Optimization of a Meropenem-Tobramycin Combination Dosage Regimen against Hypermutable and Nonhypermutable Pseudomonas aeruginosa via Mechanism-Based Modeling and the Hollow-Fiber Infection Model

Cornelia B Landersdorfer; Vanessa E Rees; Rajbharan Yadav; Kate E Rogers; Tae Hwan Kim; Phillip J Bergen; Soon-Ee Cheah; John D Boyce; Anton Y Peleg; Antonio Oliver; Beom Soo Shin; Roger L Nation; Jürgen B Bulitta

doi:10.1128/AAC.02055-17

Optimization of a Meropenem-Tobramycin Combination Dosage Regimen against Hypermutable and Nonhypermutable Pseudomonas aeruginosa via Mechanism-Based Modeling and the Hollow-Fiber Infection Model

Antimicrob Agents Chemother. 2018 Mar 27;62(4):e02055-17. doi: 10.1128/AAC.02055-17. Print 2018 Apr.

Authors

Cornelia B Landersdorfer^{1

2}, Vanessa E Rees^{3

2}, Rajbharan Yadav³, Kate E Rogers^{3

2}, Tae Hwan Kim⁴, Phillip J Bergen², Soon-Ee Cheah³, John D Boyce⁵, Anton Y Peleg^{5

6}, Antonio Oliver⁷, Beom Soo Shin⁴, Roger L Nation³, Jürgen B Bulitta⁸

Affiliations

¹ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia cornelia.landersdorfer@monash.edu.
² Centre for Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Melbourne, Australia.
³ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia.
⁴ School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, South Korea.
⁵ Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia.
⁶ Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Australia.
⁷ Servicio de Microbiología, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain.
⁸ Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, Florida, USA.

Abstract

Hypermutable Pseudomonas aeruginosa strains are prevalent in patients with cystic fibrosis and rapidly become resistant to antibiotic monotherapies. Combination dosage regimens have not been optimized against such strains using mechanism-based modeling (MBM) and the hollow-fiber infection model (HFIM). The PAO1 wild-type strain and its isogenic hypermutable PAOΔmutS strain (MIC_meropenem of 1.0 mg/liter and MIC_tobramycin of 0.5 mg/liter for both) were assessed using 96-h static-concentration time-kill studies (SCTK) and 10-day HFIM studies (inoculum, ∼10^8.4 CFU/ml). MBM of SCTK data were performed to predict expected HFIM outcomes. Regimens studied in the HFIM were meropenem at 1 g every 8 h (0.5-h infusion), meropenem at 3 g/day with continuous infusion, tobramycin at 10 mg/kg of body weight every 24 h (1-h infusion), and both combinations. Meropenem regimens delivered the same total daily dose. Time courses of total and less susceptible populations and MICs were determined. For the PAOΔmutS strain in the HFIM, all monotherapies resulted in rapid regrowth to >10^8.7 CFU/ml with near-complete replacement by less susceptible bacteria by day 3. Meropenem every 8 h with tobramycin caused >7-log₁₀ bacterial killing followed by regrowth to >6 log₁₀ CFU/ml by day 5 and high-level resistance (MIC_meropenem, 32 mg/liter; MIC_tobramycin, 8 mg/liter). Continuous infusion of meropenem with tobramycin achieved >8-log₁₀ bacterial killing without regrowth. For PAO1, meropenem monotherapies suppressed bacterial growth to <4 log₁₀ over 7 to 9 days, with both combination regimens achieving near eradication. An MBM-optimized meropenem plus tobramycin regimen achieved synergistic killing and resistance suppression against a difficult-to-treat hypermutable P. aeruginosa strain. For the combination to be maximally effective, it was critical to achieve the optimal shape of the concentration-time profile for meropenem.

Keywords: Pseudomonas aeruginosa; combination therapy; dosage regimen; dynamic infection model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology*
Meropenem / pharmacology*
Microbial Sensitivity Tests
Models, Theoretical*
Mutation / genetics
Pseudomonas aeruginosa / drug effects*
Pseudomonas aeruginosa / genetics*
Tobramycin / pharmacology*

Substances

Anti-Bacterial Agents
Meropenem
Tobramycin