Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Hospital-acquired Pneumonia and Ventilator-associated Pneumonia Recent Advances in Epidemiology and Management François Barbier, Antoine Andremont, Michel Wolff, Lila Bouadma Curr Opin Pulm Med. 2013;19(3):216-228. Abstract Purpose of review The recent evidence is reviewed on clinical epidemiology, trends in bacterial resistance, diagnostic tools and therapeutic options in hospital-acquired pneumonia (HAP), with a special focus on ventilator-associated pneumonia (VAP). Recent findings The current incidence of VAP ranges from two to 16 episodes for 1000 ventilator-days, with an attributable mortality of 3–17%. Staphylococcus aureus (with 50–80% of methicillin-resistant strains), Pseudomonas aeruginosa and Enterobacteriaceae represent the most frequent pathogens in HAP/VAP. The prevalence of carbapenemase-producing Gram-negative bacilli (GNB) and the emergence of colistin resistance are alarming. Procalcitonin seems to have a good value to monitor the response to treatment. Rapid molecular tests for the optimization of empirical therapy will be available soon. Recent studies support the use of a high-dosing regimen of colistin in HAP/VAP caused by extensively drug-resistant GNB. Linezolid may probably be preferred to vancomycin for a subset of methicillin-resistant S. aureus HAP/VAP. Given the scarcity of novel antimicrobial drugs, different approaches such as bacteriophage therapy or immunotherapy warrant further clinical evaluations. Summary HAP/VAP is a major cause of deaths, morbidity and resources utilization, notably in patients with severe underlying conditions. The development of new diagnostic tools and therapeutic weapons is urgently needed to face the epidemic of multidrug-resistant pathogens. Introduction Hospital-acquired pneumonia (HAP) is a pulmonary infection that develops in patients hospitalized for more than 48 h, either in the ICU or in other wards.[1,2] Ventilator-associated pneumonia (VAP), a subset of HAP that occurs in mechanically ventilated patients more than 48 h after tracheal intubation, is the most frequent ventilator-associated complication (VAC).[1,2] HAP/VAP represents a major cause of deaths, morbidity and resources utilization in hospitalized patients, most notably in those with severe underlying conditions.[1,3-7] The adequacy of empirical antimicrobial therapy is strongly predictive of hospital survival,[3] making the definition of patients at risk for multidrug-resistant (MDR) pathogens a pivotal challenge.[1,8–10] In this short review, we summarize the recently published data on clinical epidemiology, trends in bacterial resistance, diagnostic methods and therapeutic strategies in HAP, with a special focus on VAP. Current Clinical Epidemiology: The Burden of Hospital-acquired Pneumonia and Ventilator-associated Pneumonia The incidence of HAP ranges from five to more than 20 cases per 1000 hospital admissions. [1,11] Outside the ICU, highest rates are observed in the elderly, immunocompromised hosts, surgical patients and those receiving enteral feeding through a nasogastric tube.[1] Almost one-third of HAPs are ICU-acquired, with VAP accounting for 90% of cases. Overall, VAP occurs in 9–40% of intubated patients and represents the most frequent ICU-acquired infection.[12-14] Recent surveys from large healthcare networks reported a pooled incidence density of VAP ranging from two to 16 episodes per 1000 ventilator-days.[14,15] The daily incidence of VAP peaks between day 5 and day 9 of mechanical ventilation, whereas the cumulative incidence appears as roughly proportional to mechanical ventilation duration.[13,16,17] The main other risk factors for VAP and corresponding preventive measures are exposed in .[17–42] Patients with the acute respiratory distress syndrome (ARDS) are especially at risk, as a likely result of prolonged mechanical ventilation and heavy sedation requirement, with a cumulative incidence of ~40% after day 10.[13] Whether neuromuscular blockade agents use increases and head of bed elevation or prone positioning decreases the risk of VAP in ARDS patients has not been confirmed by recent studies.[13,31–43] Early tracheostomy (i.e. within the first 7 days of mechanical ventilation) in patients with predictable weaning difficulties does not appear as an independent predictor of VAP when compared with late tracheostomy or prolonged tracheal intubation.[22,44,45] Other potential risk factors have been recently suggested, such as etomidate use for tracheal intubation or energetic deficit during the early ICU course (at least for Staphylococcus aureus VAP),[46,47] whereas steroids (for trauma patients) or statin use could be protective.[48,49] Table 1. Effects of the main preventive measures for ventilator-associated pneumonia prevention in randomized controlled studies or last meta-analyses Intervention Year, design References Patients RRR of VAP (n) (%) Reducing the time at risk NPPV Daily SBT Daily sedation interruption Early tracheotomy 2005, meta-analysis (12 studies) [18] 2000, RCT (two ICUs) [19] 2006, RCT (five ICUs) [20] 2000, RCT (one ICU) [21] 2012, meta-analysis (7 RCTs) [22] 3030 ↓ 25% 385 No effect 144 No effect 128 No effect 1044 No effect Preventing endotracheal tube colonization and minimizing contaminated microaspirations Silver-coated ET Saline instillation before tracheal suctioning ET with SSD ET with ultrathin membrane and 2008, RCT (54 ICUs) [23] 1509 ↓ 36% 2009, RCT (one ICU) [24] 262 ↓ 54% 2010, meta-analysis (13 RCTs) 2007, RCT (one ICU) [25] [26] 2442 ↓ 48% (four RCTs) 280 ↓ 64% SSD ET with an ultrathin and tapered-shape cuff membrane Continuous control of tracheal cuff pressure Head-of-bed elevation 2008, RCT (one ICU) [27] 134 ↓ 45% 2007, RCT (two ICUs) [28] 142 No effect 2011, RCT (one ICU) [29] 122 ↓ 63% 1999, RCT (two ICUs) [30] 86 ↓ 78% 2006, RCT (four ICUs) [31] Prone position Kinetic beds Positive end-expiratory pressure Physiotherapy 2008, meta-analysis (five RCTs) 2006, meta-analysis (15 RCTs) 2008, RCT (three ICUs) 221 No effect [32] 1372 No effect [33] 1169 [34] ↓ 53% (10 RCTs) 131 ↓ 63% 1998, RCT (one ICU) [35] 46 No effect 2002,RCT (one ICU) [36] 60 ↓ 79% 2007, RCT (one ICU) [37] 180 No effect 2009, RCT (one ICU) [38] 144 No effect Modulation of colonization Oral care with chlorhexidine 2010, meta-analysis (12 RCTs) [39] 2341 ↓ 24% Probiotics 2010, RCT (one ICU) [40] 146 ↓ 47% Iseganan 2006, RCT (one ICU) [41] 709 No effect [42] 1292 No effect Closed tracheal suction system 2008, meta-analysis (nine RCTs) Data from [17]. ET, endotracheal tube; NPPV, noninvasive positive pressure ventilation; RCT, randomized controlled trial; RRR, relative risk reduction; SBT, spontaneous breathing trial; SSD, subglottic secretion drainage; VAP, ventilator-associated pneumonia. Nonventilator-associated HAPs dramatically increase both the hospital length of stay and the cost of care, and are associated with an overall mortality of 27–51%,[11,50,51] the poorer prognosis being reported in the elderly. Subsequent functional disability and accelerated cognitive impairment in aged patients surviving bacterial sepsis may increase the social burden of this nosocomial event.[52] The crude mortality of VAP ranges from 22 to 60%.[7,13,14,53] Although the prognostic weight of underlying conditions prevails in many cases, the occurrence of VAP is associated with a two-fold increase of the likelihood of in-ICU death, most notably for patients with inadequate empirical therapy.[3] The directly attributable mortality is 6–9%, but varies from 3 to 17% depending on patient subgroups.[4,5] In addition, survivors experience poorer outcome than ICU patients who do not develop VAP, with significantly longer durations of mechanical ventilation, ICU stay and hospitalization.[7] The absolute increase in hospitalization costs is estimated to be ~40 000 USD per episode.[7] The Alarming Situation of Bacterial Resistance The bacterial epidemiology of VAP ( )[54] depends on a panel of factors including mechanical ventilation duration, length of hospital and ICU stays, previous exposure to antimicrobials, local epidemiology and potential epidemic phenomenon in a given ICU.[1] Rapid changes in the oropharyngeal flora of intubated patients (even in the absence of antibiotic exposure) represent a key determinant,[55] as microaspirations of pharyngeal secretions constitute the leading physiopathological mechanism of VAP. Early-onset VAP (within the first 4 days of mechanical ventilation) usually involve respiratory pathogens from the normal, community-acquired oropharyngeal microbiota ( ), whereas late-onset VAP (occurring on day 5 of mechanical ventilation or later) mostly involve hospital-acquired and potentially MDR pathogens as a combined result of antibiotic selective pressure, cross-transmission and colonization from in-ICU environmental sources.