Ventilator-associated pneumonia in the ICU

Ventilator-associated pneumonia (VAP) is defined as pneumonia that occurs 48–72 hours or thereafter following endotracheal intubation, characterized by the presence of a new or progressive infiltrate, signs of systemic infection (fever, altered white blood cell count), changes in sputum characteristics, and detection of a causative agent [1]. VAP contributes to approximately half of all cases of hospital-acquired pneumonia [1, 2]. VAP is estimated to occur in 9–27 % of all mechanically ventilated patients, with the highest risk being early in the course of hospitalization [1, 3]. It is the second most common nosocomial infection in the intensive care unit (ICU) and the most common in mechanically ventilated patients [4, 5]. VAP rates range from 1.2 to 8.5 per 1,000 ventilator days and are reliant on the definition used for diagnosis [6]. Risk for VAP is greatest during the first 5 days of mechanical ventilation (3 %) with the mean duration between intubation and development of VAP being 3.3 days [1, 7]. This risk declines to 2 %/day between days 5 to 10 of ventilation, and 1 %/day thereafter [1, 8]. Earlier studies placed the attributable mortality for VAP at between 33–50 %, but this rate is variable and relies heavily on the underlying medical illness [1]. Over the years, the attributable risk of death has decreased and is more recently estimated at 9–13 % [9, 10], largely because of implementation of preventive strategies. Approximately 50 % of all antibiotics administered in ICUs are for treatment of VAP [2, 4]. Early onset VAP is defined as pneumonia that occurs within 4 days and this is usually attributed to antibiotic sensitive pathogens whereas late onset VAP is more likely caused by multidrug resistant (MDR) bacteria and emerges after 4 days of intubation [1, 4]. Thus, VAP poses grave implications in endotracheally intubated adult patients in ICUs worldwide and leads to increased adverse outcomes and healthcare costs. Independent risk factors for development of VAP are male sex, admission for trauma and intermediate underlying disease severity, with odds ratios (OR) of 1.58, 1.75 and 1.47–1.70, respectively [7].


Introduction
Ventilator-associated pneumonia (VAP) is defi ned as pneumonia that occurs 48-72 hours or thereafter following endotracheal intubation, characterized by the presence of a new or progressive infi ltrate, signs of systemic infection (fever, altered white blood cell count), changes in sputum characteristics, and detection of a causative agent [1]. VAP contributes to approximately half of all cases of hospital-acquired pneumonia [1], [2]. VAP is estimated to occur in 9-27 % of all mechanically ventilated patients, with the highest risk being early in the course of hospitalization [1], [3]. It is the second most common nosocomial infection in the intensive care unit (ICU) and the most common in mechanically ventilated patients [4], [5]. VAP rates range from 1.2 to 8.5 per 1,000 ventilator days and are reliant on the defi nition used for diagnosis [6]. Risk for VAP is greatest during the fi rst 5 days of mechanical ventilation (3 %) with the mean duration between intubation and development of VAP being 3.3 days [1], [7]. Th is risk declines to 2 %/day between days 5 to 10 of ventilation, and 1 %/day thereafter [1], [8]. Earlier studies placed the attributable mortality for VAP at between 33-50 %, but this rate is variable and relies heavily on the underlying medical illness [1]. Over the years, the attributable risk of death has decreased and is more recently estimated at 9-13 % [9], [10], largely because of implementation of preventive strategies. Approximately 50 % of all antibiotics administered in ICUs are for treatment of VAP [2], [4]. Early onset VAP is defi ned as pneumonia that occurs within 4 days and this is usually attributed to antibiotic sensitive pathogens whereas late onset VAP is more likely caused by multidrug resistant (MDR) bacteria and emerges after 4 days of intubation [1], [4]. Th us, VAP poses grave implications in endotracheally intubated adult patients in ICUs worldwide and leads to increased adverse outcomes and healthcare costs. Independent risk factors for develop ment of VAP are male sex, admission for trauma and intermediate underlying disease severity, with odds ratios (OR) of 1.58, 1.75 and 1.47-1.70, respectively [7].

