Combating Carbapenem-Resistant Acinetobacter baumannii by an Optimized Imipenem-plus-Tobramycin Dosage Regimen: Prospective Validation via Hollow-Fiber Infection and Mathematical Modeling

Cornelia B Landersdorfer; Rajbharan Yadav; Kate E Rogers; Tae Hwan Kim; Beom Soo Shin; John D Boyce; Roger L Nation; Jürgen B Bulitta

doi:10.1128/AAC.02053-17

Combating Carbapenem-Resistant Acinetobacter baumannii by an Optimized Imipenem-plus-Tobramycin Dosage Regimen: Prospective Validation via Hollow-Fiber Infection and Mathematical Modeling

Antimicrob Agents Chemother. 2018 Mar 27;62(4):e02053-17. doi: 10.1128/AAC.02053-17. Print 2018 Apr.

Authors

Cornelia B Landersdorfer^#^{1

2

3}, Rajbharan Yadav^#⁴, Kate E Rogers^{4

2}, Tae Hwan Kim^{5

6}, Beom Soo Shin⁶, John D Boyce⁷, Roger L Nation⁴, Jürgen B Bulitta^#⁸

Affiliations

¹ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia cornelia.landersdorfer@monash.edu jbulitta@cop.ufl.edu.
² Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
³ School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
⁴ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
⁵ Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.
⁶ School of Pharmacy, Sungkyunkwan University, Jangan-gu, Suwon, South Korea.
⁷ Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia.
⁸ Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA cornelia.landersdorfer@monash.edu jbulitta@cop.ufl.edu.

^# Contributed equally.

Abstract

We aimed to prospectively validate an optimized combination dosage regimen against a clinical carbapenem-resistant Acinetobacter baumannii (CRAB) isolate (imipenem MIC, 32 mg/liter; tobramycin MIC, 2 mg/liter). Imipenem at constant concentrations (7.6, 13.4, and 23.3 mg/liter, reflecting a range of clearances) was simulated in a 7-day hollow-fiber infection model (inoculum, ∼10^7.2 CFU/ml) with and without tobramycin (7 mg/kg q24h, 0.5-h infusions). While monotherapies achieved no killing or failed by 24 h, this rationally optimized combination achieved >5 log₁₀ bacterial killing and suppressed resistance.

Keywords: Acinetobacter baumannii; carbapenem resistance; dynamic hollow-fiber infection model; mathematical modeling; mechanism based; mechanistic; pharmacodynamics; pharmacokinetics; synergy.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acinetobacter baumannii / drug effects*
Anti-Bacterial Agents / pharmacology*
Carbapenems / pharmacology*
Imipenem / pharmacology*
Microbial Sensitivity Tests
Models, Theoretical*
Tobramycin / pharmacology*

Substances

Anti-Bacterial Agents
Carbapenems
Imipenem
Tobramycin

Grants and funding

R01 AI130185/AI/NIAID NIH HHS/United States