[1,53,54] However, MDR pathogens may be isolated in early-onset VAP when risk factors exist prior to ICU admission, and even when such risk factors are lacking [notably for Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA)],[53] enlightening the limits of this classification in the current context of bacterial resistance. Table 2. Current bacterial epidemiology of hospital-acquired pneumonia and ventilator-associated pneumonia (first episodes only): data from recent clinical trials and surveys Study/reference Country Setting Type of pneumonia Patients, n ACURASYS Ferrer et Ferrer et ANSRPSG [13•] al. [53] al. [53] [50] France Spain Spain Asia Six ICUs, Six ICUs, one one hospital hospital 20 ICUs SENTRY [54] Worldwide 73 hospitals Surveillance System VAP in ARDS HAP and HAP and HAP and HAP and patients VAPa VAPb VAP VAP 38 (VAP, 238 (VAP, 2554 (VAP, n=18) n=128) n=977) 98 31 436 100 63 54 67 – Haemophilus influenza 3 5 3 1 3 Enterobacteriaceae 35 22 19 23 26 Escherichia coli 11 8 6 5 7 Klebsiella pneumoniae 4 3 3 14 10 Bacterial documentation Gram-negative bacteria Enterobacter sp. 10 3 5 4 6 Serratia marcescens 3 – 2 <1% 3 7 8 3 – – 34 16 18 19 22 5 – 3 4 3 – – 1 22 7 21 27 16 14 28 Methicillin-susceptible 12 11 8 3 – Methicillin-resistant 9 16 8 11 – Streptococcus pneumoniae Other GP: 10 5 2 2 3 – – – – – – – – Other enterobacteria Pseudomonas aeruginosa Stenotrophomonas maltophilia Acinetobacter baumannii Gram-positive bacteria Staphylococcus aureus Other streptococci Enterococcus sp. vancomycin-resistant Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; ARDS, acute respiratory distress syndrome; GP, Gram-positive bacteria; HAP, hospitalacquired pneumonia; VAP, ventilator-associated pneumonia. No risk factor of multidrug-resistant (MDR) bacteria according to the 2005 Infectious Disease a Society of America (IDSA)/American Thoracic Society (ATS) criterion [1]. At least one risk factor of MDR bacteria according to the 2005 IDSA/ATS criterion. b Table 3. Current guidelines for the empirical treatment of hospital-acquired pneumonia, including ventilatorassociated pneumonia Reference Early-onset HAP/VAP (≤day 4 Late-onset HAP/VAP (≥day of hospital stay/MV) without 5 of hospital stay/MV) OR risk factors for MDR presence of ≥1 risk factor pathogen for MDR pathogenb a MSSA Most common (i.e. targeted) pathogens Streptococcus pneumonia and other streptococci, Haemophilus sp. Wild-type Enterobacteriaceae MRSA Pseudomonas aeruginosa Drug-resistant Enterobacteriacae Acinetobacter baumannii Stenotrophomonas maltophilia Society which issued the guidelines (date of publication) Cefepime or ceftazidime or Ceftriaxone Imipenem/cilastatin or American Thoracic Society/Infectious Diseases Society of or meropenem Levofloxacin, moxifloxacin, or or ciprofloxacin [1] Piperacillin/tazobactam or America (2005) plus Ampicillin/sulbactam Ciprofloxacin or or levofloxacin Ertapenem or Amikacin, gentamicin, or tobramycin Ampicillin/sulbactam or amoxicillin/clavulanate European Respiratory Society/European or Society of Clinical Microbiology and Infectious [10] Cefuroxime, cefotaxime or ceftriaxone Diseases/European Society of Intensive Care or Medicine (2009) Moxifloxacin or levofloxacin (not ciprofloxacin) British Society of Antimicrobial Chemotherapy (2008) Ceftazidime or Imipenem/cilastatin or meropenem or Piperacillin/tazobactam plus Ciprofloxacin or levofloxacin Aminopenicillin/b-lactamase Early-onset pneumonia with inhibitor risk factor for MDR [8] pathogen: or Cefotaxime or ceftriaxone Cefuroxime or Fluoroquinolone or Piperacillin/tazobactam Late-onset pneumonia: Depending on local epidemiology If Pseudomonas aeruginosa is suspected, treatment options include ceftazidime, ciprofloxacin, meropenem and piperacillin/tazobactam Also to be applied for severe early-onset Only if severity criteria are lacking: Cefotaxime or ceftriaxone or cefepime or Association of Medical Microbiology and Infectious Disease Canada/Canadian Thoracic Society (2008) c [9] Piperacillin-tazobactam or Imipenem/cilastatin or meropenem or Levofloxacin or moxifloxacin pneumoniad: Ceftazidime or cefepime or Piperacillin/tazobactam or Imipenem/cilastatin or merepenem plus Ciprofloxacin or levofloxacin or Gentamicin, tobramycin or amikacin In all guidelines Add vancomycin or linezolid [1,8–10] if MRSA is suspected MV, mechanical ventilation; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus. Risk factors for MDR pathogen are a current hospitalization of 5 days or more, an antimicrobial a therapy within the preceding 90 days, a high frequency of antibiotic resistance in the specific hospital unit, an immunosuppressive disease and/or therapy, and risk factors for healthcare-associated pneumonia (i.e. hospitalization for 2 days or more in the preceding 90 days, residence in a nursing home or extended care facility, home infusion therapy including antibiotics, chronic dialysis within 30 days, home wound care, and known carriage of multidrug-resistant pathogen in family members). The cephalosporins (ceftazidime and cefepime), carbapenems (imipenem/cilastatin and b meropenem), b-lactamin/b-lactamase inhibitor combination (piperacillin/tazobactam), fluoroquinolone (ciprofloxacin and levofloxacin) and aminoglycosides (amikacin, gentamicin, and tobramycin) listed above are all considered as effective against wild-type Pseudomonas aeruginosa. c Only VAP guidelines are shown here (see [9] for nonventilator HAP guidelines). Severity criteria include hypotension, sepsis syndrome, rapid progression of infiltrates and end d organ dysfunction. Resistance frequencies differ from one ICU to another and at the geographic scale, but trends converge across international surveys ( ).[14,50,54] The recent description of plasmidic linezolid resistance in MRSA elicits significant concerns.[58,59] Resistance to third-generation and fourth-generation cephalosporins in Enterobacteriaceae strains mostly depends on the expression of acquired extended-spectrum β-lactamases (ESBLs) and/or AmpC β-lactamases.[56–60] The spread of carbapenemase-producing strains is even more alarming ( ).[57] MDR isolates of P. aeruginosa are increasingly prevalent, whereas one-half to two-thirds of Acinetobacter baumannii strains causing VAP are currently carbapenem-resistant.[14,50] Polymyxins (mainly colistin) are more and more seen as a last-line therapeutic option to treat MDR Gram-negative bacilli (GNB).[61] Unfortunately, colistin resistance is now also on the rise in ICUs with high prevalence of carbapenems resistance and heavy colistin consumption.[62-64] The situation of bacterial resistance appears as critical when HAPs in nonintubated patients are considered ( ). Table 4. Prevalence of major antibiotic resistance in Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii strains causing hospital-acquired and ventilator-associated pneumonia: recent data (≥2004) from international multicentric surveillance programs Study/reference INICC SENTRY VAP [14••] HAP/VAP [54] ANSRPSG HAP + VAP (pooled) [50] Pathogen, antimicrobial Staphylococcus aureus Oxacillin 73 59/51 82 Gentamicin – 13/22 – Fluoroquinolones – 58/48 78 – 16/24 31 69 23/32 43 7 <1/<1 2 55 28/26 – 67 16/22 – 4 0/0 – Fluoroquinolones 46 40/42 30 Aminosides 28 28/34 – 40 24/29 37 Antipseudomonal cephalosporins 37 32/37 35 Carbapenemsc 43 28/34 30 Carbapenemsc 66 42/54 67 Colistin – – 1 Klebsiella pneumonia Fluoroquinolones Third-generation/fourth-generation cephalosporinsa Carbapenemsb Escherichia coli Fluoroquinolones Third-generation/fourth-generation cephalosporinsa Carbapenemsb Pseudomonas aeruginosa Piperacillin and/or piperacillin–tazobactam Acinetobacter baumannii Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; HAP, hospital-acquired pneumonia; INICC, International Nosocomial Infection Control Consortium; VAP, ventilator-associated pneumonia. Resistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible a strains of Escherichia coli and Klebsiella pneumoniae is almost exclusively because of the acquisition of plasmidic Ambler class A extended-spectrum b-lactamases (CTX-M, TEM and SHV) or AmpC-like cephalosporinases [56]. Carbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired, b plasmidic carbapenemases, either of Ambler class A (mainly KPC), B (mainly VIM and IMP-type metallo-b-lactamases, with the recently described genotype NDM-1 spreading worldwide) or D (oxacillinases, mainly OXA-48) [57]. It is noteworthy that plasmids harbouring ESBL-encoding and/or carbapenemase-encoding genes often carry other resistance genes (e.g. qnr for fluoroquinolones resistance, or aminoglycosides modifying enzymes, including the AAC(60)-1b-cr variant which also confers low level resistance to ciprofloxacin), thus conferring a multidrug-resistant phenotype as the result of a single plasmid conjugation. c Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii may involve distinct mechanisms including impermeability (loss of outer membrane porins), hyperexpression of efflux pomp systems, and carbapenemase production. Table 4. Prevalence of major antibiotic resistance in Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii strains causing hospital-acquired and ventilator-associated pneumonia: recent data (≥2004) from international multicentric surveillance programs Study/reference INICC SENTRY VAP [14••] HAP/VAP [54] ANSRPSG HAP + VAP (pooled) [50] Pathogen, antimicrobial