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Management of ventilatorassociated pneumonia: epidemiology, diagnosis andantimicrobial therapy

Expert Rev. Anti Infect. Ther. 10(5), 585596 (2012)

Matteo Bassetti*1,2, Lucia Taramasso3, Daniele Roberto Giacobbe3 and Paolo Pelosi4
Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy 2 Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Piazzale Santa Maria della Misericordia 15, 33100Udine, Italy 3 Division of Infectious Diseases, SanMartino Hospital and University ofGenoa, Genoa, Italy 4 Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Genoa, Italy *Author for correspondence: Tel.: +39 432 559355 Fax: +39 432 559360 mattba@tin.it
1

Ventilator-associated pneumonia (VAP) is the most frequent infection among patients hospitalized in intensive care units, maintaining a high morbidity and mortality. The global incidence of VAP ranges from 8 to 28%. Early-onset VAP is mainly caused by community pathogens with a favorable pattern of antibiotic sensitivity, whereas late-onset VAP is often caused by multidrug-resistant pathogens, mainly methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa and Acinetobacter spp. and enteric Gram-negative bacilli. The diagnosis of VAP remains difficult to confirm, lacking both microbiological analysis and radiological signs of high specificity. The Clinical Infection Pulmonary Score has been proposed to overcome the difficulties related to the diagnosis, but is not applicable to all patient categories. A continuous evaluation of the antimicrobial therapeutic options, along with their pharmacodynamic and pharmacokinetic profiles, is mandatory to create therapeutic protocols and reduce VAP-related mortality.
Keywords: Acinetobacter baumannii Clinical Infection Pulmonary Score Enterobacteriaceae intensive care unit
multidrug-resistant pathogens Staphylococcus aureus ventilator-associated pneumonia

Despite enormous advances in techniques for the management of mechanically ventilated patients, ventilator-associated pneumonia (VAP) remains the most frequent infection among patients hospitalized in intensive care units (ICUs) [1] . It represents a nosocomial infection that develops in ICU patients at least 48h after mechanical ventilation (MV) is established and is caused by pathogens that were incubating or not present at the time MV was started [1,2] . VAP has a greater impact on morbidity, occurring at an estimated rate of 13% per day of MV, with a 927% incidence among all intubated patients [35]. Based on the timing of onset, VAP can be divided into early-onset VAP (approximately a third of cases), occurring within 45days after intubation and mainly caused by community pathogens with a favorable pattern of antibiotic sensitivity (Streptococcus pneumoniae, Haemophilus influenzae and anaerobes of the oral cavity), and late-onset VAP (approximately two-thirds of cases), often caused by multidrug- resistant(MDR) pathogens (e.g.,Staphylococcus
10.1586/ERI.12.36

aureus, Pseudomonas aeruginosa, Enterobacteriaceae and Acinetobacter b aumannii ) selected by exposure to broad- spectrum antibiotics and responsible for greater morbidity, prolonged ICU stay and longer duration of ventilation, with estimated costs exceeding US$15,000 per occurrence [6,7]. In addition to morbidity and economic costs associated with VAP, the burden of disease is heightened by the still high mortality. In particular, the mortality rate for late-onset VAP ranges from 24 to 50% and can reach 76% in some specific settings or when lung infection is caused by high-risk pathogens [2] . Notwithstanding, mortality is heavily influenced by the disease severity at VAP onset and different values are reported in different studies, ranging between 0 and 50% [8,9] . A recent metaanalysis demonstrated that although presence, compared with absence, of VAP seems to be associated with higher mortality in critically ill patients, appropriateness of initial antimicrobial treatment in such patients may moderate this association [10] .
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Moreover, among 215ICU patients with microbiologically confirmed VAP, the presence of chronic obstructive pulmonary disease (COPD), increased Simplified Acute Physiology ScoreII (SAPSII) and shock at the day of VAP diagnosis were found as independent risk factor for mortality [11] . Conversely, mortality in trauma patients seems to be lower than in other patients, according to the data of a prospective observational study conducted in 27ICUs in Europe, probably because of different demographic characteristics and etiology [12] . Owing to concerns regarding the high morbidity and mortality, and the spread of MDR, current knowledge and recent advances in the field of epidemiology, pathogenesis and management of VAP will be discussed, along with a description of epidemiologic and etiologic patterns.
Epidemiology

The incidence of VAP has ranged from 8 to 28% in different retrospective and prospective analyses [13] . Regarding early-onset VAP, few data are available. A perspective surveillance study has been performed over a period of 9years (20012009) among 11French hospitals to estimate the incidence of VAP within 48h of ICU admission. It found an incidence of early-onset VAP of 8.3 per 1000invasive MV days (95%CI: 6.111.1), while the global incidence of VAP was 20.6 per 1000 invasive MV days (95%CI: 18.622.8) [14] . The International Nosocomial Infection Control Consortium (INICC) involved 422ICUs and reported a pooled rate of VAP of 15.8cases per 1000 ventilator days, with the highest rates reported in trauma ICUs (40cases per 1000 ventilator days) [15] . On the other hand, among 1500US hospitals, the National Healthcare Safety Network (NHSN) reported minor rates of VAP (threecases per 1000 ventilator days), with highest rates in trauma (eight cases per 1000 ventilator days) and burn (10.7cases per 1000 ventilator days) ICUs [4] . However, a comparison of INICC and NHSN is difficult to make. Reflecting the lack of a definitive diagnostic approach, the INICC adopts a definition of VAP based on clinical and radiological findings, without requiring microbiologic evidence of infection, whereas microbiologic evidence of a pathogen was required in the NHSN report, leading to a decrease in rates across the different US ICUs [16] . Moreover, VAP prevalence seems to be higher across Europe compared with in the USA (23.5cases per 1000 ventilator days), both among mixed populations and specific ICU subtypes [17] . This variability in prevalence and incidence rates underscored the need for uniform diagnostic criteria for VAP to correctly interpret the different local epidemiological reports in a global perspective [16] .
Etiology & MDR

