Purpose: To conduct a multicenter, randomized, placebo-controlled, double-blind, phase II study of BAY41-6551 (NCT01004445), an investigational drug-device combination of amikacin, formulated for inhalation, and a proprietary Pulmonary Drug Delivery System, for the treatment of Gram-negative pneumonia in mechanically ventilated patients.
Methods: Sixty-nine mechanically ventilated patients with Gram-negative pneumonia, a clinical pulmonary infection score ≥6, at risk for multidrug-resistant organisms, were randomized to BAY41-6551 400 mg every 12 h (q12h), 400 mg every 24 h (q24h) with aerosol placebo, or placebo q12h for 7-14 days, plus standard intravenous antibiotics. The combined primary endpoint was a tracheal aspirate amikacin maximum concentration ≥6,400 μg/mL (25 × 256 μg/mL reference minimum inhibitory concentration) and a ratio of area under the aspirate concentration-time curve (0-24 h) to minimum inhibitory concentration ≥100 on day 1.
Results: The primary endpoint was achieved in 50% (6/12) and 16.7% (3/18) of patients in the q12h and q24h groups, respectively. Clinical cure rates, in the 48 patients getting ≥7 days of therapy, were 93.8% (15/16), 75.0% (12/16), and 87.5% (14/16) in the q12h, q24h, and placebo groups, respectively (p = 0.467). By the end of aerosol therapy, the mean number of antibiotics per patient per day was 0.9 in the q12h, 1.3 in the q24h, and 1.9 in the placebo groups, respectively (p = 0.02 for difference between groups). BAY41-6551 was well tolerated and attributed to two adverse events in one patient (mild bronchospasm).
Conclusions: BAY41-6551 400 mg q12h warrants further clinical evaluation.