Staphylococcus aureus Oxacillin 73 59/51 82 Gentamicin – 13/22 – Fluoroquinolones – 58/48 78 – 16/24 31 69 23/32 43 7 <1/<1 2 55 28/26 – 67 16/22 – 4 0/0 – Fluoroquinolones 46 40/42 30 Aminosides 28 28/34 – Piperacillin and/or 40 24/29 37 Klebsiella pneumonia Fluoroquinolones Third-generation/fourth-generation cephalosporinsa Carbapenemsb Escherichia coli Fluoroquinolones Third-generation/fourth-generation cephalosporinsa Carbapenemsb Pseudomonas aeruginosa piperacillin–tazobactam Antipseudomonal cephalosporins 37 32/37 35 Carbapenemsc 43 28/34 30 Carbapenemsc 66 42/54 67 Colistin – – 1 Acinetobacter baumannii Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; HAP, hospital-acquired pneumonia; INICC, International Nosocomial Infection Control Consortium; VAP, ventilator-associated pneumonia. Resistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible a strains of Escherichia coli and Klebsiella pneumoniae is almost exclusively because of the acquisition of plasmidic Ambler class A extended-spectrum b-lactamases (CTX-M, TEM and SHV) or AmpC-like cephalosporinases [56]. Carbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired, b plasmidic carbapenemases, either of Ambler class A (mainly KPC), B (mainly VIM and IMP-type metallo-b-lactamases, with the recently described genotype NDM-1 spreading worldwide) or D (oxacillinases, mainly OXA-48) [57]. It is noteworthy that plasmids harbouring ESBL-encoding and/or carbapenemase-encoding genes often carry other resistance genes (e.g. qnr for fluoroquinolones resistance, or aminoglycosides modifying enzymes, including the AAC(60)-1b-cr variant which also confers low level resistance to ciprofloxacin), thus conferring a multidrug-resistant phenotype as the result of a single plasmid conjugation. c Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii may involve distinct mechanisms including impermeability (loss of outer membrane porins), hyperexpression of efflux pomp systems, and carbapenemase production. Table 4. Prevalence of major antibiotic resistance in Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii strains causing hospital-acquired and ventilator-associated pneumonia: recent data (≥2004) from international multicentric surveillance programs Study/reference INICC SENTRY VAP [14••] HAP/VAP [54] ANSRPSG HAP + VAP (pooled) [50] Pathogen, antimicrobial Staphylococcus aureus Oxacillin 73 59/51 82 Gentamicin – 13/22 – Fluoroquinolones – 58/48 78 Klebsiella pneumonia – 16/24 31 69 23/32 43 7 <1/<1 2 55 28/26 – 67 16/22 – 4 0/0 – Fluoroquinolones 46 40/42 30 Aminosides 28 28/34 – 40 24/29 37 Antipseudomonal cephalosporins 37 32/37 35 Carbapenemsc 43 28/34 30 Carbapenemsc 66 42/54 67 Colistin – – 1 Fluoroquinolones Third-generation/fourth-generation cephalosporinsa Carbapenemsb Escherichia coli Fluoroquinolones Third-generation/fourth-generation cephalosporinsa Carbapenemsb Pseudomonas aeruginosa Piperacillin and/or piperacillin–tazobactam Acinetobacter baumannii Data presented in the table are percentages. ANSRPSG, Asian Network for Surveillance of Resistant Pathogens Study Group; HAP, hospital-acquired pneumonia; INICC, International Nosocomial Infection Control Consortium; VAP, ventilator-associated pneumonia. Resistance to third-generation and fourth-generation cephalosporins in carbapenem-susceptible a strains of Escherichia coli and Klebsiella pneumoniae is almost exclusively because of the acquisition of plasmidic Ambler class A extended-spectrum b-lactamases (CTX-M, TEM and SHV) or AmpC-like cephalosporinases [56]. Carbapenems resistance in Enterobacteriaceae is almost exclusively because of acquired, b plasmidic carbapenemases, either of Ambler class A (mainly KPC), B (mainly VIM and IMP-type metallo-b-lactamases, with the recently described genotype NDM-1 spreading worldwide) or D (oxacillinases, mainly OXA-48) [57]. It is noteworthy that plasmids harbouring ESBL-encoding and/or carbapenemase-encoding genes often carry other resistance genes (e.g. qnr for fluoroquinolones resistance, or aminoglycosides modifying enzymes, including the AAC(60)-1b-cr variant which also confers low level resistance to ciprofloxacin), thus conferring a multidrug-resistant phenotype as the result of a single plasmid conjugation. c Carbapenem resistance in Pseudomonas aeruginosa and Acinetobacter baumannii may involve distinct mechanisms including impermeability (loss of outer membrane porins), hyperexpression of efflux pomp systems, and carbapenemase production. The Role of Virus in Ventilator-associated Pneumonia The Herpesviridae herpes simplex virus (HSV) and cytomegalovirus (CMV) can cause viral reactivation pneumonia in intubated patients without a usual criterion for immune deficiencies.[65] HSV replication may be documented in tracheal/bronchial aspirates from 32 to 64% of patients requiring prolonged mechanical ventilation,[66–68] with subsequent histopathological evidence of HSV bronchopneumonitis in up to 21% of patients with worsening respiratory status.[68] Patients with ARDS and those receiving steroids may be at higher risk.[65] CMV reactivation is observed in ~30% of critically ill patients experiencing multiorgan failure and prolonged ICU stay,[69] most notably in survivors of severe bacterial sepsis, and may directly involve the lung. The incidence of histologically proven CMV pneumonia may reach 30% in ARDS patients with clinical deterioration suggesting VAC and negative bronchoalveolar lavage fluid (BALF) culture.[70] Acyclovir and gancyclovir are the main therapeutic options for HSV and CMV pneumonia, respectively, but both remain to be fully evaluated by appropriate randomized controlled trials (RCTs). A positive mimivirus (Acanthamoeba polyphaga) serology has been documented in 20% of patients with suspected VAP and was associated with an increased duration of mechanical ventilation and ICU stay,[71] but a direct role of mimivirus in VAP is uncertain.[72,73] Does Fungal Ventilator-associated Pneumonia Exist in ICU Patients Without Major Immunosuppression? Colonization of the lower respiratory tract by Candida spp. affects 18–56% of intubated patients and is associated with an increased risk of bacterial VAP, most notably caused by P. aeruginosa or other MDR pathogens, and possibly a poorer outcome.[74–77] However, available data do not support a direct role of Candida spp. as a VAP-causative pathogen.[78,79] Aspergillus spp. (mainly Aspergillus fumigatus) may be involved in ~3% of late-onset VAP,[53] and invasive pulmonary aspergillosis has been proven in 15% of critically ill patients with one or more Aspergillus-positive tracheal aspirate cultures.[80] A clinical algorithm was recently proposed to assess the clinical relevance of these cultures and ease the decision to start or not a specific therapy.[80] Recent Advances in the Diagnosis of Hospital-acquired Pneumonia and Ventilator-associated Pneumonia The diagnosis of HAP/VAP is challenging and conventional strategies have been extensively reviewed in recent guidelines.[1,8–10] However, two current research areas warrant developments. First, several biomarkers have been evaluated as complementary diagnostic tools during the past years.[81,82] Studies on BALF concentrations of the soluble triggered receptor expressed on myeloid cells 1 (sTREM-1) yielded conflicting results.[83–86] C-reactive protein may lack sensitivity in ICU patients.[87,88] The diagnostic values of BALF concentrations of interleukin-1β, interleukin-8, granulocyte colony-stimulating factor and macrophage inflammatory protein-1[alpha] could be discriminative but require validation on larger cohorts,[89] as do BALF levels of plasminogen activation inhibitor 1 (PAI-1).[90] By contrast, BALF levels of Clara cell protein 10 yield poor diagnostic accuracy.[91] The usefulness of plasma levels of Clara cell protein 16 (CC-16), soluble receptor for advanced glycation end products (sRAGE) and surfactant protein D (SP-D) is unclear.[92] Copeptin,[93,94] midregional atrial natriuretic factor (MR-ANF)[95,96] and adrenomedullin[97] were evaluated as prognostic rather than diagnostic biomarkers in pneumonia. To date, the literature does not support a clinical role for these biomarkers, including procalcitonin (PCT), in predicting VAP. However, using serum PCT concentration to customize antibiotic-treatment duration in patients with VAP has been evaluated in five studies, all showing less antibiotic consumption when a PCT-based algorithm was applied, with no detrimental impact on outcomes. Consequently, in patients treated for a VAP whose serum PCT concentration is less than 0.5 ng/ml or decreased by more than 80% (compared with the peak concentration), antibiotic discontinuation may be considered at day 3 after initiation.[87,88,98-102] Conventional bacteriological methods imply an incompressible delay of 48–72 h for complete antimicrobial susceptibility testing of pneumonia-causative pathogens. Therefore, the on-going development of rapid molecular methods raises comprehensible hopes for optimizing the choice of initial drugs and avoiding the overprescription of very broad-spectrum molecules in this situation.