(ESBL)-producing Gram-negative bacilli [18,19] . Coagulasenegative staphylococci and various other organisms including anaerobic bacteria, fungi, Corynebacterium species, Moraxella species and enterococci represent rare pathogens. Overall, data from the NHSN reported that the most common pathogens isolated from patients with VAP were S.aureus (24%), P.aeruginosa (16%), Enterobacter spp. and A.baumannii (8%) [20] . Among 356ICU patients with microbiologically documented VAP in Europe, Enterobacteriaceae, S.aureus and P.aeruginosa represented the most frequent isolated pathogens (43, 33 and 23%, respectively) [21] . All of these pathogens reflected the phenomenon of growing resistance resumed with the word ESCAPE, containing the initials of the most frequent MDR microorganisms (Enterococcus faecium , S.aureus, Clostridium difficile, A.baumannii and Enterobacteriaceae) [22] . Of note, prior use of antimicrobials and hospitalization within the past 90days are risk factors particularly associated with the development of MDR organisms and MDR has a significant impact on mortality, length of and costs related to hospitalization [23,24] . Growing rates of resistance of MDR Gram-negative bacteria have been reported in the USA (Figure1) [25] . The last annual report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) showed a significant increase in prevalence of resistance strains among Enterobacteriaceae [26] . For example, among 10,952 Klebsiella pneumoniae isolates tested for third-generation cephalosporins, fluoroquinolones and amino glycosides, 35% of isolates were resistant to one or more of the three considered antibiotic classes [26] . Among non fermenting Gram-negative bacteria in Europe, MDR is also a concern. Among 8376P.aeruginosa isolates tested for at least three antibiotic classes among piperacillin/tazobactam, ceftazidime, fluoroquinolones, a minoglycosides and carbapenems, 33% were resistant to one or more of the five considered antibiotic classes, while 16% were resistant to three or more [26] . EARS-Net also reported S.aureus resistance rates to methicillin and rifampin, as outlined in Figure2[26] .
MDR Gram-negative bacteria

As previously reported, early-onset VAP is mainly caused by community pathogens with a favorable pattern of antibiotic sensitivity (S. pneumoniae, H. influenzae and anaerobes of the oral cavity), whereas late-onset VAP is often caused by MDR pathogens, mainly methicillin-resistant S.aureus (MRSA), P.aeruginosa and Acinetobacter spp. and enteric extended-spectrum b -lactamase
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MDR Gram-negative bacteria are especially common and problematic in some ICUs and they have developed numerous bials, mechanisms of drug resistance against available antimicro including b-lactamases, efflux pumps, porin mutations and binding site mutations [27] . In particular, b -lactamase-mediated resistance is a concern. The appearance of ESBLs and the diffusion of AmpC cephalosporinases now compromise the use of thirdgeneration cephalosporins [28] . Moreover, b -lactamases such IMP, VIM, K.pneumoniae carbapenemases (KPC) and OXA are increasingly seen in Gram-negative isolates, and are capable of conferring resistance to carbapenems and lead to the insurgence of VAP caused by MDR pathogens susceptible only to colistin [29] . Nevertheless, Gram-negative bacteria, especially nonfermenters, may even lose their susceptibility to colistin as a result of the combination of different resistance mechanisms, such as the outer membrane porin OprD, the AmpC cephalosporinase and a multitude of efflux pumps [30] . For example, the MYSTIC study
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Ventilator-associated pneumonia: epidemiology, diagnosis & antimicrobial therapy

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reported that 12% of P.aeruginosa strains isolated in ICUs are MDR, defined as resistance to at least ciprofloxacin, ceftazidime and gentamicin [31] . Moreover, P.aeruginosa trends toward piperacillin/tazobactam resistance were noted between 19971999 and 20002007 worldwide, with only polymyxins capable of providing an overall coverage 90% [32] .
MRSA

