomegalovirus does not appear to be highly contagious and the acquisition requires close or intimate contact with persons who are excreting the virus in their saliva or other secretions [13,14]. HHV-8 appears to be an ancient virus as it is easily detected in segregated populations such as Amazonian Amerindians from Brazil and French Guiana, and Papua New Guinea tribes. In these populations, HHV-8 seroprevalence is 18–30% in children, increases linearly with age and is very high at 40–80% or above in older people 153 [15–17], reinforcing the concept that continuous or steadystate transmission happens within families in endemic populations [18], particularly in a general context of low socioeconomic level and a traditional way of life [19]. Much less is known about children in developed countries. In fact, only a few reports showing conflicting results have been published [20,21]. In nonendemic regions, HHV-8 transmission among children occurs but is uncommon, and HHV-8 antibodies, as measured by the current tests, may not persist for long periods [21]. Such complex observations raise questions about the reliability of serological testing in low prevalence areas and the possibility of equivocal results in children, similarly to what has been described for herpes simplex virus type 2 [22]. Transmission in adult populations Transmission studies in adult populations consist mainly of retrospective investigations based on the analysis of risk factors in HHV-8-seropositive individuals. Sexual transmission is believed to be the most common route of HHV-8 transmission in adult immunocompetent populations in countries of low seroprevalence, even though viral loads found in vaginal, seminal and prostatic secretions are much lower than in saliva [23]. Hence, transmission is more likely to occur via saliva in endemic regions and high-risk groups of individuals in areas with low HHV-8 seroprevalence [24,25,26,27]. It is, however, possible that HIV-related immunosuppression or genital ulcer diseases can favor sexual HHV-8 transmission. Recent data suggests the potential sexual/horizontal route of transmission in HIV-1-infected men [28], since HHV-8 isolated in the sperm is infectious for uninfected cells in coculture studies [28]. Moreover, in men who have sex with men (MSM) AIDS patients HHV-8 seropositivity is positively associated with Chlamydia infection, gonorrhea and genital warts, and in a high seroprevalence population HHV-8 seropositivity is correlated with herpes simplex virus type 2 infection [15,29,30]. Breakages in the genital mucosa and the concentration of infected and susceptible cells in the lesional sites can furnish a tentative explanation for these findings. Finally, the timing of HHV-8 acquisition in low endemic areas (America and Northern Europe) is still undefined, but the lower prevalence of the virus in HIV-positive adolescent MSM (11.2%) compared with adult MSM (30–75%) suggest that they acquire HIV prior to HHV-8 [31]. In conclusion, the presence of HHV-8 in oral as well as in genital secretions, albeit at lower levels than those of other herpesviruses, may contribute to explaining the different patterns of host acquisition of HHV-8 worldwide. Oral transmission of HHV-8 does occur among Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 154 Skin and soft tissue infections healthy populations [32], and oral wild-type HHV-8 isolated from immunocompetent individuals is able to infect and replicate in vitro in primary oral epithelial cells [32]. Salivary shedding of HHV-8 may thus provide a possible route of nonsexual horizontal transmission of the virus among family members of classical Kaposi’s sarcoma patients and in endemic regions [33,34], but may also apply, albeit to a lesser extent, to HHV-8-susceptible individuals in areas of low endemicity [26,35]. patients, blood transfusion was apparently implicated in one of the two cases. The authors report that eight patients experienced seroreversion during follow-up. The low incidence of HHV-8 infection in this cohort of hemodialysis patients, in which other blood-borne agents are readily horizontally transmitted, suggests that horizontal nosocomial transmission of HHV-8 is a rare event. Transplant Whereas Epstein–Barr virus, traditionally considered to be spread by saliva, may be also transmitted by genital contact, blood transfusion and transplantation, HHV-8, first considered to be genitally transmitted especially among homosexual males, is increasingly being regarded as transmissible by saliva. Transfusions and hemodialysis Evidence for transmissibility of HHV-8 by transfusion has been controversial in recent years [36]. Transmissibility of the virus by this route may be limited by the cell-associated nature of the virus, the generally low seroprevalence of HHV-8 in the donor pool, the low and/or intermittent viremia among antibody-positive donors, and the low frequency of circulating virus in asymptomatic seropositive individuals. The first report was that of Blackbourne, which in 1997 evoked some concern about this issue; however, subsequent works have not been able to show any evidence of HHV-8 transmission. Two recent studies performed in high and low endemic populations seem to provide evidence for HHV-8 transmission by this route [37,38]. In a high endemic area, the reported excess risk of seroconversions in recipients of HHV-8-seropositive blood (2.8%), the timing of the occurrence of seroconversions (between 3 and 10 weeks after transfusion) and the storage-related characteristics of the transfused blood (excess risk 4.2% for blood units stored less than 4 days) render plausible the occurrence of viral transmission by this route [38]. Unfortunately, only serological and not molecular-based evidence of virus transmission is provided, and, consequently, data cannot be considered as conclusive. Evidence of blood-borne transmission of HHV-8 among injection-drug users has been suggested in several studies, but the same data might indicate that the virus is transmitted via selected sexual and/or general behaviors accompanying the use of drugs rather than the drug use itself or the possibility of blood exchange [1]. HHV-8 transmission in hemodialysis appears uncommon even though in intermediate seroprevalence areas like Greece [39], where HHV-8 seroconversion has been shown to occur in only two out of 485 hemodialysis HHV-8 can be transmitted during transplantation, and both de-novo infection and reactivated infection are associated with significant morbidity and mortality among transplant patients [40]. Immunosuppression and chronic opportunistic infection by oncogenic viruses are the main causes of cancer developing in allograft recipients. The type of the drugs used for induction and maintenance of immunosuppression and the duration of treatment influence both the incidence and the type of cancer that develops. The immunosuppressive drug sirolimus (rapamycin) has recently been shown to greatly reduce the risk of Kaposi’s sarcoma in kidney and other solid organ transplants [41]. It has also been hypothesized that prophylaxis with highly potent antivirals could play a role in avoiding HHV-8 reactivation and consequent development of Kaposi’s sarcoma [42]. Kaposi’s sarcoma is, however, still a major problem after transplant, mainly of solid organs. In a retrospective study performed on 22 posttransplant Kaposi’s sarcoma patients (12 kidney, two kidney/ pancreas, six liver and two heart), viral reactivation was the most likely cause in the majority of Kaposi’s sarcoma cases, whereas seroconversions occurred only in two cases and may have been linked to viral transmission by the graft [43]. In kidney transplant recipients, the predisposition to Kaposi’s sarcoma is associated with a high pretransplant prevalence of HHV-8 [44]. Consistently, the high HHV-8 seroprevalence in renal transplant recipients in Saudi Arabia may explain the previously reported high incidence of Kaposi’s sarcoma in that setting [45]. In 2005, we reported the first description of seroconversion with detection of HHV-8 DNA in serum of allogeneic bone marrow transplant (BMT) recipients [46]. We found that HHV-8 seroconversion is relatively common among seronegative BMT recipients receiving a BMT from a seropositive donor and is not associated with overt clinical manifestations, at least in our series of recipients. In our population, seroreversion after BMT occurred in 11 (51%) of 20 recipients who were HHV-8-seropositive before BMT, confirming data previously reported, and six recipients who became HHV8-seropositive 30 days after BMT were seronegative at Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Transmission of human herpesvirus 8 Pica and Volpi day 180. Longitudinal studies on HIV- and HHV8-seropositive patients with or without Kaposi’s sarcoma have reported changing profiles of antibody reactivity to HHV-8 over time, suggesting an incomplete recognition of latent or lytic epitopes after primary and reactivated infection. Furthermore, seroreversion has been observed in HIV-positive patients with detectable HHV-8 DNA in oral fluid and/or PBMCs. Unfortunately, the natural history of serologic reactivity to HHV-8 over time in asymptomatic healthy seropositive subjects is not clearly understood, because, to our knowledge, there have been no longitudinal studies in populations that are not immunocompromised. Immune control of HHV-8 infection Immunity is known to play a key role in the control of HHV-8 infection, because Kaposi’s sarcoma occurs mostly in immunocompromised patients, such as HIV-infected individuals, transplant recipients and the elderly. Reports of clinical improvement in Kaposi’s sarcoma when immunity is restored confirm this concept even if in some individuals Kaposi’s sarcoma worsens despite the improvement of immunological parameters [47]. Guihot et al. [48] have recently shown that patients with Kaposi’s sarcoma have significantly fewer HHV8-specific T cells than asymptomatic HHV-8 carriers, regardless of CD4 T cell count or HHV-8 load. This has been demonstrated in HIV-positive as well as in classical Kaposi’s sarcoma patients. This impairment may be responsible for the uncontrolled proliferation of HHV-8-transformed cells and the consequent occurrence of Kaposi’s sarcoma. The fact that a lack of T cell response to HHV-8 lytic antigens is associated with Kaposi’s sarcoma is consistent with the concept that such genes are important in Kaposi’s sarcoma oncogenesis. In addition, the notion is now emerging that host immunogenetic factors can influence the control of HHV-8 infection. Specifically, in HIV-negative individuals without Kaposi’s sarcoma, poorly controlled lytic and latent HHV-8 infection, as assessed by the detection of the respective antibodies, was associated with an overrepresentation of a three-locus haplotype interleukin-4 ( 1098G/ 588C/ 168C) and the functional promoter variant of interleukin-6 ( 236C), as well as interleukin12A ( 798T/277A), respectively [49]. This study provides preliminary evidence for genetic variations in cytokines that could influence the overall control of HHV-8. Conclusion Finally, although the existence of HHV-8 has been recognized for over a decade, screening for the infection remains challenging. Some of the factors which make diagnosis difficult include a large proportion of HHV- 155 8-infected individuals who do not have detectable levels of virus in peripheral blood [24,32], discordance between serological assays targeting different antigens [23], seroreversions, and difficulties in assembling gold standard positive and negative reference populations for antigen testing [40]. The main issue to be clarified is the biology of the immune response that is still poorly understood and can distort our current understanding of the epidemiology of the infection. The implications of genetic factors in the acquisition and control of HHV-8, as shown for other diseases [50], make it even more challenging to have a clear picture of the natural history of this infection. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 206–207). 1 Henke-Gendo C, Schulz TF. Transmission and disease association of Kaposi’s sarcoma-associated herpesvirus: recent developments. Curr Opin Infect Dis 2004; 17:53–57. 2 Calabrò ML, Fiore JR, Favero A, et al. Detection of human herpesvirus 8 in cervicovaginal secretions and seroprevalence in immunodeficiency virus type 1-seropositive and -seronegative women. J Infect Dis 1999; 179:1534– 1537. 3 Calabrò ML, Gasperini P, Barbierato M, et al. A search for human herpesvirus 8 (HHV-8) in HIV-1 infected mothers and their infants does not suggest vertical transmission of HHV-8. Int J Cancer 2000; 85:296–297. 4 Gessain A, Mauclere P, Van Beveren M, et al. 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Prevalence of herpes simplex virus types 1 and 2 among children and adolescents attending a sexual abuse clinic. Pediatr Infect Dis J 2006; 25:902–905. 39 Zavitsanou A, Sypsa V, Petrodaskalaki M, et al. Human herpesvirus infection in hemodialysis patients. Am J Kidney Dis 2006; 47:167–170. 23 Edelman DC. Human herpesvirus 8 – a novel human pathogen. Virol J 2005; 2:78. 24 Miller CS, Berger JR, Mootoor Y, et al. High prevalence of multiple human herpesvirus in saliva from human immunodeficiency virus-infected persons in the era of highly active antiretroviral therapy. J Clin Microbiol 2006; 44:2409– 2415. Direct relationship between CD4 cell count and probability of having HHV-8 in saliva in HIV-infected patients. 25 Widmer IC, Erb P, Grob H, et al. Human herpesvirus 8 oral shedding in HIVinfected men with and without Kaposi’s sarcoma. J Acquir Immune Defic Syndr 2006; 42:420–425. 26 Casper C, Carrel D, Miller KG, et al. HIV serodiscordant sex partners and the prevalence of human herpesvirus 8 infection among HIV negative men who have sex with men: baseline data from the EXPLORE Study. Sex Transm Infect 2006; 82:229–235. Saliva can be the main source of transmission even in HIV-negative MSM. 27 Mbulaiteye SM, Walters M, Engels EA, et al. High levels of Epstein–Barr virus DNA in saliva and peripheral blood from Ugandan mother–child pairs. J Infect Dis 2006; 193:422–426. 40 Laney AS, Peters JS, Manzi SM, et al. Use of a multiantigen detection algorithm for diagnosis of Kaposi’s sarcoma-associated herpesvirus infection. J Clin Microbiol 2006; 44:3734–3741. This paper proposes a systematic approach to optimize and standardize serological methods for the assessment of HHV-8 infection. 41 Dantal J, Soulillou JP. Immunosuppressive drugs and the risk of cancer after organ transplantation. N Engl J Med 2005; 352:1371–1373. 42 Razonable RR, Brown RA, Humar A, et al. 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Herpes simplex virus encephalitis in human UNC-93B deficiency. Science 2006; 314:308–312. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Molecular diagnostic methods in pneumonia Yvonne R. Chan and Alison Morris Purpose of review Molecular techniques offer the promise of improving diagnosis of lower respiratory tract infections. This review focuses on currently used molecular diagnostic techniques for various types of pneumonia and highlights potential future applications of this technology. Recent findings Lower respiratory tract infections result in a high degree of morbidity and mortality, but a definitive microbiologic diagnosis is often not obtained by traditional culture or serologic methods. In addition, culture of certain organisms may be difficult or require extended periods of time. Molecular techniques have the potential to improve diagnostic yield and decrease time to pathogen identification. These techniques are also helpful in the determination of drug sensitivity and the understanding of transmission and outbreaks. Most currently used techniques employ some variation of the polymerase chain reaction. Limitations include high costs, the need for specialized equipment, and problems with false-positive and -negative results. Summary Molecular diagnosis of pneumonia has the potential to improve identification of pathogens in patients with suspected lower respiratory tract infection. Limitations of molecular techniques currently prevent their widespread use, but future developments will likely lead to inclusion of these tests in routine diagnostic evaluations. Keywords diagnosis, molecular, nucleic acid, pneumonia, polymerase chain reaction Curr Opin Infect Dis 20:157–164. ß 2007 Lippincott Williams & Wilkins. Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA Correspondence to Alison Morris, MD, MS, Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA Tel: +1 412 692 2210; fax: +1 412 692 2260; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:157–164 Abbreviations CAP FDA MTD NAAT PCP PCR PFGE RFLP rRNA RT SARS community-acquired pneumonia Food and Drug Administration amplified Mycobacterium tuberculosis Direct Test nucleic acid amplification technique Pneumocystis pneumonia polymerase chain reaction pulsed-field gel electrophoresis restriction fragment length polymorphisms ribosomal RNA reverse transcriptase severe acute respiratory syndrome ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction Lower respiratory infections are a major cause of morbidity and mortality. Empiric antimicrobial therapy must be initiated based on clinical symptoms, radiographic and laboratory findings, and specific epidemiologic risk factors. Culture results typically require several days and about half of patients never have an organism established. In the case of organisms such as Mycobacterium tuberculosis, cultures may require weeks to become positive. As early intervention with appropriate antibiotics has been shown to improve mortality and may decrease transmission of infection, more rapid and sensitive tests would greatly improve the care of patients with pneumonia [1,2]. Molecular diagnostic techniques may improve our ability to quickly and efficiently diagnose infections, avoid iatrogenic complications of unnecessary antibiotics, improve outcomes by providing the right antibiotic quickly, and rapidly identify new infections and outbreaks; however, difficulties remain with the sensitivity and specificity of these tests, and they are not yet in widespread clinical use. We will review various molecular techniques and discuss the advantages and disadvantages of each (Table 1). We will then discuss selected pathogenspecific applications of these techniques. General principles of molecular techniques One of the first molecular methods applied to diagnosis of pneumonia was restriction fragment length polymorphisms (RFLP) [3]. In this technique, DNA is digested with restriction enzymes that generate fragments of different sizes and the pattern of fragment sizes is analyzed by gel electrophoresis. More recently, this technique has been adapted to generate larger fragments of DNA that are separated by pulsed-field gel electrophoresis (PFGE) [3]. Both RFLP and PFGE require growth of the organism in culture, and are therefore most 157 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 158 Respiratory infections Table 1 Advantages and disadvantages of molecular techniques compared to conventional diagnostic techniques Advantages Disadvantages More rapid Greater sensitivity Rapid identification of drug resistance Ability to track disease transmission Ability to test for multiple pathogens simultaneously Less affected by prior antimicrobial therapy Can diagnose organisms unable to be cultured Expensive reagents and equipment Need highly trained personnel Small sample volume may decrease sensitivity False-negatives possible if polymerase chain reaction inhibitors present False-positives possible in colonization or contamination Variability of noncommercial systems Lack of systematic evaluation in clinical settings useful for strain identification and examination of disease transmission rather than clinical diagnosis. Most currently used molecular techniques are based on polymerase chain reaction (PCR) technology [4]. These nucleic acid amplification tests (NAATs) directly detect microbial nucleic acid in clinical samples. The basic steps of PCR include extraction of DNA from either a cultured pathogen or from a patient sample and amplification of a target gene. At least a partial DNA sequence must be known to design primers that hybridize to specific regions of the target DNA. Enzymes are used to copy this DNA via multiple rounds of extension and denaturation, resulting in exponential amplification of the DNA of interest. The PCR products are then examined by gel electrophoresis and DNA sequencing. There are multiple PCR variations that have been developed. In nested PCR, two rounds of PCR are performed, increasing the ability to detect very small amounts of target DNA. Multiplex PCR uses multiple sets of primers to test for several targets simultaneously. Targetenriched multiplex PCR (Genaco Biomedical Products, Huntsville, Alabama, USA) is a new technique that detects up to 100 different organisms in each reaction by using Luminex technology (Luminex, Austin, Texas, USA) [5]. As many viruses are RNA-based, reverse transcriptase (RT)-PCR was developed. In RT-PCR, RNA is converted to a complementary DNA copy before PCR is performed. Because RNA is rapidly degraded after cell death, this technique detects only viable organisms, unlike PCR, which cannot distinguish living and dead organisms. Another NAAT gaining interest for clinical diagnosis is nucleic acid sequence-based amplification [6]. Nucleic acid sequence-based amplification is faster than PCR, can detect RNA or DNA and is isothermal, so it does not require a thermocycler. One of the most important developments in PCR technology was the discovery of quantitative real-time PCR [7,8]. In this technique, amplification and detection of the products occur in a single tube, thus simplifying the procedure because gel electrophoresis is not needed. The reaction is performed using fluorescent DNA intercalating dyes or fluorescent-labeled DNA probes [4]. Signal intensity increases with increasing DNA amplification and can be used to determine the number of gene copies in the original sample. Fluorescent probe technology is sophisticated and reviewed in depth elsewhere [9]. Multiplex PCR can also be performed with this technique. A new system called Masscode Technology (Qiagen, Hilden, Germany) uses primers bound by an ultraviolet photocleavable link to molecular tags of known molecular mass [10,11]. After multiplex RT-PCR, tags are liberated by irradiation and identified by mass spectrometry. MassTag technology enables detection of 22 pathogens in a single reaction. PCR can provide diagnoses earlier than cultures and in cases where standard techniques are negative. Unfortunately, this technology suffers from a number of limitations. PCR inhibitors in samples can lead to false-negative results. There may also be inadequate sample to detect DNA or ineffective release of DNA from cells during processing. Internal amplification controls can help diagnose these problems. As the tests are extremely sensitive, contamination can easily result in false-positives. Scrupulous laboratory technique must be followed, and pre- and post-amplification steps must be performed in separate areas. Real-time PCR decreases the likelihood of contamination as all steps are performed in a single tube that does not need to be opened. Tests may also be truly positive, but merely indicate colonization and not disease. Real-time PCR can help in interpretation of positive tests by quantifying organisms and establishing cutoffs that distinguish colonization from infection. Also, PCR equipment and reagents are often expensive, and PCR requires trained personnel. These difficulties are likely to decrease in the future as technology evolves. Viral pneumonia Diagnosis of viral pneumonia can be challenging. Many viruses do not grow easily in culture and serum antibody testing is often not clinically useful. Many cases of viral illness go undetected, but NAATs offer promise to improve diagnosis. Influenza RT-PCR has the potential to diagnose influenza rapidly and with high sensitivity. A recent study compared Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Molecular diagnostic methods Chan and Morris 159 real-time RT-PCR for influenza to shell vial and tube cell cultures in patients hospitalized with symptoms of pneumonia [12]. They found that PCR detected all cases diagnosed by conventional methods and an additional seven cases of influenza that were negative on culture and shell vial. The average time to obtain PCR results was 5.5 h. Another recent large-scale study examined the disease burden of influenza in children and found that 46% of cases were diagnosed by culture and PCR, 48% by PCR alone and 7% by culture alone [13]. As live vaccines are used for influenza, it will become important to distinguish live attenuated vaccine shedding from infection. One group designed a primer set that successfully discerned vaccine from active infection [14]. Realtime PCR is also able to determine if influenza is resistant to oseltamivir (Roche, Nutley, New Jersey, USA) [15]. Multiple pathogen detection RT-PCR has been developed for many other viruses such as rhinovirus, respiratory syncytial virus, human metapneumovirus and human bocavirus [16–19,20,21], but because the signs and symptoms of community-acquired pneumonia (CAP) can be nonspecific, there has been much interest in developing systems that can test for multiple viral respiratory pathogens simultaneously. Several recent studies have examined the use of multiplex technology for diagnosing patients with respiratory symptoms. A prospective observational study in adults with clinically diagnosed CAP found that multiplex PCR had a sensitivity and specificity of 85 and 92% where there was an established diagnostic gold standard [22]. In addition, PCR allowed detection of viruses that have no culture or diagnostic standard. In another study, multiplex real-time RT-PCR detected respiratory viruses in 40% more samples than fluorescent antibody testing and was usually successful when the specimen was judged inadequate for fluorescent antibody testing [23]. A similar study of PCR on nasopharyngeal aspirates detected all fluorescent antibodies or culture-positive samples and offered the additional advantage of detecting viruses where fluorescent antibodies or culture diagnosis was not available [24]. MassTag PCR has also been tested for simultaneous detection of common viral respiratory pathogens. Its detection limit appears to be 100 copies per reaction, and it correctly diagnosed 77% of samples positive by RT-PCR and/or culture [10]. In another study, MassTag PCR diagnosed a pathogen in 26 of 79 previously undiagnosed cases of influenza-like illnesses [11]. Targetenriched multiplex PCR is another new multiplex technology that has been found to have good sensitivity and specificity in limited clinical studies [5]. Microarray technology offers the ultimate potential in multiplex analysis. One study using this technology was able to process 72 clinical samples and type and subtype isolates with 95 and 72% accuracy respectively, with a turnaround time of 12 h [25]. Other microarrays have been developed to test for multiple respiratory viruses and bacteria [26], but this highly specialized technique is not yet ready for routine clinical diagnosis. Severe acute respiratory syndrome and avian influenza The recent outbreaks of severe acute respiratory syndrome (SARS) and avian influenza (H5N1) demonstrated the great utility of molecular techniques to identify and diagnose epidemics of novel pathogens. Scientists rapidly identified the agent of SARS as a coronavirus and developed several molecular diagnostic techniques [27,28]. Although the threat of SARS has diminished, it is possible that there may be a reemergence of the disease and the techniques used will likely be applied to future outbreaks of novel pathogens. The first molecular assays for SARS were based on RT-PCR. Nested and real-time PCR as well as loop-mediated isothermal amplification techniques have also been developed for diagnosis [29]. Sensitivity and specificity of these tests vary widely with ranges of 36.4–100 and 86.8–100%, respectively [30]. SARS diagnosis has been problematic even with PCR because there is a long lag time from the onset of symptoms to detectable viral levels and techniques to improve sensitivity are under study [31,32]. Infection in humans by avian influenza virus was recently reported after an outbreak in poultry [33]. These cases were confirmed using real-time PCR of nasopharyngeal samples. The World Health Organization has approved a primer and probe set that was developed at the Centers for Disease Control, and a number of other primer probe sets have been developed for use in animal and human sample testing [34,35–37]. Bacterial pneumonia An etiologic agent is often not identified in cases of bacterial CAP. As with viruses, molecular techniques that test for multiple pathogens simultaneously could improve diagnostic accuracy and allow clinicians to provide appropriate antibiotics. Molecular techniques might also be helpful in examining drug resistance, determining if resistance has been transferred from another organism, and in defining patterns of infection to identify epidemics and aid infection control efforts. Streptococcus pneumoniae Diagnostic PCR assays have targeted specific S. pneumoniae sequences. One group used RT-PCR to amplify S. pneumoniae genes in an effort to distinguish it from commensal oral isolates [38]. While unable to unambiguously distinguish pathogenic organisms, there was a trend toward a particular genetic profile in patients who were Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 160 Respiratory infections ill [38]. Another group designed a real-time RT-PCR assay of the pneumolysin gene to identify S. pneumoniae as a cause of empyema in children [39]. This assay identified S. pneumoniae in 75% of pleural fluid samples compared to historical 33% recovery in cultures. This assay, however, was much less successful at detecting pathogen from blood, even from patients with positive blood cultures. Molecular techniques such as PFGE and multilocus sequence genotyping have also been used to examine epidemiology and drug resistance in S. pneumoniae [40,41]. depending on the organism and the sample type. Another study reported sensitivities and specificities greater than 90% using real-time PCR with molecular beacons [55]. Although these techniques are sensitive compared to culture, absolute pathogen detection is still low. One study reported that real-time quantitative PCR identified a pathogen in only 37.7% of subjects with clinically diagnosed pneumonia [56]. The use of universal primers to detect the 16S rRNA gene that is evolutionarily conserved and exclusive to bacteria also holds promise for broad diagnosis [4]. Staphylococcus aureus Mycobacterium tuberculosis In S. aureus infections, molecular identification and characterization techniques have mainly been used for epidemiological purposes and detection of drug resistance rather than diagnosis. The most commonly used techniques to identify strains are PFGE or multilocus sequence genotyping [42,43,44]. Recent developments have been aimed at streamlining these techniques by combining them with PCR [45] and defining the minimum number of gene loci that enables reliable distinction of strains [42,46]. Drug resistance is most commonly tested with PFGE and various types of PCR to identify the mecA