Introduction

Intravenous antibiotics (AB) have a clinical cure rate of ~55% in mechanically ventilated patients (MVP) with pneumonia. AB inhalation delivers larger lung doses than intravenous AB, but is problematic in MVP due to inefficient and variable current delivery systems. NKTR-061, a proprietary amikacin (AMK) aerosolization system optimized for ventilator circuits, is in clinical development as an adjunct to intravenous AB therapy for the treatment of pneumonia.

Methods

In a phase II study, MVP (n = 44) received 400 mg every 24 hours or every 12 hours for 7–14 days; serial serum, tracheal aspirate and urine samples were collected on day 3. The days on vent and intravenous AB use were monitored. In a separate study, healthy subjects (n = 14) inhaled a single Technicium 99 m-labeled 400 mg dose; serum and urine were collected and lung deposition was determined with gamma scintigraphy.

Results

The AMK lung dose in healthy subjects was 172.2 mg, 43% of the nominal dose. The lung dose in MVP was 112 mg, with the difference arising from loss of drug in the ventilator circuit. The predicted peak lung AMK in healthy subjects (Figure 1) ranged from 75 to 165 μg/g. The peak tracheal aspirate AMK after NKTR-061 was 16,212 ± 3,675 μg/ml versus 14 ± 4.2 μg/ml after intravenous (15 mg/kg [1]); the peak serum AMK after NKTR-061 was 3.2 ± 0.5 μg/ml versus 47 ± 4.2 μg/ml after intravenous. NKTR-061 caused a significant (P = 0.02) dose-dependent reduction in intravenous AB use, with MVP dosed every 12 hours requiring half as much concurrent intravenous AB after 7 days of treatment as those receiving placebo [2].

Figure 1
figure 1

HS, healthy subjects; IH, inhaled; IV, intravenous.

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Conclusion

NKTR-061 achieves AMK lung exposures in MVP much greater than those after intravenous dosing. Greater lung exposure with concurrent lower overall dose and serum exposure is expected to increase efficacy, reduce the incidence of AB resistance and limit systemic AB toxicity.