A randomized trial of combination therapy versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia

Introduction

Delays in adequate antibiotic therapy for ventilator-associated pneumonia (VAP) are associated with poor outcomes, and early use of broad-spectrum antibiotics may improve clinical outcomes. However, indiscriminant use of broad-spectrum antibiotics is associated with the emergence of antibiotic-resistant bacteria, fungal infections, and increased healthcare costs. The purpose of this study was to determine optimal empiric treatment of VAP by comparing a strategy of combination therapy to monotherapy with broad-spectrum antibiotics.

Methods

In a multicenter trial, we randomized mechanically ventilated adult patients with suspected VAP that developed after 96 hours in the ICU to receive either meropenem and ciprofloxacin or meropenem alone, as initial therapy. In addition, before starting antibiotics, diagnostic specimens were obtained using either bronchoalveolar lavage with quantitative cultures or standard endotracheal aspirates.

Results

We randomized 740 patients in 28 ICUs in Canada and the United States. The baseline characteristics and etiologies of VAP were similar between groups. There was no difference in 28-day mortality between the combination and monotherapy groups (RR = 1.05, 95% confidence interval 0.78–1.42; P = 0.74). The duration of ICU and hospital stay, clinical and microbiological response to treatment, emergence of antibiotic-resistant bacteria, isolation of Clostridium difficile, and fungal colonization were similar between groups. Combination therapy resulted in a higher rate of adequate empiric therapy compared with monotherapy (93.1% vs 85.3%, P = 0.01). In a subgroup of patients with infection due to pseudomonas species, acinetobacter species and multidrug-resistant Gram-negative bacilli at enrollment (n = 56), the adequacy of initial antibiotics was 82.4% in the combination group versus 18.8% in the monotherapy group (P < 0.001); this difference was associated with an increase in the microbiological eradication of the infecting organisms (64.1% vs 29.4%, P = 0.05) but no differences in clinical outcomes.

Conclusion

In patients who have suspected VAP, empiric treatment with combination therapy, as compared with monotherapy, is safe and is associated with a higher rate of adequate antimicrobial coverage but has no effect on clinical outcomes.