Escherichia coli/ Klebsiella pneumoniae

2008 2004 2000

Pseudomonas aeruginosa

Infections due to Gram-positive bacteria are one of the leading causes of morbidity and mortality in ICUs, and MRSA represents a major problem [33] . Resistance is conferred by an additional penicillin-binding protein (PBP2a), encoded by mecA , leading to an intrinsic resistance to all b -lactams and their derivatives [34] . Although methicillin resistance is associated with mortality among patients with VAP caused by S.aureus, this association might not be causal, but is probably due to confounders, such as the adequacy of empirical treatment and severity of illness [35] . Moreover, among 30MRSA isolates, vancomycin efficacy was decreased when the isolates MICs were >1g/ml, compared with the efficacy in isolates with MICs to vancomycin <0.5g/ml [36] . According to the CDC, MICs to vancomycin between 8 and 16g/ml define vancomycin-intermediate S.aureus (VISA), whereas a MIC >32g/ml defines vancomycin-resistant S.aureus (VRSA) [37] . However, when MRSA MICs to vancomycin are at the high end of the susceptibility range, vancomycin is already less effective and patients may have a higher likelihood of recurrence and a longer length of stay in hospital [38,39] . There are some reports of S.aureus and Staphylococcus epidermidis with documented genetic resistance to linezolid, which is a synthetic oxazolidinone that shows excellent penetration into the epithelial lining fluid [40,41] . The potential clinical superiority of linezolid compared with vancomycin in MRSA pneumonia will be discussed later. The clinical impact of resistance to the lipopeptide daptomycin is not of particular concern. However, daptomycin is not suitable for the treatment of VAP because of surfactant inactivation[42].
Diagnosis of VAP in mechanically ventilated critically ill patients

Acinetobacter baumannii 0 20 40 60 80

Proportion resistant (%)

Figure1. Proportion of multidrug-resistant pathogens among Gram-negative bacteria in the USA. Multidrug resistance was defined as resistance to one or more tested antimicrobials in three or more antimicrobial classes [25] .

investigations are not predictive of specific symptoms associated with VAP. The presence of microorganisms in a respiratory sample with or without a pulmonary infiltrate on a chest radiograph has low specificity for the diagnosis of VAP. In fact, it might merely represent colonization or tracheobronchitis and not pulmonary infection. Furthermore, the timing of the clinical presentation is also important, varying from an illness of abrupt to gradual onset, associated with less or more severe sepsis and septic shock. Thus, clinical manifestations, chest radiographic pattern and laboratory investigations can be mimicked in other pathologies such as congestive heart failure, pulmonary emboli, pulmonary hemorrhage and acute lung injury/acute respiratory distress syndrome. Presentation may be different in time and severity. The early recognition of VAP, timing and severity is essential to ensure the initiation of an appropriate diagnostic and therapeutic approach. In conclusion, the evaluation of individual clinical variables, such as fever, shortness of breath, chest pain, cough, sputum production, hypoxia and leukocytosis, or chest radiograph is not helpful in the diagnosis of VAP.

Italy

The diagnosis of VAP is generally based on clinical manifestations and symptoms; infiltrates at chest radiograph; laboratory investigations; and microbiological findings. However, it is also important to identify methods to identify VAP early, and to guide clinical management and treatment.
Individual clinical variables approach

France Rifampin Germany Methicillin

UK 0 10 20 30 40

The clinical manifestations and symptoms of VAP (i.e., fever, shortness of breath, chest pain, cough, sputum production, hypoxia and leukocytosis) are nonspecific with no pathognomonic signs. A chest radiograph to confirm the presence of a pulmonary infiltrate may not provide definitive confirmation of VAP. Additionally, there is no specific pulmonary radiographic pattern that is unique to a particular microorganism. Laboratory
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Proportion resistant (%)

Figure2. Staphylococcus aureus resistance rates in Europe in 2010. Data taken from [26] .

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Combined clinical variables approach

Another approach is to consider and evaluate clinical manifestations, chest radiographic patterns and laboratory investigations in combination. The conventional diagnosis of VAP is classically characterized by the presence of [43,44] : Clinical criteria: one, two or three of the following: core temperature >38.3 or <35.5C; leukocytosis (>10,000mm-3) or leukopenia (<3000mm-3); or purulent tracheal aspirate; Radiographic criteria: new persistent (>24h) or progressive infiltrate at chest radiograph; Microbiologic criteria: positive quantitative culture of a sample obtained by bronchoalveolar lavage (BAL; 10 4cfu/ml) or protected-specimen brush (PSB; 103cfu/ml); positive blood culture unrelated to another source and obtained 48h before and after respiratory sampling; and positive pleural fluid culture in absence of previous pleural instrumentation. More recently, another definition has been proposed to determine the clinical screening of hospital acquired pneumonia and VAP [45] : the presence of new chest x-ray infiltrates plus one of the three clinical variables: fever 38C, leukocytosis or leukopenia, and purulent secretions. In acute lung injury/acute respiratory distress syndrome and for those who it is difficult to demonstrate a deterioration of radiological images, at least one of fever 38C, leukocytosis or leukopenia, and purulent secretions may suffice to warrant initial screening. The presence of new chest xray infiltrates plus at least two of the three clinical variables (fever 38C, leukocytosis or leukopenia, and purulent secretions) is accurate enough to start antimicrobial treatment and cultures. However, both individually considered or combined with the clinical and laboratory variables, chest radiograph does not seems to reach an acceptable sensitivity and specificity, when compared with post-mortem lung biopsies [46] .
Clinical Infection Pulmonary Score