gene that encodes a b-lactam-resistant penicillin-binding protein [47,48]. Molecular techniques can also be employed to distinguish community-acquired from hospital-acquired strains [49,50]. Molecular techniques have been extremely useful in evaluating patients with suspected tuberculosis. As the organism can require 2–8 weeks to grow in culture and culture may be difficult to perform in many developing areas with high burdens of tuberculosis, more rapid molecular techniques are useful in allowing appropriate treatment/isolation of patients and controlling disease worldwide. Molecular techniques have been used to track tuberculosis outbreaks, improve tuberculosis diagnosis and test for drug-resistant tuberculosis. Mycoplasma pneumoniae M. pneumoniae is notoriously difficult to culture, and diagnosis usually relies on serology. Multiple primers for PCR-based detection of M. pneumoniae have been developed and these tests can be performed on a variety of respiratory specimens [51]. There may be a poor correlation between antibody response and PCR because the pathogen can be detected in patients without respiratory disease and vice versa. A recent study tested realtime PCR at the 16S ribosomal RNA (rRNA) gene in 937 clinical samples [52]. PCR detected almost all cultureand serology-positive cases and detected an additional 20 cases that were culture-negative. PCR results were available within 2 h – a significant improvement over the 2 weeks usually required for serologic diagnosis. Realtime PCR at the P1 cytadhesin gene performed less well, detecting only 60% of Mycoplasma infections [53]. Multiple pathogen detection Techniques that analyze multiple pathogens simultaneously could prove useful in the diagnosis of bacterial pneumonia. Stralin et al. [54] compared culture to multiplex PCR for S. pneumoniae, Haemophilus influenzae, M. pneumoniae and Chlamydia pneumoniae. They examined sputum and nasopharyngeal samples from adults with CAP and controls, and found sensitivity ranging from 58 to 100% and specificity ranging from 42 to 100% One of the first applications of molecular techniques to the study of tuberculosis was the use of fingerprinting to understand outbreaks and transmission of tuberculosis. RFLP was initially used to track cases of tuberculosis with transmitted cases sharing the same fingerprint while reactivation cases had unique fingerprints [57]. More recently, rapid genomic deletion typing with multiplex PCR to detect specific strain deletions has been used to analyze outbreaks of tuberculosis, allowing public health officials to focus on cases most likely to lead to additional transmission [58]. Tuberculosis diagnosis can be difficult and time-consuming. A long period of time is required for growth and identification of tuberculosis. Smear-positive patients may be infected with tuberculosis or other mycobacteria and this determination influences treatment and isolation procedures. Multiple NAATs have been developed for tuberculosis diagnosis. The Amplified Mycobacterium tuberculosis Direct Test (MTD; Gen-Probe, San Diego, California, USA) and the Amplicor Mycobacterium tuberculosis test (Roche Diagnostic Systems, Branchburg, New Jersey, USA) are the systems that are currently Food and Drug Administration (FDA)-approved. MTD uses isothermal transcription-mediated amplification for detection of M. tuberculosis complex rRNA. The enhanced MTD is also FDA approved, has shorter processing time and can use a larger sample than the original MTD, thus increasing sensitivity. The MTD has FDA approval in smear-negative cases and may be more sensitive in these cases because it detects rRNA that is present in about 200 copies/cell. The Amplicor is PCR-based and amplifies Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Molecular diagnostic methods Chan and Morris 161 mycobacterial DNA. BD ProbeTec ET assay (BD Biosciences, Rockville, Maryland, USA) and Genotype Mycobacteria Direct (Hain Lifescience, Nehrn, Germany) are additional NAATs that are not currently approved. Several interesting new tests are under investigation and may have future clinical applications. Loop-mediated isothermal amplification (Eiken Chemical, Tokyo, Japan) is a novel NAAT that is not yet FDA-approved for tuberculosis diagnosis, but has several advantages [59]. As the reaction is isothermal, amplification and detection can be performed in a single step, and amplification efficiency is high. Sensitivity and specificity are not well known for this test. Other novel techniques that are still under investigation include the use of enzymelinked immunosorbent assays of nucleic acid-based amplification and the use of serum proteomic fingerprinting [60,61]. Two recent meta-analyses have examined clinical performance of NAATs for tuberculosis. Greco et al. [62] examined all English language studies of commercial NAATs between 1995 and 2004. They found that in smear-positive patients, NAATs had a sensitivity of 96% and a specificity of 85%. In smear-negative cases, sensitivity fell to 66%, but specificity was 98%. They found that use of at least two types of culture media, inclusion of bronchial samples and higher tuberculosis prevalence improved the diagnostic odds ratio of the tests. Flores et al. [63] performed a meta-analysis that included 84 studies of in-house NAATs. They found a wide range of sensitivity (9.45–100%) and specificity (5.6%–100%) for these assays. Nested PCR and use of the IS6110 target improved performance of these tests. The exact clinical role for NAATs is still not entirely clear and they cannot replace conventional culture techniques at this time. NAATs are most useful in patients with positive smears. A positive NAAT in a patient with sputum acid-fast bacilli is extremely likely to signal tuberculosis. A negative NAAT in a smear-positive patient may signal infection with another type of mycobacteria or might signal a false-negative NAAT. In smearnegative patients, a negative NAAT is not sufficient to rule out tuberculosis. Repeatedly positive NAATs in a smear-negative patient indicate a higher likelihood of tuberculosis in a patient with a high pretest probability. Identification of drug resistance is an important use of molecular techniques in tuberculosis. Assays to identify drug resistance involve nucleic acid amplification and assessment of the products for known resistance mutations. Two commercial assays are used to test for drug resistance. The Line Probe Assay (INNO-LiPA Rif TB Assay; Innogenetics, Ghent, Belgium) detects mutations in the rpoB gene that are associated with rifampin resistance [64]. The GenoType MTBDR assay (Hain Lifescience) detects both isoniazid and rifampin resistance by detecting the most common mutations that confer resistance [65–68]. Microarrays also hold promise for examination of drug resistance in the future, but are currently too expensive. Fungi Lower respiratory fungal infections that are either primary or disseminated can be difficult to diagnose because clinical and radiographic presentation are nonspecific, and definitive diagnosis often requires invasive procedures. Outcome may be poor because of failure to make a timely diagnosis. Traditional culture or antibody tests lack sensitivity and cannot distinguish colonization from true infection. Molecular techniques could potentially prove to have significant benefit, particularly in the immunocompromised population, but have not yet proven as useful in the diagnosis of pulmonary fungal infections as in other organisms. Aspergillus fumigatus, Coccidioides immitis and Histoplasma capsulatum Most work has focused on diagnosis of invasive Aspergillus infections. Sensitivity of PCR for Aspergillus ranges from 45 to 92% with specificity of greater than 90% for most tests [69]. Unfortunately, these tests are still labor intensive and expensive, and are susceptible to laboratory contamination. There may be some utility of combining PCR with galactomannan testing, but clinical performance of this strategy is unknown. Some promise has been shown in using a quantitative PCR for pulmonary aspergillosis [70]. A real-time PCR assay that detected 18S rRNA was found to have 100% specificity and 89% sensitivity when tested in a rabbit model, but the performance of this assay in human disease is not yet known [70]. Although PCR has been developed for other fungi such as Coccidioides and Histoplasma, these tests are fairly far from having clinical utility [69,71]. Pneumocystis The diagnosis of Pneumocystis pneumonia (PCP) is notoriously difficult given the inability to culture the responsible organism. Detection of Pneumocystis jirovecii (formerly known as Pneumocystis carinii f. sp. hominis) typically relies on microscopy, and sensitivity can be affected by sampling variability and experience of laboratory personnel. Molecular techniques could improve PCP diagnosis by detecting small amounts of the organisms’ DNA. Although conventional and nested PCR can detect Pneumocystis, there has been recent interest in the use of real-time PCR. Arcenas et al. [72] developed a real-time PCR with 100% sensitivity when compared to Calcofluor white staining of bronchoalveolar lavage. The assay also detected Pneumocystis in samples negative by staining. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 162 Respiratory infections Another recent paper compared the inter-laboratory variability of three real-time PCR assays for detecting Pneumocystis in bronchoalveolar lavage [73]. The assays correctly identified 40 of 41 cases of microscopically confirmed PCP. Use of sensitive molecular techniques might also obviate the need for invasive sampling to diagnose PCP. For example, Larsen et al. [74] reported the use of a quantitative touch-down PCR of oral washes that had a sensitivity of 88% and a specificity of 85%. One drawback of PCR-based assays to diagnose PCP is the detection of low levels of organisms that might actually represent colonization and not active infection. Conclusion The past several years have seen an enormous increase in the number and types of molecular techniques available for diagnosis of lower respiratory tract infection. NAATs offer great promise for improving diagnostic speed and accuracy, for determining the presence of drug resistance, for tracking community and hospital outbreaks, and for the evaluation of emerging pathogens. Despite their potential, several limitations currently hinder the widespread implementation of these techniques, and improvements in sensitivity and specificity, cost, and ease of use are needed before many of these tests can be adopted in clinical practice. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 219–220). 1 Leroy O, Santre C, Beuscart C, et al. A five-year study of severe communityacquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit. Intensive Care Med 1995; 21:24–31. 2 Moine P, Vercken JB, Chevret S, et al. Severe community-acquired pneumonia. Etiology, epidemiology, and prognosis factors. French Study Group for Community-Acquired Pneumonia in the Intensive Care Unit. 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Sensitivity was quite variable depending on the organism and the sample type. 55 Morozumi M, Nakayama E, Iwata S, et al. Simultaneous detection of patho gens in clinical samples from patients with community-acquired pneumonia by real-time PCR with pathogen-specific molecular beacon probes. J Clin Microbiol 2006; 44:1440–1446. A large study that reports rapid identification with excellent sensitivity using realtime PCR of six bacterial pathogens in patients with suspected pneumonia. 38 Suzuki N, Yuyama M, Maeda S, et al. Genotypic identification of presumptive Streptococcus pneumoniae by PCR using four genes highly specific for S. pneumoniae. J Med Microbiol 2006; 55:709–714. 56 Kais M, Spindler C, Kalin M, et al. Quantitative detection of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in lower respiratory tract samples by real-time PCR. Diagn Microbiol Infect Dis 2006; 55:169–178. A well-conducted study that examines the use of real-time PCR to detect various bacterial pathogens in patients with lower respiratory infection. It is one of the few studies to include a control group. 39 Lahti E, Mertsola J, Kontiokari T, et al. Pneumolysin polymerase chain reaction for diagnosis of pneumococcal pneumonia and empyema in children. Eur J Clin Microbiol Infect Dis 2006; 25:783–789. 57 Small PM, Hopewell PC, Singh SP, et al. The epidemiology of tuberculosis in San Francisco – a population-based study using conventional and molecular methods. N Engl J Med 1994; 330:1703–1709. 40 Sadowy E, Izdebski R, Skoczynska A, et al. Penicillin-nonsusceptible Streptococcus pneumoniae in Poland – phenotypic and molecular analysis. Antimicrob Agents Chemother 2006; 51:40–47. 58 Freeman R, Kato-Maeda M, Hauge KA, et al. Use of rapid genomic deletion typing to monitor a tuberculosis outbreak within an urban homeless population. J Clin Microbiol 2005; 43:5550–5554. 41 Koeck JL, Njanpop-Lafourcade BM, Cade S, et al. Evaluation and selection of tandem repeat loci for Streptococcus pneumoniae MLVA strain typing. BMC Microbiol 2005; 5:66. 59 Pai M, Kalantri S, Dheda K. New tools and emerging technologies for the diagnosis of tuberculosis: part II. Active tuberculosis and drug resistance. Expert Rev Mol Diagn 2006; 6:423–432. A comprehensive review of nucleic acid amplification tests for diagnosis of active tuberculosis and detection of drug resistance. 37 Ng LF, Barr I, Nguyen T, et al. Specific detection of H5N1 avian influenza A virus in field specimens by a one-step RT-PCR assay. BMC Infect Dis 2006; 6:40. 42 Aguiar-Alves F, Medeiros F, Fernandes O, et al. New Staphylococcus aureus genotyping method based on exotoxin (set) genes. J Clin Microbiol 2006; 44:2728–2732. Report of a novel method for detecting methicillin resistance using sequencebased genotyping of exotoxin genes to provide an alternative to RFLP-based methods. 43 Roberts JC, Cannons AC, Amuso PT, Cattani J. Virtual digest identification of secondary enzymes for use in pulsed-field gel electrophoresis of Staphylococcus aureus. J Microbiol Methods 2006; 66:362–368. 44 Vindel A, Trincado P, Gomez E, et al. Prevalence and evolution of methicillin resistant Staphylococcus aureus in Spanish hospitals between 1996 and 2002. J Clin Microbiol 2006; 44:266–270. An interesting study that tested over 2000 methicillin-resistant S. aureus strains over a 7-year period to determine predominant genetic profiles. 45 Sabat A, Malachowa N, Miedzobrodzki J, Hryniewicz W. Comparison of PCRbased methods for typing Staphylococcus aureus isolates. J Clin Microbiol 2006; 44:3804–3807. 46 Strommenger B, Kettlitz C, Weniger T, et al. Assignment of Staphylococcus isolates to groups by spa typing, SmaI macrorestriction analysis, and multilocus sequence typing. J Clin Microbiol 2006; 44:2533–2540. 47 Huletsky A, Giroux R, Rossbach V, et al. New real-time PCR assay for rapid detection of methicillin-resistant Staphylococcus aureus directly from specimens containing a mixture of staphylococci. J Clin Microbiol 2004; 42:1875– 1884. 48 Oberdorfer K, Pohl S, Frey M, et al. Evaluation of a single-locus real-time polymerase chain reaction as a screening test for specific detection of methicillin-resistant Staphylococcus aureus in ICU patients. Eur J Clin Microbiol Infect Dis 2006; 25:657–663. This study examines the diagnostic value of a real-time PCR assay for rapid detection of methicillin resistance. 60 Agranoff D, Fernandez-Reyes D, Papadopoulos MC, et al. Identification of diagnostic markers for tuberculosis by proteomic fingerprinting of serum. Lancet 2006; 368:1012–1021. An intriguing study reporting the use of serum proteomic fingerprinting to identify patients with tuberculosis. Diagnostic accuracy was good for discrimination of patients with tuberculosis compared to those with similar clinical symptoms. 61 Gill P, Ramezani R, Amiri MV, et al. Enzyme-linked immunosorbent assay of nucleic acid sequence-based amplification for molecular detection of M. tuberculosis. Biochem Biophys Res Commun 2006; 347:1151–1157. 62 Greco S, Girardi E, Navarra A, Saltini C. Current evidence on diagnostic accuracy of commercially based nucleic acid amplification tests for the diagnosis of pulmonary tuberculosis. Thorax 2006; 61:783–790. This paper is an important meta-analysis of commercial nucleic acid amplification tests for tuberculosis diagnosis. It reports sensitivity and specificity of various tests and factors that improve diagnostic odds ratios. 63 Flores LL, Pai M, Colford JM Jr, Riley LW. In-house nucleic acid amplification tests for the detection of Mycobacterium tuberculosis in sputum specimens: meta-analysis and meta-regression. BMC Microbiol 2005; 5:55. 64 Palomino JC. Newer diagnostics for tuberculosis and multidrug resistant tuberculosis. Curr Opin Pulm Med 2006; 12:172–178. An excellent review of diagnostic techniques for diagnosis and detection of drug resistance in tuberculosis. 65 Bang D, Bengard Andersen A, Thomsen VO. Rapid genotypic detection of rifampin- and isoniazid-resistant Mycobacterium tuberculosis directly in clinical specimens. J Clin Microbiol 2006; 44:2605–2608. 66 Miotto P, Piana F, Penati V, et al. Use of genotype MTBDR assay for molecular detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis clinical strains isolated in Italy. J Clin Microbiol 2006; 44:2485–2491. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 164 Respiratory infections 67 Cavusoglu C, Turhan A, Akinci P, Soyler I. Evaluation of the Genotype MTBDR assay for rapid detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis isolates. J Clin Microbiol 2006; 44:2338–2342. 68 Makinen J, Marttila HJ, Marjamaki M, et al. Comparison of two commercially available DNA line probe assays for detection of multidrug-resistant Mycobacterium tuberculosis. J Clin Microbiol 2006; 44:350–352. 69 Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in theimmunocompromisedhost.Transpl Infect Dis 2006;8:128–139. An excellent review of diagnostic techniques for fungal infection that includes discussion of current molecular techniques. 70 Gomez-Lopez A, Martin-Gomez MT, Martin-Davila P, et al. Detection of fungal DNA by real-time polymerase chain reaction: evaluation of 2 methodologies in experimental pulmonary aspergillosis. Diagn Microbiol Infect Dis 2006; 56:387–393. An analysis of two quantitative PCR assays for diagnosing pulmonary aspergillosis in a rabbit model. Sensitivity was highest for RT-PCR of the 18S rRNA gene in lung samples. 71 Umeyama T, Sano A, Kamei K, et al. Novel approach to designing primers for identification and distinction of the human pathogenic fungi Coccidioides immitis and Coccidioides posadasii by PCR amplification. J Clin Microbiol 2006; 44:1859–1862. 72 Arcenas RC, Uhl JR, Buckwalter SP, et al. A real-time polymerase chain reaction assay for detection of Pneumocystis from bronchoalveolar lavage fluid. Diagn Microbiol Infect Dis 2006; 54:169–175. 73 Linssen CF, Jacobs JA, Beckers P, et al. Inter-laboratory comparison of three different real-time PCR assays for the detection of Pneumocystis jiroveci in bronchoalveolar lavage fluid samples. J Med Microbiol 2006; 55:1229– 1235. An important study that compares the performance of real-time PCR assays for Pneumocystis in different laboratories. 74 Larsen HH, Huang L, Kovacs JA, et al. A prospective, blinded study of quantitative touch-down polymerase chain reaction using oral-wash samples for diagnosis of Pneumocystis pneumonia in HIV-infected patients. J Infect Dis 2004; 189:1679–1683. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Prognostic scoring systems: which one is best? Charles Feldman Purpose of review In the initial evaluation of patients with community-acquired pneumonia, a number of important assessments are made, including that of the severity of the illness. This assessment will determine the appropriate site of care, diagnostic workup, and choice of empiric antibiotics. A number of severity assessment tools have been developed and some of the recent findings are reviewed. Recent findings A number of studies of the efficacy of the individual scoring systems, as well as comparator studies, have been undertaken. A significant number of patients with community-acquired pneumonia in Pneumonia Severity Index classes I and II are admitted to hospital and several of these patients suffer complications. Clinical and social factors other than those contained in the scoring systems need to be taken into consideration when deciding about hospitalization of patients with community-acquired pneumonia. A number of studies of the efficacy of the various scoring systems in predicting ‘severe pneumonia’ have been undertaken, as well as studies of their accuracy in the sub-set of patients with pneumococcal infections and in the elderly. Summary The various scoring systems have reasonable sensitivity and specificity and their own strengths and weaknesses, but should always be used in association with good clinical judgment. Keywords British Thoracic Society rule, community-acquired pneumonia, CURB criteria, modified American Thoracic Society criteria, Pneumonia Severity Index Curr Opin Infect Dis 20:165–169. ß 2007 Lippincott Williams & Wilkins. Division of Pulmonology, Department of Medicine, Johannesburg Hospital and University of the Witwatersrand, Johannesburg, South Africa Correspondence to Professor Charles Feldman, MB BCh, PhD, FRCP, FCP (SA), Professor of Pulmonology, Division of Pulmonology, Department of Medicine, University of the Witwatersrand, 7 York Road, Parktown 2193, Johannesburg, South Africa Tel: +27 11 488 3840; fax: +27 11 488 4675; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:165–169 Abbreviations ATS BTS CAP PSI American Thoracic Society British Thoracic Society community-acquired pneumonia Pneumonia Severity Index ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction One of the most important and difficult evaluations in patients with community-acquired pneumonia (CAP) is an assessment of the severity of illness, which will govern the site of care, the diagnostic work-up, and the choice of the most appropriate antibiotic therapy. To this end a number of poor prognostic factors have been identified and several scoring systems have been developed to aid in this assessment [1]. One of the most widely used scoring systems is the Pneumonia Severity Index (PSI), which was derived by Fine and colleagues [2]. The scoring system uses 20 variables including age, sex, co-morbidity, vital sign abnormalities and several laboratory and radiographic parameters. On this basis five groups had been identified (I–V), which had the following predictive mortalities: group I had a mortality of 0.1%, group II 0.7%, group III 0.9%, group IV 9.3% and group V 27% [1,2]. The primary purpose of the scoring system was to identify low-risk patients who could be safely managed at home, and on the basis of the mortalities the authors suggested that groups I–III could potentially be treated as outpatients or with an abbreviated course of in-patient care [2]. Subsequently a number of national guidelines recommended that patients in risk classes I and II could safely be managed at home [1]. In contrast to the PSI is the CURB-65 score, which was derived from the British Thoracic Society (BTS) and modified BTS score [3]. These rules were developed primarily to identify patients with severe CAP at high risk of mortality. The CURB-65 scoring system uses five variables, which are confusion, raised urea (> 7 mmol/l), respiratory rate ( 30/min), blood pressure (systolic < 90 mmHg or diastolic 60 mmHg) and age 65 years, for which one point is assigned if the parameter is positive. Mortalities for the six point scores found in an international derivation and validation study were 0.7% for score 0, 3.2% for score 1, 3% for score 2, 17% for score 3, 41.5% for score 4 and 57% for score 5 [3]. The 165 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 166 Respiratory infections authors suggested that patients with scores of 0 and 1 are at low risk of mortality (< 2%) and could potentially be managed as outpatients, while those with a score of 2 are at intermediate risk of mortality (9%) and should be admitted to hospital and those with a score > 2 are at high risk of mortality (> 19%) and should be considered as having severe CAP, potentially treated in a high-care or even intensive care unit. Evaluation of severity scoring systems A number of studies have been undertaken evaluating the various scoring systems in the past year and these are reviewed in the manuscript. A comparison of severity scoring systems Aujesky and colleagues [4] prospectively evaluated the performance of three validated prognostic rules, namely the PSI, the CURB and the CURB-65 severity scores, in predicting 30-day mortality in patients with CAP. In that study 3181 patients with CAP from 32 hospital emergency departments were followed and the 30-day mortality was recorded. The discriminatory power of the rules to predict mortality was compared and their accuracy was assessed by measuring their sensitivity, specificity, predictive values and likelihood ratios. The PSI (class I–III) classified a greater proportion of patients as low risk (68%) than either CURB score < 1 (51%) or CURB-65 score < 2 (61%) and low risk patients identified by PSI had a slightly lower mortality (1.4% versus 1.7% for both CURB and CURB-65 scores). The area under the receiver operating characteristic curve was higher for the PSI (0.81) than the CURB (0.73) or CURB-65 (0.76) scores (P < 0.001 for each pair-wise comparison). The authors concluded that the PSI had a greater discriminatory power for short-term mortality in patients with CAP, defined as a greater proportion of patients at low risk, and was slightly more accurate at identifying patients at low risk than either of the CURB scores. The Pneumonia Severity Index scoring system Studies from Spain [5] and Taiwan [6] have confirmed the value of the PSI in predicting medical outcomes of patients with CAP in these settings. Investigators from the latter study recommend further prospective testing to determine whether their patients in PSI classes I and II would be appropriate for management as outpatients. The conclusions from the former study were that the PSI was inadequate for young patients with hypoxia and pleural effusion and that decisions on hospitalization should be made on clinical criteria although the PSI classification could assist clinicians in making rational decisions in this regard. Van der Eerden and co-workers [7] evaluated the ability of the PSI to predict the severity of CAP and its use as a severity of illness classification system for patients with CAP in a prospective study of 260 patients. A significant difference in various severity parameters was found between the five risk classes and a positive BTS or modified BTS rule score was significantly more prevalent in the higher risk classes. The authors concluded that PSI adequately predicts severity of CAP and can be used as a severity of illness classification system, but that clinical and social factors other than those contained in PSI need to be taken into consideration when making decisions regarding hospitalization of patients with CAP. Interestingly, two recent studies, one from the US [8] and the other from Italy [9], evaluating the management of hospitalized patients with CAP noted that a large number of patients (27% and 26% respectively) were in PSI class I or II and potentially may have been suitable for management as outpatients. Other investigators have concluded that although the PSI could help physicians in deciding about appropriate site of care, this decision should be mainly based on clinical criteria. This contention was reinforced by a recent study from Canada [10]. This was a prospective observational study of patients with low risk CAP (PSI classes I and II) who presented to six hospitals and one emergency department in Edmonton, Canada. A total of 586/3065 (19.1%) low risk patients were admitted. Multivariate analysis indicated that these patients were more likely to be female, at a hospital serving the inner city, to have diminished premorbid functional status, to have co-morbidities likely to be worsened by the pneumonia and to suffer from substance abuse or psychiatric disease. Nineteen per cent of the patients suffered one or more complications, the most important of which were progression of pneumonia to respiratory failure, necessitating mechanical ventilation (2.4%), and empyema (1.4%). Thirty-one per cent of those admitted were unable to eat or drink enough to maintain hydration by hospital day 5 or on discharge day. These authors stress the need for better rules and the importance of physician judgment in admission decisions. In one large multicentre international observational study [11] the PSI was able to predict the time to clinical stability in patients with CAP with significant positive correlation between risk class and the time to clinical stability (P < 0.0001). Another recent study from Spain [12] documented that in selected patients with CAP in PSI risk class I, II and III, who were treated with levofloxacin, in the absence of respiratory failure, unstable co-morbid conditions, complicated pleural effusions and social problems, outpatient treatment was as safe and effective as hospitalization and was associated with greater patient satisfaction. One study [13] undertaken to determine the accuracy of the PSI in predicting mortality in immunocompromised patients with CAP noted that these patients could be divided into low-risk and high-risk groups on the basis of the cause of their Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Prognostic scoring systems Feldman 167 immunocompromise. Those with low risk immunocompromise had a mortality similar to nonimmunocompromised patients and the risk could be stratified using the PSI. The CURB-65 and CRB-65 severity scores Studies from Spain [14] and from Germany [15] confirm the accuracy of both the CURB-65 and CRB-65 in classifying patients with CAP into the different mortality risk groups, allowing assessment of pneumonia severity and the risk of death. The findings from those studies were very similar to the original validation study of Lim and colleagues [3]. In one study of patients with CAP, the CURB-65 severity score outperformed both the systemic inflammatory response syndrome (SIRS) criteria and the Standardized Early Warning score (SEWS), stratifying mortality in a more clinically useful way and having more favorable operating characteristics than SIRS or SEWS [16]. Severity scoring in patients with severe pneumonia Most of the severity scoring systems used for patients with pneumonia have been derived as predictors of mortality. Buising and colleagues [17] undertook a prospective cohort study of 392 patients admitted to hospital with a diagnosis of CAP to determine the predictive value of various scoring systems to identify ‘severe pneumonia’ using both death, as well as three other clinically meaningful outcomes, including need for ICU admission, and combined outcome of death or need for ventilatory or inotropic support. The scoring systems tested were the PSI, the revised American Thoracic Society (ATS) Score and the various BTS scores. Of the patients studied, 37 (9.4%) died and 26 (6.6%) required ventilatory or inotropic support. The modified BTS severity score performed best for all four outcomes. The PSI (classes IV and V) and CURB had similar performances for each outcome. The