Pathogenesis
Th e complex interplay between the endotracheal tube, presence of risk factors, virulence of the invading bacteria and host immunity largely determine the development of VAP. Th e presence of an endotracheal tube is by far the most important risk factor, resulting in a violation of natural defense mechanisms (the cough refl ex of glottis and larynx) against microaspiration around the cuff of the tube [4], [11]. Infectious bacteria obtain direct access to the lower respiratory tract via: (1) microaspiration, which can occur during intubation itself; (2) development of a biofi lm laden with bacteria (typically Gram-negative bacteria and fungal species) within the endotracheal tube; (3) pooling and trickling of secretions around the cuff ; and (4) impairment of mucociliary clearance of secretions with gravity dependence of mucus fl ow within the airways [11]- [13]. Pathogenic material can also collect in surrounding anatomic structures, such as the stomach, sinuses, nasopharynx and oropharynx, with replacement of normal fl ora by more virulent strains [11], [12], [14]. Th is bacterium-enriched material is also constantly thrust forward by the positive pressure exerted by the ventilator. Whereas reintubation following extubation increases VAP rates, the use of non-invasive positive pressure ventilation has been associated with signifi cantly lower VAP rates [4]. Host factors such as the severity of underlying disease, previous surgery and antibiotic exposure have all been implicated as risk factors for development of VAP [1].
In addition, it has recently been noted that critically ill patients may have impaired phagocytosis and behave as functionally immunosuppressed even prior to emergence of nosocomial infection [4], [15], [16]. Th is eff ect is attributed to the detrimental actions of the anaphylatoxin, C5a, which impairs neutrophil phagocytic activity and impairs phagocytosis by neutrophils [15]. More recently, a combined dysfunction of T-cells, monocytes, and neutro phils has been noted to predict acquisition of nosocomial infection [16]. For example, elevation of regulatory T-cells (Tregs), monocyte deactivation (measured by monocyte HLA-DR expression) and neutrophil dysfunction (measured by CD88 expression), have cumulatively shown promise in predicting infection in the critically ill population, as compared to healthy controls [16].

Microbiology
Th e type of organism that causes VAP usually depends on the duration of mechanical ventilation. In general, early VAP is caused by pathogens that are sensitive to antibiotics, whereas late onset VAP is caused by multi-drug resistant and more diffi cult to treat bacteria. However, this is by no means a rule and merely a guide to initiate antibiotic therapy until further clinical infor mation is available.
Typically, bacteria causing early-onset VAP include Streptococcus pneumoniae (as well as other streptococcus species), Hemophilus infl uenzae, methicillin-sensitive Staphylo coccus aureus (MSSA), antibiotic-sensitive enteric Gram-negative bacilli, Escherichia coli, Klebsiella pneumonia, Enterobacter species, Proteus species and Serratia marcescens. Culprits of late VAP are typically MDR bacteria, such as methicillin-resistant S. aureus (MRSA), Acinetobacter, Pseudomonas aeruginosa, and extended-spectrum beta-lactamase producing bacteria (ESBL) [4]. Th e exact prevalence of MDR organisms is variable between institutions and also within institutions [1]. Patients with a history of hospital admission for ≥ 2 days in the past 90 days, nursing home residents, patients receiving chemotherapy or antibiotics in the last 30 days and patients undergoing hemodialysis at outpatient centers are susceptible to drug resistant bacteria [1], [4]. Commonly found bacteria in the oropharynx can attain clinically signifi cant numbers in the lower airways. Th ese bacteria include Streptococcus viridans, Corynebacterium, coagulase-negative staphylococcus (CNS) and Neisseria species. Frequently, VAP is due to polymicrobial infection. VAP from fungal and viral causes has a very low incidence, especially in the immunocompetent host [1].
Pathogens causing VAP, their frequency (in parenthesis) and their possible mode of multi-drug resistance, if any, are listed below [

