Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model

Jessica R Tait; Hajira Bilal; Tae Hwan Kim; Abigail Oh; Anton Y Peleg; John D Boyce; Antonio Oliver; Phillip J Bergen; Roger L Nation; Cornelia B Landersdorfer

doi:10.1016/j.jgar.2021.04.021

Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model

J Glob Antimicrob Resist. 2021 Sep:26:55-63. doi: 10.1016/j.jgar.2021.04.021. Epub 2021 May 21.

Authors

Affiliations

¹ Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia; Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.
² Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.
³ College of Pharmacy, Daegu Catholic University, Daegu, South Korea.
⁴ Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia.
⁵ Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, VIC, Australia; Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, Australia.
⁶ Biomedicine Discovery Institute, Department of Microbiology, Monash University, Melbourne, VIC, Australia.
⁷ Servicio de Microbiología, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain.
⁸ Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia. Electronic address: cornelia.landersdorfer@monash.edu.

PMID: 34023531
DOI: 10.1016/j.jgar.2021.04.021

Abstract

Objectives: Hypermutable Pseudomonas aeruginosa strains are a major challenge in cystic fibrosis. We investigated bacterial killing and resistance emergence for approved ceftazidime and tobramycin regimens, alone and in combination.

Methods: Pseudomonas aeruginosa PAOΔmutS and six hypermutable clinical isolates were examined using 48-h static concentration time-kill (SCTK) studies (inoculum ~10^7.5 CFU/mL); four strains were also studied in a dynamic in vitro model (IVM) (inoculum ~10⁸ CFU/mL). The IVM simulated concentration-time profiles in epithelial lining fluid following intravenous administration of ceftazidime (3 g/day and 9 g/day continuous infusion), tobramycin (5 mg/kg and 10 mg/kg via 30-min infusion 24-hourly; half-life 3.5 h), and their combinations. Time courses of total and less-susceptible populations were determined.

Results: Ceftazidime plus tobramycin demonstrated synergistic killing in SCTK studies for all strains, although to a lesser extent for ceftazidime-resistant strains. In the IVM, ceftazidime and tobramycin monotherapies provided ≤5.4 and ≤3.4 log₁₀ initial killing, respectively; however, re-growth with resistance occurred by 72 h. Against strains susceptible to one or both antibiotics, high-dose combination regimens provided >6 log₁₀ initial killing, which was generally synergistic from 8-24 h, and marked suppression of re-growth and resistance at 72 h. The time course of bacterial density in the IVM was well described by mechanism-based models, enabling Monte Carlo simulations (MCSs) to predict likely effectiveness of the combination in patients.

Conclusion: Results of the IVM and MCS suggested antibacterial effect depends both on the strain's susceptibility and hypermutability. Further investigation of the combination against hypermutable P. aeruginosa strains is warranted.

Keywords: Antibiotic combination; Dynamic in vitro infection model; Mathematical modelling; Optimised dosing; Pharmacodynamics; Pharmacokinetics.

Publication types

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

MeSH terms

Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Ceftazidime / pharmacology
Humans
Microbial Sensitivity Tests
Pseudomonas aeruginosa* / genetics
Tobramycin* / pharmacology

Substances

Anti-Bacterial Agents
Ceftazidime
Tobramycin