revised ATS criteria identified need for ICU admission very well, but not mortality. The CURB-65 predicted mortality well but performed less well when need for ICU admission was included as an outcome. The authors concluded that the different scoring systems have different strengths and weaknesses, but that the PSI (IV and V), CURB and modified BTS severity score provide comparable information with regard to identifying high-risk patients who need aggressive management strategies. Considering that little attention has been paid to developing prediction rules that could assist in deciding which patients with CAP should be admitted to ICU, Smyrnios and colleagues [18] studied the ability of four existing prediction rules to predict the need for ICU admission. The rules studied were the BTS rules, and the rules derived by Conte et al. [19], Leroy et al. [20], and Fine et al. [2]. The investigators evaluated 32 patients with pneumonia admitted to ICU during a 1-year period. The sensitivities of the various rules for identifying need for ICU admission were 0.72 for the BTS rules, using both rules together, and 0.47 for the Conte et al., 0.56 for the Leroy et al. and 0.84 for the Fine et al. rules. The authors concluded that the Fine et al. rule was the most sensitive and the BTS rules easiest to use but that none performed well enough for decision-making in individual patients. Ewig and colleagues [21] undertook a study to validate the modified ATS rule and two BTS rules for prediction of need for ICU admission and mortality and to provide validation of these predictions on the basis of the PSI score, bearing in mind that the modified ATS criteria were derived to identify individual patients who should be admitted to ICU. Their conclusion was that the modified ATS rule was able to predict severe pneumonia in individual patients and may be incorporated in guidelines for assessment of pneumonia severity. Furthermore they indicated that the BTS-CURB criteria achieved predictions of pneumonia severity and mortality similar to the PSI and could be used as an alternative tool to the PSI for detection of low-risk cases. Similarly, investigators from Spain [22] wished to develop and validate a clinical prediction rule for identifying patients with severe CAP. Data from an initial 1057 patients were used to derive a clinical prediction rule which was then validated in two different populations. On multivariate analysis eight independent predictors correlated with severe CAP; arterial pH < 7.3; systolic blood pressure < 90 mmHg; respiratory rate > 30/min; altered mental state; blood urea nitrogen > 30 mg/dl; oxygen arterial pressure < 54 mmHg or ratio of arterial oxygen tension to fraction of inspired oxygen < 250 mmHg; age 80 years; and multilobar or bilateral lung involvement. From the beta parameter obtained from the multivariate model a score was assigned to each variable. The model showed an area under the ROC of 0.92 and was better at identifying severe CAP than the modified ATS rule, the CURB-65 or the PSI score. Severity scoring for pneumococcal infections Although Streptococcus pneumoniae is the commonest cause of CAP, very little attention has been paid to validating the various severity scoring systems in this group of patients. Investigators from the US [23] undertook a retrospective record review to characterize the outcome of patients with pneumococcal CAP (diagnosed on positive sputum or blood cultures) in relationship to the various severity scoring systems, as well as to compare the predictive value of different sets of clinical parameters. There was good correlation between PSI, CURB, and modified CURB, as well as other composite risk stratification systems and risk Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 168 Respiratory infections of death. The addition of hypoxemia and multilobar involvement created a better stratification system. The authors concluded that the BTS criteria were easiest to use and had good specificity and negative predictive ability, while the PSI classification was more complicated but still did not take all parameters into account and that further studies were required to validate the best model for pneumococcal CAP. Investigators from Sweden [24] assessed the accuracy of the PSI, CURB-65 and modified ATS rule for predicting ICU need and mortality in bacteremic pneumococcal pneumonia. PSI IV, CURB-65 2 and the presence of one major or more than one minor risk factor in the ATS criteria had high sensitivity but lower specificity for predicting death and ICU need. The authors concluded that the PSI is the most sensitive scoring system, but that the CURB-65 is easier to use. Severity scoring systems in the elderly A number of studies have been published investigating the accuracy of the various scoring systems in the elderly [19,25,26,27]. A recent study [26] was undertaken to investigate the accuracy of the BTS guidelines for severity assessment in older patients. The study confirmed the usefulness of the recommended severity rules (CURB, CURB-65, and CRB-65) in this older cohort and also defined a new set of criteria, the SOAR criteria (systolic blood pressure, oxygenation, age and respiratory rate), as being a useful alternative for identifying severe CAP in patients of advanced age, in whom raised urea levels and confusion are common. The same investigators [27] had previously shown that in patients 65 years or older the CURB criteria were as sensitive at predicting deaths as they were in young patients, identifying 81% of deaths, but had a lower specificity (52%) apparently because raised urea and low diastolic blood pressure are not predictive of death in the elderly. Conclusion It is quite apparent from a review of all the recent studies that have been published, as well as the editorial comments that have frequently been elicited in response to these studies [28–30] that while significant strides have been made in developing severity assessment tools, we do not yet have the optimal scoring system. The commonly used scoring systems are reasonably sensitive and specific and each has its own strength and weakness. It has even been suggested that combining scoring systems, together with clinical evaluation, in order to develop an algorithm for defining site of care for patients with CAP may be the best option [29]. Thus while the various severity assessment tools are useful guides for assessment and decision-making in patients with CAP, they always need to be accompanied by appropriate physician judgment. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 218–219). 1 Lim WS, Macfarlane JT. Importance of severity of illness assessment in management of lower respiratory infections. Curr Opin Infect Dis 2004; 17:121–125. 2 Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336: 243–250. 3 Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58:377–382. Aujesky D, Auble TE, Yealy DM, et al. Prospective comparison of three validated prediction rules for prognosis in community-acquired pneumonia. Am J Med 2005; 118:384–392. This study compared the PSI and CURB scoring systems in a large number of patients with community-acquired pneumonia. The study conclusions were that the PSI was slightly more accurate at identifying low-risk cases with pneumonia and at least as accurate as the CURB severity scores at identifying high-risk patients. 4 Ortega L, Sierra M, Dominguez J, et al. Utility of a pneumonia severity index in the optimization of the diagnostic and therapeutic effort for communityacquired pneumonia. Scand J Infect Dis 2005; 37:657–663. This interesting study suggested that while the PSI is an effective tool for deciding on hospitalization and for selecting appropriate diagnostic work-up in patients with community-acquired pneumonia, it is inadequate for young patients with hypoxia or pleural effusion. 5 6 Lin CC, Lee CH, Chen CZ, et al. Value of the pneumonia severity index in assessment of community-acquired pneumonia. J Formos Med Assoc 2005; 104:164–167. 7 Van der Eerden MM, de Graaff CS, Bronsveld W, et al. Prospective evaluation of pneumonia severity index in hospitalized patients with community-acquired pneumonia. Respir Med 2004; 98:872–878. 8 Davydov L, Ebert SC, Restino M, et al. Prospective evaluation of the treatment and outcome of community-acquired pneumonia according to the pneumonia severity index in VHA hospitals. Diag Microbiol Infect Dis 2006; 54:267–275. 9 Riccioni G, Di Pietro V, Staniscia T, et al. Community acquired pneumonia in internal medicine: a one- year retrospective study based on pneumonia severity index. Int J Immunopathol Pharmacol 2005; 18:575– 586. 10 Marrie TJ, Huang JQ. Low-risk patients admitted with community-acquired pneumonia. Am J Med 2005; 118:1357–1363. This was an extremely important study investigating low risk cases admitted with community-acquired pneumonia. The study indicated that a large number of these patients suffer from significant complications and the authors emphasize the need for better scoring systems as well as the importance of physician judgment in hospitalization decisions. 11 Arnold F, LaJoie A, Marrie T, et al. Community-Acquired Pneumonia Organiza tion. The pneumonia severity index predicts time to clinical stability in patients with community-acquired pneumonia. Int J Tuberc Lung Dis 2006; 10:739– 743. This interesting study investigated the ability of the PSI to accurately predict time to clinical stability in patients with community-acquired pneumonia. 12 Carratala J, Fernandez-Sabe N, Ortega L, et al. Outpatient care compared with hospitalization for community-acquired pneumonia: a randomized trial in low-risk patients. Ann Intern Med 2005; 142:165–172. This study investigated the safety and efficacy of treating patients with communityacquired pneumonia in PSI classes I–III at home. 13 Sanders KM, Marras TK, Chan CK. Pneumonia severity index in the immunocompromised. Can Respir J 2006; 13:89–93. 14 Capelastegui A, Espana PP, Quintana JM, et al. Validation of a predictive rule for the management of community-acquired pneumonia. Eur Respir J 2006; 27:151–157. This large study investigated the CURB-65 and CRB-65 severity scoring systems in patients with community-acquired pneumonia. 15 Bauer TT, Ewig S, Marre R, et al. and the Capnetz Study. CRB-65 predicts death from community-acquired pneumonia. J Intern Med 2006; 260:93– 101. Another large study investigated the CURB-65 and CRB-65 severity scoring systems in patients with community-acquired pneumonia. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Prognostic scoring systems Feldman 169 16 Barlow GD, Nathwani D, Davey PG. The CURB-65 pneumonia severity score outperforms generic sepsis and early warning scores in predicting mortality in community-acquired pneumonia. Thorax 2006; Aug 23 [Epub ahead of print]. This interesting study compared the performance of the CURB-65 and CRB-65 severity scoring indices with generic sepsis and early warning scores (SIRS and SEWS). 17 Buising KL, Thursky KA, Black JF, et al. A prospective comparison of severity scores for identifying patients with severe community acquired pneumonia: reconsidering what is meant by severe pneumonia. Thorax 2006; 61:419–424. This very interesting study investigated the accuracy of the various severity scoring systems in assessing ‘severe’ community-acquired pneumonia. The study indicates that the different severity scores have different strengths and weaknesses as prediction tools. 18 Smyrnios NA, Schaefer OP, Collins RM, Madison JM. Applicability of prediction rules in patients with community-acquired pneumonia requiring intensive care: A pilot study. J Intensive Care Med 2005; 20:226–232. Another interesting study investigated the ability of the various severity scoring systems to predict the need for ICU admission in patients with communityacquired pneumonia. 19 Conte HA, Chen Y-T, Mehal W, et al. A prognostic rule for elderly patients admitted with community-acquired pneumonia. Am J Med 1999; 106:20–28. 20 Leroy O, Devos P, Guery B, et al. Simplified prediction rule for prognosis of patients with severe community-acquired pneumonia in ICUs. Chest 1999; 116:157–165. 21 Ewig S, de Roux A, Bauer T, et al. Validation of predictive rules and indices of severity for community acquired pneumonia. Thorax 2004; 59:421–427. 22 Espana PP, Capelastegui A, Gorordo I, et al. Development and validation of a clinical prediction rule for severe community-acquired pneumonia. Am J Respir Crit Care Med 2006; 174:1249–1256. The authors developed and validated their own prediction rule for severe community-acquired pneumonia. 23 Ioachimescu OC, Ioachimescu AG, Iannini PB. Severity scoring in communityacquired pneumonia caused by Streptococcus pneumoniae: a 5-year experience. Int J Antimicriob Agents 2004; 24:485–490. 24 Spindler C, Ortqvist A. Prognostic score systems and community-acquired bacteraemic pneumococcal pneumonia. Eur Respir J 2006; 28:816– 823. This interesting study investigated the use of severity scoring indices in the subset of patients with pneumococcal community-acquired pneumonia. 25 Sikka P, Jaafar WM, Bozkanat E, El-Solh AA. A comparison of severity of illness scoring systems for elderly patients with severe pneumonia. Intensive Care Med 2000; 26:1803–1810. 26 Myint PK, Kamath AV, Vowler SL, et al. British Thoracic Society. Severity assessment criteria recommended by the British Thoracic Society (BTS) for community-acquired pneumonia (CAP) and older patients. Should SOAR (systolic blood pressure, oxygenation, age and respiratory rate) criteria be used in older people? A compilation study of two prospective cohorts. Age Ageing 2006; 35:286–291. This is an interesting study of severity scoring indices in the elderly with communityacquired pneumonia. 27 Myint PK, Kamath AV, Vowler SL, et al. The CURB (confusion, urea, respiratory rate and blood pressure) criteria in community-acquired pneumonia (CAP) in hospitalized elderly patients aged 65 years and over: a prospective observational cohort study. Age Ageing 2005; 34:75–77. 28 Siegel RE. Clinical opinion prevails over the pneumonia severity index. Am J Med 2005; 118:1312–1313. 29 Niederman MS, Feldman C, Richards GA. Combining information from prognostic scoring tools for CAP: an American view on how to get the best of all worlds. Eur Respir J 2006; 27:9–11. 30 Ewig S, Torres A, Woodhead M. Assessment of pneumonia severity: a European perspective. Eur Respir J 2006; 27:6–8. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. New guidelines for the management of adult community-acquired pneumonia Kathryn Armitage and Mark Woodhead Purpose of review Community-acquired pneumonia is a major cause of morbidity and mortality, and is the leading cause of death from an infectious disease. International societies have published and revised guidelines aiming to improve the management of adult community-acquired pneumonia, based on the best available evidence. The aim of this review is to compare the current guideline recommendations. Recent findings Aspects of guidelines differ based on local factors including resources and antimicrobial factors, as well as the differences in interpretation of existing evidence. Summary The lack of robust evidence behind aspects of guideline recommendations as well as the lack of adherence to published guidelines both need to be addressed if the management of community-acquired pneumonia is to be improved. Keywords adherence, antibiotics, community-acquired pneumonia, guidelines Curr Opin Infect Dis 20:170–176. ß 2007 Lippincott Williams & Wilkins. Department of Respiratory Medicine, University of Manchester, Manchester Royal Infirmary, Manchester, UK Correspondence to Dr Mark Woodhead, Consultant in General and Respiratory Medicine and Honorary Lecturer, Department of Respiratory Medicine, University of Manchester, Manchester Royal Infirmary, Oxford Road, Manchester M13 9WL, UK Tel: +44 (0)161 276 4381; fax: +44 (0)161 276 4989; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:170–176 Abbreviations ATS BTS CAP ERS ICU IDSA JRS American Thoracic Society British Thoracic Society community-acquired pneumonia European Respiratory Society intensive care unit Infectious Diseases Society of America Japanese Respiratory Society ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality, and internationally is the leading cause of death from an infectious disease and the sixth leading cause of death overall. Over the past decade international societies have published and revised guidelines for the management of patients with CAP. The aim of this article is to review recent updates and highlight areas both of consensus and difference, as well as to evaluate the use of guidelines as a whole. A combined American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) guideline is due to be published early in 2007, but at the time of writing the main national and international guidelines include the ATS (2001), IDSA (2003), British Thoracic Society (BTS) (2004; www.brit-thoracic.org.uk/guidelines) and European Respiratory Society (ERS) (2005). Their aim is to standardise care by providing management strategies based on best available evidence. The evidence may be the same; however, differences exist between guidelines not only in the scope of recommendations, but also due to regional differences in patient populations, causative agents, bacterial antibiotic resistance rates, drug licensing, healthcare structure and available resources. Recommendations made by one national organisation may therefore not be applicable to other countries. Methodology Whilst most societies have restricted their guidelines to CAP, the IDSA includes acute bronchitis and empyema within its guidelines [1], while the ERS addresses all aspects of care for respiratory tract infections both in the community and hospital settings [2]. Diagnosis The diagnosis of CAP is usually defined as the presence of signs or symptoms compatible with a respiratory tract infection in the presence of new consolidation on a chest radiograph. The chest radiograph is the gold standard; however, in primary care, given the frequency of attendances for respiratory tract infection it may not be costeffective or practical for all patients with such symptoms to undergo chest radiography. The frequency of pneumonia is quoted as 5–10% among patients with symptoms of lower respiratory tract infection. The ATS recommend chest radiography if ‘symptoms and physical examination suggest the possibility of pneumonia’ [3]. The ERS similarly recommend that patients suspected of 170 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. New guidelines for adult CAP Armitage and Woodhead having pneumonia (i.e. acute cough plus new focal chest signs, dyspnoea, tachypnoea or fever for more than 4 days) should undergo radiography [1]. The BTS include a definition of pneumonia in the community as the presence of focal clinical signs without any other explanation, without emphasis on radiology [4]. There is consensus that a chest radiograph should be performed on all patients admitted to hospital with suspected pneumonia [1,2,3–9]. Microbial investigation There is little evidence to suggest that microbial investigation affects mortality, but it can provide information to assist with antibiotic selection as well as epidemiological data. Controversy still exists over sputum examination. The ATS, BTS and ERS are all in agreement that due to the wide variability in sensitivity and specificity of sputum Gram staining, based not only on a patient’s ability to expectorate, but also technical differences in slide preparation and interobserver variability, routine Gram staining should not be performed. It is suggested that sputum be sent for Gram stain only where good quality sputum is expectorated, as observed by qualified medical staff, and transported to the laboratory in a timely fashion. Thereafter, strict criteria should be used for both the quality assessment of the sputum sample and an agreed level of sensitivity adopted. Gram staining results should be considered when interpreting the significance of sputum cultures. Concordance suggests a definitive pathogen. Between 5 and 38% cases of CAP are due to mixed organisms. The ERS and ATS recommend that Gram stain results are useful to expand the breadth of antimicrobial coverage based on the discovery of an unexpected organism, unlike the IDSA which not only recommends that Gram staining is conducted on all patients, but that positive results be used to narrow the therapeutic antimicrobial spectrum. Except for the Japanese Respiratory Society (JRS), all societies recommend that two sets of blood cultures be taken from all patients admitted to hospital with pneumonia, preferably before the administration of antibiotics [1,2,3,4,6]. The JRS only recommend this in cases of severe pneumonia. Routine serological investigation and urinary antigen testing for Legionella pneumophila serogroup I and Streptococcus pneumoniae are only recommended for those with severe pneumonia by the BTS, ATS, IDS and ERS. The JRS advocates the use of urinary antigen testing for S. pneumoniae in all patients, and where appropriate Legionella and influenza A virus. Serological testing may be informative during outbreaks for epidemiological purposes, but due to the need for a convalescent sample it rarely impacts on clinical care. 171 Risk stratification Evidence shows that clinicians may both overestimate the severity of pneumonia and yet still fail to recognise those at higher risk [10,11]. All guidelines recommend that clinical judgement be supplemented by objective severity scoring. Two main tools exist to risk stratify patients with pneumonia. The Pneumonia Severity Index classifies patients in terms of their mortality based on the presence of comorbidity, vital signs and laboratory abnormalities [10] (Table 1). These data have been extrapolated to provide data to determine who can safely be treated as outpatients. Classes I and II should not require hospital admission, class III may be suitable for outpatient care, and classes IV and V require admission. Classes IV and V are considered to have a high mortality and to be at greater risk of requiring admission to the intensive care unit (ICU). The Pneumonia Severity Index has been shown to reduce the admission of low-risk patients to hospital, although not by as much as would be thought, as over one-third of low-risk patients are admitted for other reasons including lack of social support or comorbidities [12]. This risk stratification is adopted by the IDSA and discussed in the ATS guidelines. The CURB-65 score recommended by the BTS provides a complementary guide for identification of the more severely ill [4,5,13] (Fig. 1). It is simple and easily calculated based on only five variables. It too has been Table 1 Pneumonia Severity Index [10] Criteria Age Male Female Nursing home resident Comorbidity Neoplastic Liver Congestive heart failure Cerebrovascular disease Renal disease Vital signs abnormality Mental confusion Respiratory rate >30/min Systolic blood pressure <90 mmHg Temperature <35 or >408C Tachycardia >125 b.p.m Laboratory abnormalities Blood urea nitrogen >11 mmol/l Sodium <130 mmol/l Glucose >250 mg/dl Haematocrit <30% Radiographic abnormalities Pleural effusion Oxygenation parameters Arterial pH < 7.35 PaO2 < 60 mmHg SaO2 < 90% age (years)–0 age (years)–10 10 30 20 10 10 10 20 20 20 15 10 20 20 10 10 10 30 10 10 Risk class 1: age <50 year no comorbidity, no vital signs abnormality; risk class II: <70 points; risk class III: 71–90 points; risk class IV: 91– 130 points; risk class V: >130 points. Copyright 1997 Massachusetts Medical Society. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 172 Respiratory infections Figure 1 CURB-65 index [13] The CURB-65 score recommended by the British Thoracic Society provides a complementary guide for identification of the more severely ill. ICU, intensive care unit. Any of • • • • • 0 or 1 2 Likely to be suitable for home treatment validated, although with fewer patients than the Pneumonia Severity Index. The CURB-65 scoring system is also recommended by the Japanese and Swedish Guidelines [7,9]. The ERS guidelines offer both severity scores as options. All societies acknowledge that severity indicators should be used only as an adjunct to clinical judgement when deciding which patients require hospital admission. The ATS has modified the criteria used to define severe CAP requiring admission to the ICU. Previous strategies were over sensitive and lacked specificity as they defined 65–68% of all patients admitted to hospital as having severe pneumonia [6]. Revised guidelines define severe CAP as the presence of either one major criteria (need for mechanical ventilation or septic shock) or two of the three minor criteria (systolic blood pressure below 90 mmHg, multilobular disease, PaO2/FiO2 ratio below 250) [3]. The BTS defines severe CAP as a CURB-65 score of 3 or more and a score of 4 or 5 requires assessment for ICU admission, although it has not been formally tested to define the need for ICU [5]. A difficulty with the endpoint of ICU admission is that admission criteria vary from hospital to hospital. Microbiology and antibiotics Early administration of antibiotics after diagnosis of pneumonia has been shown to be associated with a decrease in mortality. The evidence for the exact timing of administration is somewhat inconclusive, however, as a Confusion Urea > 7 mmol/l Respiratory rate > 30/min Blood pressure (systolic < 90 mmHg, diastolic < 60 mmHg) Age > 65 years Consider hospital supervised treatment 3 or more Manage in hospital as severe pneumonia Assess need for ICU if CURB-65 score 4–5 subsequent trial found patients who received antibiotics within 2 h actually had worse outcomes [14,15]. The ATS and BTS advocate administration within 8 h of admission to hospital. The IDSA advocate timely administration rather than recommending specific time periods [16]. Recommended antibiotic therapy differs between the various guidelines and this is probably due to different perceptions of the importance of infections caused by atypical organisms, differences in antibiotic resistance, differences in the interpretation of the clinical relevance of antibiotic resistance as well as antibiotic licensing. Penicillin resistance among S. pneumoniae varies with levels as high as 9.2% in Spain and 15.9% in the US [17]. Resistance in the UK and Holland is much lower (quoted at 1.5 and 0.5%, respectively [18]), and these guidelines support the use of more traditional b-lactam antibiotics as first-line therapy. In Japan, the rate of S. pneumoniae resistance to macrolides is over 50% and although penicillin resistance is increasing, their use is still recommended for treatment of outpatient presumed bacterial pneumonia. The clinical significance of in-vitro resistance remains controversial. All guidelines aim to rationalise antibiotic selection based on the prevalence of different causative organisms as well as disease severity. The ATS makes further subclassification based on modifying factors such as the likelihood of drug-resistant S. pneumoniae, Gram-negative organisms and Pseudomonas aeruginosa amongst select Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. New guidelines for adult CAP Armitage and Woodhead Table 2 Modifying factors that increase the risk of infection with specific pathogens (American Thoracic Society guidelines) [3] Penicillin-resistant and drug-resistant pneumococci age >65 years b-lactam therapy in past 3 months alcoholism immune-suppressive illness (including steroids) multiple medical comorbidities exposure to child in day care centre Enteric Gram-negatives residence in nursing home underlying cardiopulmonary disease multiple medical comorbidities recent antibiotic therapy Pseudomonas aeruginosa structural lung disease corticosteroid therapy (>10 mg day) broad spectrum antibiotics of >7 days in past month malnutrition groups (Table 2). The IDSA follows similar recommendations and categorises patients in terms of comorbidities and the use of antibiotics in the preceding 3 months to identify those at greater risk of drug-resistant S. pneumoniae and Gram-negative organisms. The ERS gives criteria when P. aeruginosa might be suspected. Both the ATS and IDSA now class nursing home-acquired pneumonia as a form of hospital-acquired pneumonia. Nonsevere community-acquired pneumonia The ATS, IDSA and Canadian Thoracic Society rely on the use of advanced generation macrolides and respiratory quinolones. The ERS and BTS advocate the continued use of b-lactams as first-line therapy with the addition if required of simple macrolides (Table 3). This is in part related to resistance levels, but may also be related to the more limited experience with the newer antibiotics due to their period of licence. Resistance to the respiratory quinolones is increasingly reported which may well increase as their use becomes more widespread [19]. The JRS only advocates the use of respiratory fluoroquinolones in select groups (older, comorbidity, recent antibiotics use and in severe pneumonia) as resistance rates in Japan, particularly in those over 65 years, are above 15%. Other issues regarding their use relates to greater costs and the recent association with Clostridium difficile diarrhoea [20]. Severe community-acquired pneumonia The BTS and ERS guide antibiotic therapy based on the severity of disease. The ATS, IDSA and Canadian Thoracic Society define different management strategies based on the site of treatment and the presence of comorbidities or modifying factors and the likelihood of Pseudomonas infection (Table 4). This aims to identify groups with a higher prevalence of resistant pathogens. The American societies also distinguish between patients in the community and those in nursing homes. The ATS and IDSA both consider nursing home-acquired 173 pneumonia as a form of hospital-acquired pneumonia as specified in the 2005 hospital-acquired pneumonia guidelines [21]. This is in contrast to the BTS, whose antibiotic strategy in this group is based on evidence that the prevalence of pathogens follows the same distribution as patients in the community. Guideline impact Guidelines will only be useful if they are adopted and shown to alter outcome. Several articles have focused on the effect of adherence to guidelines on the quality of care delivered. Menendez et al. [22] concluded that nonadherence to published guidelines when selecting empirical antibiotic therapy, particularly amongst patients classified as having severe pneumonia, was associated with a higher mortality. Another study concluded that the adoption of moderate and high-intensity guideline implementation reduced the number of lowrisk patients admitted to hospital. They also found that moderate intensity guideline use increased the number of high-risk patients managed inappropriately in the community, thus supporting the adoption of high-intensity strategies. Even within this group they found that over 25% of patients were treated with inappropriate antibiotic therapy [23]. As well as varying between hospitals and the training status of physicians, nonadherence to guidelines has been found to be greater amongst nonrespiratory physicians. The adherence rate amongst intensive care units is quoted as low as 67% [24]. One factor in encouraging adherence to guidelines must be their effectiveness at delivering the information. The ATS guideline is a long document with complicated antibiotic strategies summarised on no less than