Pneumonia, Ventilator-Associated

Clinical Setting

• Empiric therapy for ventilator-associated bacterial pneumonia (VAP or VABP, defined as pneumonia that develops ≥ 48 hours of mechanical ventilation), or ventilated hospital-acquired bacterial pneumonia (vHABP). 
• 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)
  • E. coli
  • Klebsiella pneumoniae
  • Enterobacter sp.
  • Serratia marcescens
  • Pseudomonas aeruginosa
  • Acinetobacter baumannii
• Staph. aureus (often MRSA)
• Gram-negative enterics (often multi-drug resistant)

Diagnostic Considerations

• Diagnostic criteria:
  • Clinical suspicion and presence of new or progressive pulmonary infiltrates on chest radiograph PLUS two of the following:
    • Fever
    • Peripheral leucocytosis
    • Purulent tracheal secretions
• Blood cultures x 2
• Culture, gram strain of tracheal aspirate or bronchoalveolar lavage fluid should be performed in all cases of suspected VAP.
• PCR of sputum or urine antigen for L. pneumophila particularly in immunocompromised hosts.
  
• Nasopharyngeal swab for PCR detection of respiratory viruses (COVID-19, influenza, RSV and perhaps others), especially in early-onset disease or suspected nosocomial transmission.
• Nasal swab culture or PCR for MRSA (good negative predictive value, 76-99%, to rule out MRSA infection; generally poor positive predictive values, as low as 12% [Ann Pharmacother. 2019, 53:627])
• Serum procalcitonin (PCT) where available; if negative, repeat in 4-6 hrs (assumes 1-2 hr turn around time)
  • Negative predictive value for bacterial infection over 95% if PCT < 0.25 ng/mL
  • Supportive prospective multicenter surveillance study: Clin Infect Dis 2017; 65: 183
• Utility of molecular methods (e.g., a pneumonia multiplex PCR panel) to detect potential bacterial pathogens is unproven but may permit detection of pathogens whose growth is suppressed by prior antibiotics, which could result in less empiric therapy and/or better focused antimicrobial therapy.
• The suggested diagnostics may not apply or may not be feasible or available in individual clinical settings.
• DETECTED PATHOGENS MAY BE EITHER COLONIZING OR INVADING.       

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
• Aztreonam 2 gm IV q8h instead of cefepime, piperacillin-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 Enterbacterales (Lancet Infect Dis 2019;19:1299-1311).
• For suspected carbapenem-resistant Enterobacterales infection: can substitute Ceftazidime-avibactam 2.5 gm IV infused over 2 hours q 8h for Cefepime, Piperacillin-tazobactam or Meropenem (does not cover metallo-beta-lactamase producing organisms)
  
  • Imipenem-cilastatin-relebactam 1.25 gm IV infused over 30 minutes q6h or Meropenem-vaborbactam 4 gm IV infused over 3 hr q8h are also options (neither agent covers metallo-beta-lactamase producing organisms).
  • For more detail information on multiple-drug resistant Gram-negatives click here
• Cefiderocol 2 gm IV infused over 3h q8h non-inferior to Meropenem and covers carbapenem-resistant Gram-negatives (but no Gram-positive activity) (Lancet Infect Dis 2021; 21:226 and Lancet Infect Dis 2021;21:213).  See Acinetobacter pneumonia for details on treatment of VABP or ventilated HABP caued by this organism.

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 high negative predictive value (Clin Infect Dis 2020; 71:1142). 
• 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.
• 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 and Cefiderocol FDA approved for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia.