High epithelial lining fluid concentrations of NKTR-061 (inhaled amikacin) twice daily achieved in pneumonic portions of lung

Introduction

The use of systemic aminoglycosides to treat ventilated patients with Gram-negative pneumonia (GNP) is limited by their toxicity and poor penetration into the lung. Luyt and colleagues demonstrated high amikacin epithelial lining fluid (ELF) concentrations after NKTR-061 twice daily, amikacin 400 mg (3.2 ml), administration to intubated patients with pneumonia (n = 4) [1]. The present study was conducted to confirm high levels of NKTR-061 in the ELF in the pneumonic portion of the lung after 400 mg twice daily dosing.

Methods

NKTR-061 was delivered via the pulmonary drug delivery system (PDDS^®Clinical; Nektar Therapeutics) in mechanically ventilated patients with GNP for 7–14 days. The aerosol therapy was adjunctive to intravenous therapy per ATS guidelines. Twenty-eight evaluable patients received a daily dose of 800 mg in two divided doses every 12 hours. On treatment day 3, all patients underwent bronchoalveolar lavages 30 minutes post aerosol. The lung fluid was obtained from the infection-involved area of the lung.

The apparent volume of ELF recovered by bronchoalveolar lavage was determined using urea as an endogenous marker of dilution. The same day, the amikacin concentration was determined in serum collected 0.5, 1, 3, 6, 9, 12, 13, and 24 hours after delivery of the morning dose.

Results

The median ELF amikacin was 976.1 μg/ml (135.7–16,127.6), whereas the median (range) serum maximum concentration was 0.9 μg/ml (0.62–1.73). The median days of aerosol treatment was 7 days (2–10).

Conclusion

Delivery of aerosolized amikacin using the PDDS Clinical achieved very high aminoglycoside concentrations in the ELF, in the pneumonic area of the lung, while maintaining safe serum amikacin concentrations. The ELF concentrations achieved always exceeded the amikacin MIC for microorganisms usually responsible for GNP. The clinical impact of this route remains to be determined.