Antibacterial activity of human simulated epithelial lining fluid concentrations of amikacin inhale alone and in combination with meropenem against Acinetobacter baumannii

Abstract

Background: Acinetobacter baumannii(ACBN) is a MDR organism causing pneumonia in ventilated patients. High MICs often result in insufficient lung exposures, thus poor outcomes have been observed with parenteral antimicrobials. Amikacin Inhale(AMK-I), is a drug–device combination of amikacin and a Pulmonary Drug Delivery System device. We aimed to describe the pharmacodynamic profile of human simulated epithelial lining fluid(ELF) exposures of AMK-I and intravenous meropenem alone and in combination against ACBN with variable susceptibility profiles.

Methods: AMK-I ELF exposures and the ELF profile of meropenem achieved after intravenous administration were evaluated in an in vitro pharmacodynamic model. Nine ACBN with amikacin/meropenem MICs of 2–512/2 to >64 mg/L were utilized. MICs were repeated post exposure to assess the development of resistance.

Results: AMK-I monotherapy rapidly achieved and sustained bactericidal activity for isolates with amikacin MIC ≤128 mg/L. For isolates with MICs of 256 and 512 mg/L initial reductions in bacterial density were observed followed by regrowth. The combination produced similar bactericidal activity against ACBN with amikacin MICs of ≤128. While the combination regimen produced initial reductions and prolonged the duration of activity against organisms with MICs of 256 and 512 mg/L, regrowth and MIC elevations were noted during the 72-h exposure period.

Conclusion: The combination achieved rapid and sustained efficacy when amikacin MICs were ≤128 mg/L and prolonged the duration of activity compared to monotherapy for organisms with MICs 256 mg/L and 512 mg/L. These data support the utility of AMK-I as an adjunct for the treatment of pneumonia caused by A. baumannii with MICs above current susceptibility break-points.

Keywords:

• In vitro pharmacodynamics
• amikacin
• pneumonia
• A. baumannii

Acknowledgements

We acknowledge Sara Robinson, Kim Greenwood and Christina Sutherland for their assistance in conducting the study and the HPLC analysis of meropenem. We thank Michael A. Browne and Dr Leslie E. Edinboro from Quest Diagnostics for the determination of amikacin concentrations. We thank Drs Patrick T. McGann and Emil P. Lesho for the whole genome sequencing.

Disclosure statement

Dr Nicolau received grants from Bayer Pharma AG during the conduct of the study and grants from Bayer Pharma AG outside the submitted work. Dr Ghazi and Dr Grupper declare no conflicts of interest. Study design, data acquisition and manuscript preparation were determined and conducted independently by the investigators. The sponsor was given the opportunity to review and comment on the final publication prior to submission, but any modifications were made at the discretion of the investigators.

Additional information

Funding

This work was supported by an investigator initiated research grant from Bayer Pharma AG (Berlin, Germany).