five tables, but clear algorithms help to transmit the message. The IDSA does incorporate tabled information, but again it is a document that requires time to digest. The BTS guidelines offer a brief summary statement and simple presentation and management strategies, while the ERS adopts a question and answer format. With the assumption that adherence to national guidelines is associated with better outcomes, the Community Acquired Pneumonia Organisation evaluated the actual care delivered to patients hospitalised with a diagnosis of community acquired pneumonia. Performance indicators were calculated for all aspects of management including diagnosis, hospitalisation, respiratory isolation, microbiological investigation, empirical antibiotic selection and discharge. They concluded practice was frequently not in accordance with recommended guidelines and it is the role of international organisations to help to improve compliance [25]. These findings are supported by Maxwell et al. [26] in the CAPTION (CommunityAcquired Pneumonia: Towards Improving Outcomes Nationally) study. They evaluated the management of Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. respiratory fluoroquinolone, or second-, third- or fourthgeneration cephalosporin þ macrolide as above respiratory fluoroquinolone advanced macrolide þ b-lactam advanced macrolide þ respiratory fluoroquinoloneb as above intravenous b-lactam þ intravenous/ per os macrolide or doxycycline or respiratory fluoroquinolone alone intravenous azithromycin alone (doxycycline þ b-lactama) or respiratory fluoroquinolone alone Inpatient: cardiopulmonary disease modifying factors (Group 3a) Inpatient: no cardiopulmonary disease modifying factors (Group 3b) as above penicillin G or aminopenicillin or coamoxiclav or second/third-generation cephalosporin macrolide or respiratory fluoroquinolone as above amoxicillin or tetracycline European Respiratory Society as above (a) as home treated (b) amoxicillin þ macrolide or respiratory fluoroquinolone as above amoxicillin or erythromycin/ clarithromycina British Thoracic Society Advanced-generation macrolide: azithromycin or clarythromycin. b-Lactam: oral cefpodoxime, cefuroxime, high-dose amoxicillin, amoxicillin/clavulanate or intravenous ceftriaxone then oral cefpodoxime. Respiratory fluoroquinolone: levofloxacin, moxifloxacin. a Penicillin allergic/intolerant. Admitted for nonclinical reasons or previously untreated in community. b Recent antibiotic therapy. Copyright American Thoracic Society. advanced macrolide or respiratory fluoroquinolone or amoxicillin/clavulanate þ macrolide advanced macrolide or respiratory fluoroquinolone respiratory fluoroquinoloneb advanced macrolide þ b-lactam b-lactam þ macrolide or doxycycline or respiratory fluoroquinolone alone Outpatient: cardiopulmonary disease modifying factors (Group 2) macrolide or doxycycline Macrolide or doxycycline respiratory fluoroquinoloneb advanced macrolide þ amoxycillinb advanced macrolide þ augmentin Canadian Thoracic Society advanced macrolide or doxycycline Infectious Diseases Society of America Outpatient: no cardiopulmonary disease or modifying factors (Group 1) American Thoracic Society Table 3 Antibiotic therapy in nonsevere community-acquired pneumonia 174 Respiratory infections Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Infectious Diseases Society of America Canadian Thoracic Society respiratory fluoroquinolone advanced macrolide þ amoxicillin/clavulantate Nursing home outpatient as Group 2; inpatient as Group 3 respiratory fluoroquinolone or amoxicillin/clavulantate þ macrolide or second-generation cephalosporin þ macrolide (o/p) respiratory fluoroquinolone third-generation cephalosporin þ macrolide þ third-generation cephalosporin or or third-generation cephalosporin amoxicillin/clavulanate or macrolide þ respiratory fluoroquinolone þ third-generation cephalosporin or amoxicillin/clavulanate antipseudomonal cephalosporin þ ciprofloxacin carbapenem or acylureidopenpenicillin/ b-lactamase inhibitor þ ciprofloxacin European Respiratory Society same treatment as per severity coamoxiclav or second/thirdgeneration cephalosporin þ macrolide rifampicin or respiratory fluoroquinolone þ benzylpenicillin British Thoracic Society ICU, intensive care unit. Antipseudomonal b -lactam: cefepime, imipenem, meropenem, piperacillin/tazobactam. Second-generation cephalosporin: cefuroxime. Thrid-generation cephalosporin: cefotaxime, ceftriaxone. Respiratory fluoroquinolone: levofloxacin, moxifloxacin (moxifloxacin not licensed in the UK for severe community-acquired pneumonia). as Group 3a b-lactam þ either advanced macrolide or respiratory fluoroquinolone respiratory fluoroquinolone clindamycin (penicillin allergic) ICU: no risk of b-lactam þ either macrolide Pseudomonas or fluoroquinolone ICU: risk of antipseudomonal b-lactam antipseudomonal agent antipseudomonal fluoroquinolone Pseudomonas þ antipseudomonal þ ciprolfloxacin or þ antipseudomonal b-lactam or quinolonone or antipseudomonal aminoglycoside or antipseudomonal agent þ aminoglycoside þ either antipseudomonal b-lactam þ aminoglycoside respiratory fluoroquinolone b-lactam þ aminoglycoside þ macrolide or or macrolide þ macrolide nonpseudomonal fluoroquinolone American Thoracic Society Table 4 Antibiotic therapy in severe community-acquired pneumonia New guidelines for adult CAP Armitage and Woodhead 175 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 176 Respiratory infections CAP in Australian emergency departments as compared to national guidelines. They concluded that overall concordance was very low, with only 18% of antibiotics prescribed in accordance with recommended guidelines and severity assessment documented in only 5% of presentations. Maxwell et al. [26] also acknowledge that despite low compliance with guidelines in Australian emergency departments, this had no effect on patient mortality or length of stay. Performance indicators act as standards, based on evidence or consensus opinion, with which quality of medical care can be measured. The IDSA guidelines are the only guidelines to recommend specific performance indicators. There is, however, a surprising lack of quality evidence behind the majority of the guideline recommendations. As Woodhead [27] addresses in a recent Editorial, only 6.5% of ATS guidelines, 9.6% of Canadian guidelines, 15% of BTS guidelines and 21% of IDSA guidelines are based on ‘best-level’ evidence. A final word would emphasise the need for further randomised controlled trials to provide more evidence in this field. Conclusion Guidelines are here to stay and provide standards by which to guide and judge care. CAP is a diverse illness and its management has been dealt with by many guidelines. In some areas there is concurrence, in others there is not. Where guidelines differ it is often for lack of robust evidence. The highlighting of such evidence gaps should act as a spur to researchers and those funding research for the future. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 221). 1 Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Infect Dis 2003; 37:1405–1433. 2 Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections. Eur Respir J 2005; 26:1138–1180. A comprehensive review of the management of adult respiratory tract infections including community-acquired pneumonia, exacerbations of chronic obstructive pulmonary disease and bronchiectasis. 6 American Thoracic Society. Guidelines for the initial management of adults with community-acquired pneumonia: diagnosis, assessment of severity, and initial antimicrobial therapy. Am Rev Respir Dis 1993; 148:1418– 1426 7 Miyashita N, Matsushima T, Oka M. The JRS Guidelines for the Management of Community-acquired Pneumonia in Adults: an update and new recommendations. Intern Med 2006; 45:419–428. 8 Mandell LA, Marrie TJ, Grossman RF, et al. Summary of Canadian guidelines for the initial management of community-acquired pneumonia: an evidencebased update by the Canadian Infectious Disease Society and the Canadian Thoracic Society. Can Respir J 2000; 7:371–382. 9 Hedlund J, Stralin K, Ortqvist A, Holmberg H. Swedish guidelines for the management of community-acquired pneumonia in immunocompetent adults. Scand J Infect Dis 2005; 37:791–805. 10 Fine MJ, Auble TE, Yearly DM, et al. A prediction rule to identify low risk patients with community-acquired pneumonia. N Engl J Med 1997; 336:243–250. 11 Neill AM, Martin IR, Weir R, et al. Community-acquired pneumonia aetiology and usefulness of severity criteria on admission. Thorax 1996; 51:1010– 1016. 12 Marrie TJ, Lau CY, Wheeler SL, Wong CJ, et al. A contolled trial of a critical pathway for treatment of community-acquired pneumonia. JAMA 2000; 283:749–755. 13 Lim WS, Van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58:377–382. 14 Meehan TP, Fine MJ, Krumholz HM, et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 1997; 278:2080–2084. 15 Houck PM, Bratzler DW, Nsa W, et al. Timing of antibiotic administration and outcomes for Medicare patients hospitalised with community-acquired pneumonia. Arch Intern Med 2004; 164:637–644. 16 Mandell LA. Update on community-acquired pneumonia. Postgrad Med 2005; 118:35. 17 Johnson DM, Stilwell MG, Fritsche TR, Jones RN. Emergence of multidrugresistant Streptococcus pneumoniae: report from the SENTRY Antimicrobial Surveillance Program (1999–2003). Diagn Microbiol Infect Dis 2006; 56:69–74. 18 European Antimicrobial Resistance Surveillance System. European resistance rates [online]. Bilthoven: EARSS; 2006. http://www.rivm.nl/earss 19 Moran G. Approaches to treatment of community-acquired pneumonia in the emergency department and the appropriate use of fluoroquinolones. J Emerg Med 2006; 30:377–387. 20 Pepin J, Saheb N, Coulombe M, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea. Clin Infect Dis 2005; 41:1254–1260. 21 American Thoracic Society and Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator associated and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 17:388–416. 22 Menendez R, Ferrando D, Valles JM, Vallterra J. Influence of deviation from guidelines on the outcome of community-acquired pneumonia. Chest 2002; 122:612–617. 23 Yealy DM, Auble TE, Stone RA, Lave JR. Effects of increasing the intensity of implementing pneumonia guidelines. Ann Intern Med 2005; 143:881–894. 24 Menendez R, Torres A, Zalacain R, Aspa J. Guidelines for the treatment of community-acquired pneumonia: predictors of adherence and outcome. Am J Med 2005; 172:757–762. 3 Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the management of adults with community-acquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163:1730–1754. 25 Ramirez JA, and Community-Acquired Pneumonia Organization Investigators. Worldwide perspective of the quality of care provided to hospitalized patients with community-acquired pneumonia: results from the CAPO International Cohort Study. Semin Respir Crit Care Med 2005; 26:543–552. 4 Macfarlane JT, Boswell T, Douglas G, et al. BTS guidelines for the management of community-acquired pneumonia in adults. Thorax 2001; 56 (Suppl 4): IV1–IV64. 26 Maxwell DJ, McIntosh KA, Pulver LK, Easton KL. Empirical management of community acquired pneumonia in Australian emergency departments. Med J Aust 2005; 183:520–524. 5 Macfarlane JT, Boldy D. 2004 update of BTS pneumonia guidelines: what’s new? Thorax 2004; 59:364–366. 27 Woodhead M. Community-acquired pneumonia guidelines: much guidance, but not much evidence. Eur Respir J 2002; 20:1–3. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. How long should we treat community-acquired pneumonia? Nikole M. Scaleraa and Thomas M. File Jr.a,b Purpose of review The studies reviewed in this article suggest that a shorter duration of antibiotic therapy is comparable to standard therapy in the treatment of community-acquired pneumonia and promotes reduction of adverse events, microbial resistance, cost, and improved patient compliance. Recent findings Community-acquired pneumonia has traditionally been treated with a 7–14-day course of antimicrobial therapy. Since there have been few well controlled trials regarding the optimal duration of therapy, however, there has been no consensus on length of therapy among different organizational guidelines. Several recent studies have demonstrated that shorter course antibiotic regimens are effective in the treatment of community-acquired pneumonia. Summary Short-course antibiotic therapy is equivalent to standard length of therapy for clinical cure and bacterial eradication. Minimization of drug exposure, however, reduces selection pressure for resistant strains, strengthens patient compliance, and potentially reduces adverse events such as Clostridium difficile infections. Keywords antimicrobial therapy, community-acquired pneumonia, duration of therapy Curr Opin Infect Dis 20:177–181. ß 2007 Lippincott Williams & Wilkins. a Summa Health System, Akron and bNortheastern Ohio Universities College of Medicine, Rootstown, Ohio, USA Correspondence to Thomas M. File Jr, Summa Health System, 75 Arch Street, Suite 105, Akron, OH 44304, USA Tel: +1 330 375 3894; fax: +1 330 375 6680; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:177–181 Abbreviations ATS AUC CAP IDSA MIC American Thoracic Society area under the concentration–time curve community-acquired pneumonia Infectious Diseases Society of America minimum inhibitory concentration ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction Community-acquired pneumonia (CAP) is an important lower respiratory tract infection associated with significant morbidity, mortality, and rising medical costs. Approximately 5.6 million cases of CAP are diagnosed annually with in the order of 1 million hospitalizations in the United States [1]. Streptococcus pneumoniae is a common cause of CAP and has exhibited increasing multidrug resistance [2]. Therefore, judicious antibiotic use is indicated to hinder further development of antimicrobial resistance. CAP has traditionally been treated with a 7–14-day course of antimicrobial therapy, but there has been a paucity of evidence to support any strong recommendations concerning appropriate duration of therapy. Previous treatment guidelines published by the Infectious Diseases Society of America (IDSA), and the American Thoracic Society (ATS) do not provide a strong consensus due to lack of randomized controlled trials to determine optimal length of therapy. In 2003, in an evidence-based guideline [2], IDSA recommended that antibiotic therapy should be continued until 72 h after the patient is afebrile for pneumococcal pneumonia and at least 2 weeks therapy for atypical pneumonia. In another evidence-based guideline [3], the ATS generally recommends a 7–10-day course of therapy for pneumococcal pneumonia and a 10–14-day duration for atypical pneumonia. The ATS guideline, however, recognized that shorter course therapy of 5–7 days may be possible due to agents such as azithromycin which have long serum and tissue half-lives. Rationale for short-course therapy The goals of therapy are to eradicate the causative pathogen, promote resolution of clinical symptoms and prevent emergence of resistant organisms [4]. There are potential advantages to short-course therapy in general and for CAP in particular. Short-course regimens (i.e., <7 days) are theoretically advantageous in reducing antimicrobial resistance and favoring improved patient compliance. Decreased total drug exposure minimizes the selection pressure for resistant strains and lessens the impact on endogenous flora [4]. Guillemot et al. [5] demonstrated that prolonged treatment (defined as >5 days duration) and low antibiotic doses were associated with increased risk of nasopharyngeal carriage of penicillin-resistant Streptococcus pneumoniae (PRSP) by 3.5 and six-fold, respectively. Patient compliance is shown to rapidly decline after 5 days of therapy or after initial resolution of symptoms [4,6]. Less frequent dosing, short-course regimens, and decreased incidence of 177 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 178 Respiratory infections adverse events contribute to better clinical outcomes and improved compliance. In brief, the concept for short-course therapy is to ‘hit hard and stop early’. To be effective, a shorter course of therapy must be based on sound pharmacokinetic and pharmacodynamic data. Specifically, it is the ability of an antimicrobial to achieve adequate tissue penetration and drug concentration at the site of infection for a sufficient length of time [7,8]. It is anticipated that with use of appropriate antimicrobial agents, high clinical and microbiological cure rates will be possible with short-course regimens. Antimicrobial agents exhibit pharmacodynamic properties which generally fall into one of three patterns: concentrationdependent killing with prolonged postantibiotic effects measured by maximum concentration/minimum inhibitory concentration (MIC); concentration/time-dependent killing with moderate-prolonged postantibiotic effects measured by area under curve to MIC (AUC0–24)/ MIC; and time greater than MIC measured (no postantibiotic effects). Providers can utilize their knowledge of the antibiotics’ known pharmacodynamic profiles to select the most appropriate agent, dosing amount, interval, and duration [9,10]. Prior experience with short-course therapy for community-acquired pneumonia In the early years of antibiotic use, regimens less than 7–14 days were recommended in standard texts. For example, recommendations provided in the Textbook of medicine, edited by Cecil and McDermott in 1948, recommended intramuscular penicillin 15, 20 000 units every 3 h for 5–7 days [11]; Harrison et al.[12], two decades later, recommended 60 000–600 000 units every 6 h until the patient was afebrile for 48–72 h. Others also recommended treatment until the patient was afebrile for 48 h [13]. If temperature is used as a barometer of clinical improvement or stability, short-course antimicrobial therapy of 5 days’ duration will be appropriate for the majority of patients. In a prospective, multicenter cohort study of 686 adults hospitalized with CAP, the median time to becoming afebrile was 2 days as defined by a temperature of 38.38C (1018F) and 3 days if defined as either 37.88C (1008F) or 37.28C (998F) [14]. Therefore, if patients with pneumonia are treated for 3 days after becoming afebrile, the total duration of therapy would be 5 or 6 days for most patients depending on the definition of fever. One of only a few earlier studies which addressed the concept of short-course therapy for uncomplicated primary pneumonia prior to 2000 was conducted in 73 patients aged 12–60 years (mean age 30 years) who were treated at a teaching hospital in Nigeria [15]. All patients had evidence of pneumonia on chest radiographs, and the majority (65 patients) received benzyl penicillin only. Antibiotic therapy was initiated and continued until the patient was afebrile (temperature 37.28C; 998F) for 24 h. Organisms were identified in 42 cases, mainly S. pneumoniae, in the sputum cultures of 38 patients, 19 of whom were bacteremic. Antibiotics were administered for less than 3 days in 80% of the patients, and the average duration of therapy for the entire study population was 2.54 days. Patients were discharged from the hospital after an average of 4 days, and follow-up chest radiographs showed complete resolution within an average of 25.6 days (range 14–56 days). The investigator concluded that, in the treatment of pneumonia, antibiotics could be stopped after the patient had been afebrile for 24 h, reducing the length of hospitalization and exposure to antibiotic. Review of recent studies Several articles have been published over the last 5 years that support short-course therapy. The study outcome of one antimicrobial agent, however, cannot necessarily be extrapolated to other classes of antibiotics due to the differences in pharmacokinetics and pharmacodynamics [16]. Adequate tissue penetration and drug concentration at the infection site need to be achieved for a sufficient length of time to maintain efficacy [4]. The following represents newer studies classified by type of antimicrobial agents. Short-course beta lactam therapy A randomized, double-blind, placebo-controlled, noninferiority trial from The Netherlands compared a 3-day versus 8-day course of amoxicillin in adult inpatients who had substantially improved after an initial 3 days of therapy for mild to moderate-severe CAP [pneumonia severity index (PSI) score 110] [17]. After 72 h of intravenous amoxicillin, afebrile patients with subjective improvement in respiratory symptoms and overall condition were randomized to 5 days of oral amoxicillin or placebo. One hundred and eighty-six patients where initially evaluated, of whom 46 (25%) did not achieve significant improvement at 72 h. One hundred and nineteen patients were eventually randomized. Clinical success rates were equal (93%) for both groups suggesting no difference in efficacy of the regimens (difference 0.1; 95% CI 9 to 10). Important differences between the patient groups included a higher proportion of smokers and more severe CAP scores at onset of treatment in the 3-day group. S. pneumoniae was the most frequently identified pathogen. A disproportionate number of parapneumonic effusions (11% versus 2.4%), prolonged hospitalizations (11 days versus 6 days, P < 0.01) and increased incidence of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa (20% versus 1.7%) were identified in the nonrandomized group (n ¼ 46) who had persistent symptoms after the initial 3-day intravenous amoxicillin therapy. An accompanying editorial by Paul [18] validates the notion of Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Community-acquired pneumonia Scalera and File 179 short-course therapy for CAP and also suggests that this same approach should be explored for other infections. The efficacy of short-course beta lactam therapy was previously demonstrated in the pediatric population with upper respiratory tract infections, tonsillopharyngitis, otitis media, and sinusitis [19,20]. The MASCOT (Pakistan) and ISCAP (India) trials showed that a 3-day course of amoxicillin was equally effective to a 5-day course of therapy in over 4000 patients in the treatment of CAP [21,22]. No significant differences in rates of relapse or adverse events were noted. Nonadherence was significantly associated with treatment failures in both studies and specifically with those receiving 5-day duration of therapy (P < 0.0001). In a Dominican study by Schrag et al., short-course, high-dose amoxicillin (90 mg/kg/day for 5 days versus 40 mg/kg/day for 10 days) promoted favorable adherence (P ¼ 0.02) and a significant reduction in PRSP carriage (P ¼ 0.03), which exemplifies the concept of hit hard and stop early [4,6]. Short-course fluoroquinolone therapy Promising data have been generated from levofloxacin and gemifloxacin studies because the pharmacodynamic properties of the fluoroquinolones are amenable to short-course and high-dose antimicrobial therapy. Fluoroquinolones act by concentration-dependent bactericidal activity. Therefore, higher doses of fluoroquinolones are able to achieve higher area under the concentration–time curve (AUC) to minimal inhibitory concentration (MIC) ratios and greater peak plasma concentration (Cmax) to MIC ratios [23–25]. Higher ratios provide for more rapid bacterial killing and prevention of further emerging resistance. Dunbar et al. [26] published a randomized, double-blind, active treatment-controlled, noninferiority study comparing a short-course, higher-dose regimen (750 mg for 5 days) versus a standard dose regimen (500 mg for 10 days) of levofloxacin in 528 adults with mild to severe CAP (PSI I through IV). Clinical success rates (92.4% versus 91.1%, respectively) and bacterial eradication rates (93.2% versus 92.4%, respectively) were similar, suggesting equal effectiveness of both regimens. The 750 mg levofloxacin dose was well tolerated. It is unclear, however, if equal tolerability exists for those with renal insufficiency since patients with a creatinine clearance of under 50 ml/min were excluded from the study. Significant improvement in subjective resolution of fever (P ¼ 0.006) and greater likelihood of defervescence (P ¼ 0.027) were observed in the 750 mg dose group at day 3. These results suggest that shorter hospitalizations, fewer missed work days, and a more expedient return to usual daily activities for the patient may impact cost savings. In a subset analysis of the study by Dunbar et al., Shorr et al. [27] specifically evaluated the same regimens in patients 65 years of age or older. Clinical success rates (89% and 91.9% for the 750 and 500 mg arms, respectively; 95% CI 7.1 to 12.7) were equally effective for treating CAP. Good tolerability was observed as this is extremely important in the elderly population who experience polypharmacy and frequent drug side effects due to declining metabolism and excretion. File et al. [28] in a double-blind, randomized study compared a 5 and 7-day course of gemifloxacin in 510 adults for outpatient treatment of mild to moderate CAP (T.M. File Jr et al., in preparation). No difference in clinical cure rates or adverse events was identified. S. pneumoniae was the most common pathogen isolated and had 100% bacterial eradication from the 5-day treatment group, including multidrug resistant strains. Short-course macrolide therapy Macrolides, specifically azithromycin and clarithromycin, are commonly used for the treatment of communityacquired or atypical pneumonias. Azithromycin has a unique pharmacological profile due to a long half-life of approximately 60 h and good pulmonary penetration, which facilitates use of shorter duration therapy [29]. In fact, a single 500 mg dose of azithromycin achieves high lung parenchymal levels which are well above the MICs for significant respiratory pathogens for up to 4 days [30,31]. Several studies have evaluated different short-course azithromycin regimens with good outcomes. Socan [32] demonstrated equivalent efficacy between 3 and 5-day courses of azithromycin in a retrospective review of 148 adults with atypical pneumonia. O’Doherty et al. [31] compared azithromycin (500 mg for 3 days) versus clarithromycin (250 mg twice daily for 10 days) in 203 patients (12–75 years of age) with no difference in rate of clinical cure. Sopena et al. [33] compared a 3-day course of azithromycin to a 10-day course of clarithromycin in 70 patients, which were equivalent in efficacy. Two recent studies have introduced the novel use of a single-dose of a microsphere formulation of azithromycin [29,34]. A randomized, double-blind, noninferiority study associated with 56 centers worldwide compared a single 2 g microsphere azithromycin formulation with 500 mg of levofloxacin for 7 days in 423 adults with mild to moderate CAP [29]. Clinical cure rates were equivalent (89.7% versus 93.7%, respectively; treatment difference 4%; 95% CI 9.7 to 1). Significant diarrhea lasting less than 48 h was reported by patients (12.3% azithromycin versus 4.7% levofloxacin, P ¼ 0.0063), but no cases of C. difficile were identified. Drehobl et al. [34] demonstrated that a single 2 g dose of microsphere azithromycin was equivalent to 1 g of clarithromycin XL for 7 days duration in rates of clinical success and bacterial eradication in patients with mild to moderate CAP. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 180 Respiratory infections The single 2 g dose microsphere azithromycin formulation optimizes pharmacodynamics by significantly increasing the Cmax and 24-h AUC ratios by two and three times those observed with a single 500 mg dose [29]. This concept of ‘front loading’ maximizes drug exposure when the bacterial burden is high at initial presentation. Significant implications include the notion of directly observed therapy (DOT), which would heavily impact patient compliance and minimize selection pressure for resistance. patients with bacteremic S. aureus pneumonia because of the risks for associated endocarditis and deep-seated infection; patients with extrapulmonary infection (especially meningitis); patients with P. aeruginosa pneumonia; and patients with infection caused by other less common pathogens. Short-course therapy improves patient compliance and promotes reduction of microbial resistance, cost, and adverse events such as C. difficile infections. Telithromycin, a ketolide, has emerged as an effective antimicrobial agent for the treatment of CAP. Tellier et al. [35] performed a randomized, double-blind, parallel-group phase III clinical trial comparing a 10-day course of clarithromycin to a 5 or 7-day course of telithromycin in 575 adults with CAP. Equivalent efficacy in clinical cure and bacterial eradication rates were demonstrated. No statistical comparison was performed between the 5 and 7-day telithromycin groups. Significantly lower hospitalization rates were identified with the 7-day telithromycin group versus the clarithromycin group (0.5/100 patients versus 3.7/100 patients, respectively; P ¼ 0.026) and lower hospitalization costs ($16 091 versus $86 205; difference 37 847; 95% CI 77 953 to 2259). References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 220). 1 Niederman MS, McComb JI, Unger AN, et al. The cost of treating communityacquired pneumonia. Clin Ther 1998; 20:820–837. 2 Mandell LA, Bartlett JG, Dowell SF, et al. Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin Inf Dis 2003; 37:1405–1433. 3 Niederman MS, Mandell LA, Anzueto A, et al. Guidelines for the management of adults with community-acquired pneumonia: diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163:1730–1754. 4 File TM Jr. Clinical efficacy of newer agents in short-duration therapy for community-acquired pneumonia. Clin Infect Dis 2004; 39:S159–S164. 5 Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. JAMA 1998; 279:365–370. 6 Schrag SJ, Pena C, Fernandez J, et al. Effect of short-course, high dose amoxicillin therapy on resistant pneumococcal carriage: a randomized trial. JAMA 2001; 286:49–56. 7 Nicolau DP. Predicting antibacterial response from pharmacodynamic and pharmacokinetic profiles. Infection 2001; 29 (Suppl 2):11–15. 8 Craig WA. Pharmacodynamics of antimicrobials: general concepts and applications. In: Nightingale C, Marakawa T, Ambrose PG, editors. Antimicrobial pharmacodynamics in theory and clinical practice. London: Informa; 2002. pp. 1–22. 9 Andes D, Craig WA. Animal model pharmacokinetics and pharmacodynamics: a critical review. Int J Antimicrob Agents 2002; 19:261–268. Meta-analysis of short-course regimens Due to the increasing amount of new literature addressing short-course antibiotic regimens, meta-analyses are needed to develop a consensus on the optimal duration of therapy to successfully treat CAP. Li et al. [36] completed a meta-analysis of 15 randomized controlled trials composed of 2796 patients comparing short-course (7 days) versus standard (>7 days) therapy. All classes of antibiotics were represented, although a majority of the studies addressed azithromycin use. No difference in clinical success was observed between short-course and standard length of therapy (difference 0.89; 95% CI 0.78–1.02). Mortality, adverse events, and bacterial eradication rates were equivalent in both groups. These results demonstrate that short-course antimicrobial therapy is equivalent to standard length of therapy as supported by several recent review articles [4,7,37–39]. Conclusion Based upon the aforementioned studies, short-course antimicrobial therapy is equivalent to standard length or therapy for treatment of CAP. Due to differences in pharmacodynamics, duration is difficult to define in a uniform fashion for all antibiotics [40,41]. We agree with the recent IDSA/ATS guidelines which recommend that patients with CAP should be treated for a minimum of 5 days, should be afebrile for 48–72 h, and should have no more than one CAP-associated sign of clinical instability before stopping therapy [41]. Longer duration of therapy may be required for patients who fail initial antimicrobial therapy. Also, short-term therapy is not recommended for 10 Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998; 26:1–10. 