[103] Such tools should reliably identify both the most common pathogens and their most frequent resistance genotypes within a time ranging from 2 to 6 h. Real-time PCR, in-situ DNA hybridization and mass spectrometry are currently the leading investigation methods.[104] Several systems are already commercialized for direct analysis of clinical samples such as blood cultures and swabs (most notably for MRSA screening). However, and despite promising preliminary results, [103-105] no system has been validated so far for direct application on BALF or tracheal aspirates in suspected VAP/HAP. Oversensitivity and quantification of bacterial loads may represent important issues. Indeed, genetic material from more than 15 distinct pathogens (including bacteria, virus and fungi) can be detected in BALF from ICU patients, most of them being not reliably considered as causative for the current pneumonia episode.[106] Antimicrobial Treatment of Hospital-acquired Pneumonia and Ventilator-associated Pneumonia Delayed effective therapy increases hospital mortality in HAP/VAP patients, making the choice of empirical drugs a crucial dilemma.[1,6] To improve the likelihood of adequate coverage, current guidelines ( ) usually recommend an antipseudomonal combination therapy except for early-onset pneumonia with no risk factor for MDR bacteria.[1,8–10] Facing the epidemic of ESBL-producing enterobacteria and other MDR-GNB, antipseudomonal carbapenems (imipenem/cilastatin and meropenem) have become the most empirically prescribed β-lactams in European ICU for HAP/VAP.[51] Despite limited lung diffusion,[10] aminoglycosides should be preferred to fluoroquinolones, given the resistance frequencies in P. aeruginosa and the possibility to achieve bactericidal lung concentrations with a high-dosing regimen (e.g. 25 mg/kg for amikacin). Empirical indications of polymyxins in patients at risk for carbapenem-resistant GNB should be clarified in updated guidelines.[107] Table 3. Current guidelines for the empirical treatment of hospital-acquired pneumonia, including ventilatorassociated pneumonia Early-onset HAP/VAP (≤day 4 Reference of hospital stay/MV) without risk factors for MDR Late-onset HAP/VAP (≥day 5 of hospital stay/MV) OR presence of ≥1 risk factor pathogena for MDR pathogenb MRSA MSSA Streptococcus pneumonia and Most common (i.e. other streptococci, targeted) pathogens Haemophilus sp. Wild-type Enterobacteriaceae Pseudomonas aeruginosa Drug-resistant Enterobacteriacae Acinetobacter baumannii Stenotrophomonas maltophilia Society which issued the guidelines (date of publication) Cefepime or ceftazidime or Ceftriaxone Imipenem/cilastatin or American Thoracic Society/Infectious Diseases Society of or meropenem Levofloxacin, moxifloxacin, or or ciprofloxacin [1] Piperacillin/tazobactam or America (2005) plus Ampicillin/sulbactam Ciprofloxacin or or levofloxacin Ertapenem or Amikacin, gentamicin, or tobramycin European Respiratory Ampicillin/sulbactam or Society/European amoxicillin/clavulanate Society of Clinical Microbiology and Ceftazidime or Imipenem/cilastatin or or meropenem Diseases/European Cefuroxime, cefotaxime or or Piperacillin/tazobactam Society of Intensive Care ceftriaxone Infectious Medicine (2009) [10] plus or Ciprofloxacin or Moxifloxacin or levofloxacin levofloxacin (not ciprofloxacin) Early-onset pneumonia with risk factor for MDR pathogen: Cefotaxime or ceftriaxone or Fluoroquinolone Aminopenicillin/b-lactamase inhibitor British Society of Antimicrobial [8] Chemotherapy (2008) or Cefuroxime or Piperacillin/tazobactam Late-onset pneumonia: Depending on local epidemiology If Pseudomonas aeruginosa is suspected, treatment options include ceftazidime, ciprofloxacin, meropenem and piperacillin/tazobactam Only if severity criteria are Also to be applied for lacking: severe early-onset pneumoniad: Cefotaxime or ceftriaxone or Association of Medical Microbiology and Infectious Disease Canada/Canadian Thoracic Societyc (2008) [9] cefepime Ceftazidime or cefepime or or Piperacillin-tazobactam Piperacillin/tazobactam or or Imipenem/cilastatin or Imipenem/cilastatin or meropenem merepenem or plus Levofloxacin or moxifloxacin Ciprofloxacin or levofloxacin or Gentamicin, tobramycin or amikacin In all guidelines [1,8–10] Add vancomycin or linezolid if MRSA is suspected MV, mechanical ventilation; MDR, multidrug-resistant; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible Staphylococcus aureus. Risk factors for MDR pathogen are a current hospitalization of 5 days or more, an antimicrobial a therapy within the preceding 90 days, a high frequency of antibiotic resistance in the specific hospital unit, an immunosuppressive disease and/or therapy, and risk factors for healthcare-associated pneumonia (i.e. hospitalization for 2 days or more in the preceding 90 days, residence in a nursing home or extended care facility, home infusion therapy including antibiotics, chronic dialysis within 30 days, home wound care, and known carriage of multidrug-resistant pathogen in family members). The cephalosporins (ceftazidime and cefepime), carbapenems (imipenem/cilastatin and b meropenem), b-lactamin/b-lactamase inhibitor combination (piperacillin/tazobactam), fluoroquinolone (ciprofloxacin and levofloxacin) and aminoglycosides (amikacin, gentamicin, and tobramycin) listed above are all considered as effective against wild-type Pseudomonas aeruginosa. c Only VAP guidelines are shown here (see [9] for nonventilator HAP guidelines). Severity criteria include hypotension, sepsis syndrome, rapid progression of infiltrates and end d organ dysfunction. Re-assessment is mandatory at day 2–3, both to correct inadequate regimens when appropriate and to avoid an overconsumption of broad-spectrum drugs.[1,8–10] Antimicrobials must be stopped when the diagnosis is not bacteriologically validated, except for particular situations.[10] When pneumonia is confirmed, the antimicrobial spectrum must be narrowed whenever possible on the basis of susceptibility testing. Monotherapy is conceivable provided that the empirical regimen was adequate, the patient's condition improves and the causative pathogens do not exhibit extensive resistance patterns.[10] Even not validated in HAP/VAP, retrocession to β-lactam/β-lactamase inhibitor might be discussed for ESBL-producing enterobacteria with minimal inhibitory concentration (MIC) below the break-point values.[108,109] A control sample should be obtained to assess bacterial load kinetics and detect precocious resistant mutants. [10] The 8-day standard duration of treatment can be safely shortened by monitoring plasma PCT levels.[100] Longer treatments may be discussed in cases of immunosuppression, unfavourable clinical response or extensively drug-resistant pathogens.[10] Colistin appears as effective as other antimicrobial classes for VAP caused by MDR-GNB.[110] The optimal dosing regimen of this concentration-dependent antibiotic is still debated; however, an intravenous loading dose of 9 million units followed by 4.5 million units twice daily (with protocolized adaptation in case of renal failure) may be an adequate scheme,[111] in accordance with previous pharmacokinetic/pharmacodynamic data,[112] the median colistin dose being correlated with clinical and microbiological success rates.[113] The incidence of colistin-induced nephrotoxicity is 18–43%, especially with a high-dosing regimen or when other nephrotoxic drugs are prescribed.[111,113,114] The nephroprotective effect of ascorbic acid co-administration during colistin therapy should be evaluated in clinical practice.[115] Experimental data suggest that inhaled colistin should be used as an adjunctive therapy to reach high lung concentrations,[116] but available clinical evaluations yielded ambiguous results,[117–120] and further RCTs are needed to clarify this issue. Other inhaled antimicrobials have been tested in experimental or clinical VAP caused by MDR-GNB, namely ceftazidime,[121,122] imipenem/cilastatin,[123] amikacin[124] and tobramycin.[118,125] Nebulized ceftazidime/amikacin combination does not improve the course of clinical P. aeruginosa VAP when compared with intravenous administration.[122] Both vancomycin and linezolid are recommended for the therapy of suspected or proven MRSA pneumonia.[1,8–10] In experimental models, linezolid is associated with faster bacterial clearances and a lower histological severity of pneumonia,[126–128] with better pharmacokinetic/pharmacodynamic profiles[127] and a possible immunomodulatory effect.[129] However, previous meta-analysis did not demonstrate a superiority of linezolid in terms of clinical cure and bacteriological eradication. [130,131] In a recent RCT,[132] linezolid was associated with a higher clinical success rate and a lower incidence of renal impairment than vancomycin, but all-cause 60-day fatality rates were similar in both groups. We believe that linezolid should be preferred to vancomycin when other risk factors of acute kidney injury are present and for HAP/VAP caused by MRSA strains with vancomycin MIC higher than 1 mg/l, a cut-off associated with vancomycin therapy failure.