To improve the sensitivity and specificity of VAP diagnosis, it has been proposed to combine and score the individual values, generating the Clinical Infection Pulmonary Score (CPIS) [47] . The CPIS is obtained from: clinical manifestations and symptoms; infiltrates at chest radiograph; laboratory investigations; Table1. Clinical Pulmonary Infection Score chart.
Diagnostic feature
Tracheal secretions Chest x-ray infiltrate Temperature (C) White blood cells (10 /l)
9

and microbiological findings (Table1) . Different modifications of CPIS have been suggested. In the original and modified CPIS, in addition to the variables reported above, the level of oxygenation has been included, while the semiquantitative culture of tracheal aspirate is not considered mandatory [48] . In the original paper from Pugin etal. it was reported that in a limited number of mechanically ventilated patients with different diseases, a CPIS equal to or higher than 6 out of a maximum of 12 was correlated with high bacterial counts isolated from the lower respiratory tract and able to predict pulmonary infection with a high specificity and sensitivity of 93 and 100%, respectively [47] . Successively, Fartoukh etal. found that clinical prediction alone was inaccurate, but a modified CPIS, incorporating a Gram stain of respiratory tract secretions, improved diagnostic accuracy [49] . The diagnostic accuracy was enhanced and the likelihood ratio for pneumonia based on a score greater than 6 increased from a baseline of 1.46 (using the CPIS) to 1.67 if a Gram stain of blind protected samples was obtained and to 1.77 if a Gram stain of a directed sample was obtained. Nonetheless, the authors cautioned that further refinement of the clinical scoring approach was necessary to improve the diagnostic accuracy in patients suspected of having VAP. In a large range of studies, including a dishomogeneous population of patients mechanically ventilated and recovered in an ICU, CPIS does not appear to be sufficiently accurate compared with a BAL fluid-established diagnosis with a sensitivity between 30 and 89% and specificity between 17and 80% [4956] . The major limitations about the appropriate evaluation of CPIS in the diagnosis of VAP are related to: the dishomogeneous population of patients investigated; the limitation of BAL to diagnose VAP with high sensitivity and specificity; the different threshold of CPIS to diagnose VAP; and the interobserver variability to calculate CPIS. We believe that to improve and optimize the efficacy of CPIS to diagnose VAP it is important to take into account the clinical condition of the patient, the underlying disease and the alteration at chest radiograph. It is evident that in a previous disease condition markedly affecting the temperature, leukocytes, tracheal secretions and oxygenation, as well as chest radiograph, the role of CPIS to diagnose VAP is markedly affected. Thus, we believe that CPIS might have a more relevant role in clinical conditions

0
Rare None 36.5 and 38.4 4.0 and 11.0 >240 or ARDS Negative

1
Abundant Diffuse 38.5 and 38.9 <4.0 or >11.0 Positive

2
Abundant and purulent Localized 39.0 or 36.5 <4.0 or >11.0 plus band forms 0.5 <240 or no ARDS Positive plus positive Gram stain

PaO2/FiO2mmHg Microbiology

Microbiology not relevant in the case of the modified Clinical Pulmonary Infection Score. Determination is only positive for the purpose of the modified Clinical Pulmonary Infection Score. ARDS: Acute respiratory distress syndrome; FiO2: Fraction of inspired oxygen; PaO2: Partial pressure of oxygen in arterial blood.

