Ventilator-Associated Pneumonia

25.1 Introduction

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in mechanically ventilated patients and second most common infection in critical care units [1–3]. VAP is an important clinical identity that can influence morbidity and mortality of critically ill patients. The incidence of VAP varies depending on the criteria used for diagnosis and is reported to be approximately 9–27% of all mechanically ventilated patients [4]. Depending on the definition used, VAP rates range from 1.2 to 8.5 per 1000 ventilator days [5].

25.2 Definition

According to 2016 Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) guidelines, VAP is defined as pneumonia occurring more than 48 h after endotracheal intubation whereas hospital-acquired pneumonia (HAP) is defined as pneumonia not incubating at the time of admission to the hospital but occurring at 48 h or more after admission [6]. HCAP referred to as health care-associated pneumonia has been excluded from 2016 guidelines. HCAP was previously defined as pneumonia acquired in healthcare facilities like nursing homes, haemodialysis centres, rehabilitation centres, outpatient clinics and during hospitalization in previous 3 months. This term has been excluded from the guidelines now [6].

25.3 Epidemiology

According to the National Healthcare Safety Network (NHSN), there has been a steady decline in the VAP rates in the USA with reporting incidence varying from 0.0 to 5.8/1000 ventilator days [7]. However, recently published data showed that approximately 10% of patients on mechanical ventilation develop VAP [8, 9] and there is underreporting. The incidence of VAP in neurocritical care patients varies depending on the definition used. The VAP rates range from 4 to 31.3% according to different studies [10, 11], and development of VAP adversely affects the outcome. Neurological patients are at higher risk of developing pneumonia [10] due to decreased consciousness, impaired protective airway reflexes and dysphagia. The presence of neurological disease is an independent risk factor for the development of VAP and also for failure of VAP resolution with initial antibiotic therapy [12, 13]. NHSN reported incidence of VAP in neurocritical care units ranging from 2.1 (neurosurgical units) to 3.0 (neurological units)/1000 ventilator days [14]. In neurocritical care unit, Glasgow coma score < 6, more severe brain injury and presence of cervical fracture with neurological deficit have a specificity of 97% for prediction of VAP.

VAP is associated with increased ICU stay, increased number of ventilator days and increased cost of care [15]. Recent data has revealed that the duration of mechanical ventilation increased from 7.6 to 11.5 days and hospital stay from 11.5 to 13.1 days in patients with VAP compared to patients without VAP [16, 17]. The risk of death also increases by 1.8—fourfold in patients with VAP. Mortality caused by VAP is defined as the percentage of deaths that would not have occurred in the absence of infection. It is difficult to determine attributable mortality to VAP as several cofactors affect mortality in ICU patients [16]. However, few studies have studied the attributable risk of death due to VAP and have reported as approximately 9–13% [18, 19], but this rate has decreased over time. This is not the same in neurocritical care patients. Few studies have shown no association between VAP and increased mortality in intubated NICU patients [10].

VAP is generally divided into early onset and late onset VAP. Early VAP is VAP that occurs within 5–7 days of mechanical ventilation, while late VAP is VAP that occurs more than 5–7 days [20, 21]. This distinction was made as early VAP was usually attributed to antibiotic sensitive pathogen and late onset VAP was more likely caused by multidrug-resistant pathogens [2, 4] but according to recent literature, the bacteriological difference has not been clear, and studies have found no relation between timing of VAP and risk of MDR organisms [22–24]. The difference in various studies has been in the timing of VAP (time zero of definition). Thus, differentiating VAP on the basis of timing may lead to under-treatment of patients with early onset VAP or delay in the starting of appropriate antibiotic therapy. The risk of VAP is approximately 1%/day, being higher in initial days, and this decreases as time passes to 3% in the first 5 days, then 2% between the fifth to tenth days, and then 1%/day of mechanical ventilation [25].

25.4 Pathogenesis

The main pathogenic mechanism in the development of VAP is the pulmonary aspiration of the colonized oropharyngeal secretions across the tracheal tube cuff. These days high-volume low-pressure cuffs (HVLP) are used in the endotracheal tubes. When these cuffs are inflated, folds appear along the cuff surface which cause micro- and macroaspiration of oropharyngeal secretions [26]. Another conduit of infection is through the tube itself [27]. The bacteria adhere to the internal surface of the tube forming a biofilm [28, 29] and translocate into the lungs with inspiration. Patients can be colonized either exogenously or endogenously, exogenously can be colonized from the hand, equipment, invasive devices and hospital environment or endogenously from the organisms present in the oropharynx, tracheal tube and gastrointestinal tract.