[133,134] New antibiotics that may complete the therapeutic arsenal for HAP/VAP are scarce. Lipoglycopeptides (i.e. dalbavancin, oritavancin and telavancin) are bactericidal for MRSA strains with high vancomycin MIC.[135] Telavancin is not inferior to vancomycin for the treatment of MRSA pneumonia, but may be associated with an increased incidence of acute kidney injury. [136] Ceftaroline[137,138] and ceftobiprole,[139] two new-generation cephalosporins, and iclaprim,[140] a dihydrofolate reductase inhibitor, are also active against MRSA. None of these drugs are currently approved by the US Food and Drug Administration (FDA) for the treatment of MRSA HAP/VAP. Novel carbapenem-sparing molecules for the treatment of MDR-GNB include temocillin,[141] a 6-hydroxymethyl-ticarcilline with activity against ESBL-producing and AmpC-producing enterobacteria, and avibactam (formerly NXL104),[142–145] which restores the activity of various β-lactams (e.g. ceftazidime) in isolates producing Ambler class A (ESBL and KPC-type carbapenemase) and AmpC β-lactamases (including P. aeruginosa); these two promising antibiotics remain to be evaluated in HAP/VAP. New Therapeutic Approach for Ventilator-associated Pneumonia Bacteriophages are viruses that infect bacteria in a species-specific way. In animal studies, phage therapy can both prevent and cure P. aeruginosa, Klebsiella pneumoniae and Streptococcus pneumoniae pneumonia.[146–149] These recent results may be a first basis towards further clinical trials, notably for difficult-to-treat MDR pathogens. Next, and despite an inappropriate bacterial spectrum, macrolides have immunomodulatory and anti-inflammatory effects that may be of interest in HAP/VAP.[150] A short course of clarithromycin may ease the cure of otherwise adequately treated VAP and modulate the risk of death from septic shock or multiorgan failure.[151–152] Macrolides also inhibit P. aeruginosa quorum sensing, but the clinical impact of this property remains to be confirmed.[153] Finally, in a recent RCT, monoclonal antibodies targeting the type III secretion system, a major pseudomonal virulence factor in pneumonia,[154] reduced the incidence of VAP in patients with P. aeruginosa tracheal colonization.[155] Further evaluation of immunotherapy in HAP/VAP is warranted. Conclusion An increasing burden of HAP/VAP may be expected in the coming years, as a result of intensification of care, progressive ageing and a growing prevalence of severe underlying diseases in ICU patients. The current epidemiology of bacterial resistance is more alarming than ever. In this context, the implementation of preventive policies is of major importance. [17] Both diagnosis and treatment of HAP/VAP remain challenging and justify intensive research work for the development and validation of molecular diagnostic tools, new drugs for MDR pathogens, and nonantibiotic therapeutic options. Sidebar Key Points HAP/VAP are the most common acquired infections in critically ill patients, and are responsible for high morbidity and mortality in this population. The main concern on antimicrobial resistance currently relates to GNB, with the worldwide spread of carbapenemase-producing strains and the emergence of colistin resistance. Molecular assays directly applicable on respiratory samples are urgently needed, both to improve the adequacy of empirical therapy and to spare broadspectrum drugs. A few novel drugs in the pipeline remain to be fully assessed in HAP/VAP caused by MDR pathogens. New therapeutic approaches such as phage therapy and immunotherapy warrant clinical evaluation in this context. References 1. American Thoracic Society–Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171:388–416. 2. Anand N, Kollef MH. The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP. Semin Respir Crit Care Med 2009; 30:3–9. 3. Agrafiotis M, Siempos II, Ntaidou TK, Falagas ME. Attributable mortality of ventilator-associated pneumonia: a meta-analysis. Int J Tuberc Lung Dis 2011; 15:1154–1163. 4. Melsen WG, Rovers MM, Koeman M, Bonten MJ. Estimating the attributable mortality of ventilator-associated pneumonia from randomized prevention studies. Crit Care Med 2011; 39:2736–2742. 5. Timsit JF, Zahar JR, Chevret S. Attributable mortality of ventilator-associated pneumonia. Curr Opin Crit Care 2011; 17:464–471. * At the ICU scale, this study estimates that VAP accounts for ~1% of all deaths when the overall mortality is 23% at day 30. 6. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002; 165:867–903. 7. Kollef MH, Hamilton CW, Ernst FR. Economic impact of ventilator-associated pneumonia in a large matched cohort. Infect Control Hosp Epidemiol 2012; 33:250–256. *This recent matched case–control study from a large US database confirmed that patients with VAP (n = 2238; VAP incidence = 1.3 episode per 1000 ventilator-days) had significantly longer durations of mechanical ventilation (21.8 versus 10.3 days), ICU stay (20.5 versus 11.6 days) and hospitalization (32.6 versus 19.5 days) than patients without VAP. 8. Masterton RG, Galloway A, French G, et al. Guidelines for the management of hospital-acquired pneumonia in the UK: report of the working party on hospital-acquired pneumonia of the British Society for Antimicrobial Chemotherapy. J Antimicrob Chemother 2008; 62:5–34. 9. Rotstein C, Evans G, Born A, et al. Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Can J Infect Dis Med Microbiol 2008; 19:19–53. 10. Torres A, Ewig S, Lode H, Carlet J. Defining, treating and preventing hospital-acquired pneumonia: European perspective. Intensive Care Med 2009; 35:9–29. 11. Chawla R. Epidemiology, etiology, and diagnosis of hospital-acquired pneumonia and ventilator-associated pneumonia in Asian countries. Am J Infect Control 2008; 36:S93–S100. 12. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009; 302:2323–2329. 13. Forel JM, Voillet F, Pulina D, et al. Ventilator-associated pneumonia and ICU mortality in severe ARDS patients ventilated according to a lung-protective strategy. Crit Care 2012; 16:R65. *In this recent RCT including 339 patients with severe ARDS, the overall prevalence of VAP was 29%, with a cumulative incidence of ~40% after 10 days of mechanical ventilation. In contrast to older studies, no significant association between neuromuscular blockades agents use and the risk of VAP was observed in this study. 14. Rosenthal VD, Bijie H, Maki DG, et al. International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for 2004–2009. Am J Infect Control 2012; 40:396–407. **In this article, the International Nosocomial Infection Control Consortium (INICC) reports a pooled mean VAP incidence of 15.8 episodes for 1000 ventilator-days in 386 ICUs of 36 countries on the 2004–2009 period. This incidence was lower than the 24 episodes per 1000 ventilator-days incidence reported by the same network between 2002 and 2005, an evolution that probably reflects the advances made in prevention policies during the latest period. 15. Lee GM, Kleinman K, Soumerai SB, et al. Effect of nonpayment for preventable infections in U.S. hospitals. N Engl J Med 2012; 367:1428–1437. 16. Cook DJ, Walter SD, Cook RJ, et al. Incidence of and risk factors for ventilator-associated pneumonia in critically ill patients. Ann Intern Med 1998; 129:433–440. 17. Bouadma L, Wolff M, Lucet JC. Ventilator-associated pneumonia and its prevention. Curr Opin Infect Dis 2012; 25:395–404. 18. Hess DR. Noninvasive positive-pressure ventilation and ventilator-associated pneumonia. Respir Care 2005; 50:924–929. 19. Marelich GP, Murin S, Battistella F, et al. Protocol weaning of mechanical ventilation in medical and surgical patients by respiratory care practitioners and nurses: effect on weaning time and incidence of ventilator-associated pneumonia. Chest 2000; 118:459–467. 20. Lellouche F, Mancebo J, Jolliet P, et al. A multicenter randomized trial of computer-driven protocolized weaning from mechanical ventilation. Am J Respir Crit Care Med 2006; 174:894–900. 21. Kress JP, Pohlman AS, O'Connor MF, Hall JB. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471–1477. 22. Wang F, Wu Y, Bo L, et al. The timing of tracheotomy in critically ill patients undergoing mechanical ventilation: a systematic review and meta-analysis of randomized controlled trials. Chest 2011; 140:1456–1465. 23. Kollef MH, Afessa B, Anzueto A, et al. Silver-coated endotracheal tubes and incidence of ventilator-associated pneumonia: the NASCENT randomized trial. JAMA 2008; 300:805–813. 24. Caruso P, Denari S, Ruiz SA, et al. Saline instillation before tracheal suctioning decreases the incidence of ventilator-associated pneumonia. Crit Care Med 2009; 37:32–38. 25. Muscedere J, Rewa O, McKechnie K, et al. Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med 2011; 39:1985–1991. 26. Lorente L, Lecuona M, Jimenez A, et al. Influence of an endotracheal tube with polyurethane cuff and subglottic secretion drainage on pneumonia. Am J Respir Crit Care Med 2007; 176:1079–1083. 27. Poelaert J, Depuydt P, De Wolf A, et al. Polyurethane cuffed endotracheal tubes to prevent early postoperative pneumonia after cardiac surgery: a pilot study. J Thorac Cardiovasc Surg 2008; 135:771–776. 