Consider adding INHALED antibiotics for ventilator-associated pneumonia

Questions will come up about adding nebulized antibiotics for gram-negative ventilator-associated pneumonia (VAP). About one in three patients fail IV antibiotics for VAP and poor lung penetration of common VAP antibiotics may contribute to this. Adding inhaled antibiotics may help reach the site of action. But evidence for benefit is weak. Plus inhaled antibiotics may cause adverse effects, such as bronchospasm or hypoxemia.

Start with IV antibiotics alone for most VAP cases. Lean toward adding an inhaled aminoglycoside or colistin to IV therapy for a highly multidrug resistant organism. For instance, consider adding amikacin or tobramycin nebs to IV amikacin or IV tobramycin for a Pseudomonas VAP that's only susceptible to tobramycin "see table 1 for doses".

NPS-adv

Table (1). Dosing and Administration Considerations for Inhaled Antibiotics in VAP
Inhaled Antibiotic	Dosing Regimens (Adults)	Comments
Amikacin	400 mg nebulized Q12H or Q24H. 25 mg/kg/day, for 3 days (administered with ceftazidime). 300 mg (with 120 mg fosfomycin), nebulized Q12H for 10 days (or until extubation).	Reconstitution methods not described. Monitoring of blood levels not necessary due to low systemic absorption with the inhalational route of administration. Side effects include hypoxemia. Administered along with fosfomycin as part of the amikacin fosfomycin inhalation system (AFIS).
Ceftazidime	15 mg/kg nebulized every 3 hours for 8 days (administered along with amikacin).	Side effects include hypoxemia. May cause discoordination of breathing that necessitates sedation.
Colistin/Colistimethate 33 mg CBA = 80 mg Colistimethate = 1 million IU	100 to 150 mg CBA, nebulized over 10 to 20 minutes, Q12H. 400 mg CBA, nebulized over 60 minutes, Q8H for 7 to 19 days. 2.5 mg/kg/day CBA, nebulized over 10 to 15 minutes. 1.2 to 3 million IU, nebulized Q24H. 4 million IU, nebulized Q8H.	Reconstitute powder for injection with 2 to 4 mL sterile water. Positive outcomes in respiratory infections have been demonstrated more frequently with inhaled colistin than with polymyxin B, while colistimethate is associated with fewer side effects than colistin. Additionally, inhaled polymyxin B has not been formally studied for the treatment of VAP. Once diluted, colistimethate is hydrolyzed to colistin and one of its active components, Polymyxin E1, which is a pulmonary toxin. To avoid tissue damage and possible death, colistimethate should be used as soon as possible after mixing, and never stored for longer than 24 hours. Side effects include throat irritation, cough, chest tightness, bronchospasm, and bronchoconstriction, and are more likely to occur in patients with chronic lung disease. Bronchodilators and oxygen can be used to treat bronchoconstriction when it occurs. May cause discoordination of breathing that necessitates sedation.
Fosfomycin	Administered along with amikacin as part of the amikacin fosfomycin inhalation system (AFIS). 120 mg (with 300 mg amikacin), nebulized and inhaled, Q12H for 10 days (or until extubation).	Should not be used alone due to rapid emergence of resistance. Side effects of the AFIS regimen were very similar to placebo, and included diarrhea and pleural effusion.
Tobramycin	300 mg nebulized for 15 to 20 minutes, Q12H.	Reconstitute preservative-free tobramycin powder for injection with normal saline to a final concentration of 40 mg/mL. Tobramycin nebulizer solution is also commercially available (e.g., TOBI 300 mg/5 mL ampules). Monitoring of drug blood levels not necessary for patients with normal renal function. Side effects reported with preservative-free tobramycin powder for injection include cough and bronchoconstriction (more likely to occur in patients with airway hyper-reactivity). Side effects with tobramycin nebulizer solution (TOBI) in cystic fibrosis patients include voice alteration and transient tinnitus. Tobramycin nebulizer solution (TOBI) is formulated for use with the Pari LC Plus nebulizer, and should not be mixed with dornase alpha (Pulmozyme).

Also consider adding inhaled antibiotics as a last resort for any gram-negative VAP not adequately improving on IV therapy alone. But don't replace IV antibiotics with inhaled ones. Using inhaled antibiotics alone isn't likely to be more beneficial. Work with respiratory therapy to create protocols, since proper administration may "make or break" the benefit of an inhaled antibiotic. Verify the ventilator's humidifier is turned off during administration and expiratory filters are changed after each treatment.

Try to use preservative-free formulations. Preservatives may increase the risk of bronchospasm. Consider pretreating with albuterol if you can't avoid preservatives and in patients who smoke or have asthma, COPD, etc. Use colistin as soon as possible after mixing. A toxic metabolite can develop after mixing that can injure the lungs.

NPS-adv

---

References

1. Kalil AC, Metersky ML, Klompas M, 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. Clin Infect Dis. 2016 Sep 1;63(5):e61-e111.
2. Le J, Ashley ED, Neuhauser MM, Brown J, et al. Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy. 2010 Jun;30(6):562-84.
3. Wenzler E, Fraidenburg DR, Scardina T, Danziger LH. Inhaled Antibiotics for Gram-Negative Respiratory Infections. Clin Microbiol Rev. 2016 Jul;29(3):581-632.

---