Why have trials of inhaled antibiotics for ventilator-associated infections failed?

Two recent large randomized placebo-controlled clinical trials of adjunctive inhaled therapy for the treatment of ventilator-associated pneumonia failed to show a mortality effect or more rapid resolution of pneumonia symptoms. Does the failure of these studies to reach their endpoints suggest the end of inhaled therapy? This review will explain why inhaled therapy may still have an important role in the treatment of ventilated patients.

The recent interest in inhaled antimicrobial therapy is driven by the global emergence of increasingly resistant bacteria to systemic therapy. As fast as the pharmaceutical pipeline delivers more powerful systemic antibiotics to the ICU, the bacteria evolve and develop resistance to them. The hypothesis of recent trials has been that adjunctive inhaled therapy will make systemic treatment more effective. This review summarizes the available data from the two recent multisite randomized Phase 2 and Phase 3 trials of inhaled antimicrobials as adjunctive therapy and suggests why they failed to achieve their endpoints. When given properly, these drugs can provide high concentrations of drug in the lung that could not be achieved with intravenous antibiotics without significant systemic toxicity. The results of these trials and the data from many other smaller trials are compelling us to re-examine the indications for inhaled therapy as well as what clinical outcomes are most important.

This review summarizes current evidence describing the use of inhaled antibiotics for the treatment of bacterial ventilator-associated infections. Future investigations need to reevaluate the design and the outcomes that are most important in this era of multidrug-resistant bacteria.