28. Valencia M, Ferrer M, Farre R, et al. Automatic control of tracheal tube cuff pressure in ventilated patients in semirecumbent position: a randomized trial. Crit Care Med 2007; 35:1543–1549. 29. Nseir S, Zerimech F, Fournier C, et al. Continuous control of tracheal cuff pressure and microaspiration of gastric contents in critically ill patients. Am J Respir Crit Care Med 2011; 184:1041–1047. 30. Drakulovic MB, Torres A, Bauer TT, et al. Supine body position as a risk factor for nosocomial pneumonia in mechanically ventilated patients: a randomised trial. Lancet 1999; 354:1851–1858. 31. van Nieuwenhoven CA, Vandenbroucke-Grauls C, van Tiel FH, et al. Feasibility and effects of the semirecumbent position to prevent ventilator-associated pneumonia: a randomized study. Crit Care Med 2006; 34:396–402. 32. Abroug F, Ouanes-Besbes L, Elatrous S, Brochard L. The effect of prone positioning in acute respiratory distress syndrome or acute lung injury: a meta-analysis. Areas of uncertainty and recommendations for research. Intensive Care Med 2008; 34:1002–1011. 33. Delaney A, Gray H, Laupland KB, Zuege DJ. Kinetic bed therapy to prevent nosocomial pneumonia in mechanically ventilated patients: a systematic review and meta-analysis. Crit Care 2006; 10:R70. 34. Manzano F, Fernandez-Mondejar E, Colmenero M, et al. Positive-end expiratory pressure reduces incidence of ventilator-associated pneumonia in nonhypoxemic patients. Crit Care Med 2008; 36:2225–2231. 35. Ntoumenopoulos G, Gild A, Cooper DJ. The effect of manual lung hyperinflation and postural drainage on pulmonary complications in mechanically ventilated trauma patients. Anaesth Intensive Care 1998; 26:492–496. 36. Ntoumenopoulos G, Presneill JJ, McElholum M, Cade JF. Chest physiotherapy for the prevention of ventilator-associated pneumonia. Intensive Care Med 2002; 28:850–856. 37. Templeton M, Palazzo MG. Chest physiotherapy prolongs duration of ventilation in the critically ill ventilated for more than 48 h. Intensive Care Med 2007; 33:1938–1945. 38. Patman S, Jenkins S, Stiller K. Physiotherapy does not prevent, or hasten recovery from, ventilator-associated pneumonia in patients with acquired brain injury. Intensive Care Med 2009; 35:258–265. 39. Labeau SO, Van de Vyver K, Brusselaers N, et al. Prevention of ventilator-associated pneumonia with oral antiseptics: a systematic review and meta-analysis. Lancet Infect Dis 2011; 11:845–854. 40. Morrow LE, Kollef MH, Casale TB. Probiotic prophylaxis of ventilator-associated pneumonia: a blinded, randomized, controlled trial. Am J Respir Crit Care Med 2010; 182:1058–1064. 41. Kollef M, Pittet D, Sanchez Garcia M, et al. A randomized double-blind trial of iseganan in prevention of ventilator-associated pneumonia. Am J Respir Crit Care Med 2006; 173:91–97. 42. Siempos II, Ntaidou TK, Falagas ME. Impact of the administration of probiotics on the incidence of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials. Crit Care Med 2010; 38:954–962. 43. Mounier R, Adrie C, Francais A, et al. Study of prone positioning to reduce ventilator-associated pneumonia in hypoxaemic patients. Eur Respir J 2010; 35:795–804. 44. Trouillet JL, Luyt CE, Guiguet M, et al. Early percutaneous tracheotomy versus prolonged intubation of mechanically ventilated patients after cardiac surgery: a randomized trial. Ann Intern Med 2011; 154:373–383. * This recent RCT compared immediate versus late (after day 15 from randomization) tracheostomy in 216 cardiac surgery patients still ventilated 4 days after the surgical procedure: the prevalence of VAP was similar in both groups (46 versus 44%, respectively, P = 0.77). 45. Terragni PP, Antonelli M, Fumagalli R, et al. Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial. JAMA 2010; 303:1483–1489. 46. Asehnoune K, Mahe PJ, Seguin P, et al. Etomidate increases susceptibility to pneumonia in trauma patients. Intensive Care Med 2012; 38:1673–1682. 47. Faisy C, Candela Llerena M, Savalle M, et al. Early ICU energy deficit is a risk factor for Staphylococcus aureus ventilator-associated pneumonia. Chest 2011; 140:1254–1260. 48. Roquilly A, Mahe PJ, Seguin P, et al. Hydrocortisone therapy for patients with multiple trauma: the randomized controlled HYPOLYTE study. JAMA 2011; 305:1201–1209. 49. Makris D, Manoulakas E, Komnos A, et al. Effect of pravastatin on the frequency of ventilator-associated pneumonia and on intensive care unit mortality: open-label, randomized study. Crit Care Med 2011; 39:2440–2446. 50. Chung DR, Song JH, Kim SH, et al. High prevalence of multidrug-resistant nonfermenters in hospital-acquired pneumonia in Asia. Am J Respir Crit Care Med 2011; 184:1409–1417. 51. Rello J, Ulldemolins M, Lisboa T, et al. Determinants of prescription and choice of empirical therapy for hospital-acquired and ventilator-associated pneumonia. Eur Respir J 2011; 37:1332–1339. 52. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA 2010; 304:1787–1794. 53. Ferrer M, Liapikou A, Valencia M, et al. Validation of the American Thoracic Society–Infectious Diseases Society of America guidelines for hospital-acquired pneumonia in the intensive care unit. Clin Infect Dis 2010; 50:945–952. 54. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis 2010; 51 (Suppl 1):S81–S87. 55. Hyllienmark P, Martling CR, Struwe J, Petersson J. Pathogens in the lower respiratory tract of intensive care unit patients: impact of duration of hospital care and mechanical ventilation. Scand J Infect Dis 2012; 44:444–452. * This retrospective, monocentric study reports the distribution of bacterial isolates from tracheal aspirates in 346 mechanically ventilated patients acocording to the duration of mechanical ventilation. The prevalence of cefotaxime-resistant pathogen was as high as 23% upon day 1 of mechanical ventilation. 56. Hawkey PM, Jones AM. The changing epidemiology of resistance. J Antimicrob Chemother 2009; 64 (Suppl 1):i3–i10. 57. Nordmann P, Naas T, Poirel L. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 2011; 17:1791–1798. 58. Morales G, Picazo JJ, Baos E, et al. Resistance to linezolid is mediated by the cfr gene in the first report of an outbreak of linezolid-resistant Staphylococcus aureus. Clin Infect Dis 2010; 50:821–825. 59. Sanchez Garcia M, De la Torre MA, Morales G, et al. Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA 2010; 303:2260–2264. 60. Jacoby GA. AmpC beta-lactamases. Clin Microbiol Rev 2009; 22:161–182. 61. Livermore DM. Has the era of untreatable infections arrived? J Antimicrob Chemother 2009; 64 (Suppl 1):i29–i36. 62. Zagorianou A, Sianou E, Iosifidis E, et al. Microbiological and molecular characteristics of carbapenemase-producing Klebsiella pneumoniae endemic in a tertiary Greek hospital during 2004-2010. Euro Surveill 2012; 17. ** This recent study conducted in a single Greek ICU reported that colistin resistance increased from 3.5 to 20.8% in carbapenemase-producing (KPC and/or VIM) K. pneumoniae strains between 2004 and 2010, as a likely result of increasing colistin consumption. 63. Bogdanovich T, Adams-Haduch JM, Tian GB, et al. Colistin-resistant, Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae belonging to the international epidemic clone ST258. Clin Infect Dis 2011; 53:373–376. 64. Antoniadou A, Kontopidou F, Poulakou G, et al. Colistin-resistant isolates of Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster. J Antimicrob Chemother 2007; 59:786–790. 65. Lopez-Giraldo A, Sialer S, Esperatti M, Torres A. Viral-reactivated pneumonia during mechanical ventilation: is there need for antiviral treatment? Front Pharmacol 2011; 2:66. 66. De Vos N, Van Hoovels L, Vankeerberghen A, et al. Monitoring of herpes simplex virus in the lower respiratory tract of critically ill patients using real-time PCR: a prospective study. Clin Microbiol Infect 2009; 15:358–363. 67. Linssen CF, Jacobs JA, Stelma FF, et al. Herpes simplex virus load in bronchoalveolar lavage fluid is related to poor outcome in critically ill patients. Intensive Care Med 2008; 34:2202–2209. 68. Luyt CE, Combes A, Deback C, et al. Herpes simplex virus lung infection in patients undergoing prolonged mechanical ventilation. Am J Respir Crit Care Med 2007; 175:935–942. 69. Limaye AP, Kirby KA, Rubenfeld GD, et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 2008; 300:413–422. 70. Papazian L, Doddoli C, Chetaille B, et al. A contributive result of open-lung biopsy improves survival in acute respiratory distress syndrome patients. Crit Care Med 2007; 35:755–762. 71. Vincent A, La Scola B, Forel JM, et al. Clinical significance of a positive serology for mimivirus in patients presenting a suspicion of ventilator-associated pneumonia. Crit Care Med 2009; 37:111–118. 72. Costa C, Bergallo M, Astegiano S, et al. Detection of mimivirus in bronchoalveolar lavage of ventilated and nonventilated patients. Intervirology 2012; 55:303–305. 73. Dare RK, Chittaganpitch M, Erdman DD. Screening pneumonia patients for mimivirus. Emerg Infect Dis 2008; 14:465–467. 