a) What are the principles behind empiric antimicrobial management in a patient with confirmed ventilator-associated pneumonia (VAP)?                                         (70% marks)

b) What are the theoretical advantages and disadvantages of using nebulised antibiotics for management of VAP? (30% marks)

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College answer

Principles – 30%
General

  • Early treatment
  • Optimal cultures – Sputum, BAL, mini-BAL, blood – depending on local policy

Microorganism

  • Likely organisms – previous cultures, antibiotic exposure, comorbidities and local flora
  • At 14 days will need to cover MRSA, Pseudomonas and other resistant gram negatives

Antibiotics

    • Adequate dose and frequency to achieve adequate tissue levels
    • Consideration of organ function and extracorporeal effects
      • AKI, augmented clearance, CRRT
    • Mention of two antibiotics
      • Gram positive – Vancomycin, linezolid etc
      • Gram negative – Piperacillin-tazobactam, cefepime, meropenem
        • Consider two agents for antipseudomonal cover
    • Deescalation
    • Short course or long course

Nebulised – 40%
Advantages

  • Increased local concentrations in lung parenchyma
  • Reduced system toxicity from high dose intravenous antibiotics
  • Concentrations above resistance emergence threshold and so may reduce resistant strain selection

Disadvantages

    • Limited evidence primarily based on observational studies
    • Limited pharmacopeia – primarily polymixins and aminoglycosides
      • Colistin and tobramycin most studied
    • Antibiotics with concentration-dependent and post antibiotic effect better suited to intermittent regime than drugs requiring continuous concentration above MIC
    • Dosing unclear
    • Specialised nebuliser – ultrasonic or vibrating mesh
    • Ventilator dysfunction – filter obstruction
    • Possible mucosal toxicity and bronchospasm and bronchorrhoea

Examiners Comments:

Tendency not to read the question, so to write about definition, diagnosis or risk of VAP rather than principles of management in confirmed disease. Nebulised antibiotics poorly understood. Frequently no antibiotic choice given. No organisms other than basic classification. Few mentioned "resistant" organisms.

Discussion

This question was done quite poorly (13.6% passed), perhaps because it extends somewhat beyond the usual ICU antibiotic decisonmaking patterns (where everybody gets Tazocin). It was probably also difficult to earn full marks, as the marking rubric only adds up to 70%. Anyway:

Factors which influence antibiotic agent selection:

  • Duration of ventilation
    • Early VAP: less than five days of ventilation- more likely to have normal respiratory pathogens sensitive to third-generation cephalosporins
    • Late VAP: more than five days of ventilation - more likely to have enteric Gram-negatives, S.aureus and Pseudomonas.
  • Previous use of antibiotics:
    • If they haven't had any antibiotics in the previous month, it may be ok to use a monotherapy with a non-antipseudomonal beta-lactam eg. ceftriaxone or amoxycillin-clavulanate.
    • If they have had some antibiotics recently, you may need to escalate to an antipseudomonal beta-lactam or a carbapenem, eg. tazocin, meropenem, cefepime, and so forth.
  • Local prevalence of resistance
  • Risk factors for resistant pathogens (eg. prolonged hospitalisation, residence in a nursing home, chronic dialysis, etc) 
  • Host defence factors (eg. immunocompetence)
  • Lung and intracellular penetration of the drug
    • If MRSA is suspected, linezolid is a better choice than vancomycin.
    • If Legionella is suspected, a fluoroquinolone should be added, as they have better intracellular penetration.

Factors which influence antibiotic course timing and duration:

  • Confirmation of the diagnosis of VAP
    • Therapy should begin immediately, i.e. there is a survival disadvantage in waiting for sputum results
  • Appearance of culture and sensitivity results 
    • Deescalation and the narrowing of the antimicrobial spectrum should be based on culture findings.
  • Response to therapy 
  • Empiric duration: 7 days.  In the classical era of intensive care medicine, people were treated with quite long courses of antibiotics (14-21 days) but this does not appear to confer any sort of survival advantage (Pugh et al, 2011).