Impaired immune function of the body also plays a role [30]. In normal individuals, there are various defence mechanisms to prevent translocation of pathogen in the lower airways like epiglottis, adduction of true and false vocal cords, cough reflex and mucociliary clearance in the upper airways; however, these body defence mechanisms are impaired in intubated patients [2, 27]. Moreover, host factors like underlying disease, previous surgery and antibiotics are regarded as risk factors for VAP [4].

25.5 Microbiology

Common pathogens causing VAP include aerobic gram-negative bacilli, e.g. pseudomonas, Escherichia coli, Enterobacter, Klebsiella, Acinetobacter and gram-positive cocci, e.g. Staphylococcus aureus and Streptococcus [31, 32]. The difference in the organisms depends on the hospital flora and the host factors. There is increased risk of VAP with S. aureus, Haemophilus and Streptococcus pneumonia infection in trauma and neurologic patients [33]. VAP can be polymicrobial also. Every hospital has its own data of the organism responsible for early and late onset VAP.

25.5.1 Risk Factors for MDR VAP Include [22, 23, 34, 35]

Intravenous (IV) antibiotic use within the previous 90 days
Septic shock at the time of VAP
Acute respiratory distress syndrome (ARDS) preceding VAP
≥5 days of hospitalization prior to the occurrence of VAP
Acute renal replacement therapy prior to VAP onset

However, coma present at the time of ICU admission is associated with lower risk of MDR VAP [36]. This may be that neurotrauma patients have an increased propensity to develop VAP early in ICU admission (which is due to sensitive organisms).

25.6 Diagnosis

The clinical diagnosis of VAP is difficult because clinical findings are non-specific. At present, there is no universally accepted gold standard criteria for VAP [37]. IDSA/ATS 2016 guidelines for management of VAP recommend clinical diagnosis of VAP based upon a new lung infiltrate PLUS clinical features suggesting infectious nature of the infiltrate like new onset of fever, purulent secretions, leukocytosis and decline in oxygenation [6].

Radiographic abnormalities of VAP include alveolar infiltrates, air bronchograms and silhouetting of adjacent solid organs. Diagnosis is confirmed when lower respiratory tract sampling identifies a pathogen. As there is increasing risk of MDR pathogens and risks associated with initial ineffective therapy, the cultures of respiratory secretions should be obtained from all the patients with suspected VAP [4]. Samples should be sent prior to initiation of antibiotics or change of antibiotic therapy as antibiotics reduce the sensitivity of both microscopic analysis and cultures [38, 39]. Whether to send blood culture of a patient with VAP depends on the clinical picture of the patient. Approximately, 15% of patients with VAP are bacteraemic [40, 41], and patients with bacteraemic VAP are at higher risk of morbidity and mortality than non-bacteraemic patients. Moreover, these positive blood cultures may indicate a non-pulmonary source of infection.

25.7 Sampling of the Respiratory Tract

There are two methods of sampling of the respiratory tract—invasive and non-invasive. Non-invasive sampling refers to endotracheal aspirates and invasive involves bronchoscopic bronchoalveolar lavage (BAL), protected specimen brushing (PSB) and blind bronchial sampling, i.e., miniBAL.

According to the IDSA/ATS guidelines, it is recommended that non-invasive sampling with semi-quantitative cultures be done to diagnose VAP rather than invasive sampling with quantitative cultures or non-invasive sampling with qualitative cultures. Rationale for non-invasive sampling is that it can be done more rapidly with fewer complications and resources, and studies have shown that there is no difference in mortality or length of stay in ICU whether sampling is done by either approach [42]. The threshold for quantitative cultures for different samples is as follows:

For PSB > 1000 colony forming units/mL
For BAL > 10,000 cfu/mL
For endotracheal aspirates >1,000,000 cfu/mL

However, European Society of Intensive Care Medicine and European Society of Infectious Diseases suggest preference for invasive sampling method with quantitative cultures. Rationale behind this is that there would be less antibiotic exposure and good antibiotic stewardship with this approach [43]. The practice depends on the individual institution protocol. A positive microbiological sample in a patient with normal chest radiograph suggests tracheobronchitis.