74. Azoulay E, Timsit JF, Tafflet M, et al. Candida colonization of the respiratory tract and subsequent pseudomonas ventilator-associated pneumonia. Chest 2006; 129:110–117. 75. Delisle MS, Williamson DR, Perreault MM, et al. The clinical significance of Candida colonization of respiratory tract secretions in critically ill patients. J Crit Care 2008; 23:11–17. 76. Williamson DR, Albert M, Perreault MM, et al. The relationship between Candida species cultured from the respiratory tract and systemic inflammation in critically ill patients with ventilator-associated pneumonia. Can J Anaesth 2011; 58:275–284. 77. Hamet M, Pavon A, Dalle F, et al. Candida spp. airway colonization could promote antibiotic-resistant bacteria selection in patients with suspected ventilator-associated pneumonia. Intensive Care Med 2012; 38:1272–1279. 78. Meersseman W, Lagrou K, Spriet I, et al. Significance of the isolation of Candida species from airway samples in critically ill patients: a prospective, autopsy study. Intensive Care Med 2009; 35:1526–1531. 79. Wood GC, Mueller EW, Croce MA, et al. Candida sp. isolated from bronchoalveolar lavage: clinical significance in critically ill trauma patients. Intensive Care Med 2006; 32:599–603. 80. Blot SI, Taccone FS, Van den Abeele AM, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 2012; 186:56–64. * The authors of this multicentric observational study propose and validate a clinical algorithm to distingusih colonization from invasive pulmonary aspergillosis in mechanically ventilated patients without usual criteria for immune deficiency. 81. Blasi F, Bocchino M, Di Marco F, et al. The role of biomarkers in low respiratory tract infections. Eur J Intern Med 2012; 23:429–435. 82. Fagon JY. Biological markers and diagnosis of ventilator-associated pneumonia. Crit Care 2011; 15:130. 83. Anand NJ, Zuick S, Klesney-Tait J, Kollef MH. Diagnostic implications of soluble triggering receptor expressed on myeloid cells-1 in BAL fluid of patients with pulmonary infiltrates in the ICU. Chest 2009; 135:641–647. 84. Gibot S, Cravoisy A, Levy B, et al. Soluble triggering receptor expressed on myeloid cells and the diagnosis of pneumonia. N Engl J Med 2004; 350:451–458. 85. Oudhuis GJ, Beuving J, Bergmans D, et al. Soluble triggering receptor expressed on myeloid cells-1 in bronchoalveolar lavage fluid is not predictive for ventilator-associated pneumonia. Intensive Care Med 2009; 35:1265–1270. 86. Palazzo SJ, Simpson TA, Simmons JM, Schnapp LM. sTREM-1 as a diagnostic marker of ventilator-associated pneumonia. Respir Care 2012; 57:2052–2058. 87. Palazzo SJ, Simpson T, Schnapp L. Biomarkers for ventilator-associated pneumonia: review of the literature. Heart Lung 2011; 40:293–298. 88. Ramirez P, Garcia MA, Ferrer M, et al. Sequential measurements of procalcitonin levels in diagnosing ventilator-associated pneumonia. Eur Respir J 2008; 31:356–362. 89. Conway Morris A, Kefala K, Wilkinson TS, et al. Diagnostic importance of pulmonary interleukin-1beta and interleukin-8 in ventilator-associated pneumonia. Thorax 2010; 65:201–207. 90. Srinivasan R, Song Y, Wiener-Kronish J, Flori HR. Plasminogen activation inhibitor concentrations in bronchoalveolar lavage fluid distinguishes ventilator-associated pneumonia from colonization in mechanically ventilated pediatric patients. Pediatr Crit Care Med 2011; 12:21–27. 91. Vanspauwen MJ, Linssen CF, Bruggeman CA, et al. Clara cell protein in bronchoalveolar lavage fluid: a predictor of ventilator-associated pneumonia? Crit Care 2011; 15:R14. 92. Determann RM, Millo JL, Waddy S, et al. Plasma CC16 levels are associated with development of ALI/ARDS in patients with ventilator-associated pneumonia: a retrospective observational study. BMC Pulm Med 2009; 9:49. 93. Boeck L, Eggimann P, Smyrnios N, et al. The Sequential Organ Failure Assessment score and copeptin for predicting survival in ventilator-associated pneumonia. J Crit Care 2012; 27:523e.1–523e.9. 94. Seligman R, Papassotiriou J, Morgenthaler NG, et al. Copeptin, a novel prognostic biomarker in ventilator-associated pneumonia. Crit Care 2008; 12:R11. 95. Boeck L, Eggimann P, Smyrnios N, et al. Midregional pro-atrial natriuretic peptide and procalcitonin improve survival prediction in VAP. Eur Respir J 2011; 37:595–603. 96. Seligman R, Papassotiriou J, Morgenthaler NG, et al. Prognostic value of midregional pro-atrial natriuretic peptide in ventilator-associated pneumonia. Intensive Care Med 2008; 34:2084–2091. 97. Bello S, Lasierra AB, Minchole E, et al. Prognostic power of proadrenomedullin in community-acquired pneumonia is independent of aetiology. Eur Respir J 2012; 39:1144–1155. 98. Bloos F, Marshall JC, Dellinger RP, et al. Multinational, observational study of procalcitonin in ICU patients with pneumonia requiring mechanical ventilation: a multicenter observational study. Crit Care 2011; 15:R88. 99. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010; 375:463–474. 100. Schuetz P, Briel M, Christ-Crain M, et al. Procalcitonin to guide initiation and duration of antibiotic treatment in acute respiratory infections: an individual patient data meta-analysis. Clin Infect Dis 2012; 55:651–662. ** This meta-analysis pooled 4221 adult patients with respiratory tract infections from 14 clinical trials (including 242 patients with VAP and 79 with other HAP) and confirmed that PCT was a reliable and safe tool for guiding the duration of antibiotic therapy in patients with confirmed pneumonia. A significant 2.2-day reduction of antibiotic exposure was allowed in VAP patients with PCT-guided therapy, which is of crucial importance in light of the current epidemiology of bacterial resistance. 101. Stolz D, Smyrnios N, Eggimann P, et al. Procalcitonin for reduced antibiotic exposure in ventilator-associated pneumonia: a randomised study. Eur Respir J 2009; 34:1364–1375. 102. Wolff M, Bouadma L. What procalcitonin brings to management of sepsis in the ICU. Crit Care 2010; 14:1007. 103. Endimiani A, Hujer KM, Hujer AM, et al. Are we ready for novel detection methods to treat respiratory pathogens in hospital-acquired pneumonia? Clin Infect Dis 2011; 52 (Suppl 4):S373–S383. 104. Lung M, Codina G. Molecular diagnosis in HAP/VAP. Curr Opin Crit Care 2012; 18:487–494. 105. Bogaerts P, Hamels S, de Mendonca R, et al. Analytical validation of a novel high multiplexing real-time PCR array for the identification of key pathogens causative of bacterial ventilator-associated pneumonia and their associated resistance genes. J Antimicrob Chemother 2012; 68:340–347. ** This novel closed-cartridge kit combining multiplex PCR with real-time microarray detection has recently shown promising results for the detection of 13 major VAP-causative pathogens and 24 relevant β-lactam resistance genes (including ESBL and carbapenemases) on a collection of reference strains and clinical isolates. 106. Bousbia S, Papazian L, Saux P, et al. Repertoire of intensive care unit pneumonia microbiota. PLoS One 2012; 7:e32486. * This recent study combining rDNA sequencing and pathogen-targeted PCRs on BALF of ICU patients revealed that up to 16 distinct pathogens could be identified in a single specimen (including bacteria, virus and fungi), most of them being not reliably considered as causative for the current pneumonia episode. In this work, the number of bacterial species by positive sample was even higher in control patients (4.61 ± 2.95) than in those with confirmed VAP (3.49 ± 2.87) or nonventilator in-ICU HAP (3.43 ± 2.22). 107. Falagas ME, Rafailidis PI. When to include polymyxins in the empirical antibiotic regimen in critically ill patients with fever? A decision analysis approach. Shock 2007; 27:605–609. 108. Leclercq R, Canton R, Brown DF, et al. EUCAST expert rules in antimicrobial susceptibility testing. Clin Microbiol Infect 2013; 19:141–160. 109. Rodriguez-Bano J, Navarro MD, Retamar P, et al. beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis 2012; 54:167–174. 110. Florescu DF, Qiu F, McCartan MA, et al. What is the efficacy and safety of colistin for the treatment of ventilator-associated pneumonia? A systematic review and meta-regression. Clin Infect Dis 2012; 54:670–680. 111. Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-interval colistin administration in critically ill patients: is this the right dosing strategy? A preliminary study. Clin Infect Dis 2012; 54:1720–1726. ** One of the most exciting recent articles on the use of high-dose colistin regimen in ICU-acquired infections because of MDR pathogens, including VAP. 112. Plachouras D, Karvanen M, Friberg LE, et al. Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by Gram-negative bacteria. Antimicrob Agents Chemother 2009; 53:3430–3436. 113. Vicari G, Bauer SR, Neuner EA, Lam SW. Association between colistin dose and microbiologic outcomes in patients with multidrug resistant Gram-negative bacteremia. Clin Infect Dis 2013; 56:398–404. 114. Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system. Clin Infect Dis 2011; 53:879–884. 115. Yousef JM, Chen G, Hill PA, et al. Ascorbic acid protects against the nephrotoxicity and apoptosis caused by colistin and affects its pharmacokinetics. J Antimicrob Chemother 2012; 67:452–459. 