11 Cecil RL, McDermott W, editors. Textbook of medicine. 7th ed. Philadelphia: WB Saunders Co.; 1948. 12 Harrison TR, Resnick WR, Wintrobe MM, et al., editors. Principles of internal medicine. 5th ed. New York: McGraw Hill; 1967. 13 Witt RL, Hamburger M. The nature and treatment of pneumococcal pneumonia. Med Clin North Am 1963; 47:1257–1270. 14 Halm EA, Fine MJ, Marrie TJ, et al. Time to clinical stability in patients hospitalized with community-acquired pneumonia: implications for practice guidelines. JAMA 1998; 279:1452–1457. 15 Awunor-Renner C. Length of antibiotic therapy in in-patients with primary pneumonias. Ann Trop Med Parasitol 1979; 73:235–240. 16 Mandell LA, File TM Jr. Short-course treatment of community-acquired pneumonia. Clin Infect Dis 2003; 37:761–763. 17 el Moussaoui R, de Borgie CAJM, van den Broek P. Effectiveness of discontinuing antibiotic treatment after three days versus eight days in mild to moderate-severe community-acquired pneumonia: randomized, double blind study. BMJ 2006; 332:1355. This nice study used a physiological approach, based on the response within the first 72 h of therapy, to decide on a strategy of duration of therapy. 18 Paul J. Commentary: what is the optimal duration of antibiotic therapy? BMJ 2006; 332:1358. 19 Pichicero M. Short courses of antibiotic in acute otitis media and sinusitis infections. J Int Med Res 2000; 28 (Suppl):25A–36A. 20 Guay DR. Short course antimicrobial therapy for upper respiratory tract infections. Clin Ther 2000; 22:673–684. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Community-acquired pneumonia Scalera and File 181 21 MASCOT group. Clinical efficacy of three days versus five days of oral amoxicillin for the treatment of childhood pneumonia: a multicentre doubleblind trial. Lancet 2002; 360:835–841. 22 ISCAP study group. Three day versus five day treatment with amoxicillin for nonsevere pneumonia in young children: a multicentre randomized controlled trial. BMJ 2004; 328:791–794. 23 File TM Jr. A new dosing paradigm: high-dose, short-course fluoroquinolone therapy for community-acquired pneumonia. Clinical Cornerstone 2003; Suppl 3:S21–S28. 24 Saravolatz L, Manzor O, Check C, et al. Antimicrobial activity of moxifloxacin, gatifloxacin, and six fluoroquinolones against Streptococcus pneumoniae. J Antimicrob Chemother 2001; 47:875–877. 25 Zelenitsky SA, Ariano RE, Iacovides H, et al. AUC0-t/MIC is a continuous index of fluoroquinolone exposure and predictive of antibacterial response for Streptococcus pneumoniae in an in vitro infection model. J Antimicrob Chemother 2003; 51:905–911. 26 Dunbar LM, Wunderink RG, Habib MP, et al. High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis 2003; 37:752–760. 27 Shorr AF, Zadeikis N, Xiang JX, et al. A multicenter, randomized, double-blind, retrospective comparison of 5- and 10-day regimens of levofloxacin in a subgroup of patients aged 65 years with community-acquired pneumonia. Clin Ther 2005; 27:1251–1259. 28 File Jr TM, Mandell LA. Is short course gemifloxacin therapy effective in at-risk community-acquired pneumonia (CAP) patients? [abstract]. In: Abstracts of the 44th Annual Meeting of IDSA; 12–15 October 2006; Toronto. Alexandria: IDSA; 2006. Abstract 437. 31 O’Doherty B, Muller O, and azithromycin study group. Randomized, multicentre study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of adults with mild to moderate community-acquired pneumonia. Eur J Clin Microbiol Infect Dis 1998; 17:828–833. 32 Socan M. Treatment of atypical pneumonia with azithromycin: comparison of a 5-day and a 3-day course. J Chemother 1998; 10:64–68. 33 Sopena N, Martinez-Vazquez C, Rodriguez-Suarez JR, et al. Comparative study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of community-acquired pneumonia in adults. J Chemother 2004; 16:102–103. 34 Drehobl MA, De Salvo MC, Lewi DE, Breen JD. Single-dose azithromycin microspheres vs. clarithromycin extended release for the treatment of mild to moderate community-acquired pneumonia in adults. Chest 2005; 128: 2230–2237. 35 Tellier G, Chang JR, Asche CV, et al. Comparison of hospitalization rates in patients with community-acquired pneumonia treated with telithromycin for 5 or 7 days or clarithromycin for 10 days. Curr Med Res Opin 2004; 20:739– 747. 36 Li JZ, Winston L, Moore H, Bent S. Effectiveness of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis of randomized controlled trials. In Abstracts of the 46th ICAAC meeting; 17–20 September 2006, San Francisco. Washington, DC: ICAAC; 2006. Abstract L-1458 37 Goff DA. Short-duration therapy for respiratory tract infections. Ann Pharmacother 2004; 38 (9 suppl):S19–S23. 38 Blasi F. Value of short-course antimicrobial therapy in community-acquired pneumonia. Int J Antimicrob Agents 2005; 26 (suppl 3):S148–S155. 39 Kolditz M. Short-course antimicrobial therapy for community-acquired pneumonia. Treat Respir Med 2005; 4:231–239. 29 D’Ignazio J, Camere MA, Lewis DE, et al. Novel, single-dose microsphere formulation of azithromycin versus 7-day levofloxacin therapy for treatment of mild to moderate community-acquired pneumonia in adults. Antimicrob Agents Chemother 2005; 49:4035–4041. 40 File TM Jr, Niederman MS. Antimicrobial therapy of community-acquired pneumonia. Infect Dis Clin North Am 2004; 18:993–1016. 30 Baldwin DR, Wise R, Andrews JM, et al. Azithromycin concentrations at the sites of pulmonary infection. Eur Resp J 1990; 3:886–890. 41 IDSA/ATS Consensus Guidelines on the Management of CommunityAcquired Pneumonia in adults. Clin Infect Dis (in press). Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Performance measures for pneumonia: are they valuable, and are process measures adequate? Dale W. Bratzlera, Wato Nsaa and Peter M. Houckb Purpose of review Pneumonia has been the target of large national initiatives to measure and report quality of care. Measures of pneumonia care are now being used for public reporting and pay-forperformance in an effort to increase provider accountability for healthcare quality in the USA. Increasingly, concerns have been raised about the potential for unintended consequences of performance measurement and reporting that might lead to patient harm. Recent findings Since 1999, there have been substantial improvements in performance on measures of pneumonia processes of care, and patient clinical outcomes have improved. The association between improved clinical outcomes and processes of care for pneumonia, however, is not clear based on available national data. The increasing use of process measures for hospital accountability has created the continual need to re-evaluate the relationship between processes being measured and desired patient outcomes. While there is little direct evidence of unintended consequences of performance measurement, concerns have been raised about the potential for direct or indirect harm to patients. Summary Measuring processes of care for pneumonia is feasible and appears to have accelerated the pace of quality improvement. There is an ongoing need to develop new measures of pneumonia quality that focus on patient outcomes, care transitions, and efficiency of care. Keywords performance measurement, quality assessment, unintended consequences Curr Opin Infect Dis 20:182–189. ß 2007 Lippincott Williams & Wilkins. a Oklahoma Foundation for Medical Quality, Oklahoma City, Oklahoma and Department of Epidemiology, University of Washington, Seattle, Washington, USA b Correspondence to Dale W. Bratzler, DO, MPH, QIOSC Medical Director, Oklahoma Foundation for Medical Quality, 14000 Quail Springs Parkway, Suite 400, Oklahoma City, OK 73134, USA Tel: +1 405 840 2891; fax: +1 405 840 1343; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:182–189 Abbreviations CMS JCAHO Centers for Medicare & Medicaid Service Joint Commission on Accreditation of Healthcare Organization ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction It is well documented that large opportunities exist to improve the quality and safety of healthcare [1–4,5,6]. Studies have documented widespread underuse of effective treatments that can reduce patient mortality, overuse of unnecessary treatments, and errors that result in excess morbidity and mortality. The slow pace of improvement in quality has led to calls for strategies such as public reporting and pay-for-performance to accelerate the rates of improvement and to create greater provider accountability for healthcare quality [7,8]. Not surprisingly, care of patients with pneumonia has been the target of a variety of quality measurement and reporting initiatives [9,10]. Pneumonia is the second most common cause of hospitalization of the elderly, accounting for approximately 770 000 admissions annually in the United States [11,12]. Despite publication of guidelines for management of pneumonia [13,14], there is little evidence that dissemination of guidelines alone has resulted in improvements in care [15–17]. This review will discuss the current state of performance measurement for pneumonia and highlight the challenges and potential consequences of relying on measures of processes of care to assess and report quality. Framework for measurement of quality In 1966, Donabedian proposed that we can measure the quality of healthcare by observing its structure, process, and outcomes [18,19]. Structural measures often reflect resources that are available to provide care, such as characteristics of the facility, accreditation status, and medical staff attributes. Structural data are usually easy to measure and lend themselves to activities such as licensing and accreditation surveys. Recent structural measures that have been promoted by the Leapfrog Group include use of computerized physician order entry, selective referral of patients to high-volume providers for certain procedures, and use of intensivists to provide care in hospital intensive care units [20,21]. There is limited research, however, demonstrating that measures of structure correlate well with other markers of healthcare quality [20]. Much more commonly utilized to assess healthcare quality are measures of process and outcomes of care. Process measures reflect components of the encounter between the healthcare provider and the patient and represent aspects of care that are generally within the control of the provider. Outcome measures reflect the patient’s 182 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Performance measures for pneumonia Bratzler et al. 183 subsequent health status, which may include satisfaction with care, functional status, morbidity, mortality, or parameters such as length of stay or costs of care. While generally regarded as the indicators that are most meaningful to patients or payers, outcome measures may reflect patient factors that are not within the control of the provider [22]. There are advantages and disadvantages of process and outcomes measures [23]. Process measures are usually captured using explicit, predefined criteria to assess compliance with recommended care guidelines. Process measures are generally considered ‘actionable’ because they are within the control of the provider and usually do not require risk adjustment for patient or provider characteristics. Process measures can be captured more quickly than outcome measures because outcomes of interest may occur infrequently and require long periods of time after care provision to be assessed. Because many episodes of inappropriate process of care do not result in patient harm, process indicators are considered more sensitive measures of quality. Because measurement of outcomes usually requires capturing detailed information about patient characteristics for the purposes of risk adjustment, process measures often have less data collection burden. To be useful for quality improvement, however, measures of process must be linked to the desired outcome and must be reliable and clinically important [24]. Process of care measures require continual maintenance to reflect the most contemporary clinical evidence. Outcome measures, while more difficult to assess, may provide a more comprehensive view of quality than process measures that reflect a small proportion of the care received by patients. Current US initiatives to measure and report quality of pneumonia care Two of the largest initiatives focused on the quality of pneumonia care are the Centers for Medicare & Medicaid Service’s (CMS) National Pneumonia Project and the Joint Commission on Accreditation of Healthcare Organization’s (JCAHO) ORYX initiatives [9,10]. CMS began data collection from a large national cohort of pneumonia patients in 1994 and subsequently implemented the National Pneumonia Project in 1999 with the goal of improved quality of care for patients with pneumonia. Routine measurement of performance and feedback of process measure data to hospitals has occurred since 1999. In 1997, JCAHO’s ORYX initiative was implemented to integrate performance measurement data into its accreditation process and to support accredited hospitals in their quality improvement efforts. In July 2002, accredited hospitals were required to collect data on standardized or ‘core’ performance measures, and measures of pneumonia quality were included in the list of core topics a hospital could choose from. Working collaboratively, CMS and JCAHO aligned the specifications for all of their common performance measures in an effort to reduce the burden of data collection on hospitals. With the passage of the Medicare Modernization Act in 2003, hospitals were encouraged to voluntarily submit performance data on 10 measures of quality reflecting care for patients with acute myocardial infarction, heart failure, and pneumonia. Failure to submit and allow public reporting of this quality data resulted in hospitals losing 0.4% of their Medicare annual payment update. The provisions of the reporting requirements went into effect on 1st July 2004, and approximately 98.3% of eligible hospitals began voluntary reporting the 10 measures of quality. The American Hospital Association, the Federation of American Hospitals, and the American Association of Medical Colleges, with additional representation from CMS, JCAHO, and private sector groups, formed the Hospital Quality Alliance creating a national infrastructure for publicly reporting the quality of hospital care [25]. Performance rates for measures of quality for pneumonia are publicly available for most US hospitals on the Hospital Compare website sponsored by the Department of Health and Human Services or on the Quality Check website sponsored by JCAHO [26,27]. The recently passed Deficit Reduction Act of 2005 required CMS to expand the number of measures that hospitals must report to receive their full Medicare payment update. For those hospitals that do not report, the payment update for fiscal year 2007 and each subsequent fiscal year will be reduced by 2.0 percentage points. Current measures of pneumonia quality that have been implemented by CMS and JCAHO are limited to processes of care. The current process of care measures implemented nationally are summarized in Table 1. Process measures that reflect care at the time of admission (oxygenation assessment, blood cultures, antibiotic timing, and antibiotic selection) and care provided before discharge (influenza and pneumococcal vaccination) are based on published guidelines for the management of patients with community-acquired pneumonia [13,14] and the consensus of a national technical expert panel [9]. In addition, measures such as antibiotic selection and timing are supported by process-outcome associations observed in very large, random samples of Medicare pneumonia hospitalizations. With broad national implementation of measures of quality for pneumonia care now being reported by the vast majority of acute care hospitals in the United States, several questions can be addressed. Has performance on the process measures improved? From 1998 through 2004, CMS used contractor organizations to randomly select and perform chart audits on state-specific samples of Medicare patients hospitalized with pneumonia. Trends in selected pneumonia process measures are summarized in Tables 2 and 3. There has Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 184 Respiratory infections Table 1 National Pneumonia Project process of care measures Measures PN-1 PN-2 PN-3a PN-3b PN-4 PN-5 PN-5a PN-5b PN-5c PN-6 PN-6a PN-6b PN-7 Oxygenation assessment Pneumococcal vaccination Blood cultures performed within 24 h prior to or 24 h after hospital arrival for patients who were transferred or admitted to the ICU within 24 h of hospital arrival Blood cultures performed in the emergency department collected prior to initial antibiotic received in hospital Adult smoking cessation advice/counseling Antibiotic timing (median) Initial antibiotic received within 8 h of hospital arrival Initial antibiotic received within 4 h of hospital arrival Initial antibiotic received within 6 h of hospital arrival Initial antibiotic selection for community-acquired pneumonia in immunocompetent patients Initial antibiotic selection for community-acquired pneumonia in immunocompetent patients – ICU patients Initial antibiotic selection for community-acquired pneumonia in immunocompetent patients – non-ICU patients Influenza vaccination been improvement on all of the measures of process of care ranging from a 7.4% relative improvement in oxygenation assessment to a more than 500% relative increase in pneumococcal vaccination/screening from 1998 to 2004. Similarly, there have been substantial changes in patterns of empiric antibiotic selection for patients admitted with pneumonia, with marked improvements in guideline adherence. Similar improvements in processes of care for pneumonia have been reported by JCAHO [6]. Since 2004, hospitals participating in public reporting to receive the full Medicare annual payment update have been submitting data on processes of care for a near census of US pneumonia hospitalizations. National performance on selected process measures and calculated national benchmarks based on hospital self-submitted data are summarized in Fig. 1 [28]. Have patient outcomes improved? In addition to improvements in processes of care, there have been improvements in patient clinical outcomes (Table 4). Average length of hospital stay has shortened and readmission rates have remained relatively stable. There has been a 22.8% relative reduction in in-hospital mortality and a 15.1% relative reduction in 30-day mortality rates. While patient-level risk adjustment variables are available only for the 1998 and 2000 cohorts (all presented results are unadjusted and not stratified for patient risk), it is unlikely that severity of illness for patients hospitalized with pneumonia declined from 1998 to 2004, and the average age of the patients that were evaluated increased over this time frame. Can improvements in patient outcomes be attributed to improved performance on process measures? Attributing improved patient outcomes to the demonstrated improvements in processes of care for pneumonia is more difficult. It is possible that patient outcome improvements could be due to changes in unmeasured processes of care or secular trends in better medical care of hospitalized patients. For instance, the greatest Table 2 National performance trends on selected process measures collected as a part of the Medicare National Pneumonia Projecta,b Selected process measures 1998 2000 2002 2003 2004 P-valuec Patients, n First antibiotic dose within 4 h (%; 95% CI) First antibiotic dose within 8 h (%; 95% CI) Blood culture within 24 h (%; 95% CI) Oxygenation assessment in 24 h (%; 95% CI) Pneumococcal vaccination/ screening (%; 95% CI) Influenza vaccination/screening (%; 95% CI) 24 925 56.9; 56.3–57.6 23 067 59.2; 58.6–59.9 7801 63.8; 62.7–64.9 6883 66.7; 65.5–67.9 7142 69.8; 68.6–71.0 <0.001 82.7; 82.2–83.2 84.4; 83.9–84.9 87.6; 86.8–88.3 90.4; 89.6–91.1 89.5; 88.6–90.3 <0.001 61.2; 60.5–61.8 62.3; 61.6–62.9 60.4; 59.2–61.6 63.7; 62.4–65.0 72.6; 71.5–73.7 <0.001 92.1; 91.7–92.4 94.0; 93.7–94.3 98.1; 97.8–98.4 98.6; 98.3–98.8 98.9; 98.6–99.2 <0.001 7.7; 7.4–8.1 14.8; 14.3–15.3 27.9; 26.8–29.0 36.8; 35.6–38.0 50.3; 49.0–51.6 <0.001 9.7; 9.3–10.2 12.2; 11.7–12.8 28.8; 27.5–30.1 36.7; 35.3–38.2 47.1; 45.6–48.6 <0.001 a Based on national random samples of cases that were selected from paid Medicare claims with a principal diagnosis of pneumonia (International Classification of Disease, Ninth Edition, Clinical Modification, ICD-9-CM, codes of 480.0 through 483.8, 485 through 486, or 487.0) or a principal diagnosis of septicemia or acute respiratory failure (ICD-9-CM codes 038.XX or 518.81) and a secondary diagnosis of pneumonia. All charts were independently abstracted by Centers for Medicare & Medicaid Service’s Clinical Data Abstraction Centers. b All results have been weighted to reflect adjustment based on the state-specific sampling scheme and are restricted to patients age 65 years and older. c Based on Cochran-Armitage x2 test for trend. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Performance measures for pneumonia Bratzler et al. 185 Table 3 National performance trends for initial antibiotic selection for pneumonia patientsa,b,c,d Initial antibiotic selection Non-ICU patients n Beta lactam monotherapy (%; 95% CI) Beta lactam þ macrolide (%; 95% CI) Beta lactam þ quinolone (%; 95% CI) Beta lactam þ other antibiotic (%; 95% CI) Quinolone monotherapy (%; 95% CI) Quinolone þ macrolide (%; 95% CI) Quinolone þ other antibiotic (%; 95% CI) Macrolide monotherapy (%; 95% CI) Other regimens (%; 95% CI) ICU patients n Beta lactam þ macrolide (%; 95% CI) Beta lactam þ quinolone (%; 95% CI) Quinolone þ vancomycin/ clindamycin Beta lactam monotherapy (%; 95% CI) Macrolide monotherapy (%; 95% CI) Quinolone monotherapy (%; 95% CI) Other regimens (%; 95% CI) 1998 2000 2002 2003 2004 P-valuee 14 963 39.9; 39.1–40.7 14 094 23.0; 22.3–23.7 5221 16.3; 15.3–17.3 4630 11.3; 10.4–12.2 4437 12.8; 11.9–13.9 <0.001 24.9; 24.2–25.6 22.8; 22.1–23.5 25.5; 24.4–26.8 32.6; 31.3–34.0 35.8; 34.4–37.2 <0.001 8.5; 8.0–8.9 12.3; 11.7–12.8 13.8; 12.9–14.8 13.8; 12.8–14.9 14.5; 13.5–15.6 <0.001 6.1; 5.7–6.5 3.9; 3.6–4.3 3.9; 3.4–4.4 2.9; 2.5–3.4 3.6; 3.1–4.2 <0.001 14.2; 13.6–14.7 31.1; 30.3–31.8 34.5; 33.2–35.8 33.7; 32.4–35.1 28.9; 27.6–30.3 <0.001 3.0; 2.7–3.3 4.2; 3.9–4.6 5.8; 5.2–6.5 5.9; 5.2–6.6 6.0; 5.3–6.7 <0.001 1.5; 1.3–1.7 2.4; 2.2–2.7 3.0; 2.5–3.4 3.1; 2.6–3.7 2.4; 2.0–2.9 <0.001 3.1; 2.8–3.4 2.8; 2.6–3.1 2.1; 1.7–2.5 1.5; 1.2–1.9 1.9; 1.5–2.3 <0.001 1.3; 1.1–1.4 1.0; 0.9–1.2 1.0; 0.8–1.3 1.0; 0.7–1.3 1.6; 1.2–2.0 <0.001 1819 29.0; 26.9–31.1 1621 25.6; 23.5–27.8 509 29.9; 25.9–34.0 455 33.9; 29.5–38.4 520 33.9; 29.8–38.1 0.002 11.3; 9.9–12.8 22.3; 20.3–24.4 24.3; 20.7–28.3 28.5; 24.5–33.0 21.5; 18.1–25.3 <0.001 3.8; 3.0–4.8 5.8; 4.7–7.0 7.2; 5.0–9.7 8.4; 6.0–11.3 5.7; 3.9–8.1 <0.001 31.5; 29.4–33.7 18.2; 16.3–20.2 10.9; 8.4–14.0 14.5; 11.4–18.1 13.5; 10.6–16.7 <0.001 1.9; 1.3–2.7 1.2; 0.7–1.8 1.4; 0.6–2.8 0.2; 0.0–1.2 1.1; 0.4–2.5 9.5; 8.1–10.9 21.8; 19.8–23.9 20.0; 16.6–23.8 15.6; 12.4–19.3 17.9; 14.7–21.5 <0.001 16.2; 14.6–18.0 12.1; 10.5–13.8 13.3; 10.5–16.6 9.0; 6.5–12.0 13.7; 10.8–16.9 0.005 0.020 a Based on national random samples of cases that were selected from paid Medicare claims with a principal diagnosis of pneumonia (International Classification of Disease, Ninth Edition, Clinical Modification, ICD-9-CM, codes of 480.0 through 483.8, 485 through 486, or 487.0) or a principal diagnosis of septicemia or acute respiratory failure (ICD-9-CM codes 038.XX or 518.81) and a secondary diagnosis of pneumonia. All charts were independently abstracted by Centers for Medicare & Medicaid Service’s Clinical Data Abstraction Centers. b All results have been weighted to reflect adjustment based on the state-specific sampling scheme and are restricted to patients age 65 years and older. c Percentages may add up to more than 100% because some patients received three or more antibiotics within the first 24 h of hospitalization. d Patients who did not receive an initial antibiotic within 24 h of hospital arrival and those patients who were potentially immunocompromised are excluded from the results in this table. e Based on Cochran-Armitage x2 test for trend. reduction in patient mortality between 1998 and 2004 for Medicare pneumonia patients was due to lower mortality for severely ill patients who were admitted to the intensive care unit (Table 4), which may reflect improvements in the management of other processes of intensive care that were not measured. While it is difficult to attribute improvements in outcomes directly to improvements in the processes of care with currently available national measures of quality, other investigators have demonstrated improvements in patient outcomes based on implementation of ‘bundles’ of processes for pneumonia care [29–32,33]. Challenges to the use of process measures for pneumonia For healthcare quality measures to be useful, they must be meaningful, scientifically sound, generalizable, and interpretable [34,35]. In addition to the disadvantages of process measures previously discussed, a number of challenges specifically affect the utility of the current process measures that are used to profile hospital quality. ‘Off-label’ use of performance measures When national efforts to measure hospital performance on pneumonia care were initiated, the indicators were designed to support quality improvement efforts rather than public accountability. With implementation of public reporting and the advent of pay-for-performance demonstrations, there is now considerable pressure on measure developers to carefully modify the process measures to specify the population eligible for the process and to account for as many exclusions, contraindications, and clinical exceptions to the process being measured as possible [23]. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 186 Respiratory infections Figure 1 Benchmarks for the National Pneumonia Project performance measures Average performance and benchmarks are based on 4249 hospitals that voluntarily reported self-collected data on 264 667 patients to the QIO Clinical Warehouse in the fourth quarter of 2005. Data are restricted to patients who are 18 years of age or older. Benchmarks are calculated using the Achievable Benchmarks of Care methodology [28]. Table 4 National trends for selected clinical outcomes collected as a part of the Medicare National Pneumonia Projecta,b All patients n Average length of stay (median; SD) In-hospital mortality (%; 95% CI) 30-day mortality (%; 95% CI) 30-day readmission, (%; 95% CI) ICU Patientsd n Average length of stay (median; SD) In-hospital mortality (%; 95% CI) 30-day mortality (%; 95% CI) 30-day readmission (%; 95% CI) Non-ICU patients n Average length of stay (median, SD) In-hospital mortality (%; 95% CI) 30-day mortality (%; 95% CI) 30-day readmission (%; 95% CI) 1998 2000 2002 2003 2004 P-valuec 24 925 6.7; 5.0, 5.4 23 067 6.6; 5.0, 5.5 7801 6.4; 5.0, 5.8 6883 6.1; 5.0, 5.1 7142 6.2; 5.0, 4.9 <0.001 9.2; 8.8–9.5 9.5; 9.1–9.9 10.2; 9.5–10.9 7.8; 7.2–8.5 7.1; 6.5–7.7 <0.001 15.3; 14.8–15.7 15.5; 15.1–16.0 16.3; 15.8–16.8 18.9; 18.3–19.4 15.7; 14.9–16.5 18.3; 17.4–19.2 12.5; 11.8–13.3 18.2; 17.2–19.1 12.9; 12.1–13.7 16.3; 15.4–17.2 <0.001 0.002 2741 9.1; 7.0, 8.2 2454 9.5; 7.0, 8.8 727 9.7; 7.0, 10.0 636 9.7; 7.0, 8.9 630 8.4; 7.0, 6.1 23.5; 21.9–25.1 23.2; 21.5–24.9 21.3; 18.5–24.3 17.2; 14.3–20.5 11.9; 9.5–14.7 <0.001 30.5; 28.8–32.2 19.6; 18.0–21.4 30.6; 28.8–32.4 21.8; 20.0–23.8 27.7; 24.6–30.9 21.4; 18.2–24.9 21.0; 17.8–24.5 22.0; 18.4–26.0 17.8; 14.9–21.1 21.4; 17.9–25.1 <0.001 0.212 22 184 6.4; 5.0, 4.9 20 613 6.3; 5.0, 4.8 7074 6.0; 5.0, 5.0 6247 5.8; 5.0, 4.3 6512 6.0; 5.0, 4.7 <0.001 7.3; 7.0–7.7 7.8; 7.5–8.2 8.9; 8.3–9.6 7.0; 6.3–7.6 6.6; 6.0–7.2 0.215 13.3; 12.8–13.7 15.1; 14.6–15.6 14.6; 14.1–15.0 18.6; 18.0–19.1 14.3; 13.5–15.1 18.0; 17.1–19.0 11.7; 10.9–12.5 17.8; 16.9–18.9 12.4; 11.6–13.2 15.9; 15.0–16.8 0.002 0.003 0.959 a Based on national random samples of cases that were selected from paid Medicare claims with a principal diagnosis of pneumonia (International Classification of Disease, Ninth Edition, Clinical Modification, ICD-9-CM, codes of 480.0 through 483.8, 485 through 486, or 487.0) or a principal diagnosis of septicemia or acute respiratory failure (ICD-9-CM codes 038.XX or 518.81) and a secondary diagnosis of pneumonia. All charts were independently abstracted by Centers for Medicare & Medicaid Service’s Clinical Data Abstraction Centers. b All results have been weighted to reflect adjustment based on the state-specific sampling scheme and are restricted to patients age 65 years and older. c Based on Cochran-Armitage x2 test for trend for categorical variables and regression analysis for the length of stay. d Admitted to the intensive care unit within 24 h of hospital arrival. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Performance measures for pneumonia Bratzler et al. 187 Measures maintenance and time lags The science of measuring performance in healthcare is relatively new and there are few explicit rules for changing an accepted measure in response to advances in knowledge [36]. The process of care measures for pneumonia are based on published guidelines and the consensus of experts in pneumonia care (many of whom are authors of the guidelines) and, while dynamic, the mechanism to modify or replace existing measures is complex. Simple modifications to a performance measure such as adding a new medication as an acceptable process or inserting a new exclusion into a measure to restrict the denominator population take from 6 to 12 months on average. In addition to continual review of published literature and guidelines on pneumonia care, measure developers are responsible for updating chart review criteria and measure specifications, updating data collection tools, software, and analytic algorithms, and providing education to providers on imminent changes. Time lags in the modification of clinical practice guidelines to reflect contemporary research have resulted in additional delays in updates to performance measures for pneumonia and loss of synchronization between guidelines and measures. Need for validation For all of the performance measures that hospitals must submit to be fully eligible for the annual Medicare payment updates, the medical records from which the data were collected are subject to random validation audit. Because this validation audit occurs through independent reabstraction of the medical record, all measure specifications including data element abstraction instructions must be explicit and unambiguous so that two independent chart reviewers produce the same results when evaluating the same medical record. Proof of effectiveness For a process measure to be valid there must be a strong relationship between the process being measured and the desired patient outcome. Ideally, process measures would be based on evidence from multiple randomized clinical trials linking performance of the process to improved patient outcomes. Many process measures that have been developed for pneumonia quality improvement purposes, however, have been based on observational studies or on expert consensus. The validity of several process measures that are a part of the national efforts to improve pneumonia care has recently been challenged. For example, while published guidelines for the management of community-acquired pneumonia [13,14] had recommended the routine performance of blood cultures for patients admitted to the hospital, this practice has been questioned [37,38,39 –41]. Based on a review of evidence, updated guidelines [42], and expert consensus, the national measure for performance of blood cultures had to be modified [43]. Unintended consequences of performance measurement and reporting Public release of hospital performance on measures of quality is typically undertaken to improve transparency and empower patients to make better choices about where to seek treatment, to increase hospital accountability for quality of care, and to enable regulators, accreditors, and payers to track hospital performance over time. These data are increasingly being used to reward high performance through pay-for-performance compensation. Relatively little is known, however, about the impacts of public reporting on the quality of patient care or patient outcomes, and concerns have been raised about the possible unintended consequences of performance measurement and reporting [44,45 –47]. Lindenauer [47] recently classified unintended consequences into those that have the potential to result in direct patient harm and those that may cause harm indirectly. Direct harm Direct harm occurs when inappropriate care is given to a patient in the pursuit of high scores on a performance measure. For example, concerns have been raised about the performance measure to administer the first antibiotic dose within 4 hours of hospital arrival to patients with pneumonia [48,49 –51]. Since the initiation of public reporting and pay-for-performance projects targeting pneumonia process measures, there have been anecdotal reports of inappropriate administration of antibiotics to emergency department patients (i.e., prior to or in the ultimate absence of a pneumonia diagnosis) in order to boost performance measure rates [47,49 –51]. Similarly, the process measure for routine performance of blood cultures for pneumonia patients raised concerns about unintended consequences when it was suggested there was potential patient harm from indiscriminant performance of blood cultures [52]. Indirect harm Another potential consequence of performance measurement and reporting is indirect harm. This is most often reported as a diversion of resources to focus on those processes of care that are being measured (‘playing to the test’) at the expense of other aspects of clinical care where the opportunity to improve quality and patient outcomes may be greater [47,53]. For instance, is it possible that an emergency department might prioritize care for a patient with symptoms that suggested pneumonia over a patient who presented to the emergency department with abdominal pain who was just as sick or sicker because hospital performance is reported for antibiotic timing in pneumonia patients but not for abdominal pain patients? Conclusion Are process measures for pneumonia valuable? Probably. National efforts to collect and report hospital Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 188 Respiratory infections 10 JointCommissiononAccreditationofHealthcareOrganizations.PneumoniaCore Measure Set.http: // www . jointcommission . org / PerformanceMeasurement / PerformanceMeasurement/Pneumonia+Core+Measure+Set.htm. [Accessed 16 November 2006] performance on these measures appear to have accelerated the pace of process improvement with concomitant improvement in important patient outcomes. Are the current process measures for pneumonia adequate? Clearly not. CMS has already announced the development of a clinically validated, risk-adjusted 30-day mortality measure for Medicare patients admitted to the hospital with pneumonia (H. M. Krumholz, personal communication) and there is a need for additional measures of quality that would evaluate other patient outcomes, transitions of care from one healthcare setting to another, and efficiency of care. There is also a need in future efforts to measure and promote quality of care for pneumonia to anticipate, monitor, and respond to the unintended consequences of performance measurement. 12 Fry AM, Shay DK, Holman RC, et al. Trends in hospitalizations for pneumonia among persons aged 65 years or older in the United States, 1988–2002. JAMA 2005; 294:2712–2719. This article summarizes the epidemiology of hospital admissions for pneumonia showing an increasing rate of hospitalizations and an increased proportion of pneumonia patients with comorbid chronic illness. Acknowledgements 15 Halm EA, Atlas SJ, Borowsky LH, et al. Understanding physician adherence with a pneumonia practice guideline: effects of patient, system, and physician factors. Arch Intern Med 2000; 160:98–104. The authors would like to thank Nancy Lawler and Tracy Senat for their review and comments on an earlier version of this manuscript. The analyses upon which this publication is based were performed in part under Contract Number 500-02-OK-03, funded by the Centers for Medicare & Medicaid Services, an agency of the US Department of Health and Human Services. The content of this publication does not necessarily reflect the views of policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. The authors assume full responsibility for the accuracy and completeness of the ideas presented. (Publication number: 010_HIOK0412_1106) References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 217). 1 Chassin MR, Galvin RW. The urgent need to improve healthcare quality. N Engl J Med 1998; 280:1000–1005. 2 Committee on Quality of Healthcare in America, Institute of Medicine. Crossing the quality chasm: a new health system for the 21st century. Washington, D.C.: National Academies Press; 2001. 3 McGlynn EA, Asch SM, Adams J, et al. The quality of healthcare delivered to adults in the United States. N Engl J Med 2003; 348:2635–2645. 4 National Healthcare Quality Report, 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/qual/nhqr05/nhqr05.htm. [Accessed 17 November 2006] 5 Jha AK, Li Z, Orav EJ, Epstein AM. Care in U.S. hospitals: the Hospital Quality Alliance program. N Engl J Med 2005; 353:265–274. This is an analysis of national quality data submitted to the Hospital Quality Alliance demonstrating variation across hospitals and indicators on process measure performance. Williams SC, Schmaltz SP, Morton DJ, et al. Quality of care in U.S. hospitals as reflected by standardized measures, 2002–2004. N Engl J Med 2005; 353:255–264. This paper summarizes 2-year trends in performance on measures of quality for acute myocardial infarction, heart failure, and pneumonia for JCAHO-accredited hospitals. 6 7 Altman DE, Clancy C, Blendon RJ. Improving patient safety: five years after the IOM report. N Engl J Med 2004; 351:2041–2043. 8 Leape LL, Berwick DM. Five years after To Err Is Human: what have we learned? JAMA 2005; 293:2384–2390. 9 Centers for Medicare & Medicaid Services. Pneumonia. http://www.medqic. org/pneumonia. [Accessed 16 November 2006] 11 Russo CA, Elixhauser A. Hospitalizations in the elderly population, 2003. Statistical Brief #6. May 2006. Agency for Healthcare Research and Quality, Rockville, MD. http: // www.hcup-us.ahrq.gov / reports / statbriefs / sb6.pdf. [Accessed 16 November 2006] 13 Niederman MS, Mandell LA, Anzueto A, et al., American Thoracic Society. Guidelines for the management of adults with communityacquired pneumonia. Diagnosis, assessment of severity, antimicrobial therapy, and prevention. Am J Respir Crit Care Med 2001; 163:1730– 1754. 14 Mandell LA, Bartlett JG, Dowell SF, et al., Infectious Diseases Society of America. Update of practice guidelines for the management of communityacquired pneumonia in immunocompetent adults. Clin Infect Dis 2003; 37:1405–1433. 16 Switzer GE, Halm EA, Chang CC, et al. Physician awareness and selfreported use of local and national guidelines for community-acquired pneumonia. J Gen Intern Med 2003; 18:816–823. 17 Flanders SA, Halm EA. Guidelines for community-acquired pneumonia: are they reflected in practice? Treat Respir Med 2004; 3:67–77. 18 Donabedian A. Evaluating quality of medical care. Milbank Mem Fund Q 1966; 44:166–206. 19 Donabedian A. The quality of care. How can it be assessed? JAMA 1988; 260:1743–1748. 20 Meyer GS, Massagli MP. The forgotten component of the quality triad: can we still learn something from ‘structure’? Jt Comm J Qual Improve 2001; 27:484–493. 21 The Leapfrog Group. The Leapfrog Safety Practices. http://www.leapfrog group.org/for_hospitals/leapfrog_safety_practices. [Accessed 17 November 2006] 22 Brook RH, McGlynn EA, Cleary PD. Measuring quality of care. N Engl J Med 1996; 335:966–970. 23 Rubin HR, Pronovost P, Diette GB. The advantages and disadvantages of process-based measures of healthcare quality. Int J Qual Healthcare 2001; 13:469–474. 24 Metersky ML, Abend SL, Meehan TP. What have we learned about how to measure quality of care for patients with community-acquired pneumonia? Respir Care Clin N Am 2005; 11:87–98. This is an excellent and comprehensive review of current measures of quality used to profile pneumonia care. The article summarizes national measures and highlights additional measures that are not part of ongoing national performance measurement efforts. 25 Centers for Medicare & Medicaid Services. Hospital Quality Alliance. http:// www . cms . hhs . gov/HospitalQualityInits/15_HospitalQualityAlliance.asp. [Accessed 16 November 2006] 26 Department of Health and Human Services. Hospital Compare. http:// www.hospitalcompare.hhs.gov. [Accessed 16 November 2006] 27 Joint Commission on Accreditation of Healthcare Organizations. Quality Check. http://www.qualitycheck.org/consumer/searchQCR.aspx. [Accessed 16 November 2006] 28 University of Alabama at Birmingham Center for Outcomes and Effectiveness Research & Education. Achievable Benchmarks of Care. http://main.uab.edu/ show.asp?durki=14527. [Accessed 16 November 2006] 29 Benenson R, Magalski A, Cavanaugh S, Williams E. Effects of a pneumonia clinical pathway on time to antibiotic treatment, length of stay, and mortality. Acad Emerg Med 1999; 6:1243–1248. 30 Dean NC, Silver MP, Bateman KA, et al. Decreased mortality after implementation of a treatment guideline for community-acquired pneumonia. Am J Med 2001; 110:451–457. 31 Battleman DS, Callahan M, Thaler HT. Rapid delivery and appropriate antibiotic selection reduce length of hospital stay of patients with communityacquired pneumonia: link between quality of care and resource utilization. Arch Intern Med 2002; 162:682–688. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Performance measures for pneumonia Bratzler et al. 189 32 Chu LA, Bratzler DW, Lewis RJ, et al. Improving the quality of care for patients with pneumonia in very small hospitals. Arch Intern Med 2003; 163:326–332. 33 Dean NC, Bateman KA, Donnelly SM, et al. Improved clinical outcomes with utilization of a community-acquired pneumonia guideline. Chest 2006; 130:794–799. This article updates work started in 2001 to implement a local guideline to improve pneumonia care and outcomes. After implementation of a pneumonia ‘bundle’, riskadjusted patient mortality and readmission rates declined. 34 McGlynn EA. Choosing and evaluating clinical performance measures. Jt Comm J Qual Improv 1998; 24:470–479. 35 O’Malley AS, Clancy C, Thompson J, et al. Clinical practice guidelines and performance indicators as related – but often misunderstood – tools. Jt Comm J Qual Saf 2004; 30:163–171. 36 McClellan MB, Loeb JM, Clancy CM, et al. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in chronic heart failure [letter]. Ann Intern Med 2005; 142:386–387. While focused on measures of heart failure care, this letter highlights the challenges in maintaining performance measures that incorporate contemporary clinical science. 37 Chalasani NP, Valdecanas MA, Gopal AK, et al. Clinical utility of blood cultures in adult patients with community-acquired pneumonia without defined underlying risks. Chest 1995; 108:932–936. 38 Corbo J, Griedman B, Bijur P, Gallagher EJ. Limited usefulness of initial blood cultures in community acquired pneumonia. Emerg Med J 2004; 21:446–448. 39 Kennedy M, Bates DW, Wright SB, et al. Do emergency department blood cultures change practice in patients with pneumonia? Ann Emerg Med 2005; 46:393–400. The authors demonstrate that blood cultures obtained in the emergency department for patients with pneumonia rarely alter patient care. 40 Chang NN, Murray CK, Houck PM, et al. Blood cultures and susceptibility results and allergy history do not influence fluoroquinolone use in the treatment of community-acquired pneumonia. Pharmacotherapy 2005; 25:59–66. In this study, fluoroquinolones were often used to continue treatment of pneumonia patients even in the presence of penicillin-susceptible strains of Streptococcus pneumoniae in patients without documented beta lactam allergy. 41 Walls RM, Resnick J. The Joint Commission on Accreditation of Healthcare Organization’s and Centers for Medicare and Medicaid Service’s communityacquired pneumonia initiative: what went wrong? Ann Emerg Med 2005; 46:409–411. This editorial again highlighted the concerns that the national performance measure for performance of blood cultures in pneumonia patients was not evidence-based. 42 BTS Pneumonia Guidelines Committee. BTS guidelines for the management of community acquired pneumonia in adults: 2004 update. http://www.britthoracic.org.uk/c2/uploads/MACAPrevisedApr04.pdf. [Accessed16 November 2006] 43 Bratzler DW. Blood cultures in pneumonia patients [letter]. Ann Emerg Med 2006; 47:580–581. This letter highlights the process of changing the national process of care measure for blood cultures in pneumonia patients. 44 Marshall MN, Shekelle PG, Leatherman S, Brook RH. The public release of performance data. What do we expect to gain? A review of the evidence. JAMA 2000; 283:1866–1874. 45 Werner RM, Asch DA. The unintended consequences of publicly reporting quality information. JAMA 2005; 293:1239–1244. This review provides a comprehensive discussion of the potential for unintended consequences of publicly reporting information about quality and highlights the relative lack of data showing that public reporting improves patient clinical outcomes. 46 Wachter RM. Expected and unanticipated consequences of the quality and information technology revolutions. JAMA 2006; 295:2780–2783. This article discusses the expected but also unanticipated consequences of the implementation of performance measurement in healthcare, and the potential unintended consequences of rapid deployment of health information technology. 47 Lindenauer PM. Getting a good report card: unintended consequences of the public reporting of hospital quality. AHRQ Morbidity & Mortality Rounds on the Web. http://www.webmm.ahrq.gov/case.aspx?caseID=137. [Accessed 16 November 2006] This is an excellent web-based case report and discussion that highlights the potential for unintended consequences of performance measurement. The framework of potential direct and indirect patient harm from performance measurement is described. 48 Infectious Diseases Society of America. Misuse of pneumonia guidelines raises concerns. IDSA News 2006; 15:1–16. 49 Metersky ML, Sweeney TA, Getzow MB, et al. Antibiotic timing and diagnostic uncertainty in Medicare patients with pneumonia. Chest 2006; 130:16– 21. This paper reviews some of the specific concerns of unintended consequences of measurement of pneumonia quality and highlights that a significant proportion of pneumonia patients who present to an emergency department will have an unclear clinical picture at the time of arrival. 50 Waterer GW, Kessler LA, Wunderink RG. Delayed administration of anti biotics and atypical presentation in community-acquired pneumonia. Chest 2006; 130:11–15. The authors report on the findings from a prospective evaluation of patients presenting to an emergency department and suggest that the observed relationship between first-dose antibiotic timing and patient outcomes for pneumonia may in fact be due to atypical patient presentations. 51 Houck PM. Antibiotics and pneumonia: is timing everything or just a cause of more problems? Chest 2006; 130:1–3. The editor reviews the issues surrounding the controversy about the relationship between first-dose antibiotic timing and patient mortality and discusses the issues that have been raised since the advent of public accountability related to performance measurement. 52 Metersky M, Ma A, Bratzler DW, Houck PM. Predicting bacteremia in patients with community-acquired pneumonia. Am J Resp Crit Care Med 2004; 169:342–347. 53 Casalino LP. The unintended consequences of measuring quality on the quality of medical care. N Engl J Med 1999; 341:1147–1150. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Prevention measures for ventilator-associated pneumonia: a new focus on the endotracheal tube Paula Ramireza, Miquel Ferrerb and Antoni Torresb Purpose of review The aim of this article is to analyze the aspects related to the endotracheal tube which may influence the development of ventilator-associated pneumonia and to review the possible measures of prevention. Recent findings The endotracheal tube participates in the pathogenesis of ventilator-associated pneumonia by the elimination of natural defense mechanisms, thereby allowing the entry of bacteria by the aspiration of subglottic secretions or the formation of biofilm on the endotracheal tube. The preventive measures of ventilator-associated pneumonia related to the endotracheal tube include these two mechanisms. It has been suggested that substitution of the endotracheal tube by early tracheostomy may reduce the risk of ventilator-associated pneumonia. Summary Aspiration of the subglottic secretions seems to be an effective measure with little risk; decontamination or exhaustive control of the sealing of the cuff has not demonstrated a positive risk/benefit balance. The causal relationship between biofilm and ventilator-associated pneumonia has not been clearly established. Treatment of the biofilm with antibiotics, changes in the composition of the endotracheal tube or mechanical cleansing have achieved a reduction or elimination of the biofilm but their effect on the incidence of ventilator-associated pneumonia has not been studied. The benefit of early tracheostomy in reducing ventilator-associated pneumonia is still controversial. Keywords biofilm, prevention, selective digestive decontamination, subglottic secretions, tracheostomy, ventilation-associated pneumonia Curr Opin Infect Dis 20:190–197. ß 2007 Lippincott Williams & Wilkins. a Intensive Care Unit, Hospital Universitario La Fe, Valencia and bRespiratory Intensive and Intermediate Care Unit, Department of Pneumology, Clinical Institute of the Thorax, Hospital Clinic, Barcelona, Spain Correspondence to Antoni Torres, MD, Servei de Pneumologia, Institut Clı́nic del Tòrax, Hospital Clinic, Villarroel, 170. E-08036 Barcelona, Spain Tel/fax: +34 93 227 55 49; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:190–197 Abbreviations CASS ETT ICU SDD SSD VAP continuous aspiration of subglottic secretions endotracheal tube intensive care unit selective decontamination of the digestive tract subglottic secretions drainage ventilator-associated pneumonia ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction In the Corpus Hippocraticum on air in the year 400 BC, Hippocrates mentioned tracheal intubation as a method of ventilating the lungs [1]. Since then, intubation, the endotracheal tube (ETT) itself, and the incorporation of mechanical ventilation have progressed enormously. Despite technological advances, mechanical ventilatorassociated pneumonia (VAP) continues to be a frequent and feared complication [2,3]. The pathogenesis of VAP is closely related to the presence of the ETT and some authors have even suggested that the name of the disease be changed to endotracheal tube-associated pneumonia [4,5]. The insertion of the ETT is an aggressive maneuver that often produces lesions in the tracheal mucosa and the implantation of exogenous and endogenous bacterial inoculum [6]. The presence of the ETT annuls the cough reflex, leads to accumulation of secretions in the subglottic space and does not totally impede their entry into the lung, thereby making it an ideal surface for the formation of biofilm and a risk factor for the development of sinusitis [5–11]. In this article we review all the aspects of the pathogenesis of VAP in relation to the ETT, which have been studied in an attempt to prevent the development of this type of pneumonia. Subglottic secretions The accumulation of secretions from the oropharynx or the gastrointestinal tract in the subglottic space may be demonstrated by radiography [7] or the quantification of the material obtained by local aspiration [12]. Endogenous or exogenous colonization of these secretions is practically unavoidable and the causal relationship with VAP has been well established [6,12–15]. Preventive measures aimed at avoiding VAP include impeding the leakage between the tube and the tracheal wall, and aspiration or sterilization of the secretions. 190 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Ventilator-associated pneumonia Ramirez et al. 191 Control of cuff pressure The maintenance of correct cuff pressure (Pcuff) is essential in patients receiving mechanical ventilation [6,16,17]. Excessive pressure may compromise the microcirculation of the tracheal mucosa and cause ischemic lesions [18,19], while insufficient Pcuff impedes ventilation with positive pressure and may allow the entry of subglottic secretions between the tube and the trachea. Rello et al. [10] analyzed the effect that Pcuff has on the development of VAP in the first 8 days of mechanical ventilation and demonstrated that a maintained Pcuff greater than 20 cmH2O is associated with lower risk. Multivariate analysis, however, only showed that Pcuff maintained at less than 20 cmH2O is an independent risk factor in the subgroup of patients without antibiotic treatment [10]. This was the only study aimed at relating a determined Pcuff value with the risk of developing VAP. Several studies have reported the leakage of secretions despite the maintenance of a correct Pcuff and even at greater than the normal limits [20–22] but did not analyze whether this entry influenced the appearance of VAP. Neither have studies on methods to achieve better control of Pcuff analyzed the effect of these maneuvers on VAP [23–25], except in one case [26] in which better control of Pcuff by an automatic system did not reduce the incidence of VAP. Many studies have evaluated better techniques and their relationship with the aspiration of secretions beyond the endotracheal cuff. The leakage of secretions despite a correct Pcuff has been explained by the formation of folds in the cuff allowing longitudinal leakage [20–22]. The elimination of these folds has been achieved with the use of lubricating gels (effective during 24–120 h) [27], silicone pressure cuffs [28], or the use of low-pressure cuffs [29], yet it has not been proven whether these improvements have been accompanied by a lower incidence of VAP. Therefore, although it is obvious that adequate healthcare intubation and mechanical ventilation must be accompanied by correct Pcuff and that the leakage of secretions to the bronchial tree depends on the Pcuff and its characteristics, there is scarce scientific evidence [10] justifying a close relationship between these elements and the appearance of VAP. Subglottic secretions drainage Based on the inefficacy of the Pcuff in avoiding aspiration and on the considerable volume of secretions that accumulate in the subglottic space [7], a new ETT was developed (HI-LO Evac tube; Mallinckrodt, Hazelwood, Missouri, USA). This new tube has an independent dorsal lumen, which makes it possible to aspirate the subglottic secretions. Four randomized prospective studies have evaluated the effect intermittent or continuous aspiration of subglottic secretions (CASS) has on the appearance of VAP (Table 1) [12,14,15,30]. In all the studies the number of episodes of VAP were reduced but statistical significance was only achieved in two studies (accumulated incidence and rate of incidence per 1000 days of mechanical ventilation) [14,15]. With respect to the influence of subglottic secretions drainage (SSD) on the time of the appearance of VAP, three studies coincide in that SSD produces a delay in the development of VAP (all with statistical significance) [12,15,30]. A fourth study [14] distinguished between the influence of SSD on early and late onset VAP and observed that no changes were produced in the incidence of early VAP. This was attributed to early VAP being more related to the process of intubation. Aspiration of subglottic secretions does not seem to have any effect on mortality, the duration of mechanical ventilation or intensive care unit (ICU) or hospital stay [14,15,30]. The effect of SSD on the colonization of the subglottic space and the trachea has only been evaluated in one study [12] which found that SSD achieved a lower increase in the rate of contamination during ICU stay (þ6.6% versus þ21.2% in the trachea and þ2.1% versus þ33.4% in the subglottic space). Aspiration of subglottic secretions does not affect all the microorganisms involved in pulmonary colonization/infection in the same way. The protective effect described by Valles and Smulders [14,15,30] is derived from a fall in the number of pneumonias caused by Grampositive germs. Mahul did not specify the etiology of the pneumonia based on the use or not of SSD, and in the study by Kollef, the number of pneumonias was too small for any conclusion to be drawn [12,30]. The different effect on the microorganism may be secondary to the selection of late VAP or may be due, at least in part, to a direct action of SSD on the cause of infection. The SSD diminishes the quantity of microorganisms which reach the bronchial tree and since the inoculum necessary to cause VAP by Gram-positive cocci is much greater than that necessary in the case of Enterobacteriaceae or Pseudomonas aeruginosa [31,32], this quantitative effect may explain the differences observed. Another possible explanation is based on the fact that not all microorganisms follow the same pattern of airway colonization [33–36]. P. aeruginosa and probably other nonfermenting Gram-negative bacteria seem to have a greater ability to adhere and colonize the tracheal epithelial cells than buccal or oropharyngeal cells [37–39]. In the studies Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. CASS 160/183 Cardiac surgery Kollef et al. [30] CASS 76/77 Polyvalent Valles et al. [15] ASS, aspiration of subglottic secretions; VAP, ventilator-associated pneumonia; IR, incidence rate episodes of pneumonia/1000 days of ventilation; Time VAP, mechanical ventilation days before onset of VAP; tMV, duration of mechanical ventilation; ICU LOS, intensive care unit length of stay; IASS, intermittent aspiration of subglottic secretions; NE, not evaluated; CASS: continuous aspiration of subglottic secretions. 