There has been continuous search for a rapid identification of bacteria so that antibiotics can be started early. Certain new automated microscopy methods such as ID/AST system using genomic and phenotypic techniques are in development [44].

25.8 Role of Biomarkers

IDSA 2016 guidelines recommend using clinical criteria alone for starting antibiotics in patients with suspected VAP and not on serum procalcitonin level plus clinical criteria. Evidence of PCT in patients with suspected VAP is not strong enough [45, 46]. Procalcitonin levels can be useful to stop/discontinue antibiotic therapy in patients with confirmed VAP and it can also be used as a prognostic marker [47, 48]. Other markers such as c reactive protein and soluble triggering receptor expressed on myeloid cells (sTREM-1) have minimal diagnostic value [49, 50].

Other diagnostic methods which have been in use to diagnose VAP include clinical pulmonary infection score, HELICS criteria and Johannson criteria.

25.9 Other diagnostic criteria

Clinical pulmonary infection score (CPIS) was developed by Pugin and colleagues to facilitate the diagnosis of VAP using clinical variables [51]. It gives a score of 0–2 for temperature, leucocytosis, PaO₂/FiO₂ ratio, chest radiography, tracheal secretions and culture of tracheal aspirate. The maximum score is 12 and a score > 6 is diagnostic of VAP. The limitation of CPIS was that there was a lot of interobserver variability in CPIS calculation hampering its routine use in clinical trials. The recent evidence suggests that CPIS can diagnose VAP with sensitivity and specificity of only 65% and 64%, respectively [52].

The HELICS [53] criteria are used for VAP surveillance in Europe. These rely on a combination of clinical, radiological and microbiological criteria and classify pneumonia from PN1 to PN5 based on microbiological method used.

The Johannson criteria diagnosed VAP with the presence of new/progressive infiltrates on chest X-ray associated with at least 2 of 3 clinical features—leucocytosis, purulent secretions and temperature greater than 38 °C. The sensitivity and specificity of these criteria are 69% and 75%, respectively [54].

The diagnosis of VAP is more problematic in neuro-ICU due to ubiquitous nature of clinical findings related to primary brain injury such as fever, leucocytosis and altered mental status. There is a huge variability in diagnosis and treatment of VAP in neurocritical care patients. According to a recent study, the clinical features significantly more prevalent in surveillance VAP as compared to clinical VAP were change in sputum character, tachypnea, oxygen desaturation, higher CPIS score and persistent infiltrate on chest X-ray but not positive sputum culture [11].

25.10 Ventilator-Associated Events

The United States Centre for Disease Control and Prevention (CDC) has adopted a new method of ICU surveillance employing ventilator-associated events (VAE) as a potential metric to assess quality of care in ICU. VAE include ventilator-associated complications (VAC) and infection-related ventilator-associated complications (IVAC) [55, 56]. These definitions are used for surveillance and quality improvement of the ICUs. These definitions fail to detect many patients with VAP and do not aid in management at the bedside level.

25.11 Differential Diagnosis

VAP has to be differentiated from many conditions that can have similar clinical or radiological findings. These are:

1.
Ventilator-associated tracheobronchitis (VAT): VAT is characterized by signs of respiratory infection such as increase in volume and purulence of the secretions, fever, leukocytosis but no radiological infiltrates suggestive of consolidation in chest X-ray. No antibiotic therapy is recommended for patients with VAT. It leads to more antibiotic resistance than benefits.
2.
Aspiration pneumonitis: This can be differentiated from VAP by history and microscopic analysis of respiratory secretions. Aspiration pneumonitis can get secondarily infected with organisms leading to aspiration pneumonia.
3.
Pulmonary embolism with infarction: The clinical features in embolism may suggest risk factors for embolism in these cases.
4.
Acute respiratory distress syndrome (ARDS): The patients with ARDS will have negative cultures of respiratory secretions.
5.
Pulmonary haemorrhage: There will be frank bleeding in cases of pulmonary haemorrhage and blood mixed with purulent secretions in VAP.
6.
Lung contusion: The patient would have history of trauma along with negative cultures.