Diagnosis
At the present time, there is no universally accepted, gold standard diagnostic criterion for VAP. Several clinical methods have been recommended but none have the needed sensitivity or specifi city to accurately identify this disease [17]. Daily bedside evaluation in conjunction with chest radiography can only be suggestive of the presence or absence of VAP, but not defi ne it [18]. Clinical diagnosis of VAP can still miss about a third of VAPs in the ICU compared to autopsy fi ndings and can incorrectly diagnose more than half of patients, likely due to poor interobserver agreement between clinical criteria [8], [18], [19]. Postmortem studies comparing VAP diagnosis with clinical criteria showed 69 % sensitivity and 75 % specifi city, in comparison to autopsy fi ndings [20]. Th e American Th oracic Society (ATS) and the Infectious Diseases Society of America (IDSA) guidelines recommend obtaining lower respiratory tract samples for culture and microbiology [1]. Analysis of these samples can be quantitative or qualitative. Th is guideline also allows use of tracheal aspirates for their negative predictive value (94 % for VAP). Johanson et al. described clinical criteria for diagnosis of VAP as follows [21]: Th e clinical pulmonary infection score (CPIS) takes into account clinical, physiological, microbiological and radiographic evidence to allow a numerical value to predict the presence or absence of VAP (Table 1) [18], [22]. Scores can range between zero and 12 with a score of ≥ 6 showing good correlation with the presence of VAP [22]. Despite the clinical popularity of the CPIS, debate continues regarding its diagnostic validity. One metaanalysis of 13 studies evaluating the accuracy of CPIS in diagnosing VAP reported pooled estimates for sensitivity and specifi city for CPIS as 65 % (95 % CI 61-69 %) and 64 % (95 % CI 60-67 %), respectively [23]. Despite its apparent straightforward calculation, the inter-observer variability in CPIS calculation remains substantial, jeopardizing its routine use in clinical trials [24]. Of all the criteria used to calculate the CPIS, only timedependent changes in the PaO 2 /FiO 2 ratio early in VAP may provide some predictive power for VAP outcomes in clinical trials, namely clinical failure and mortality [25]. However, a trial by Singh and colleagues [26] demonstrated that the CPIS is an eff ective clinical tool for determining whether to stop or continue antibiotics for longer than 3 days. In that study, antibiotics were discontinued at day 3 for patients who had been randomized to receive ciprofl oxacin instead of standard of care, if their CPIS remained ≤ 6. Mortality and length of ICU stay did not diff er despite a shorter duration (p = 0.0001) and lower cost (p = 0.003) of antimicrobial therapy in the experimental as compared with the standard therapy arm, and the development of anti microbial resistance was lower among patients whose antibiotics were discontinued compared to those who received standard of care. 1. New or progressive radiographic consolidation or infi ltrate. In addition, at least 2 of the following: 2. Temperature > 38 °C 3. Leukocytosis (white blood cell count ≥ 12,000 cells/ mm 3 ) or leukopenia (white blood cell count < 4,000 cells/mm 3 )