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in which these parameters are minimally Calculate patients CPIS affected at ICU entry. A specific population of patients could show these characteristics, such as brain trauma or brain Yes No Does the CPIS = 6? injury patients. In fact, Pelosi etal. demonstrated that CPIS could predict VAP with Is the CPIS <4? Yes high sensitivity and specificity early on in Are tracheobronchial a selected population of patients suffering No secretions available for Gram stain? from brain injury [57] . Nonetheless, these Yes finding cannot be directly transferred to a more dishomogeneous group of patients. Yes Microbiological Initiate The most common method to diagnose culture therapy VAP is the quantitative analysis of the BAL, as discussed below. However, it has Are pus cells and Recalculate Microbiological No been clearly demonstrated that BAL is not organisms present? CPIS daily culture always so specific and sensitive when compared with immediate postmortem pulMicrobiological Stop therapy Continue monary biopsy. The consequence of this Yes Stop therapy culture if CPIS = 6 therapy if CPIS is the overall uncertainty of both BAL and if started on day 3 >6 on day 3 CPIS to diagnose VAP [45,56] . Treat on Gram Finally, some parameters included in stain and local CPIS are subjective and depend on the epidemiology experience of the observer [53] . The quantification and evaluation of the quality of Figure3. Flowchart for using the Clinical Pulmonary Infection Score. secretions is not easily performed at the CPIS: Clinical Pulmonary Infection Score. bedside, and the chest radiograph interpretation might show a high intraobserver variability. The level of oxygenation depends on the ventilation is often not specific. CPIS may be helpful tool to confirm VAP setting used, which is not included in the CPIS. We believe that and for monitoring antibiotic treatment and clinical evolution. to improve the specificity and sensitivity of CPIS to diagnose It appears to only be helpful to diagnose VAP in standardized VAP in the ICU, a selected population of patients with no major populations of patients, such as those affected by brain trauma alteration of parameters included in CPIS at ICU entry should and injury. Further studies are required to better identify the atbe considered. Of course, this dramatically reduces the num- bedside role of the CPIS in the clinical management of critically ber of patients in whom CPIS might be relevant. Evaluation of ill mechanically ventilated patients. secretions, interpretation of chest radiographs and oxygenation should be considered in patients with brain injury. Role of bacteriological analysis to diagnose VAP However, although the CPIS seems to play a minor role in the Many studies have evaluated the value of bacteriological data in diagnosis of VAP, it should be considered to identify patients at establishing the diagnosis of VAP compared with patho logical, risk of VAP and to monitor the adequacy of the antibiotic treat- clinical or other bacteriological criteria. The quantitative analyment and clinical management. It is our opinion that when the sis of the bacteriological data are usually considered the gold CPIS is higher than or equal to 6, microbiological analysis as well standard in the diagnosis of VAP. as appropriate empirical antibiotic treatment should be considered Quantitative cultures might be obtained by different methods, (Figure3) . Furthermore, it has been clearly demonstrated that the including BAL, protective BAL (pBAL), PSB or tracheal aspirate CPIS might have a relevant role in monitoring the evolution of (TA), which overall appear to be equivalent for the diagnosis VAP, to predict the outcome early, as well as to guide the duration of VAP. In general, compared with a pathologically confirmed of the antibiotic treatment [58] . It has been found that oxygen- diagnosis of VAP, BAL shows a sensitivity between 19 and 83% ation and temperature are the first parameters to improve when and specificity between 45 and 100%; PSB shows a sensitivity adequate treatment has been given to patients affected by VAP [59] . between 36 and 83% and specificity between 50 and 95%; pBAL In a prospective randomized controlled study it has been shown shows a sensitivity between 39 and 80% and specificity between that the use of CPIS could be associated with an early withdrawal 66 and 100%; and TA shows a sensitivity between 44 and 87% of the antibiotic treatment, with a marked reduction in associated and specificity between 31 and 92% [62] . costs [60] . However, these positive findings were not confirmed in Several factors might affect the sensitivity and specificity of BAL in the diagnosis of VAP: prior antibiotic treatment that other nonrandomized observational studies [61] . In conclusion, clinical manifestations are usually considered to might considerably decrease the sensitivity of cultures of BAL confirm or diagnose VAP. Chest radiograph may be sensitive but samples; the inconsistency of tracheal and alveoli microbiological
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Table2. Pharmacokinetic/pharmacodynamic parameters and usual clinical dosage for agents commonly used for Gram-negative coverage in ventilator-associated pneumonia.
Drug Usual clinical dosage for VAP PK/PD parameter predictive of breakpoint efficacy
Time > MIC

b -lactams
Piperacillin/tazobactam Ceftazidime Cefepime Meropenem Imipenem Doripenem 4.5 g q.i.d. or in prolonged (4 h) or continous infusion 2 g t.i.d. or in continous infusion 2 g t.i.d. 12 g t.i.d./q.i.d. in prolonged (3 h) or continuous infusion 1 g t.i.d. 0.5 g t.i.d. 7mg/kg q.d. 15mg/kg q.d. 400mg t.i.d. 500mg b.i.d. or 750mg q.d. AUC/MIC Cmax /MIC

Aminoglycosides
Gentamycin Amikacin

Fluoroquinolones
Ciprofloxacin Levofloxacin

AUC: Area under the curve; b.i.d.: Two times a day; PD: Pharmacodynamic; PK: Pharmacokinetic ; q.d.: Once a day; q.i.d.:Four times a day; t.i.d.: Three times a day; VAP: Ventilator-associated pneumonia.

cultures when compared with the pathological samples; and the variability in different sites of sampling of culture in the lung. Some studies clearly question the reliability of microbiological cultures obtained from the tracheobronchial tree or alveolar side for the diagnosis of VAP [45,46,49] . In these studies quantitative cultures were obtained through conventional techniques (BAL, pBAL, PSB or TA) and were compared with histological and microbiological references. Sensitivities for diagnosis of VAP were extremely low, ranging from 36 to 91%, with specificities ranging from 45 to 92%. It is common experience that bacteriological cultures require some days for the results to be available. For these reasons, alternative methods to better identify patients at risk of VAP earlier have been developed and investigated. One such approach is the analysis of the number of inflammatory cells and Gram stains. The presence of over 2% inflammatory cells had a sensitivity of 7586% and a specificity of 7898% in diagnosing VAP. Furthermore, the presence of bacteria in Gram stains of BAL specimens had a sensitivity of 4490% and specificity of 49100% in identifying patients with VAP. However, it should be remembered that the accuracy of Gram stains is slightly better for Gram-positive than Gram-negative microorganisms. In conclusion, bacteriologic data do not increase the accuracy of diagnosis when compared with clinical diagnosis. Quantitative cultures obtained by different methods, including BAL, pBAL, PSB or TA seem to be roughly equivalent in diagnosing VAP. The rapid availability of cytological data, including inflammatory cells and Gram stains, might be helpful in i nitial therapeutic decisions in patients with suspected VAP,
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but may clearly be influenced by antibiotic treatment and infecting microorganisms.

