Pneumonia, Ventilator-Associated

Clinical Setting

• Ventilator-associated bacterial pneumonia (VAP or VABP), ventilated hospital-acquired bacterial pneumonia (HBAP). Defined as pneumonia that develops ≥ 48 hours of mechanical ventilation.
• Empiric therapy:
  
  • Diagnostic criteria:
    • Clinical suspicion and presence of new or progressive pulmonary infiltrates on chest radiograph PLUS two of the following:
      • Fever
      • Peripheral leukocytosis
      • Purulent tracheal secretions
    • Proposed surveillance diagnostic criteria: Clin Infect Dis 57:1742, 2013.
• Empiric therapy for ventilated hospital-acquired bacterial pneumonia
• Culture, gram strain of tracheal aspirate or lavage fluid should be performed in all cases of suspected VAP.
• Differential diagnosis includes:
• Non-bacterial pathogens
  
• Fever due to ischemia, malignancy, drug-induced pneumonia
• Infiltrates due to congestive heart failure
• For full list: Scand J Infect Dis 46:868, 2014.
• 2017 European Guidelines: (Eur Respir J 2017; 50: 1700582). 2016 IDSA Guidelines: Clin Infect Dis 63:e61, 2016 (full article); executive summary: Clin Infect Dis 63:575, 2016.
• For prophylaxis, see Comments

Etiologies

• Early-onset (<5 days in the hospital, no other risk factors for multi-drug resistant (MDR) organisms)
• Strep. pneumoniae
• H. influenzae
  
• Enteric gram-negative bacilli
• Late-onset (≥ 5 days in the hospital, risk factors of MDR organisms present)
• Staph. aureus (often MRSA)
• Gram-negative enterics (often multi-drug resistant)
• E. coli
• Klebsiella pneumoniae
• Enterobacter sp.
• Serratia marcescens
• Pseudomonas aeruginosa
• Acinetobacter baumannii

Primary Regimens

• Low risk of MRSA (ICU prevalence <10-20%), no risk factors for MDR pathogens,
• Cefepime 2 gm IV q8h
• Piperacillin-tazobactam  4.5 gm IV q6h (not recommended if ESBL-producing organism is suspected)
• Meropenem 1 gm IV q8h
• Levofloxacin 750 mg IV/po q24h (not recommended if ESBL-producing organism is suspected)
• More severe disease, i.e., sepsis, hypotension, rapid progression of infiltrates on chest radiograph indicating high risk of mortality; MDR risk factor, MRSA prevalence >10-20%
• Vancomycin 15-20 mg/kg IV q8-12h to achieve preferred target AUC₂₄ 400-600 μg/mL x hr (see vancomycin AUC dosing calculator; alternative is trough of 15-20 μg/mL) + (Cefepime 2 gm IV q8h or Piperacillin-tazobactam 4.5 gm q6h or Meropenem 1 gm q8h)
  • If Legionella suspected, add Levofloxacin 750 mg po/IV q24h or Azithromycin 500 mg IV q24h to the regimen.
  • To increase likelihood that at least one drug will be active, if Pseudomonas or MDR Gram-negative suspected, add:
    • Ciprofloxacin 400 mg IV q8h or Levofloxacin 750 mg IV q24h or Tobramycin 5-7 mg/kg IV q24h or Amikacin 15-20 mg/kg IV q24h
• Duration of therapy: See Antimicrobial Stewardship

Alternative Regimens

• Linezolid 600 mg IV q12h can be substituted for Vancomycin
• Substitute Ceftazidime-avibactam 2.5 gm IV infused over 2 hours q 8h for Cefepime, Piperacillin-tazobactam or Meropenem if carbapenem-resistant enterobacteriaceae is suspected
• Aztreonam 2 gm IV q8h instead of cefepime, piperacilli-tazobactam, or meropenem for patients with severe IgE-mediated hypersensitivity to beta-lactams.  However, unlike these other agents, aztreonam is not active against S. aureus or S.pneumoniae and hence should add vancomycin pending culture results.
• Ceftolozane-tazobactam 3 g IV q8h covers pseudomonas and ESBL-producing Enterobacteriaceae (Lancet Infect Dis 2019 Dec;19(12):1299-1311).

Antimicrobial Stewardship

• If  S. aureus nares screen is negative for MRSA no need to empirically cover for MRSA, and if coverage initiated, de-escalation  is safe with a negative predictive value of 96.1% (Clin Infect Dis 2019 Oct 1. pii: ciz974. doi: 10.1093/cid/ciz974). 
• Duration of therapy is not well defined.
• For relatively susceptible pathogens treat for 8 days.
• For Staph. aureus, MRSA in particular, or more resistant organisms (e.g., Pseudomonas, Acinetobacter, Stenotrophomonas) treat for longer, e.g., 14 days.
• Alternatively, can trend serum procalcitonin levels
• Retrospective cohort study found that 1-3 days of therapy was as effective as > 3 days for patients with suspected VAP and minimal and stable ventilator settings defined as daily minimum PEEP of ≤5 cm H₂O and daily minimum FiO2 <40% for at least 3 days from the first day of antibiotics (Clin Infect Dis 64:870, 2017).

Comments

• If MDR pathogens are suspected, initial coverage should be broad and then streamlined based on culture and susceptibility results.
• In literature review, ESKAPE pathogens etiologic in 80% of patients: Curr Opin Pulm Med 20:252, 2014.
• Risk factors for MDR organisms:
• Antimicrobial therapy in preceding 90 days.
• Current hospitalization of 5 days or more.
• Septic shock at time of VAP
• Acute renal replacement therapy prior to onset of VAP
• Antibiotic resistance prevalent in the community or specific hospital unit
• Empiric regimen of choice may vary based on local prevalence and susceptibility of pathogens, known prior colonization with MDR organisms, prior treatment history, severity of illness.
• Prevention/prophylaxis of VAP (Am J Infect Control 42:34, 2014):
• Elevate head of bed by 30º or more.
• Remove NG endotracheal tubes as soon as possible.
• Continuous subglottic suctioning (Crit Care Med 43:22, 2015; Crit Care Med 43:227, 2015).
• Chlorhexidine oral care.
• Silver-coated endotracheal tubes may reduce incidence of VAP: JAMA 300:805, 2008; JAMA 300:842, 2008.
• Prevention of VAP in patients with post cardiac arrest and targeted hypothermia management (N Engl J Med. 2019; 381:1831-1842). 
  
  • Multicenter, double-blind, randomized , placebo-controlled trial in adults (where available)
    • VAP in first 7 days: Placebo: 34%; Amoxicillin-clavulanatae 19 %, p 0.03
• Imipenem-cilastatin-relebactam now FDA approved for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.