25.12 Treatment

Clinical suspicion of VAP mandates early antimicrobial therapy. Once VAP is suspected clinically, antibiotic therapy should be started as early as possible [6] and in cases of septic shock, should be started within an hour. Delay in treatment and inappropriate antibiotic are associated with higher mortality [57, 58].

All intensive care units should have a local antibiogram specific to their population. The regimens for empiric treatment of VAP should be based on local prevalence of pathogen and antimicrobial susceptibility [6].

25.13 Multidrug-/Pandrug-Resistant/Extensively Drug-Resistant Bacteria

Multidrug resistance in gram-negative bacilli is defined as acquired nonsusceptibility to at least one agent in three different antimicrobial classes [59]. Pan resistance refers to resistance to all antibiotics recommended for empiric treatment of VAP. Extensively drug-resistant bacteria are those bacilli resistant to atleast one agent in all but two antimicrobial classes.

Empiric therapy should include an agent with activity against S. aureus, Pseudomonas and other gram-negative bacilli. The treatment depends on whether the patient has risk factors for MDR VAP, or risk factors for MDR Pseudomonas and other gram-negative bacilli, or risk factors for MRSA. For patients with risk factors of MDR, empiric broad spectrum multidrug therapy is recommended. Once the culture reports are available, therapy should be deescalated according to the sensitivity pattern [60, 61]. If a patient is already on antibiotics, empiric therapy should be with a drug from a different class as the pathogen may be resistant to the initial class of antibiotic.

25.13.1 Risk Factors for MDR VAP Include [22, 23, 34, 35]

Intravenous (IV) antibiotic use within the previous 90 days
Septic shock at the time of VAP
Acute respiratory distress syndrome (ARDS) preceding VAP
≥5 days of hospitalization prior to the occurrence of VAP
Acute renal replacement therapy prior to VAP onset

25.13.2 Risk Factors for MDR Pseudomonas and Other Gram-Negative Bacilli Include

Treatment in an ICU in which >10% of gram-negative bacilli are resistant to an agent being considered for monotherapy
Treatment in an ICU in which local antimicrobial susceptibility rates among gram-negative bacilli are not known

25.13.3 Risk Factors for MRSA Include

Treatment in a unit in which >10 to 20% of S. aureus isolates are methicillin resistant
Treatment in a unit in which the prevalence of MRSA is not known

If no MDR VAP risk factors exist, and no risk factor for MDR Pseudomonas and other gram-negative bacilli exist, then either of the following antibiotics can be used:

Piperacillin–tazobactam 4.5 g IV every 6 h/Cefepime 2 g IV every 8 h/Levofloxacin 750 mg IV daily.

If MDR VAP risk factors are present, the patients should receive two agents with activity against Pseudomonas aeruginosa and other gram-negative bacilli and one agent with activity against MRSA:

Piperacillin–tazobactam 4.5 g IV every 6 h/Cefepime 2 g IV every 8 h/Ceftazidime 2 g IV every 8 h/Imipenem 500 mg IV every 6 h/Meropenem 1 g IV every 8 h/Aztreonam 2 g IV every 8 h.

Plus an aminoglycoside, which can be:

Amikacin 15–20 mg/kg IV daily/Gentamicin 5–7 mg/kg IV daily/Tobramycin 5–7 mg/kg IV daily
Or: An antipseudomonal fluoroquinolone such as ciprofloxacin (400 mg IV every 8 h) or levofloxacin (750 mg IV daily)
Or: A polymyxin, IV colistin or polymyxin B, may be appropriate if highly resistant Pseudomonas spp., Acinetobacter spp. and Enterobacteriaceae (including Klebsiella pneumoniae) is suspected

Plus: Linezolid 600 mg IV every 12 h/Vancomycin 15 mg/kg.

If there are no risk factors for MDR VAP but risk factors for MDR pseudomonas and gram-negative bacilli, then two agents should be used for gram-negative bacilli. And, if the patient also has MRSA risk factors, then an MRSA agent should also be given.

Patients who do not have risk factors for MDR gram-negative bacilli but do have risk factors for MRSA should receive one agent with activity against P. aeruginosa and other gram-negative bacilli and one agent with activity against MRSA:

Piperacillin tazobactam/cefepime/ceftazidime/levofloxacin/ciprofloxacin/+ linezolid/vancomycin.