116. Lu Q, Girardi C, Zhang M, et al. Nebulized and intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa. Intensive Care Med 2010; 36:1147–1155. 117. Korbila IP, Michalopoulos A, Rafailidis PI, et al. Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin Microbiol Infect 2010; 16:1230–1236. 118. Arnold HM, Sawyer AM, Kollef MH. Use of adjunctive aerosolized antimicrobial therapy in the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii ventilator-associated pneumonia. Respir Care 2012; 57:1226–1233. 119. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, et al. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother 2010; 65:2645–2649. 120. Lu Q, Luo R, Bodin L, et al. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology 2012; 117:1335–1347. 121. Ferrari F, Lu Q, Girardi C, et al. Nebulized ceftazidime in experimental pneumonia caused by partially resistant Pseudomonas aeruginosa. Intensive Care Med 2009; 35:1792–1800. 122. Lu Q, Yang J, Liu Z, et al. Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Am J Respir Crit Care Med 2011; 184:106–115. * This RCT compared nebulized ceftazidime plus amikacin therapy (n = 20) versus intravenous administration of these drugs (n = 17) in VAP caused by P. aeruginosa: no statistical difference was observed in terms of treatment success (70 versus 55%, respectively), superinfections or antibiotic-induced changes in lung aeration as measured by computed tomography. However, emergence of resistance under therapy was exclusively observed in patients receiving intravenous antibiotics. 123. Radhakrishnan M, Jaganath A, Rao GS, Kumari HB. Nebulized imipenem to control nosocomial pneumonia caused by Pseudomonas aeruginosa. J Crit Care 2008; 23:148–150. 124. Niederman MS, Chastre J, Corkery K, et al. BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gram-negative pneumonia. Intensive Care Med 2012; 38:263–271. 125. Hallal A, Cohn SM, Namias N, et al. Aerosolized tobramycin in the treatment of ventilator-associated pneumonia: a pilot study. Surg Infect (Larchmt) 2007; 8:73–82. 126. Luna CM, Bruno DA, Garcia-Morato J, et al. Effect of linezolid compared with glycopeptides in methicillin-resistant Staphylococcus aureus severe pneumonia in piglets. Chest 2009; 135:1564–1571. 127. Martinez-Olondris P, Rigol M, Soy D, et al. Efficacy of linezolid compared to vancomycin in an experimental model of pneumonia induced by methicillin-resistant Staphylococcus aureus in ventilated pigs. Crit Care Med 2012; 40:162–168. 128. Docobo-Perez F, Lopez-Rojas R, Dominguez-Herrera J, et al. Efficacy of linezolid versus a pharmacodynamically optimized vancomycin therapy in an experimental pneumonia model caused by methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 2012; 67:1961–1967. 129. Yoshizawa S, Tateda K, Saga T, et al. Virulence-suppressing effects of linezolid on methicillin-resistant Staphylococcus aureus: possible contribution to early defervescence. Antimicrob Agents Chemother 2012; 56:1744–1748. 130. Beibei L, Yun C, Mengli C, et al. Linezolid versus vancomycin for the treatment of Gram-positive bacterial infections: meta-analysis of randomised controlled trials. Int J Antimicrob Agents 2010; 35:3–12. 131. Kalil AC, Murthy MH, Hermsen ED, et al. Linezolid versus vancomycin or teicoplanin for nosocomial pneumonia: a systematic review and meta-analysis. Crit Care Med 2010; 38:1802–1808. 132. Wunderink RG, Niederman MS, Kollef MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis 2012; 54:621–629. ** In the ZEPHYR RCT, per-protocol analysis showed that linezolid (n = 172) was associated with a higher clinical success rate than vancomycin (n = 176) in proven MRSA pneumonia at end-of-study evaluation (58 versus 47%, P = 0.042). However, all-cause 60-day fatality rates (16 versus 17%, respectively) and the overall incidence of adverse effects were similar in both groups, even if renal impairment was more frequent with vancomycin (8 versus 18%, respectively). 133. Choi EY, Huh JW, Lim CM, et al. Relationship between the MIC of vancomycin and clinical outcome in patients with MRSA nosocomial pneumonia. Intensive Care Med 2011; 37:639–647. * In this retrospective study including 70 patients with MRSA HAP, about half of the MRSA isolates had vancomycin MIC ≥ 1.5 mg/l. Patients infected with these strains showed slower clinical response and higher relapse rate than patients infected with low vancomycin MIC isolates. 134. Haque NZ, Zuniga LC, Peyrani P, et al. Relationship of vancomycin minimum inhibitory concentration to mortality in patients with methicillin-resistant Staphylococcus aureus hospital-acquired, ventilator-associated, or health-care-associated pneumonia. Chest 2010; 138:1356–1362. 135. Zhanel GG, Calic D, Schweizer F, et al. New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin. Drugs 2010; 70:859–886. 136. Rubinstein E, Lalani T, Corey GR, et al. Telavancin versus vancomycin for hospital-acquired pneumonia due to Gram-positive pathogens. Clin Infect Dis 2011; 52:31–40. 137. Farrell DJ, Castanheira M, Mendes RE, et al. In vitro activity of ceftaroline against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae: a review of published studies and the AWARE Surveillance Program (2008–2010). Clin Infect Dis 2012; 55 (Suppl 3):S206–S214. 138. File TM Jr, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis 2012; 55 (Suppl 3):S173–S180. 139. Widmer AF. Ceftobiprole: a new option for treatment of skin and soft-tissue infections due to methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008; 46:656–658. 140. Krievins D, Brandt R, Hawser S, et al. Multicenter, randomized study of the efficacy and safety of intravenous iclaprim in complicated skin and skin structure infections. Antimicrob Agents Chemother 2009; 53:2834–2840. 141. Balakrishnan I, Awad-El-Kariem FM, Aali A, et al. Temocillin use in England: clinical and microbiological efficacies in infections caused by extended-spectrum and/or derepressed AmpC beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 2011; 66:2628–2631. 142. Ehmann DE, Jahic H, Ross PL, et al. Avibactam is a covalent, reversible, nonbeta-lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A 2012; 109:11663–11668. 143. Walkty A, DeCorby M, Lagace-Wiens PR, et al. In vitro activity of ceftazidime combined with NXL104 versus Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals (CANWARD 2009 study). Antimicrob Agents Chemother 2011; 55:2992–2994. 144. Castanheira M, Sader HS, Farrell DJ, et al. Activity of ceftaroline-avibactam tested against Gram-negative organism populations, including strains expressing one or more beta-lactamases and methicillin-resistant Staphylococcus aureus carrying various staphylococcal cassette chromosome mec types. Antimicrob Agents Chemother 2012; 56:4779–4785. 145. Lagace-Wiens PR, Tailor F, Simner P, et al. Activity of NXL104 in combination with beta-lactams against genetically characterized Escherichia coli and Klebsiella pneumoniae isolates producing class A extended-spectrum beta-lactamases and class C beta-lactamases. Antimicrob Agents Chemother 2011; 55:2434–2437. 146. Debarbieux L, Leduc D, Maura D, et al. Bacteriophages can treat and prevent Pseudomonas aeruginosa lung infections. J Infect Dis 2010; 201:1096–1104. 147. Morello E, Saussereau E, Maura D, et al. Pulmonary bacteriophage therapy on Pseudomonas aeruginosa cystic fibrosis strains: first steps towards treatment and prevention. PLoS One 2011; 6:e16963. 148. Chhibber S, Kaur S, Kumari S. Therapeutic potential of bacteriophage in treating Klebsiella pneumoniae B5055-mediated lobar pneumonia in mice. J Med Microbiol 2008; 57:1508–1513. 149. Witzenrath M, Schmeck B, Doehn JM, et al. Systemic use of the endolysin Cpl-1 rescues mice with fatal pneumococcal pneumonia. Crit Care Med 2009; 37:642–649. 150. Mouktaroudi M, Giamarellos-Bourboulis EJ. Macrolides for the therapy of nosocomial infections. Curr Opin Infect Dis 2012; 25:205–210. 151. Giamarellos-Bourboulis EJ, Pechere JC, Routsi C, et al. Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia. Clin Infect Dis 2008; 46:1157–1164. 152. Spyridaki A, Raftogiannis M, Antonopoulou A, et al. Effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by Gram-negative bacteria: results from a randomized clinical study. Antimicrob Agents Chemother 2012; 56:3819–3825. 153. van Delden C, Kohler T, Brunner-Ferber F, et al. Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial. Intensive Care Med 2012; 38:1118–1125. 154. Le Berre R, Nguyen S, Nowak E, et al. Relative contribution of three main virulence factors in Pseudomonas aeruginosa pneumonia. Crit Care Med 2011; 39:2113–2120. 155. Francois B, Luyt CE, Dugard A, et al. Safety and pharmacokinetics of an anti-PcrV PEGylated monoclonal antibody fragment in mechanically ventilated patients colonized with Pseudomonas aeruginosa: a randomized,double-blind, placebo-controlled trial. Crit Care Med 2012; 40:2320–2326. 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. 321–322). Acknowledgements None Curr Opin Pulm Med. 2013;19(3):216-228. © 2013 Lippincott Williams & Wilkins