20 versus 40 RR 1.98 CI 1.03–3.82 NE 12 7 versus 6 2 P < 0.001 6 2 versus 3 1 P ¼ 0.006 4 versus 4 P, NS 9 7 versus 12 4 P, NS 22 2 versus 19 4 P, NS 4 5versus 3 .5 P, NS 6 4 versus 7 5 P, NS 13 1 versus 11 1 P, NS 1.5 3 versus 1.9 5 P, NS IASS Polyvalent Smulders et al. [14] 75/75 4 versus 16 RR 0.22 CI 0.06–0.81 18 versus 33 RR 1.76 CI 0.99–3.12 5 versus 8 RR 0.61 CI 0.27–1.4 9 versus 23 P < 0.001 40 versus 36 P, NS NE NE NE IASS Polyvalent Mahul et al. [12] 70/75 13 versus 29 P < 0.05 NE 16 11 versus 8 5 P < 0.05 NE 16 versus13 P, NS ICU LOS tMV (days) Mortality (%) Time VAP (days) VAP (IR) VAP (%) Type ASS Cases/controls Population Table 1 Prospective and randomized studies analyzing the effects of subglottic secretions drainage 192 Respiratory infections by Mahul et al. [12] and Valles et al. [15], these authors found that there was no colonization prior to the subglottic secretions in a considerable proportion (40% and 16.6%, respectively) of the VAP produced by nonfermenting Gram-negative bacilli. If P. aeruginosa does not colonize or multiply in the subglottic area, the preventive measure of VAP affecting the subglottic secretions will not influence the pneumonia caused by this microorganism. Rello et al. [10] also evaluated the effect of CASS on the risk of developing VAP. In a series of 83 patients receiving mechanical ventilation, they found that the failure of CASS was an independent risk factor for VAP (RR 5.29; 95% CI 1.24–22.64). In studies in humans no adverse effect of SSD has been detected even when establishing the safety of the device was one of the main objectives [30]. Berra et al. [40], however, carried out a study of CASS in sheep and found diffuse lesions in the tracheal mucosa secondary to aspiration. Aspiration of subglottic secretions is a preventive measure which, in clinical practice, does not seem to have severe adverse effects and has shown the capacity of diminishing the incidence of VAP, although the data available to date do not have sufficient statistical power. Decontamination of subglottic secretions Selective decontamination of the digestive tract (SDD), including topical antibiotic application in the oropharynx and the gastrointestinal tract, and the parenteral administration of antibiotics, is a controversial measure aimed at preventing nosocomial infections, and the results of the different studies are not concordant. The most recent meta-analysis [41,42] indicates that SDD would be fundamentally effective in surgical or trauma patients probably due to the use of parenteral antibiotics, and not to topical application. On the other hand, there are abundant data indicating that SDD may promote the appearance of antibiotic resistance and, thus, its systematic use has not been recommended [2,43]. The belief, by some authors, of the lesser importance of the gastrointestinal tract as a source of VAP-producing microorganisms [35] particularly when fulfilling the recommendation of maintaining a semi-recumbent position in all patients receiving mechanical ventilation [44], has led to the application of more local decontamination measures. Modulation of the bacterial flora of the oropharynx by topical antibiotics [45–48] or antiseptics [49] has been effective in the prevention of VAP but its use has again been modified according to the possibility of the appearance of bacterial resistance. A new, more sophisticated version includes continuous infusion of the Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Ventilator-associated pneumonia Ramirez et al. 193 antibiotic solution in the subglottic space by the dorsal HI-LO lumen Mallinckrodt Evac tube with frequent oropharyngeal aspiration: 30 trauma patients were randomly assigned to receive this measure versus 31 controls. The authors described a lower incidence of VAP, the later appearance of VAP, and lower colonization of the bronchial tree [50]. Decontamination in a more or less extensive region seems to have clear beneficial effects with respect to the control of nosocomial infections and may even influence the mortality. The probable effect that these maneuvers seem to have in the selection of microorganisms resistant to antibiotics, however, impedes their generalized use. The indication should be modified on the basis of the characteristics of the unit in which they are performed and the type of patient involved. The bacteria are found in the biofilm as are the causal agents of the infection but they do not always fulfill the postulations of Koch [59]. The correlation between the bacteria present in the biofilm and the etiology of the pneumonia has been analyzed by two authors. Feldman et al. [60] observed that in 13 patients with pneumonia, study of the biofilm of the ETT withdrawn demonstrated the same microorganism in eight cases. Adair et al. [61] observed this correlation in 70% of the patients with pneumonia and in none of the patients who did not develop this complication. The implication of biofilm in the pathogenesis of VAP has not been completely clarified since it may be the source of the infection or may be a reservoir of potentially pathogenic bacteria [62]. Numerous studies, however, have been aimed at preventing, eliminating or decontaminating the biofilm. Biofilm Biofilm is a complex structure made up of bacteria. Bacteria acquire a hypometabolic sessile form, and through the regulation by specific genes secrete a polymeric extracellular substance that makes them strongly adhere to each other and the chosen substrate. Biofilm has been widely studied by industrial microbiology and the findings have been applied to clinical microbiology [51]. The implication of biofilm in infections caused by the presence of artificial endocorporal devices has gained great importance in recent years [52–54]. The nature of biofilm is viscous and adherent, making elimination difficult. Bacteria embedded in biofilm are protected by this mechanical effect, by the difficulty for antibiotics to penetrate and by having greater resistance to antibiotics. Antibiotic resistance is due to the hypometabolic state of the bacteria as well as a genetic regulation that is very close to that which modulates the formation of biofilm itself [55]. Pseudomonas spp. is the paradigm of bacteria that use biofilm as part of their pathogenic arsenal, and its presence in the biofilm has been related to recurrent VAP by this microorganism [56,57]. In 1986 Sottile et al. [58] were the first to detect the presence of biofilm in 25 ETTs used in critically ill patients; 84% were totally covered and 16% partially covered. Later, Inglis et al. [8] found biofilm in 100% of the tubes analyzed, including 17 that had been used for less than 24 h. Microbiologic analysis observed bacteria in 73% of the cases, mainly Pseudomonas spp. and Enterobacteriaceae. These authors simulated mechanical ventilation in vitro with the tubes analyzed and found that the bacteria were projected at least 15 cm with an elliptic distribution [8]. As occurs with other infections potentially related to biofilm, it is difficult to establish a causal relationship. Prevention of the formation of biofilm In an in-vitro study, Jones et al. demonstrated that tubes covered in an antiseptic solution did not present the formation of biofilm [63,64]. These results were also confirmed in vitro showing a lesser degree of colonization in tubes impregnated with chlorhexidine and silver carbonate (P < 0.01). Analysis of the ETT after 5 days demonstrated permanence of the antiseptic in 45% [65]. The in-vivo study was performed in 16 sheep receiving mechanical ventilation. Fifty per cent of the tubes were covered with silver sulfadiazine and chlorhexidine. After 24 h the sheep were sacrificed and a greater presence of intensely colonized biofilm was observed in the ETT of the control group as was greater colonization of the circuit of the respirator (both data statistically significant). Tracheal colonization was greater, albeit not significantly, in the control group (P ¼ 0.119 and P ¼ 0.052 for the total number of tracheas colonized and for the degree of colonization, respectively). Colonization of the pulmonary parenchyma was statistically higher in the control group. The bacteria isolated were identical to those found in the oropharyngeal samples and ETT for each sheep [66]. The use of biomaterial covered with silver for the prevention of nosocomial infections is a measure currently being studied in endovascular and urinary catheters, with demonstrated efficacy in the latter [67]. Olson et al. [68] studied the use of silver-coated ETT in five dogs versus six controls after the administration of a buccal inoculum of P. aeruginosa. After 96 h of mechanical ventilation, the group with the silver-coated ETT showed lower colonization of the ETT by aerobic bacteria (P ¼ 0.009) and by P. aeruginosa (P ¼ 0.076), lesser, albeit not statistically significant, tracheal and main bronchi colonization, and a lower colonization of the pulmonary parenchyma by Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 194 Respiratory infections aerobic bacteria (P ¼ 0.010) and P. aeruginosa (P ¼ 0.055). The use of silver-coated ETT achieved a delay in the appearance of ETT colonization (P ¼ 0.016) and a lower degree of inflammation of the pulmonary parenchyma by histologic study (P < 0.001) [68]. The search for biomaterial and variations of the same to avoid the formation of biofilm is a promising field but has yet to prove its clinical efficacy. On the other hand, part of the economic costs which the commercialization of these devices may represent should be carefully evaluated. Elimination of biofilm Complete mechanical elimination of the mucus and biofilm adhered on the internal surface of the ETT is not possible with the usual aspiration tubes. A device capable of performing mechanical cleansing of the interior of the ETT has recently been designed: the mucus shaver. This device is a tube with an inflatable balloon with two rings on the end. Once the balloon has been inflated in the interior of the ETT, the rings obliterate the tube. The extraction of the tube eliminates all the adhered mucus. Kolobow et al. [69] tested this device in six sheep undergoing mechanical ventilation versus a control group made up of two other sheep. No technical problem or harmful effect was observed in the ventilatory mechanisms and each use of the mucus shaver obtained a mean of 0.35 0.29 g of mucus. After 72 h, electron microscopy analysis of the ETT in the control group showed extensive biofilm formation while this was absent in the study group [69]. The same authors repeated the experience in 12 intubated sheep with ETT impregnated with a silver-sulfadizine solution. Six sheep were treated with the mucus shaver every 6 h. In contrast to the control group, no biofilm was found in the interior of the ETT in the study group after 72 h of mechanical ventilation [70]. This same work group compared the effect of biofilm on the use of parenteral cefotaxime and cefuroxime and gentamycin administered in aerosol. The characteristics of the patients were similar even with respect to the time of mechanical ventilation prior to the study of the ETT. The ETT of the 24 patients treated with parenteral cephalosporins developed biofilm in all the cases and in 62.5% potentially pathogenic microorganisms were found. The ETT of the 12 patients treated with aerosolized gentamycin developed biofilm in 41.6% of the cases but no pathogenic bacteria were isolated. The authors made sequential measurements of the concentration of the antibiotics in the interior of the ETT 2 h after each administration. The concentrations of the cephalosporins were insufficient to inhibit bacterial growth while gentamycin was able to maintain correct concentrations. With respect to the possible appearance of resistance after a 3-year period, only some strains of gentamycin-resistant Staphylococcus aureus have been reported [73]. The use of gentamycin in aerosol may be useful in clinical practice although further studies are necessary to confirm these results. As with the maneuvers designed to treat the biofilm, systematic recommendation requires clinical trials to measure the impact on the incidence of VAP. Early tracheostomy Decontamination of the biofilm Tracheostomy allows oral alimentation and communication and facilitates oral and bronchial cleansing [74]. This technique is not without risk, however, and, thus, its indication and timing should be carefully evaluated [75]. Studies evaluating the possible beneficial effects of early tracheostomy included a population with expected prolonged mechanical ventilation, mainly in patients with trauma or severe cerebral lesions. Several retrospective or non-randomized studies have evaluated early tracheostomy with varied results: a decrease in ICU stay [76,77], a reduction in the duration of mechanical ventilation [76,77–79], a decrease in the incidence of VAP [76,79], a reduction in costs [78] and even an absence of beneficial effects [80]. The two reports including the aims of analyzing the effect of early tracheostomy on the incidence of VAP were retrospective and the criteria used to define pneumonia were not adequate [76,79]. Since biofilm is formed by bacteria, their elimination would also mean the disappearance of the biofilm. Thus, the group of Adair et al. studied the effect of digestive decontamination (amphotericin B, tobramycin and polymyxin) on the biofilm and observed a reduction in colonization by enterobacteria but a persistence of the biofilm formed by Gram-positive bacilli and Pseudomonas spp. On the other hand, the concentration of the antibiotics used in the ETT was erratic and was often lower than the minimum inhibitory concentration necessary, particularly in the case of tobramycin [71,72]. Five methodologically correct, prospective, randomized studies analyzed this subject [81–84,85] and again the results were heterogeneous. The duration of mechanical ventilation diminished in three out of the five studies, with no differences being observed in two. The length of ICU stay was reduced in two and did not differ in the other two. The mortality was reduced in one of the three studies in which this was analyzed and the incidence of VAP only fell in one of the four studies analyzing this endpoint (Table 2). This variability may be due to a lack This novel system of ETT cleansing requires further larger clinical trials to corroborate its clinical efficacy and the absence of undesirable effects in critically ill patients receiving mechanical ventilation. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 30/30 < 8 days Multiple injury Barquist et al. [85] 60/60 2 days Respiratory failure Rumbak et al. [84] 21/23 Next operative day Burns Saffle et al. [83] 51/55 <8 days Multiple injury Rodriguez et al. [82] ET, early tracheotomy; tMV, duration of mechanical ventilation; ICU LOS, intensive care unit length of stay; VAP, ventilator-associated pneumonia. NE: not evaluated. 5 versus 25 P < 0.005 32 versus 62 P < 0.005 of homogeneity in regard to the type of population and the temporal definition of early tracheostomy. With respect to VAP the diagnostic criteria used also differed. In two studies quantitative microbiologic cultures were not used [81,83] and in those using clinical manifestations together with quantitative culture one observed a reduction in the incidence of VAP [84] and the other did not [85]. 97 versus 90 P, NS 100 versus 96 P, NS 19 versus 26 P, NS 7 versus 16 P, NS 78 versus 96 P < 0.05 18 versus 23 P, NS 16 1 versus 37 4 P < 0.05 58 6 versus 57 8 P, NS 5 1 versus 16 4 P < 0.001 25 6 versus 25 7 P, NS 58 versus 61 P, NS 39 versus 23 P, NS 31/31 Head injury Bouderka et al. [81] 5 days 15 7 versus 18 11 P ¼ 0.02 12 1 versus 32 3 P < 0.05 36 5 versus 31 5 P, NS 7 2 versus 17 5 P < 0.001 21 8 versus 21 9 P, NS NE VAP (%) tVM (days) Cases/controls ET definition Population Table 2 Prospective and randomized studies comparing early and late tracheotomy ICU LOS Mortality (%) Ventilator-associated pneumonia Ramirez et al. 195 A recent meta-analysis concluded that early tracheostomy achieves a reduction in the duration of mechanical ventilation and ICU stay but does not modify either the mortality or the risk of VAP [86]. Conclusion The presence of ETT is currently unavoidable in most patients undergoing mechanical ventilation and its presence as a foreign endocorporal body participates in the appearance of VAP. The ETT eliminates some of the natural defense mechanisms of the airway and provides a vehicle through which the microorganisms may pass to the interior of the lung by the entry of subglottic secretions or the formation of biofilm on the surface of the ETT. The accumulation and posterior entry of contaminated subglottic secretions into the lung seems to have a relevant role in the pathogenesis of VAP. Thus, subglottic aspiration may be an effective measure of prevention. Selective decontamination or more exhaustive than usual control of Pcuff have not, to date, demonstrated evident benefits. The causal association between VAP and the biofilm of the ETT has not been strongly established, although, in any case, the biofilm would act as a reservoir of bacteria. The measures tested to treat the biofilm have been able to reduce or eliminate their presence but have not as yet proven to be effective in avoiding VAP. The substitution of the ETT by tracheostomy does not seem to be an effective measure to diminish the incidence of VAP. To date, the actions studied with respect to the ETT have not been able to counteract the deleterious effects of this device as a factor favoring VAP but the advances achieved indicate a more favorable future. Acknowledgements Supported by CIBER (CB06/06/0028), 2005 SGR 00822, and IDIBAPS. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 217–218). 1 Hypocrates. Corpus Hippocraticum. Biblioteca Clásica Gredos. Spanish 1st edition. Madrid: Editorial Gredos; 2000. Niederman MS, Craven DE. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. 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Oropharyngeal decontamination decreases incidence of ventilator-associated pneumonia: A randomized, placebo-controlled, double-blind clinical trial. JAMA 1991; 265:2704–2710. 23 Young PJ, Basson C, Hamilton D, et al. Prevention of tracheal aspiration using the pressure-limited tracheal tube cuff. Anaesthesia 1999; 54:559– 563. 24 Farre R, Rotger M, Ferrer M, et al. Automatic regulation of the cuff pressure in endotracheally-intubated patients. Eur Respir J 2002; 20:1010–1013. 25 Abdelatti MO. A cuff pressure controller for tracheal tubes and laryngeal mask airways. Anaesthesia 1999; 54:981–986. 26 Ferrer M, Valencia M, Farre R, et al. Automatic control of tracheal tube cuff pressure in mechanically-ventilated patients in semirecumbent position [abstract]. Proc Am Thorac Soc 2006; 3:A525. 27 Blunt MC, Young PJ, Patil A, et al. Gel lubrication of the tracheal tube cuff reduces pulmonary aspiration. Anesthesiology 2001; 95:377–381. 28 Young PJ, Burchett K, Harvey I, et al. The prevention of pulmonary aspiration with control of tracheal wall pressure using a silicone cuff. Anaesth Intensive care 2000; 28:660–665. 29 Young PJ, Pakeerathan S, Blunt MC, et al. A low-volume, low-pressure tracheal tube cuff reduces pulmonary aspiration. Crit Care Med 2006; 34:632–639. A new model of low volume low pressure ETT is tested in an experimental model and in anesthetized patients showing a decrease in the incidence of aspiration. 48 Rodriguez-Roldan JM, Altuna-Cuesta A, Lopez A, et al. Prevention of nosocomial lung infection in ventilated patients: Use of an antimicrobial pharyngeal nonabsorbable paste. Crit Care Med 1990; 18:1239–1242. 49 DeRiso AJII, Ladowski JS, Dillon TA, et al. Chlorexidine gluconate 0.12% oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic systemic antibiotic use in patients undergoing cardiac surgery. Chest 1996; 109:1556–1561. 50 Pneumatikos I, Koulouras V, Nathanail C, et al. Selective decontamination of subglottic area in mechanically ventilated patients with multiple trauma. Intensive Care Med 2002; 28:432–437. 51 Donlan RM, Costerton W. Biofilms: Survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 2002; 15:167–193. 52 Donlan RM. Biofilm formation: a clinically relevant microbiological process. Clin Infect Dis 2001; 33:1387–1392. 53 Gilbert P, McBain AJ. Biofilms: their impact on health and their recalcitrance toward biocides. Am J Infect Control 2001; 29:252–255. 54 Donlan RM. Biofilms and device-associated infections. Emerg Infect Dis 2001; 7:277–281. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Ventilator-associated pneumonia Ramirez et al. 197 55 Stewarts PS, Costernon JW. Antibiotic resistance of bacteria in biofilms. Lancet 2001; 358:135–138. 56 Prince AS. Biofilms, antimicrobial resistance, and airway infection. N Engl J Med 2002; 347:1110–1111. 72 Adair CG, Gorman SP, O’Neill FB, et al. Selective decontamination of the digestive tract (SDD) does not prevent the formation of microbial biofilms on endotracheal tubes. J Antimicrob Chemother 1993; 31:689 – 697. 57 Cai S, Zhang J, Qian G. Correlation of endotracheal tube biofilm and recurrent ventilator-associated pneumonia with Pseudomonas aeruginosa. Zhonghua Jie HeHe Hu Xi Za Zhi 2001; 24:339–341. 73 Adair CG, Gorman SP, Byers LM, et al. Eradication of endotracheal tube biofilm by nebulised gentamycin. Intensive Care Med 2002; 28:426– 431. 58 Sottile FD, Marrie TJ, Prough DS, et al. Nosocomial pulmonary infection: possible etiologic significance of bacterial adhesion to endotracheal tubes. Crit Care Med 1986; 14:267–270. 74 Heffner JE, Miller KS, Sahn SA. Tracheostomy in the intensive care unit. Part I: Indications, technique, management. Chest 1986; 90:269–274. 59 Davis BD. Evolution of microbiology and of microbes. In: Davis BD, Dulbecco H, Eisen N, et al., editors. Microbiology, 3rd ed. Philadelphia: Harper and Row; 1980. p. 7. 60 Feldman C, Kassel M, Cantrell J, et al. The presence and sequence of endotracheal tube colonization in patients undergoing mechanical ventilation. Eur Respir J 1999; 13:546–551. 61 Adair C, Gorman SP, Feron BM, et al. Implications of endotracheal tube biofilm for ventilator-associated pneumonia. Intensive Care Med 1999; 25:1072–1076. 62 Bauer TT, Torres A, Ferrer R, et al. Biofilm formation in endotracheal tubes. Association between pneumonia and the persistence of pathogens. Monaldi Arch Chest Dis 2002; 57:84–87. 63 Jones DS, McGovern JG, Woolfson AD, et al. Physicochemical characterization of hexetidine-impregnated endotracheal tube poly (vinyl chloride) and resistance to adherence of respiratory bacterial pathogens. Pharm Res 2002; 19:818–824. 64 Jones DS, McMeel S, Adair CG, et al. Characterization and evaluation of novel surfactant bacterial antiadherent coatings for endotracheal tubes designed for the prevention of ventilator-associated pneumonia. J Pharm Pharmacol 2003; 55:43–52. 65 Pacheco-Fowler V, Gaonkar T, Wyer PC, et al. Antiseptic impregnated endotracheal tubes for the prevention of bacterial colonization. J Hosp Infect 2004; 57:170–174. 66 Berra L, De Marchi L, Yu ZX, et al. Endotracheal tubes coated with antiseptics decrease bacterial colonization of the ventilator circuits, lungs and endotracheal tube. Anesthesiology 2004; 100:1446–1456. 67 Stickler DJ. Biomaterials to prevent nosocomial infections: is silver the gold standard? Curr Opin Infect Dis 2000; 13:389–393. 68 Olson ME, Harmon BG, Kollef MH. Silver-coated endotracheal tubes associated with reduced bacterial burden in the lungs of mechanically ventilated dogs. Chest 2002; 121:863–870. 69 Kolobow T, Berra L, Li Bassi G, et al. Novel system for complete removal of secretions within the endotracheal tube. The mucus shaver. Anesthesiology 2005; 102:1063–1065. A new system designed for a complete removal of biofilm, the mucus shaver, is successfully tested in this study. 70 Berra L, Curto F, Li Bassi G, et al. Antibacterial-coated tracheal tubes cleaned with the mucus shaver. A novel method to retain long-term bactericidal activity of coated tracheal tubes. Intensive Care Med 2006; 32:888–893. Mucus shaver use in eight sheep resulted in a lower colonization of endotracheal tubes, trachea and ventilator circuits. 71 Gorman SP, Adair CG, O’Neill FB, et al. Influence of selective decontamination of the digestive tract on microbial biofilm formation on endotracheal tubes from artificially ventilated patients. Eur J Clin Microbiol Infect Dis 1993; 12:9–17. 75 Heffner JE, Miller KS, Sahn SA. Tracheostomy in the intensive care unit. Part II: Complications. Chest 1986; 90:430–436. 76 Möller MG, Slaikeu JD, Bonelli P, et al. Early tracheostomy versus late tracheostomy in the surgical intensive care unit. Am J Surg 2005; 189: 293–296. In this retrospective study early tracheostomy resulted in a decreased ICU stay, a reduction in the duration of mechanical ventilation and in the incidence of VAP. 77 Armstrong PA, McCarthy MC, Peoples JB. Reduced use of resources by early tracheostomy in ventilator-associated patients with blunt trauma. Surgery 1998; 124:766–767. 78 Arabi Y, Haddad S, Shirawi N, et al. Early tracheostomy in intensive care trauma patients improves resource utilization: a cohort study and literature review. Crit Care 2004; 8:R347–R352. 79 Lesnik I, Rappaport W, Fulginiti J, et al. The role of early tracheostomy in blunt, multiple organ trauma. Am Surg 1992; 58:346–349. 80 Sugerman HJ, Wolfe L, Pasquale MD, et al. Multicenter, randomized, prospective trial of early tracheostomy. J Trauma 1997; 43:741–747. 81 Bouderka MA, Kakhir B, Bouaggad A, et al. Early tracheostomy versus prolonged endotracheal intubation in severe head injury. J Trauma 2004; 57:251–254. 82 Rodriguez JL, Steinberg SM, Luchetti FA, et al. Early tracheostomy for primary airway management in the surgical critical care setting. Surgery 1990; 108:655–659. 83 Saffle JR, Morris SE, Edelman L. Early tracheostomy does not improve outcome in burn patients. J Burn Care Rehabil 2002; 23:431– 438. 84 Rumbak MJ, Newton M, Truncale T, et al. A prospective, randomized, study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal intubation (delayed tracheotomy) in critically ill medical patients. Crit Care Med 2004; 32:1689–1694. 85 Barquist ES, Amortegui J, Hallal A, et al. Tracheostomy in ventilator dependent trauma patients: a prospective, randomized intention-to-treat study. J Trauma 2006; 60:91–97. This describes a prospective and randomized study in 60 trauma patients. Early tracheostomy (<8 days) was performed in 30 patients and no differences were found in duration of mechanical ventilation, VAP incidence or length of ICU stay. 86 Griffiths J, Barber VS, Morgan L, et al. Systematic review and meta-analysis of studies of the timing of tracheostomy in adult patients undergoing artificial ventilation. BMJ 2005; 330:1243–1246. This recent meta-analysis concluded that early tracheostomy leads to a reduction in the duration of mechanical ventilation and ICU stay but does not modify either the mortality or the risk of VAP. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Therapy of nontuberculous mycobacterial disease David E. Griffith Purpose of review Nontuberculous mycobacterial disease, especially pulmonary disease, is increasingly encountered by clinicians. Therapy of the most common nontuberculous mycobacterial pathogen, Mycobacterium avium complex, improved with the introduction of macrolide-containing regimens, but treatment for this and most other nontuberculous mycobacterial pathogens remains difficult. Recent findings Treatment trials with macrolide-containing regimens for Mycobacterium avium complex lung disease have yielded generally favorable outcomes. Studies consistently show that in-vitro susceptibility to macrolides remains the only invitro susceptibility for Mycobacterium avium complex that correlates with in-vivo response. Patients who have macrolide-resistant Mycobacterium avium complex isolates are much harder to treat and have higher mortality than patients with macrolide-susceptible isolates. Studies also consistently show that patients who fail therapy, even those who remain macrolide susceptible in vitro, are more difficult to treat than patients without previous therapy. Summary There have been no significant treatment advances for Mycobacterium avium complex lung disease, and nontuberculous mycobacterial disease in general, since the advent of the newer macrolides. It has become clear that the best opportunity for treatment success is the first treatment effort. It is also clear that protection against the emergence of macrolide-resistant Mycobacterium avium complex isolates is critically important. For further progress in the treatment of these pathogens, new and more active drugs must be developed. Keywords ethambutol, macrolide, Mycobacterium avium complex, Mycobacterium kansasii, nontuberculous mycobacteria, rifabutin Curr Opin Infect Dis 20:198–203. ß 2007 Lippincott Williams & Wilkins. University of Texas Health Center at Tyler, Tyler, Texas, USA Correspondence to David E. Griffith, MD, Professor of Medicine, University of Texas Health Center at Tyler, 11937 US Highway 271, Tyler, TX 75708, USA Tel: +1 903 877 7267; fax: +1 903 877 5566; e-mail: [email protected] Current Opinion in Infectious Diseases 2007, 20:198–203 Abbreviations AFB MAC MIC NTM t.i.w. TNF acid-fast bacilli Mycobacterium avium complex minimum inhibitory concentration nontuberculous mycobacterial 3 times weekly tumor necrosis factor ß 2007 Lippincott Williams & Wilkins 0951-7375 Introduction The history of treatment for nontuberculous mycobacterial (NTM) lung disease can be divided into two distinct eras. The first was the era of antituberculous medications which were used primarily because of the clinical similarities between tuberculosis and NTM disease. Although the antituberculous drugs had less activity against most NTM diseases compared to their activity against Mycobacterium tuberculosis, they were still associated with some treatment success for many NTM species including M. avium complex (MAC). The current era emerged after the appearance of AIDS, which was associated with severe disseminated NTM infections, primarily due to MAC. The major advance in this era was the discovery that the macrolides, clarithromycin and azithromycin, had significantly better activity against MAC than antituberculous medications alone. Although a major step forward from the era of antituberculous medications, it is increasingly clear that the macrolides and macrolide-containing regimens too frequently yield disappointing results for patients with disease due to MAC and other NTM pathogens. The following discussion of treatment for NTM disease will focus on MAC lung disease for three reasons. (1) Although limited, there are more published treatment data about MAC than any other NTM disease. (2) MAC lung disease is the most commonly encountered NTM disease syndrome and the most clinically important to the largest number of clinicians. (3) MAC best exemplifies important, sometimes counter-intuitive and frequently frustrating differences between the treatment of NTM diseases and tuberculosis. Treatment of M. avium complex lung disease Field et al. [1] recently published a comprehensive review of treatment studies for MAC lung disease. To summarize, these studies support two important conclusions about the role of macrolides in MAC lung disease: (1) 198 Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Nontuberculous mycobacterial disease Griffith in-vitro susceptibility for macrolides is the only in-vitro susceptibility for MAC that correlates with in-vivo response and (2) in spite of significant limitations, macrolides remain the cornerstone of multidrug therapy for MAC lung disease. M. avium complex lung disease and macrolide in-vitro susceptibility In an early multicenter trial clarithromycin was given either as monotherapy or with various companion drugs to MAC lung disease patients [2]. Seventy-one per cent of patients had persistently negative sputum acid-fast bacilli (AFB) cultures at the end of treatment and patients who failed therapy or relapsed usually had an acquired resistance to clarithromycin. In a subsequent single-center, noncomparative trial of MAC lung disease, patients received clarithromycin initially as monotherapy with companion medications added either after 4 months of macrolide monotherapy or with conversion of sputum to AFB culture-negative, whichever occurred first [3]. Fifty-eight per cent became sputum AFB culture-negative and 21% showed significant reductions in sputum positivity with clarithromycin monotherapy. At 6 months, three patients developed clarithromycin-resistant MAC isolates, which were associated with clinical and microbiologic relapse. In a similar single-center, noncomparative trial, patients with MAC lung disease received azithromycin initially as monotherapy, with companion medications added as in the study cited above [3,4]. On azithromycin alone, 38% of these patients had conversion of sputum to AFB culture-negative, while an additional 38% had a decrease in sputum culture-positivity while on azithromycin montherapy. Two patients eventually developed macrolide-resistant MAC isolates. These studies in patients with MAC lung disease, combined with macrolide monotherapy trials for human immunodeficiency virus-seropositive patients with disseminated MAC disease, are the basis for the assertion that macrolides are the only (single) agents used for treatment of MAC disease for which there is a correlation between in-vitro susceptibility and in-vivo (clinical) response [2–5]. Specifically, treatment success correlates with in-vitro macrolide susceptibility, while conversely, patients who have MAC isolates that are macrolide resistant do not respond favorably to macrolide-containing regimens. This fundamental relationship has not been established for any other agent in the treatment of MAC lung disease. The revised American Thoracic Society NTM disease guidelines will recommend that clarithromycin is the only drug recommended for susceptibility testing for 199 new, previously untreated MAC isolates [6]. Clarithromycin is recommended as the ‘class agent’ for testing of the newer macrolides since clarithromycin and azithromycin share cross-resistance and susceptibility. The utility of susceptibility testing for other agents is unproven and remains controversial. Macrolide-containing regimens for M. avium complex lung disease Subsequent studies have demonstrated the efficacy, albeit variable, of both daily and intermittent macrolide-containing regimens for the treatment of MAC lung disease. In an early analysis of patients treated with clarithromycin-containing regimens including ethambutol and rifabutin or rifampin and initial streptomycin, 92% of the patients had sustained conversion of sputum to AFB culture-negative [7]. In another study, in MAC lung disease patients who received a daily azithromycin-containing regimen with companion drugs similar to those given in the clarithromycin study cited above, 59% of the patients had sustained conversion of sputum to AFB culture-negative [8]. A study from Japan evaluated the effect of daily clarithromycin with ethambutol, rifampin and kanamycin intramuscularly 3 times weekly (t.i.w.) for the