Presence of purulent secretions
Respiratory samples can be obtained using several techniques: Th e ATS/IDSA guidelines note that use of a bronchoscopic bacteriologic strategy has been shown to reduce 14-day mortality when compared with a clinical strategy (16.2 % vs. 25.8 %, p = 0.02) [1]. When samples are obtained by BAL techniques (BAL, mini-BAL or PSB), the diagnostic threshold is 10 3 colony forming units (cfu)/ml for protected specimen brushing and 10 4 cfu/ml for BAL. In one multicenter study, BAL-and PSB-based diagnosis was associated with signifi cantly more antibiotic-free days (11.5 ± 9.0 vs. 7.5 ± 7.6, p < 0.001) compared to guideline-based clinical diagnosis alone [27]. Th is study also demonstrated short-term mortality benefi t in the BAL/PSB group. More recent evidence from the Canadian Clinical Trials study of 740 suspected VAP patients randomized to BAL or tracheal suctioning suggests that (excluding patients known to be colonized/ infected with pseudomonas species or MRSA) similar clinical outcomes and overall use of antibiotics is observed when either BAL with quantitative culture or endotracheal aspiration with non-quantitative culture is used for diagnosis [28]. Th is fi nding was confi rmed by a Cochrane meta-analysis of 1,367 patients which again found no diff erence in mortality in the invasive vs. noninvasive groups (26.6 % and 24.7 %, respectively), in quantitative versus qualitative cultures (relative risk 1.53, 95 % CI 0.54-4.39) or in antibiotic use [29]. 1. Endotracheal aspirate: Easiest to obtain, does not require provider involvement. Once specimens are obtained, the sample is sent for Gram stain, culture and sensitivity. Th e Gram stain can provide crucial initial clues to the type of organism(s) and whether or not the material is purulent (defi ned as ≥ 25 neutrophils and ≤ 10 squamous epithelial cells per low power fi eld) [1], [12]. Culture results can be reported as semi-quantitative and/or quantitative values. Semiquantitative values obtained by endotracheal sampling are considered positive when the agar growth is moderate (+++) or heavy (++++), while quantitative positivity is defi ned as ≥ 10 5 cfu/ml. Exact speciation of pathogen bacteria and their sensitivity to antibiotics can take a few days, but provides invaluable information.
Mechanically ventilated patients in the ICU receive frequent chest X-rays and presence of infi ltrate(s) and/or consolidation is considered part of diagnostic criteria and is widely used. However, there are several clinical conditions that have radiographic appearances similar to VAP. Th ese conditions are commonly encountered in mechanically ventilated patients and include aspiration and chemical pneumonitis, atelectasis, congestive heart failure, acute respiratory distress syndrome (ARDS), pleural eff usion and intra-alveolar hemorrhage to name a few. Hence, reliance on chest radiography for the diagnosis of VAP is not advisable. Th ere is poor correlation between radiographic signs (alveolar infi ltrates, air broncho grams) and histopathological diagnosis of pneumonia [12]. Th e sensitivity and specifi city of presence of infi ltrates on chest X-ray is also not encouraging [12]. On the fl ip-side, the negative predictive value of infi ltrates may have clinical utility. In a meta-analysis by Klompas, the presence or absence of fever, elevated white blood cell count, or purulent secretions did not substantively predict the probability of infection; however, the absence of a new infi ltrate on a plain radiograph lowered the likelihood of VAP [18].
VAP must be distinguished from tracheo-bronchitis. Clinical features of these diseases can overlap, but only VAP will demonstrate the presence of hypoxia and the presence of infi ltrate/consolidation on chest radiography [12].
Recently, the Centers for Disease Control and Prevention (CDC) rolled out new surveillance criteria for possible or probable VAP [17]. Th e goals were to capture other common complications of ventilator care, to improve objectivity of surveillance to allow comparability across centers for public reporting, and to minimize gaming [30]. Per these new criteria, a period of at least 2 days of stable or decreasing ventilator settings (daily minimum positive end-expiratory pressure [PEEP] or fraction of inspired oxygen [FiO 2 ]) followed by consistently higher settings for at least 2 additional calendar days is required before a patient can be said to have a ventilator-associated condition (VAC). Most VACs are attributable to pneumonia, pulmonary edema, atelectasis, or ARDS, conditions which all have well researched prevention and management strategies [31]. Signs of infection/infl ammation (abnormal temperature or whitecell count and administration of one or more new antibiotics for at least 4 days) classify the patient as an "infection-related ventilator-associated complication, " or IVAC. Presence of purulent secretions (according to quantitative Gram staining criteria) and pathogenic culture data will label the patient as possible or probable VAP. Patients with an IVAC and purulent secretions alone or pathogenic cultures alone have "possible pneumonia"; those with both purulent secretions and positive quantitative or semiquantitative cultures have "probable pneumonia". Probable pneumonia is also defi ned by suggestive histopathological features, positive pleuralfl uid cultures, or diagnostic tests for legionella and selected viruses. Chest radiograph fi ndings have been excluded in the new criteria because of their subjectivity without increased accuracy. Th is is not intended to reduce the role of radiography in clinical care. At the present time, the new CDC algorithm is for surveillance purposes only.
In the United States, VAP has been proposed as an indicator of quality of care in public reporting, and its prevention is a national patient safety goal. Th e threat of non-reimbursement and fi nancial penalties for this diagnosis has put pressure on hospitals to minimize VAP rates [13]. Th is has resulted in potential artifacts in surveil lance with more than 50 % of non-teaching medical ICUs in the United States reporting VAP rates close to zero [30], [32]. Th ese rates are an order of magnitude lower than those in European centers, which utilize similar preventive and treatment strategies suggesting that reductions in VAP rates may not refl ect improvements in prevention so much as subjective surveillance biases. It is anticipated that the new CDC surveillance paradigm for ventilator-associated events will help achieve a more realistic VAP rate.