Biomarkers & VAP diagnosis

In order to improve the sensitivity and specificity of clinical and microbiological diagnosis of VAP, the laboratory analysis of specific biomarkers has been proposed and investigated. Several biomarkers have been proposed for diagnosing VAP, but few of them have been found to be reliable [62] . Among them, the most important are procalcitonin (PCT) and C-reactive protein (CRP). Serum PCT levels had better performance than alveolar PCT concentrations, with a sensitivity and a specificity varying according to the etiology and the severity of the disease. On the other hand, a CRP higher than 10mg/dl has been reported to be associated with VAP. The major limitations of these parameters is that several factors might increase both PCT and CRP, minimizing its efficiency to detect VAP early [63] . Furthermore, they need continuous daily monitoring, which has a major impact on economic resources, especially in ICUs with a large number of patients. In conclusion, several biomarkers have been evaluated to improve the diagnosis of VAP. Among them PCT and CRP appear to be the most promising but with major intrinsic limitations. Further studies are warranted to better define their role in clinical practice taking into account the costs. Furthermore, another important biomarker is represented by the detection of Aspergillus galactomannan (GM; a cellwall c onstituent released during tissue invasion) in BAL f luid (BAL-GM) for diagnosing VAP caused by Aspergillus spp.
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Thenew findings that BAL-GM is a valuable test for diagnosing invasive pulmonary aspergillosis in apparently immunocompetent ICU patients set a new and practice-changing standard and one that comes without the requirement for additional procedures or novel technologies. All that is needed is to submit a sample for GM testing from fluid obtained during BAL, a commonly performed diagnostic procedure for VAP [64] .
Antimicrobial treatment of VAP

The treatment of VAP remains a difficult and complex challenge influenced by various factors, for example the frequent absence of definitive diagnosis of VAP and the presence of MDR pathogens[2,65] . Two principles guide the strategy of antibiotic therapy for VAP. The first is the initial administration of appropriate antibiotics potentially active on causative pathogens, whereas the second is the shortening of inappropriate therapy. The strategy of de-escalation attempts to unify these two principles within a single strategy, optimizing patient outcome and minimizing the emergence of antibiotic resistance at the same time. In addition to these principles it is necessary to ensure that the administration of antibiotics satisfies certain requirements, such as the appropriate dose and dosing intervals, the optimal duration of treatment and the monitoring of drug levels and drug i nteractions. The lack of adherence to these minimal requirements can result in reduced or excessive tissue concentration Box1. American Thoracic Society initial empiric therapy for of the drugs and lead, respectively, to the hospitalacquired pneumonia, ventilator-associated pneumonia and occurrence of antibiotic resistance and lack healthcare-associated pneumonia in patients with late-onset disease of therapeutic efficacy or to toxicity despite or risk factors for multidrugresistant pathogens and all disease severity. a qualitatively correct treatment. When VAP is suspected, the initial treat- Potential pathogens ment regimen is often chosen without the Streptococcus pneumonia, Haemophilus influenzae, methicillin-sensitive Staphylococcus aureus, antibiotic-sensitive enteric Gram-negative bacilli ( Escherichia identification of the responsible pathogen. coli, Klebsiella pneumoniae, Enterobater spp., Proteus spp., Serratia Marcescens), However, the epidemiology may change MDR pathogens ( Pseudomonas aeruginosa, K. pneumoniae ESBL+, Acinetobacter in different hospitals and even in ICUs spp.), Legionella pneumophila and methicillin-resistant S. aureus within the same hospital. Knowledge of the bacteria primarily associated with VAP Combination antibiotic therapy Antipseudomonal cephalosporin (cefepime, ceftazidime) in the different local realities can help or in the selection of the correct empirical Antipseudomonal carbapenem (imipenem, meropenem) treatment regimen [66,67] . or A guideline-based approach based on b-lactam/ b-lactamase inhibitor (piperacillintazobactam) local antibiotic susceptibility patterns can plus reduce the overall use of antibiotics, the Antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin) selective pressure for MDR bacteria and the outcome of VAP [68,69]. The treatment or must be initiated as soon as possible, being Aminoglycoside (amikacin, gentamicin, tobramycin) the outcome strictly related to the delay plus of administration of active antimicrobial Linezolid or vancomycin drugs. Therefore, an empirical treatment is If an ESBL- strain, such as Klebsiella pneumoniae, or an Acinetobacter species is suspected a carbapenem is reliable choice. recommended when VAP is clinically sus- a If Legionella pneumophila is suspected, the combination antibiotic regimen should include a macrolide pected and the de-escalation of the chosen (e.g., azithromycin) or a fluoroquinolone (e.g., ciprofloxacin or levofloxacin) should be used rather than an regimen has to be made when microbiologi- aminoglycoside. If methicillin-resistant Staphylococcus aureus risk factors are present or there is a high incidence locally. cal data become available [70,71]. However, ESBL: Extended-spectrum b -lactamase; MDR: Multidrug resistant. although de-escalation therapy appears to Data taken from [81].
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correlate with lower mortality, it is not applicable to the cases in which the etiological diagnosis of pneumonia is not reached because of different factors, such as inadequate sampling, corticosteroid therapy, initiation of antimicrobial drugs before sampling difficult-to-isolate strains[7274]. or the presence of Except for the treatment of nonfermenting Gram-negative bacteria such as P.aeruginosa and A.baumannii, the duration of the empiric therapy may be shortened in patients with a good clinical response, from the traditional 1421days to 8days of drug administration [75,76] . In order to shorter the duration of antibiotic treatment, PCT-guided antibiotic therapy in patients with respiratory tract infections appears to reduce antibiotic use without affecting overall mortality or length of stay in the hospital [77] . Moreover, a short, as opposed to long, course of antibiotics did not adversely affect mortality, length of ICU stay or recurrence rates of patients with VAP [78] . A correct anti biotic administration must take account of drug pharmacokinetic profile. A single daily dose regimen is appropriate for amino glycosides and fluoriquinolones (concentration dependent), while more frequent administrations of lower doses are appropriate for b -lactams and other time-dependent antimicrobial, in order to obtain adequate values of the area under the curve above the MIC for the different antibiotics (Table2) . The lung penetration of the different drugs is another pharmacokinetic