initial 2–6 months of therapy followed by the addition of a quinolone given daily. Eighty-four per cent of patients had sustained conversion of sputum to AFB culture-negative [9]. In a more recent study, Kobashi and Matsushima [10] reported 71 patients with MAC lung disease who received at least 12 months of therapy including clarithromycin (either 400 or 600 mg/day), rifampin and ethambutol plus streptomycin for the first 12 months of therapy. It is noteworthy that these authors used a lower dose of clarithromycin than was used in previous studies. Fifty-eight per cent converted their sputum to AFB culture-negative within 6 months; however, 39% relapsed after discontinuation of medication. The species, M. intracellulare or M. avium, did not affect sputum conversion rate or clinical improvement. In early trials of intermittent therapy, azithromycin was given t.i.w. while companion medications were given daily or azithromycin and all companion medications were given on a t.i.w. basis [8]. Fifty-five per cent of patients with the first regimen and 65% of patients receiving the second (all intermittent) regimen had sustained conversion of sputum to AFB culture-negative. At 6 months, t.i.w. clarithromycin and companion drugs was associated with conversion of sputum to AFB culture-negative in 78% of patients [11]. Lam et al. [12] recently published the results of a multicenter MAC treatment trial involving 91 patients with moderate to severe MAC lung disease who received Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 200 Respiratory infections t.i.w. therapy with a macrolide (usually clarithromycin), rifamycin (usually rifampin) and ethambutol with or without inhaled interferon-g. Fifty-eight patients completed at least 1 year of therapy. Forty-nine patients (54%) had primarily cavitary disease, while 42 (46%) had primarily noncavitary or nodular/bronchiectatic disease. Treatment responses included 44% with improved AFB culture results (20% with cavitary disease, 71% in the nodular/bronchiectatic group) although the culture conversion to negative rate was only 13% (4% cavitary, 24% nodular/bronchiectatic). Treatment response rates did not differ between those patients who received clarithromycin or azithromycin or between those who received rifampin or rifabutin. Culture response was significantly lower for patients with cavitary disease, AFB smear-positive result at baseline, history of previous treatment for MAC and shorter duration of ethambutol use. From this study, it appears that patients with moderate to severe MAC lung disease or those who have failed previous treatment attempts should not receive intermittent therapy for MAC lung disease. Most published studies of MAC lung disease patients treated with a macrolide-containing regimen have employed an injectable agent early (in the first 2–4 months) in the course of therapy [3,4,7–10]. Recently, Kobashi et al. [13] published a prospective comparative trial in MAC lung disease patients of regimens including rifampin, ethambutol and clarithromycin with or without intramuscular streptomycin 15 mg/kg/t.i.w. In this trial, 73 patients received oral antimicrobials with streptomycin and 73 received oral antimicrobials without streptomycin. The sputum conversion rate at the completion of treatment was significantly higher in the group receiving streptomycin than in the group without the injectable agent. There were, however, no significant differences in the sputum relapse rate and clinical improvement (symptoms and radiographic findings) between the two treatment groups. There have been no head-to-head trials comparing clarithromycin- and azithromycin-containing regimens. It is assumed that the two agents can be used interchangeably for patients intolerant of one agent. The choice of a rifamycin, rifampin or rifabutin, has also not been directly compared. Rifabutin is theoretically superior to rifampin because of better in-vitro activity than rifampin for MAC and better in-vivo activity for prophylaxis and treatment of disseminated MAC disease in studies of HIV-seropositive patients [14,15]. Rifabutin has less hepatic cytochrome P450 stimulation than rifampin, resulting in less effect on other drug levels compared to rifampin. In spite of these differences, no study has demonstrated that rifampin-containing regimens result in increased treatment failure rates or promote the emergence of macrolide-resistant MAC isolates com- pared to rifabutin-containing regimens [7–10]. Additionally, in multidrug regimens that contain rifabutin, rifabutin is the drug least well tolerated and most often associated with adverse events [7–9]. Aspects of M. avium complex and nontuberculous mycobacterial therapy that differ from tuberculosis in-vitro susceptibility testing The greatest frustration with MAC treatment regimens is a consequence of the expectation that NTM infections should ‘behave’ in a predictable manner similar to M. tuberculosis, i.e. treatment regimens should be based on in-vitro susceptibility testing and the organism (and disease) should respond to antimicrobial agents based on in-vitro susceptibility results. The most difficult aspect of MAC therapy for most clinicians to understand is the lack of a clear association between in-vitro susceptibility results and clinical (in-vivo) response, for almost all agents with the notable exceptions of clarithromycin and azithromycin, as previously discussed. For many NTM species, including MAC, laboratory cutoffs for ‘susceptible’ and ‘resistant’ do not have a demonstrable clinical correlate, and have not been confirmed to be clinically meaningful. There is, therefore, little data to validate susceptibility testing for MAC and other NTM species (M. abscessus, M. simiae, M. malomoense, etc.) as a guide for choosing antibiotics for treatment of these organisms. The clinician should use in-vitro susceptibility data for many NTM species with the awareness that, unlike tuberculosis, NTM disease may not be eradicated in a given patient with therapy based on in-vitro susceptibility results. A prospective, controlled and comparative study, begun in the late 1980s in Great Britain, evaluated antituberculosis medications for treatment of MAC lung disease [16]. Patients received rifampin and ethambutol or rifampin, ethambutol and isoniazid. Seventy-five patients entered the study, 11 patients were treatment failures and 10 had relapses. Forty-five (60%) were alive at 5 years, of which 23 (31%) were confirmed cured. There was no correlation between treatment response and in-vitro susceptibility of the patient’s MAC isolate to any of the agents utilized. Kobashi et al. [17] recently reported the results of drug susceptibility testing and clinical outcome from 52 patients with pulmonary MAC disease who were treated with rifampin, ethambutol, clarithromycin and streptomycin. Thirty patients had M. avium and 22 patients had M. intracullulare isolated from their sputum. Generally, there were slightly lower minimum inhibitory concentrations (MICs) for M. intracellulare compared to M. avium, but there were no significant differences in clinical response to medication between the two species. There was no relationship between clinical response and the Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Nontuberculous mycobacterial disease Griffith MICs for rifampin, ethambutol and streptomycin, although, consistent with previous findings, clinical efficacy did correlate with clarithromycin MICs. In the previously cited trial from Kobashi et al. [13] comparing multidrug regimens with or without streptomycin, clinical outcome with streptomycin did not correlate with in-vitro susceptibility to streptomycin. The explanation(s) for the apparent dichotomy between in-vitro susceptibility results and in-vivo response (clinical outcome) for most MAC treatment agents is (are) currently not known. There are, however, some very important implications of this observation. As noted, there has not been a demonstrated correlation between ethambutol in-vitro susceptibility and clinical response [16,17]. The importance of ethambutol in multidrug MAC treatment regimens, however, regardless of in-vitro susceptibility results, is demonstrated in two studies. In the previously cited study by Lam et al. [12] the duration of ethambutol use was associated with improved microbiological response for patients receiving an intermittent clarithromycin-containing regimen. In a second study of patients with macrolide-resistant MAC isolates (described in detail below), the exclusion of ethambutol from treatment regimens was a major risk factor for the development of macrolide-resistant MAC [18]. It would be potentially risky to the patient for a physician to exclude ethambutol from a multidrug MAC treatment regimen based on in-vitro susceptibility results. Clinical consequences of macrolide-resistant M. avium complex disease In contrast to most drugs, the demonstration of in-vitro resistance to macrolide has a significant clinical impact. Griffith et al. [18] recently published the clinical features and outcome of 51 patients with macrolideresistant (MIC 32 mg/ml) MAC lung disease identified over a 15-year period at a single center. Of these 51 patients, 27 patients had primarily cavitary disease, while 24 patients had primarily nodular/bronchiectatic disease. Sequencing of the 23S ribosomal RNA gene showed that 49/51 macrolide-resistant MAC isolates (96%) had the previously described point mutation in the macrolidebinding region (peptidyltransferase) of the 23 S ribosomal RNA gene at adenine 2058 or 2059. This mutation results in cross-resistance between clarithromycin and azithromycin. The major risk factors for development of macrolide resistance were the use of macrolide monotherapy or the combination of macrolide with only a quinolone as a companion drug. There was no apparent difference in risk for the development of macrolide resistance between patients who had been treated with clarithromycin or azithromycin and those that received daily or intermittent therapy. The development of macrolide resistance had a profound effect on the 201 patients’ response to therapy. Sputum conversion to AFB culture-negative with macrolide-resistant MAC disease occurred in 11/14 (79%) patients who received more than 6 months of aminoglycoside therapy combined with surgical resection of diseased lung (usually a debulking procedure). Culture conversion was achieved in only 2/37 (5%) of patients who did not have both prolonged parenteral therapy and surgical resection. The 1-year mortality for patients who remained AFB culture-positive was 34% compared to 0% for those patients who became AFB culture-negative. The development of macrolide-resistant MAC disease is very difficult to treat successfully and ominous from the perspective of prognosis. The value of adding additional drugs to which the organism appears susceptible in vitro to standard therapy is unknown. A recent study from Canada involving patients primarily with nodular bronchiectatic disease suggested that clofazimine with clarithromycin and ethambutol was effective and prevented the emergence of MAC resistant isolates [19]. Clofazimine has not been effective for treatment or prophylaxis of disseminated MAC disease and is contraindicated for AIDS patients because of increased mortality with some clofazimine containing regimens [20]. The study by Field and Cowie [19] yielded impressive microbiological results, but it is unclear how much of that response was attributable to the clofazimine. Similarly, the role of other agents, especially the 8-methoxy fluoroquinolone, moxifloxacin, is not defined. Although some MAC isolates show ‘susceptible’ MICs to moxifloxacin, it is unknown if these agents have significant in-vivo activity against MAC. Effect of prior therapy MAC therapy is complicated by a second difficult to explain observation. Patients who have failed prior MAC therapy, with or without a macrolide, have lower sputum conversion rates with macrolide-containing treatment regimens, even with macrolide-susceptible MAC isolates, than do patients with no prior therapy [7–9,12]. Kobashi and Matsushima [21] recently reported a series of patients who failed therapy and were retreated with either the same macrolide-containing regimen or a regimen that also included a newer quinolone. Consistent with previous observations, they found that in these patients clinical or microbiologic improvement could not be achieved after a failed attempt at therapy. It is clear that the best chance for treatment success in MAC lung disease is the first treatment effort. M. avium complex reinfection A third complicating factor is that patients who appear to have disease relapse, either during or after therapy, are often reinfected by new strains of MAC [22]. Certainly, reinfection can occur in tuberculosis patients, especially Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. 202 Respiratory infections those with severe immune compromise. Reinfection would not be expected, however, in immune-competent tuberculosis patients with the apparent frequency that it occurs in patients with MAC lung disease. For patients who initially have sputum conversion to culture-negative while on medication, but who subsequently develop positive cultures for MAC after discontinuing therapy, many of these patients are reinfected by new MAC strains (genotypes) rather than manifesting disease relapse with their initial MAC strain [22]. The timing of the positive culture is strongly associated with either relapse or reinfection. Patients who initially convert their sputum but stop therapy after only 6–10 months of negative cultures and then have multiple positive cultures are likely to have relapse of disease with the original MAC strain. Patients who complete 10–12 months of negative cultures on therapy but then have either single or multiple positive MAC cultures are more likely to have reinfection with a new MAC strain. The reinfection isolates are uniformly susceptible to macrolides and are almost exclusively seen in the patients with underlying bronchiectasis. Other nontuberculous mycobacteria Multiple isolates, either due to relapse or reinfection, are usually associated with recurrence of clinical symptoms and are an indication of renewed clinical disease requiring reinstitution of MAC therapy, while single reinfection MAC isolates that occur after completion of therapy may not be a harbinger of renewed or progressive MAC disease requiring therapy. There is growing concern about the impact of tumor necrosis factor-a inhibitors on the development and severity of tuberculosis disease. It is unclear if the tumor necrosis factor-a inhibitors have the same impact on NTM pathogens, although sporadic case reports are surfacing [28]. Until there is more information, clinicians should use the tumor necrosis factor-a inhibitors with caution in patients with diagnosed or suspected NTM disease. Miscellaneous aspects of M. avium complex therapy Field and Cowie [26] have also recently published a review of clinical aspects, including therapy, for other NTM species. This review demonstrates the relative paucity of recently published studies in this area. One study of 15 patients who received t.i.w. rifampin, ethambutol and clarithromycin suggests that intermittent therapy for M. kansasii disease can be successful [27]. With the number of potent new drugs with excellent in-vitro activity against M. kansasii, such as the 8-methoxy fluoroquinolones (e.g. moxifloxacin), it is possible that even shorter (6–9 months) treatment courses might be effective as well. Surgery plays an important role in the therapy of patients with NTM lung disease, especially due to organisms for which there is no established or effective treatment modality, such as macrolide-resistant MAC lung disease [12]. In general, the more difficult an organism is to treat medically (such as M. abscessus), the more likely that surgery will be an important adjunct to the medical therapy. Although limited, knowledge is accumulating about the acquisition and pathogenesis of NTM infections. Accordingly, strategies to prevent NTM infections are also evolving. It has become clear, for instance, that avoidance of tap water in any form, in the cleaning of instruments and the handling of clinical specimens, is critical for the avoidance of nosocomial NTM infection and pseudoinfection [6,29]. Ethambutol ocular toxicity occurs more frequently in the treatment of MAC lung disease patients than in patients taking ethambutol for tuberculosis. The risk appears to be greater when ethambutol is given on a daily basis versus intermittent (t.i.w.) administration [23]. In one study of 229 patients receiving ethambutol as part of MAC lung disease therapy, 6% of patients on daily therapy compared to 0% on t.i.w. therapy developed ethambutol ocular toxicity [23]. Conclusion MAC can also be associated with a hypersensitivity-like lung disease following inhalation of the organism via an infected aerosol. This syndrome has been most frequently associated with hot tub use and therefore has been labeled ‘hot tub lung’. In addition to hot tubs and other standing water exposures, a case of hypersensitivity-like lung disease has been reported as a consequence of aerosol exposure associated with a household shower [24]. So far there is not consensus about therapy as patients frequently improve spontaneously with avoidance of the infected aerosol [25]. Most experts, however, recommend steroid therapy for patients with severe hypersensitivity-like disease [6,25]. The limitations of macrolide-containing regimens for MAC lung disease and other NTM infections are all too evident. Some clear messages for treatment of MAC lung disease are, however, emerging. First, the initial treatment effort is the best chance for cure. If treatment for cure is the goal, it is better to be aggressive initially than to begin therapy tentatively and become more aggressive with time. It is also clear that the macrolide in the multidrug treatment regimen must be protected with adequate companion drugs to prevent the emergence of a macrolide-resistant MAC strain. Lastly, isolation of MAC late in the course of therapy or after therapy has been completed is frequently due to reinfection rather than disease relapse. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Nontuberculous mycobacterial disease Griffith The inescapable conclusion is that the next era in NTM disease therapy will require better antimicrobial agents with improved in-vitro and in-vivo activity against MAC, as well as other NTM species. Although there is not a strong effort to develop new drugs for NTM disease per se, there is unprecedented activity in the development of new antituberculous drugs, spurred by the emergence of extensively drug-resistant M. tuberculosis strains [30]. Some of these drugs will also have activity against NTM species, such as the diarylquinilines [31]. Perhaps as in the past, the next era of NTM therapy will be ushered in as a byproduct of therapeutic advances for a related process. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 220–221). 1 Field SK, Fisher D, Cowie RL. Mycobacterium avium complex pulmonary disease in patients without HIV infection. Chest 2004; 126:566–581. 2 Dautzenberg BD, Piperno P, Diet C, et al. Clarithromycin in the treatment of Mycobacterium avium lung infections in patients without AIDS. Chest 1995; 107:1035–1040. 3 Wallace RJ Jr, Brown BA, Griffith DE, et al. Initial clarithromycin monotherapy for Mycobacterium avium-intracellulare complex lung disease. Am J Respir Crit Care Med 1994; 149:1335–1341. 4 Griffith DE, Brown BA, Girard WM, et al. Azithromycin activity against Mycobacterium avium complex lung disease in patients who were not infected with human immunodeficiency virus. Clin Infect Dis 1996; 23:983–989. 5 Chaisson RE, Benson CA, Dube MP, et al. Clarithromycin therapy for bacteremic Mycobacterium avium complex disease. A randomized, double-blind, doseranging study in patients with AIDS. Ann Intern Med 1994; 121:905–911. Griffith DE, Aksamit T, Brown-Elliot B, et al. An official ATS statement: Diagnosis, treatment and prevention of nontuberculous mycobacteria. Am J Respir Crit Care Med 2007; 175:367–416. A consensus statement from the American Thoracic Society covering all clinical aspects of NTM disease and most NTM clinical pathogens. 6 7 Wallace RJ Jr, Brown BA, Griffith DE, et al. Clarithromycin regimens for pulmonary Mycobacterium avium complex. The first 50 patients. Am J Respir Crit Care Med 1996; 153:1766–1772. 8 Griffith DE, Brown BA, Girard WM, et al. Azithromycin-containing regimens for treatment of Mycobacterium avium complex lung disease. Clin Infect Dis 2001; 32:1547–1553. 9 Tanaka E, Kimoto T, Tsuyuguchi K, et al. Effect of clarithromycin regimen for Mycobacterium avium complex pulmonary disease. Am J Respir Crit Care Med 1999; 160:866–872. 10 Kobashi Y, Matsushima T. The effect of combined therapy according to the guidelines for the treatment of Mycobacterium avium complex pulmonary disease. Intern Med 2003; 42:670–675. 11 Griffith DE, Brown BA, Cegielski P, et al. Early results (at 6 months) with intermittent clarithromycin-including regimens for lung disease due to Mycobacterium avium complex. Clin Infect Dis 2000; 30:288–292. 12 Lam PK, Griffith DE, Aksamit TR, et al. Factors related to response to intermittent treatment of Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006; 173:1283–1289. One of only a few prospective multicenter comparative trials for treatment of MAC lung disease. Disappointing results for a t.i.w. clarithromycin-containing regimen suggesting that patients with severe MAC lung disease or those who had failed previous therapy should not receive intermittent therapy. 13 Kobashi Y, Matsushima T, Oka M. A double-blind randomized study of aminoglycoside infusion with combined therapy for pulmonary Mycobacterium avium complex disease. Respir Med 2007; 101:130–138. A relatively large prospective comparative study demonstrating microbiological benefit of adding an aminoglycoside early in the treatment course for MAC lung disease patients. 203 14 Dautzenherg B, Castellani P, Pellegrin JL, et al. Early bactericidal activity of rifabutin versus that of placebo in treatment of disseminated Mycobacterium avium complex bacteremia in AIDS patients. Antimicrob Agents Chemother 1996; 40:1722–1725. 15 Nightingale SD, Cameron DW, Gordin FM, et al. Two controlled trials of rifabutin prophylaxis against Mycobacterium avium complex infections in AIDS. N Engl J Med 1993; 329:828–833. 16 The Research Committee of the British Thoracic Society. Pulmonary disease caused by Mycobacterium avium-intracellulare in HIV-negative patients: fiveyear follow-up patients receiving standardized treatment. Int J Tuberc Lung Dis 2002; 67:628–634. 17 Kobashi Y, Yoshida K, Miyashita N, et al. Relationship between clinical efficacy of treatment of pulmonary Mycobacterium avium complex disease and drug-sensitivity testing of Mycobacterium avium complex isolates. J Infect Chemother 2006; 12:195–202. One in a series of studies demonstrating the lack of correlation between in-vitro susceptibilities for drugs used in the therapy of MAC lung disease, with the exception of macrolides, and clinical response. 18 Griffith DE, Brown-Elliott BA, Langsjoen B, et al. Clinical and molecular analysis of macrolide resistance in Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2006; 174:928–934. A large study demonstrating the risk factors for developing macrolide-resistant MAC lung disease as well as the adverse clinical consequences and difficulty treating patients who have macrolide-resistant MAC lung disease. 19 Field SK, Cowie RL. Treatment of Mycobacterium avium-intracellulare complex lung disease with a macrolide, ethambutol, and clofazimine. Chest 2003; 124:1482–1486. 20 Chaisson RE, Keiser P, Pierce M, et al. Clarithromycin and ethambutol with or without clofazimine for the treatment of bacteremic Mycobacterium avium complex disease in patients with HIV infection. AIDS 1997; 11: 311 –317. 21 Kobashi Y, Matsushima T. The microbiological and clinical effects of com bined therapy according to guidelines on the treatment of pulmonary Mycobacterium avium complex disease in Japan – including a follow-up study. Respiration 2007; [Epub ahead of print]. One in a series of studies demonstrating the difficulty in effectively treating MAC lung disease patients who have failed previous therapy. 22 Wallace RJ Jr, Zhang Y, Brown-Elliott BA, et al. Repeat positive cultures in Mycobacterium intracellulare lung disease after macrolide therapy represent new infections in patients with nodular bronchiectasis. J Infect Dis 2002; 186:266–273. 23 Griffith DE, Brown-Elliott BA, Shepherd S, et al. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med 2005; 172:250–253. 24 Marras TK, Wallace RJ Jr, Koth LL, et al. Hypersensitivity pneumonitis reaction to Mycobacterium avium in household water. Chest 2005; 127: 664 –671. 25 Hanak V, Kalra S, Aksamit TR, et al. Hot tub lung: presenting features and clinical course of 21 patients. Respir Med 2006; 100:610–615. Review of clinical presentation and therapy for a series of patients with MAC hypersensitivity-like lung disease. Avoidance of antigen is the critical element for clinical improvement. 26 Field SK, Cowie RL. Lung disease due to the more common nontuberculous mycobacteria. Chest 2006; 129:1653–1672. A review of disease manifestations of multiple NTM pathogens including MAC. This review highlights the relative paucity of recent published data for most NTM species. 27 Griffith DE, Brown-Elliott BA, Wallace RJ Jr. Thrice-weekly clarithromycincontaining regimen for treatment of Mycobacterium kansasii lung disease: results of a preliminary study. Clin Infect Dis 2003; 37:1178–1182. 28 Marie I, Heliot P, Roussel F, et al. Fatal Mycobacterium peregrinum pneumonia in refractory polymyositis treated with infliximab. Rheumatology 2005; 44:1201–1202. 29 Mehta AC, Prakash UBS, Garland R, et al. American College of Chest Physicians and American Association for Bronchoscopy Consensus Statement: prevention of flexible bronchoscopy-associated infection. Chest 2005; 128:1742–1755. 30 deSouza MVN. Current status and future prospects for new therapies for pulmonary tuberculosis. Curr Opin Pulm Med 2006; 12:167–171. Lists some new agents in development for treatment of tuberculosis. 31 Andries K, Verhasselt P, Guillemont J, et al. A diarylquinone drug active on the ATP sythase of Mycobacterium tuberculosis. Science 2005; 307: 223 –227. Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Bibliography Current World Literature This bibliography is compiled by clinicians from the journals listed at the end of this publication. It is based on literature entered into our database between 1 December 2005 and 30 November 2006 (articles are generally added to the database about two and a half months after publication). In addition, the bibliography contains every paper annotated by reviewers; these references were obtained from a variety of bibliographic databases and published between the beginning of the review period and the time of going to press. The bibliography has been grouped into topics that relate to the reviews in this issue. Papers considered by the reviewers to be of special interest Papers considered by the reviewers to be of outstanding interest The number in square brackets following a selected paper, e.g. [7], refers to its number in the annotated references of the corresponding review. Current Opinion in Infectious Diseases 2007, 20:204–236 # 2007 Lippincott Williams & Wilkins 0951-7375 Skin and soft tissue infections Cellulitis and acute bacterial skin infections Related review: Acute bacterial skin infections and cellulitis (pp. 118–123) Barry JS, Burge JA, Byles DB, Morgan MS. Severe invasive beta haemolytic group A streptococcal cellulitis and eyelid necrosis treated with linezolid. Br J Ophthalmol 2006; 90:1204. [02] Bryant AE, Bayer CR, Huntington JD, Stevens DL. Group A streptococcal myonecrosis: Increased vimentin expression after skeletal-muscle injury mediates the binding of Streptococcus pyogenes. J Infect Dis 2006; 193:1685–1692. Currie BJ. Group A streptococcal infections of the skin: molecular advances but limited therapeutic progress. Curr Opin Infect Dis 2006; 19:132–138. Fry L, Powles AV, Corcoran S, Rogers S, Ward J, Unsworth DJ. HLA Cw*06 is not essential for streptococcal-induced psoriasis. Br J Dermatol 2006; 154:850–853. Gach JE, Carr RA, Charles Holmes R. Nodal follicular dendritic cell sarcoma of the axilla presenting as cellulitis. Br J Dermatol 2006; 154:177–178. Goettsch WG, Bavinck JNB, Herings RMC. Burden of illness of bacterial cellulitis and erysipelas of the leg in the Netherlands. J Eur Acad Dermatol Venereol 2006; 20:834–839. 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[06] Contents Skin and soft tissue infections 204 Cellulitis and acute bacterial skin infections 204 Management of mycetoma 205 New fungal nail infections 205 Wound healing: theory and practice Vol 20 No 2 April 2007 217 Prevention measures for ventilatorassociated pneumonia: a new focus on the endotracheal tube 218 Prognostic scoring systems in community-acquired pneumonia: which one is best 219 Molecular diagnostic methods in pneumonia 205 Infectious keratitis 220 How long should we treat communityacquired pneumonia? 206 Human herpesvirus 8 (transmission and infection of human cells) 220 Therapy of atypical mycobacterial infection 207 Herpes skin infections excluding HHV 8 221 New guidelines for community-acquired pneumonia 210 Staphylococcal skin and soft tissue infections 211 Tropical skin infections including leprosy 213 Infestations 213 Miscellaneous fungal infection excluding mycetoma and nail infections 221 Macrolides for chronic respiratory infection 221 Tuberculosis 225 Viral infections, including SARS and influenza 213 Papillomavirus infections 228 Antibiotic treatment, susceptibility patterns and resistance 215 Acne vulgaris 230 COPD including cystic fibrosis 215 Miscellaneous bacterial skin infections including anthrax 231 Legionella and other causes of nosocomial respiratory infection 216 Miscellaneous 232 Bacterial pneumonia Respiratory infections 234 Upper respiratory infections 216 Anti-viral therapy of respiratory infections 235 Fungal infections 217 Performance measures for pneumonia: are they valuable, and are process measures adequate? 235 Pnemocystis pneumonia Ibia E. 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Diagn Microbiol Infect Dis 2006; 55:351–356. Kermani T, Baddour LM. Diabetic muscle infarction mistaken for infectious cellulitis. Ann Intern Med 2006; 145:555–556. Koning S, Mohammedamin RSA, vander Wouden JC, vanSuijlekom Smit LWA, Schellevis FG, Thomas S. Impetigo: incidence and treatment in Dutch general practice in 1987 and 2001 - results from two national surveys. Br J Dermatol 2006; 154:239–243. Koning S, Van Der Wouden JC. Treatment for impetigo [editorial]. BMJ 2004; 329:695–696. Lazzarini L, Conti E, Tositti G, de Lalla F. Erysipelas and cellulitis: clinical and microbiological spectrum in an Italian tertiary care hospital. J Infect 2005; 51:383–389. Mokni M, Dupuy A, Denguezli M, et al. Risk factors for erysipelas of the leg in Tunisia - A multicenter case-control study. Dermatology 2006; 212:108–112. 236 Miscellaneous Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin resistant S. aureus infections among patients in the emergency department. 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