Once the culture reports are available, the antibiotic therapy should be deescalated according to the culture sensitivity report. The de-escalation to monotherapy can occur in most of the cases but if there is infection with pseudomonas and the patient is still in septic shock or at increased risk of death, then 2 antibiotics should be continued.

Aerosolized colistin, polymyxin or aminoglycosides can be used as adjunctive therapy (in combination with IV antibiotics) in patients with VAP caused by multidrug-resistant gram-negative bacilli, such as Acinetobacter baumannii or P. aeruginosa [62, 63]. This increases the antibiotic concentrations at the site of infection and is useful for treatment of organisms that have high MICs to systemic antimicrobial agents. If the patient improves clinically, and is able to take medications orally, intravenous antibiotics can be switched to oral.

Duration of therapy: The 2016 Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) recommend 7-day course of treatment and it can be prolonged or shortened based on the clinical response, and improvement in radiological and laboratory parameters. Serum levels of procalcitonin can be useful in decision to stop the antibiotic. With values <0.25 mcg/L or when there is decrease in the PCT value by more than 80%, antibiotics can be discontinued.

25.14 Prognosis

All-cause mortality associated with VAP ranges from 20 to 50% in different studies [6], but the attributable mortality is 9–13%. The factors associated with increased mortality are: bacteraemia, shock, coma, respiratory failure, ARDS, severe underlying comorbid disease and infection with MDR organisms.

25.15 Prevention of VAP

The various modalities used to prevent VAP are as follows:

1.
Head-up position: As aspiration of pathogens is the main cause of VAP, preventing aspiration in intubated patients must be a priority. There is evidence that patients in supine position have more chances of aspiration of gastric contents than patients in head-up position [64, 65]. The head end of the bed should be elevated to 30–45° [66].
2.
Subglottic suction device: Endotracheal or tracheostomy tubes with subglottic suction tube should be used in patients who are expected to require more than 48 h of mechanical ventilation [66]. The secretions pooled over the cuff of the tube may get aspirated. Studies have shown that patients with these tubes have lesser VAP rate, reduced duration of mechanical ventilation and reduced ICU stay [67].
3.
Oral care: Oral care with chlorhexidine mouthwash has proven its role in reducing VAP [68] and so should be used regularly in intubated patients.
4.
Strict hand hygiene: The biofilm formation on the tube can be reduced by strict hand hygiene practices, closed suction systems and use of heat and moisture exchangers.
5.
Reducing the duration of mechanical ventilation: This can be achieved by daily sedation vacation and spontaneous breathing trials and assessment of readiness to extubate.

Various studies have been conducted on other modalities but no conclusive results were presented. Selective decontamination of the digestive tract may increase the growth of resistant bacteria and so it is not widely practiced [69, 70]. Similarly, administration of probiotics and use of silver-coated endotracheal tubes have not shown promising results in the form of any significant decrease in the VAP rate or days on mechanical ventilation or hospital stay and are not recommended.

25.16 VAP Bundles

Implementation of various evidence-based interventions together to decrease the rate of VAP forms VAP bundle. There is no consensus which care processes to be included in these bundles but they have shown reduction in VAP rates in various studies [71] and should be implemented.

Key Points

Ventilator-associated pneumonia (VAP) is the most common nosocomial infection in mechanically ventilated patients and second most common infection in critical care units.
Neurological patients are at higher risk of developing pneumonia due to decreased consciousness, impaired protective airway reflexes and dysphagia.
VAP is associated with increased ICU stay, increased number of ventilator days and increased cost of care.
There is increased risk of VAP with S. aureus, Haemophilus and S. pneumonia infection in neurologic patients.
The diagnosis of VAP is more problematic in neuro-ICU due to ubiquitous nature of clinical findings related to primary brain injury such as fever, leucocytosis and altered mental status.
The regimens for empiric treatment of VAP should be based on local prevalence of pathogen and antimicrobial susceptibility.
For patients with risk factors of MDR, empiric broad spectrum multidrug therapy is recommended. Once the culture reports are available, therapy should be deescalated according to the sensitivity pattern.

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25. Ventilator-Associated Pneumonia

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