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factor to consider. For example, higher vancomycin serum concentrations may be necessary to achieve appropriate lung concentrations to optimize treatment outcomes in VAP caused by MRSA, whereas linezolid demonstrates adequate penetration into lung and other soft tissues with sustained concentrations above the MIC for MRSA, for the majority of the dosing interval [79] . Moreover, pharmacokinetics are influenced by the altered physiology (presence of multiple organ impairment) and associated pharmacology in the critically ill patient undergoing MV. With some limitations, the application of software such as Monte Carlo simulation may provide the doses and infusion duration that should be used to treat critically ill patients [80] . The initial empiric therapy recommended by the American Thoracic Society for the treatment of VAP should be based on the presence or absence of risk factors for MDR pathogens, such as prolonged hospitalization (5days or more), admission from a healthcare-related facility and recent antibiotic therapy [81] . The ATS principles for healthcare-associated pneumonia and VAP are outlined in Box 1. A recent published paper that aimed to improve compliance with these guidelines and assess outcomes has demonstrated that the adherence to empirical recommended treatment was associated with increased mortality [82] . However, as discussed earlier, MDR may lead to a reduction in susceptibility and also to a guideline-based therapy, so clinicians are forced to use new drugs that have been recently marketed or a combination of already known antimicrobial agents, trying to overcome resistanceespecially among Gram-negative bacteria, where colistin often remains the only therapeutic option availablewith one study showing a synergistic activity with rifampin [83] . The use of tigecycline, although active against MDR Acinetobacter spp., is questioned because of its bacteriostatic mechanism and low concentrations in serum and
Late onset (>5 days) Antibiotics in preceding 90 days >5 days of hospitalization Immunosuppressed Long-term care facility resident Chronic hemodialysis

epithelial lining fluid, with high mortality reported among tigecyclinetreated patients with VAP and bacteremia [84] . Regarding hospital-acquired pneumonia caused by Gram-positive pathogens such as MRSA, both telavancin and linezolid result in significantly greater clinical cure rates compared with vancomycin [8588] . In the PhaseIII noninferiority study, a subgroup analysis revealed that patients with VAP exhibited a trend toward higher clinical cure rates with telavancin relative to vancomycin [85] . The European Medical Agency (EMA) has recently approved telavancin for the treatment of adults with hospital-acquired pneumonia, including VAP, known or suspected to be caused by MRSA, but only when other treatments (e.g., other antibiotics) are not suitable because of the increased risk of renal toxicity of telavancin compared with vancomycin. Also, the data of the recently completed and published Zephyr trial suggested a clinical superiority of linezolid compared with vancomycin, with higher rates of successful clinical response, acceptable safety and tolerability profile for the treatment of proven MRSA nosocomial pneumonia. Microbiologic responses paralleled clinical outcomes, and MRSA clearance was 30% greater with linezolid than with vancomycin. A difference of at least 20% persisted until late follow-up, suggesting that linezolid treatment may result in more complete bacterial eradication [89] . The higher rate of nephrotoxicity with vancomycin may partially reflect the use of adjusted vancomycin doses in this trial, as recommended by current clinical guidelines [90] . A higher incidence of renal injury was seen in patients with vancomycin trough levels >20g/ml on day3, as previously reported [91] .
Conclusion

Amikacin or levofloxacin or ciprofloxacin (if resistance rate in Pseudomonas aeruginosa isolates within the hospital <40%)

In conclusion, an effective antimicrobial therapy and the appropriate use of supportive measures remain essential in the treatment of VAP (Figure4) . However, because of the progressive reduction of bacterial susceptibility to currently used antimicrobials in ICUs and the high mortality related to VAP caused by MDR strains, a continuous evaluation of the therapeutic options, along with their pharmacodynamic and pharmaco k inetic profiles, is mandatory to create better therapeutic protocols and reduce VAP-related mortality.
Linezolid

Meropenem/imipenem/ doripenem or piperacillin/tazobactam

Expert commentary & five-year view

Re-evaluation after 4872 h in light of microbiological results and clinical conditions and de-escalation

Figure4. Empiric antibiotic therapy in patients with ventilator-associated pneumonia and the risk factors indicated in the box.

