Aerosolized antibiotics for ventilator-associated pneumonia

Ventilator-associated pneumonia (VAP) caused by multidrug-resistant bacteria continues to be a major cause of morbidity and mortality in our ICUs. We have a limited choice of antibiotics to combat the resistant bacterial flora prevalent in many units. Besides, most systemically administered antibiotics fail to attain therapeutic concentrations in the lung. This has led many clinicians to resort to aerosolized antibiotics, often as an adjuvant to systemic therapy in the treatment of VAP. The use of inhaled antibiotics is based on sound rationale, with the possibility of delivering a high concentration of the drug to the target site. Furthermore, the emergence of resistant organisms may also be reduced with preservation of the gut flora. An added advantage may be to cut down the duration of systemic antibiotics, and perhaps, even use inhaled antibiotics are monotherapy.

Inhalational antibiotic therapy is not a new therapeutic modality; a 1975 study of ICU patients used polymyxin B in the atomized form or by endotracheal instillation in intubated patients as prophylaxis against pneumonia. (1) Predictably, such unlimited, universal, largely prophylactic therapy resulted in a high level of polymyxin resistance and high mortality.

Does inhalational therapy really work?

Although theoretically rational, there is a paucity of evidence with the use of aerosolized antibiotic therapy regarding efficacy, appropriate dosing, and method of administration.  Most of the evidence is from retrospective observational studies with no large randomized controlled trial that has addressed the efficacy of inhalational therapy. Zampieri et al. performed a meta-analysis comparing the combination of intravenous and aerosolized antibiotics with intravenous administration alone in the treatment of VAP. (2) The antibiotics used included gentamicin, amikacin, tobramycin, ceftazidime, and colistin. The likelihood of clinical cure was significantly higher with combined therapy; however, there was no significant difference in microbiological cure rates, ICU or hospital mortality, ventilation days, and ICU length of stay. In another meta-analysis, intravenous colistin was compared with adjunctive inhalational colistin therapy. This study reported a significantly higher clinical response, microbiological eradication, and infection-related mortality. (3) There was no difference in overall mortality or nephrotoxicity.

A retrospective cohort study compared intravenous colistin alone with combination therapy in patients with microbiologically proven VAP. (4) Cure rates were significantly higher with combination therapy; however, no difference was noted in all-cause ICU or hospital mortality. Similar findings were also observed in a retrospective case-control study; (5) Acinetobacter baumanni was the most common organism, followed by Klebsiella pneumoniae, and Pseudomonas aeruginosa in this study. A higher clinical cure was observed with combination therapy; however, there was no difference in mortality or pathogen eradication. There are few randomized controlled studies that have compared inhalational to intravenous therapy. The results have been mixed, with reports of reduction in the clinical pulmonary infection score (CPIS), (6) and microbiological cure with unchanged clinical outcomes. (7) A recent study using a combination of aerosolized amikacin and fosfomycin revealed no difference in CPIS, clinical cure, or mortality. (8)

Do we use inhalational therapy considering the mixed evidence?

Although there is no firm evidence of benefit yet, inhaled antibiotics seem to improve clinical and microbiological cure rates. Importantly, inhalational therapy has not led to adverse outcomes among available studies. Considering the often dismal outcomes from multi-drug resistant VAP and the relative paucity of effective antibiotics, it may be reasonable to administer aerosolized therapy, especially if conventional intravenous therapy proves ineffective.

Dosing

The dose of aerosolized antibiotics varies widely between different studies. However, based on the limited data available, the following doses may be reasonable for VAP or ventilator-associated tracheobronchitis.

Colistin:  150 mg (5 million units of colistimethate sodium) BD

Gentamicin and tobramycin: 300 mg BID

Amikacin: 400 mg BID

Points to remember when administering aerosolized colistin

  • In India, the commonly available formulation is colistimethate sodium (polymyxin E), which is a prodrug. Do remember the conversion formula:

80 mg colistimethate sodium (prodrug) = 30 mg colistin base activity = approximately 1,000,000 (1 million) units of colistimethate sodium

  • Use normal or half normal saline for dilution in a total volume of 3–5 ml; administer the solution immediately after reconstitution. Although jet and ultrasonic nebulizers are commonly used, vibrating plate nebulizers may be preferable.
  • If the patient is prone to bronchospasm, pre-treatment with nebulized salbutamol is recommended.
  • The ventilator filter at the expiratory end of the circuit may get clogged with aerosolization; some guidelines recommend replacing the filter after every dose.

 

References

  1. Feeley TW, du Moulin GC, Hedley-Whyte J, Bushnell LS, Gilbert JP, Feingold DS. Aerosol Polymyxin and Pneumonia in Seriously Ill Patients. N Engl J Med. 1975 Sep 4;293(10):471–5.
  2. Zampieri FG, Nassar Jr AP, Gusmao-Flores D, Taniguchi LU, Torres A, Ranzani OT. Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care [Internet]. 2015 Dec [cited 2018 Dec 29];19(1). Available from: http://ccforum.com/content/19/1/150
  3. Valachis A, Samonis G, Kofteridis DP. The Role of Aerosolized Colistin in the Treatment of Ventilator-associated Pneumonia: A Systematic Review and Metaanalysis*. Crit Care Med. 2015 Mar 1;43(3):527–33.
  4. Korbila IP, Michalopoulos A, Rafailidis PI, Nikita D, Samonis G, Falagas ME. Inhaled colistin as adjunctive therapy to intravenous colistin for the treatment of microbiologically documented ventilator-associated pneumonia: a comparative cohort study. Clin Microbiol Infect. 2010 Aug 1;16(8):1230–6.
  5. Kofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D, et al. Aerosolized plus Intravenous Colistin versus Intravenous Colistin Alone for the Treatment of Ventilator-Associated Pneumonia: A Matched Case-Control Study. Clin Infect Dis. 2010 Dec 1;51(11):1238–44.
  6. Palmer LB, Smaldone GC, Chen JJ, Baram D, Duan T, Monteforte M, et al. Aerosolized antibiotics and ventilator-associated tracheobronchitis in the intensive care unit*. Crit Care Med. 2008 Jul 1;36(7):2008–13.
  7. Rattanaumpawan P, Lorsutthitham J, Ungprasert P, Angkasekwinai N, Thamlikitkul V. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gram-negative bacteria. J Antimicrob Chemother. 2010 Dec 1;65(12):2645–9.
  8. Kollef MH, Ricard J-D, Roux D, Francois B, Ischaki E, Rozgonyi Z, et al. A Randomized Trial of the Amikacin Fosfomycin Inhalation System for the Adjunctive Therapy of Gram-Negative Ventilator-Associated Pneumonia: IASIS Trial. Chest. 2017 Jun 1;151(6):1239–46.

 

 

 

 

 

 

 

 

 

 

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