Nebulised antibiotics in VAP:

Rationale for use of nebulised antibiotics for VAP

  • Clinical response to antibiotics in VAP is poor even in highly susceptible organisms
  • The bacteria involved often have high MICs 
  • Drugs which are most effective for VAP (eg. vancomycin, aminoglycosides) have poor lung tissue penetration
  • Logically, clinical response should improve if one were to deliver these agents directly to the affected tissue
  • The patient is already intubated, permitting a convenient route of delivery which bypasses the upper airway mucosa and negates some of the patient tolerance factors
  • A higher local concentration could be achieved thereby

Advantages

  • Higher local concentration should be well above MIC even for intermediately sensitive strains; these concentrations woild not be tolerated if given intravenously
  • The concentration may be sufficiently high to prevent the emergence of resistance
  • Systemic toxicity should be reduced:
    • Lower total antibiotic doses may be used
    • The drugs which are most toxic (eg. aminoglycosides) are absorbed the least
    • Microflora of the gut will not be altered
  • A shorter course may be possible

Disadvantages

  • Bronchospasm may occur
  • Circuit filters will get obstructed
  • Pulmonary accumulation of the drug may occur, which may have local toxic effects (often this is due to excipients rather than the antibiotic itself)
  • The exact dose is difficult to determine
  • Measuring serum levels is not reassuring of a satisfactory effect

Practical constraints

  • A special nebuliser is required
  • Continuous nebulisation is possible for drugs with time-dependent killing, but this will also kill the expiratory circuit filter.
  • Not all antibiotics can be delivered in this fashion (the greatest amount of experience is with tobramycin)
  • The drug needs to be diluted in a carrier fluid, which affects the chemical stability of the drug
  • Viscosity of the solution increases with added antibiotic molecules, and this increases the droplet size.  Those droplets have to stay somewhere between 0.5 to 3 µm in diameter, otherwise they will just uselessly deposit on the tubing and mucosa.

Evidence

  • The 2018 meta-analysis by Xu et al pooled data from 15 studies and found a signficantly higher rate of clinical recovery with nebulised antibiotics.
  • Microbial eradication was also improved, although the benefit was only observed with colistin
  • There was no signal for improved mortality, but also no evidence of any increase in toxicity
  • These studies were numerous and small in scale, which decreases the methodological quality of the meta-analysis, and they were pooled with observational studies. 
  • The meta-analysis of trials on this topic is generally frustrated by poor research design and lack of standards. "Investigators have often used off the shelf nebulizers with no standardized dosing", lamented Lucy Palmer in her 2019 article titled  "Why have trials of inhaled antibiotics for ventilator-associated infections failed?" 

Society support

  • The 2016 IDSA guidelines recommend inhaled antibotics only for VAP when it is caused by Gram negatives for which aminoglycosides or colistin are the only choices based on suceptibility testing.
  • The European Society of Clinical Microbiology and Infectious Diseases disagreed, making a recommendation for "avoiding the use of nebulized antibiotics in clinical practice, due to a weak level of evidence of their efficacy"  (Rello et al, 2017)

References

References

Pugh, Richard, et al. "Short‐course versus prolonged‐course antibiotic therapy for hospital‐acquired pneumonia in critically ill adults." Cochrane Database of Systematic Reviews 10 (2011).

Swanson, Joseph, and Diana Wells. "Empirical antibiotic therapy for ventilator-associated pneumonia." Antibiotics 2.3 (2013): 339-351.

Park, David R. "Antimicrobial treatment of ventilator-associated pneumonia." Respiratory care 50.7 (2005): 932-955.

Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. American Thoracic Society, Infectious Diseases Society of America. Am J Respir Crit Care Med. 2005;171(4):388.

Xu, Feng, et al. "Aerosolized antibiotics for ventilator-associated pneumonia: a pairwise and Bayesian network meta-analysis." Critical Care 22.1 (2018): 301.

Ehrmann, Stephan, et al. "Nebulized antibiotics in mechanically ventilated patients: a challenge for translational research from technology to clinical care." Annals of intensive care 7.1 (2017): 78.

Palmer, Lucy B. "Why have trials of inhaled antibiotics for ventilator-associated infections failed?." Current opinion in infectious diseases 32.2 (2019): 163-168.

Kalil, Andre C., et al. "Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society." Clinical Infectious Diseases 63.5 (2016): e61-e111.

Rello, Jordi, et al. "Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases." Clinical Microbiology and Infection 23.9 (2017): 629-639.