Treatment
Selecting the appropriate antibiotic depends on the duration of mechanical ventilation. Late onset VAP (> 4 days) requires broad spectrum antibiotics whereas early onset (≤ 4 days) can be treated with limited spectrum antibiotics [1]. An updated local antibiogram for each hospital and each ICU based on local bacteriological patterns and susceptibilities is essential to guide optimally dosed initial empiric therapy [1]. With any empiric antibiotic regimen, de-escalation is the key to reduce emergence of resistance [33]. Delays in initiation of antibiotic treatment may add to the excess mortality risk with VAP [1]. Tables 2 and 3 highlight the recommended treatment regimens for VAP.
Owing to the high rate of resistance to monotherapy observed with P. aeruginosa, combination therapy is always recommended. Acinetobacter species respond best to carbapenems (also active against ESBL positive Enterobacteriaceae), colistin, polymyxin B and ampicillin/sulbactam [36], [37]. Although MDR organisms are usually associated with late-onset VAP, recent evidence suggests that they are increasingly associated with earlyonset VAP as well [37], [38]. Th e role of inhaled antibiotics in the setting of failure of systemic antibiotics is unclear [1]. Th e usual duration of treatment for earlyonset VAP is 8 days and longer in the case of late-onset VAP or if MDR organisms are suspected or identifi ed [39]- [41].
Despite therapy, if no response is observed, it may be prudent to reconsider the diagnosis, reassess the organism being treated or search for other reasons for signs and symptoms. Because of the challenges associated with diagnosing VAP, especially early in the course, the IDSA/ATS guidelines highlight the importance of reassessing patients at 48-72 hours once pertinent data are available to determine whether the patient should continue antibiotic therapy for VAP or whether an alternative diagnosis should be pursued. In one study, Swoboda et al. [42] found that half of the empiric antibiotic use for VAP in two surgical ICUs was prescribed for patients without pneumonia.

Prevention
Th ere are multiple recommended measures for prevention of VAP. Th ese measures are summarized in Table 4 [43]- [46]. Institutions or ICUs may observe a reduction in VAP rates by utilizing a 'VAP-bundle' approach [44], [47] using elements depicted in Table 4. Th e 5-element Institute of Healthcare Improvement (IHI) VAP bundle [47] includes: Head of bed elevation, oral care with chlorhexidine, stress ulcer prophylaxis, deep venous thrombosis prophylaxis, and daily sedation assessment and spontaneous breathing trials. Each of these elements has been shown to reduce the incidence of VAP although the quality of evidence supporting the eff ectiveness and importance of each intervention has been questioned. Even studies using VAP bundles have been criticized as failing to demonstrate clinical and cost eff ectiveness [48]. A before-after study which systematically implemented a VAP prevention bundle using IHI methodology showed a Optimal dosage includes adjusting for hepatic and renal failure. Trough levels for vancomycin (15-20 mcg/ml), amikacin (< 5 mcg/ml), gentamicin (< 1 mcg/ml) and tobramycin (< 1 mcg/ml) should be measured frequently to avoid untoward systemic side eff ects. All recommended doses are for intravenous infusion. Usual duration of therapy is 8 days unless treatment is for multidrug resistant organisms, in which case treatment will be for 14 days.
signifi cant reduction in VAP rates, antibiotic use and MRSA acquisition [43]. Th ere was no reduction, however, in duration of mechanical ventilation or ICU admission. Th e IHI emphasizes the need for high (95 %) overall compliance rates with VAP bundles although this particular study reported overall bundle compliance rates of 70 %.
Issues with completeness of documentation may underestimate compliance, which remains an important feature of VAP bundle prevention strategies. Another important contribution towards VAP prevention and shortening periods of antibiotic exposure was a recent prospective study (n = 129), which concluded that a single-dose of  Table 2 Pseudomonas aeruginosa Double coverage recommended. See Table 2 Acinetobacter species Carbapenem e. g., imipenem + cilastin; 1 g every 8 hours;  antibiotics within 4 h of intubation may be eff ective in preventing early onset VAP in a cohort of comatose patients [49]. A randomized clinical trial is needed to address this question.

Conclusion
VAP occurs frequently and is associated with signifi cant morbidity in critically ill patients. Th e primary obstacle in diagnosing VAP is the absence of gold standard criteria and, therefore, VAP continues to be an inconspicuous clinical syndrome. Th ere is enough evidence to indicate that VAP is preventable and that hospitals can decrease VAP rates, a factor that the new CDC VAP defi nitions are poised to demonstrate more objectively. Th e diagnostic challenge of VAP has multiple implications for therapy. Although a CPIS score > 6 may correlate with VAP, the sensitivity, specifi city and inter-rater agreement of this criterion alone are not encouraging. Microbiological data should be used for tailoring antibiotic therapy and not be restricted only to diagnosis. Th e pitfall in using empiric antibiotics for suspicion of VAP is the potential for antibiotic overuse, emergence of resistance, unnecessary adverse eff ects and potential toxicity. Th e major goals of VAP management are early, appropriate antibiotics in adequate doses followed by de-escalation based on microbiological culture results and the clinical response of the patient. Antimicrobial stewardship programs involving pharmacists, physicians and other healthcare providers optimize antibiotic selection, dose, and duration to increase effi cacy in targeting causative pathogens and allow the best clinical outcome.