Format

Send to

Choose Destination
Antimicrob Agents Chemother. 2019 Oct 21. pii: AAC.01679-19. doi: 10.1128/AAC.01679-19. [Epub ahead of print]

Meropenem-tobramycin combination regimens combat carbapenem-resistant Pseudomonas aeruginosa in the hollow-fiber infection model simulating augmented renal clearance in critically ill patients.

Author information

1
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
2
Centre for Medicine Use and Safety, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia.
3
The University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
4
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Florida, USA.
5
Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
6
Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
7
Centre for Translational Anti-infective Pharmacodynamics, The University of Queensland, Brisbane, Queensland, Australia.
8
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia cornelia.landersdorfer@monash.edu.

Abstract

Augmented renal clearance (ARC) is common in critically ill patients and is associated with sub-therapeutic concentrations of renally-eliminated antibiotics. We investigated the impact of ARC on bacterial killing and resistance amplification for meropenem and tobramycin regimens, in monotherapy and combination. Two carbapenem-resistant Pseudomonas aeruginosa isolates were studied in static-concentration time-kill studies. One isolate was examined comprehensively in a 7-d hollow-fiber infection model (HFIM). Pharmacokinetic profiles representing substantial ARC (creatinine clearance 250mL/min) were generated in the HFIM for meropenem (1g or 2g administered 8-hourly as 30-min infusions; 3g/d or 6g/d as continuous infusions [CI]) and tobramycin (7mg/kg 24-hourly as 30-min infusion) regimens. The time-courses of total and less-susceptible populations and MICs were determined for the monotherapies and all four combination regimens. Mechanism-based mathematical modeling (MBM) was performed. In the HFIM, maximum bacterial killing with any meropenem monotherapy was ∼3-log10 CFU/mL at 7h, followed by rapid regrowth with increases in resistant populations by 24h (MICmeropenem up to 128mg/L). Tobramycin monotherapy produced extensive initial killing (∼7-log10 at 4h) with rapid regrowth by 24h, including a substantial increase in resistant populations (MICtobramycin 32mg/L). Combination regimens containing meropenem administered intermittently or as 3g/d CI suppressed regrowth for ∼1-3d, with rapid regrowth of resistant bacteria. Only meropenem 6g/d CI combined with tobramycin suppressed regrowth and resistance over 7d. MBM well-described bacterial killing and regrowth for all regimens. The mode of meropenem administration was critical for the combination to be maximally effective against carbapenem-resistant P. aeruginosa.

PMID:
31636062
DOI:
10.1128/AAC.01679-19

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center