VAP still remains the most frequent infection among patients hospitalized in ICUs and is associated with high economic costs and mortality, especially when lung infection is caused by high-risk pathogens, such as MRSA, ESBL-producing Gramnegative bacteria, and MDR P.aeruginosa and A.baumannii. The paucity of currently used agents active against these MDR strains u nderlines the importance
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of antimicrobial development. However, few new antibiotics have been advanced into clinical practice for the treatment of most of the MDR pathogens, e specially Gram-negative bacteria. Therefore, containing the spread of these resistant pathogens remains crucial and an optimized prescription of suitable antibiotics is mandatory. Moreover, the diagnosis of VAP in the severely ill patients remains a clinical dilemma. In the presence of a previous disease condition markedly affecting the temperature, leukocytes, tracheal secretions and oxygenation, as well as chest radiograph, the role of CPIS to diagnose VAP remains uncertain. CPIS might be useful when these parameters are minimally affected at ICU entry, such as in trauma or brain injury patients, but not in a more dishomogeneus population. CPIS might be an important tool to predict outcomes earlier as well as to guide the duration of antibiotic treatment, but further studies are required to better identify the role of CPIS in the clinical management of critically ill mechanically ventilated patients. Furthermore, regarding diagnosis difficulties, bacteriological data do not increase the accuracy of diagnosis when compared with clinical diagnosis. Quantitative cultures obtained by different methods, including BAL, pBAL, PSB or TBA seem to be roughly equivalent for the diagnosis of VAP. The rapid availability of cytological data, including inflammatory cells and Gram stains, might be helpful in initial therapeutic decisions in patients with suspected VAP, although they are clearly influenced by antibiotic treatment and infecting microorganism. Several biomarkers have also been evaluated to improve the diagnosis of VAP. Among them, PCT and CRP appear to be the most promising but with major intrinsic limitations, such as the presence of several factors that might increase both PCT and CRP, minimizing their efficiency for the early detection of Key issues

VAP. Further studies are warranted to better define the role of PCT and CRP in clinical practice taking into account the costs. The antimicrobial treatment of VAP remains a difficult and complex challenge influenced by various factors, for example the frequent absence of definitive diagnosis of VAP and the presence of MDR pathogens. When VAP is suspected, the initial treatment regimen is often chosen without the identification of the responsible pathogen. However, the epidemiology may change in different hospitals and even in ICUs within the same hospital. Knowledge of the bacteria primarily associated with VAP in the different local realities canhelp in the selection of the correct empirical treatment regimen. In conclusion, because of the progressive reduction of bacterial susceptibility to currently used antimicrobials and the high m ortality related to VAP caused by MDR strains, a continuous evaluation of the therapeutic options, along with theirpharmacodynamic and pharmacokinetic profiles, is mandatory.
Financial & competing interests disclosure

M Bassetti serves on scientific advisory boards for Pfizer, Inc., Merck Serono, Novartis, Shionogi and Co., Ltd, and Astellas Pharma, Inc.; and has received funding for travel or speaker honoraria from Pfizer, Inc., Merck Serono, Novartis, GlaxoSmithKline, Gilead Sciences, Inc., SanofiAventis, Cephalon, Inc., Bayer Schering Pharma, Janssen and Astellas Pharma, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Ventilator-associated pneumonia (VAP) has a great impact on morbidity, occurring at an estimated rate of 13% per day of mechanical ventilation, with a 927% incidence among all intubated patients. VAP can be divided in early-onset VAP occurring within 45days after intubation and mainly caused by community pathogens withafavorable pattern of antibiotic sensitivity, and late-onset VAP, often caused by multidrug-resistant (MDR) pathogens (e.g.,Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacterobacteriaceae and Acinetobacter baumannii ). Although methicillin resistance is associated with mortality among patients with VAP due to S.aureus, this association might not be causal, but probably due to confounders, such as the adequacy of empirical treatment and severity of illness. The clinical manifestations and symptoms of VAP are nonspecific and no pathognomonic signs are present. To improve the sensitivity and specificity of VAP diagnosis, it has been proposed to combine and score the individual values, generating the Clinical Infection Pulmonary Score (CPIS). It is our opinion that when the CPIS is greater than or equal to 6, microbiological analysis as well as appropriate empiric antibiotic treatment should be considered. The quantitative analysis of the bacteriological data are usually considered the gold standard in the diagnosis of VAP. Several biomarkers have been evaluated to improve the diagnosis of VAP, among them procalcitonin and C-reactive protein appear to be the most promising but with major intrinsic limitations. Two principles guide the strategy of antibiotic therapy for VAP. The first is the initial administration of appropriate antibiotics, potentially active on causative pathogens, whereas the second is the shortening of inappropriate therapy. A guideline-based approach based on local antibiotic susceptibility patterns can reduce the overall use of antibiotics, the selective pressure for MDR bacteria and the outcome of VAP. Regarding VAP caused by Gram-positive pathogens such as methicillin-resistant S.aureus, both telavancin and linezolid result in significantly greater clinical cure rates compared with vancomycin.

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