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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
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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.
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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
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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
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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).
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29 Cox VC, Zed PJ. Once-daily cefazolin and probenecid for skin and soft tissue
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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
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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
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Br Med J 2005; 330:129–132.
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Narahari SR, Ryan TJ, Mahadevan KS, et al. Role of Indian systems of
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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
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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
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(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
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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).
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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,
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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
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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
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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
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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
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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
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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
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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
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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).
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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
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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
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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).
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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
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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
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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
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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).
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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
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with community-acquired pneumonia: diagnosis, assessment of severity,
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13 Lim WS, Van der Eerden MM, Laing R, et al. Defining community acquired
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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
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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
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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
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of adults with community-acquired pneumonia: diagnosis, assessment of
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amoxicillin therapy on resistant pneumococcal carriage: a randomized trial.
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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.
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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)
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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
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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).
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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
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2
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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
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A consensus statement from the American Thoracic Society covering all clinical
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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
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Griffith DE, Brown BA, Girard WM, et al. Azithromycin-containing regimens
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9
Tanaka E, Kimoto T, Tsuyuguchi K, et al. Effect of clarithromycin regimen for
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10 Kobashi Y, Matsushima T. The effect of combined therapy according to the
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11 Griffith DE, Brown BA, Cegielski P, et al. Early results (at 6 months) with
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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
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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
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16 The Research Committee of the British Thoracic Society. Pulmonary disease
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17 Kobashi Y, Yoshida K, Miyashita N, et al. Relationship between clinical
efficacy of treatment of pulmonary Mycobacterium avium complex disease
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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
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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
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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
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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:
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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selected paper, e.g. [7], refers to its number in
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review.
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# 2007 Lippincott Williams & Wilkins
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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
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Jones RN, Li Q, Kohut B, Biedenbach DJ, Bell J, Turnidge JD.
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236 Miscellaneous
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Management of mycetoma
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204
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Skin and soft tissue infections Infectious keratitis 205
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