Aerosolized Ceftazidime for Prevention of Ventilator-Associated Pneumonia and Drug Effects on the Proinflammatory Response in Critically Ill Trauma Patients

G. Christopher Wood, Pharm.D., Bradley A. Boucher, Pharm.D., FCCP, Martin A. Croce, M.D., Scott D. Hanes, Pharm.D., Vanessa L. Herring, B.S., Timothy C. Fabian, M.D.

Disclosures

Pharmacotherapy. 2002;22(8) 

In This Article

Abstract and Introduction

Study Objectives: To evaluate the safety and efficacy of aerosolized ceftazidime for prevention of ventilator-associated pneumonia (VAP) and to evaluate the effects of the drug on the proinflammatory response.
Design: Prospective, randomized, double-blind, placebo-controlled clinical trial.
Setting: University teaching hospital.
Patients: Forty critically ill trauma patients at high risk for VAP.
Intervention: Within 48 hours of admission to the intensive care unit (ICU), patients were randomly assigned to receive aerosolized ceftazidime 250 mg every 12 hours or placebo (normal saline) for up to 7 days. Bronchoalveolar concentrations of tumor necrosis factor- (TNF- ), interleukin (IL)-1 , IL-6, and IL-8 were determined at baseline and the end of therapy (days 4-7).
Measurements and Main Results: The frequency of VAP in patients receiving aerosolized ceftazidime was 73% lower than that in patients receiving placebo at ICU day 14 (15% vs 55%, p=0.021), and 54% lower for the entire ICU stay (30% vs 65%, p=0.022). No clinically significant changes in bacterial culture and sensitivity patterns were observed. No adverse events from aerosolized ceftazidime were reported. Pulmonary TNF- , IL-1 , and IL-8 concentrations were attenuated in the ceftazidime group compared with those in the placebo group (p<0.001, p=0.02, and p=0.003). The frequency of VAP was related directly to changes in TNF- and IL-1 (p<0.001, p=0.02).
Conclusions: Aerosolized ceftazidime decreased the frequency of VAP in critically ill trauma patients, without adversely affecting ICU flora. Aerosolized ceftazidime also may attenuate the proinflammatory response in the lung.

Ventilator-associated pneumonia (VAP) is common in critically ill patients. This perilous complication is associated with increased length of intensive care unit (ICU) stay, hospital stay, and days of mechanical ventilation.[1,2,3,4,5,6] Development of VAP also may independently increase mortality by an estimated 30%.[2,5,7,8,9] Trauma patients are particularly susceptible to developing VAP compared with other ICU populations, with the overall prevalence approaching 45% in severely injured patients.[3,10,11,12] A safe and effective method to prevent VAP would significantly improve patient outcomes and decrease health care costs. Unfortunately, no widely accepted therapy to prevent VAP exists, although aerosolized and endotracheally instilled antibiotics have been studied for this indication with some success.

Aerosolized antimicrobials theoretically are attractive for preventing pneumonia because of high drug concentrations achieved in the lung and limited systemic drug exposure that could minimize bacterial resistance and reduce toxicity. Three of five trials in the 1970s were successful at preventing pneumonia, but these results were tempered by the emergence of atypical pathogens and bacterial resistance to the antibiotics administered.[13,14,15,16,17,18] These findings may have been a consequence of indiscriminate treatment with aerosolized antibiotics in patients at low risk for pneumonia. More recently, two trials of prophylactic aerosolized and endotracheally instilled antibiotics were effective at preventing VAP without causing adverse changes in microbial flora.[19,20] This likely was due to limiting the duration of therapy and including only patients at high risk for pneumonia (i.e., patients receiving mechanical ventilation). Although these data appear promising, definitive conclusions regarding aerosolized antibiotics for VAP prevention cannot be made because of the major methodologic shortcomings of these trials.

In addition to preventing bacterial growth, limited data show that aerosolized antimicrobials may attenuate the pulmonary acute-phase response.[21,22] In particular, cephalosporins have been shown to attenuate endotoxin-stimulated release of proinflammatory cytokines in vitro.[23] This is important because inflammatory dysregulation in critical illness may lead to endothelial damage, immunosuppression, and increased development of infections including pneumonia. Elevated pulmonary levels of proinflammatory cytokines such as tumor necrosis factor- (TNF- ), interleukin (IL)-1 , IL-6, and IL-8 have been associated with increased development of pneumonia, acute respiratory distress syndrome, and mortality.[24,25,26,27] These cytokines also may enhance the growth of pathogenic bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus.[28] Based on these data, we developed a randomized, double-blind clinical trial to evaluate the safety and efficacy of aerosolized ceftazidime versus placebo for the prevention of VAP in critically ill trauma patients, and to evaluate the effect of aerosolized ceftazidime versus placebo on the proinflammatory response.

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