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J Antimicrob Chemother. 2016 Nov;71(11):3157-3167. Epub 2016 Aug 11.

Resistance suppression by high-intensity, short-duration aminoglycoside exposure against hypermutable and non-hypermutable Pseudomonas aeruginosa.

Author information

1
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia.
2
Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA.
3
Servicio de Microbiología, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria de Palma, Palma de Mallorca, Spain.
4
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USA.
5
d3 medicine LLC, Parsippany, NJ, USA.
6
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville campus), Parkville, Victoria 3052, Australia cornelia.landersdorfer@monash.edu.

Abstract

OBJECTIVES:

Hypermutable bacteria are causing a drastic problem via their enhanced ability to become resistant. Our objectives were to compare bacterial killing and resistance emergence between differently shaped tobramycin concentration-time profiles at a given fAUC/MIC, and determine the tobramycin exposure durations that prevent resistance.

METHODS:

Static concentration time-kill studies over 24 h used Pseudomonas aeruginosa WT strains (ATCC 27853 and PAO1) and hypermutable PAOΔmutS. fAUC/MIC values of 36, 72 and 168 were assessed at initial inocula of 106 and 104 cfu/mL (all strains) and 101.2 cfu/mL (PAOΔmutS only) in duplicate. Tobramycin was added at 0 h and removed at 1, 4, 10 or 24 h. Proportions of resistant bacteria and MICs were determined at 24 h. Mechanism-based modelling was conducted.

RESULTS:

For all strains, high tobramycin concentrations over 1 and 4 h resulted in more rapid and extensive initial killing compared with 10 and 24 h exposures at a given fAUC/MIC. No resistance emerged for 1 and 4 h durations of exposure, although extensive regrowth of susceptible bacteria occurred. The 24 h duration of exposure revealed less regrowth, but tobramycin-resistant populations had completely replaced susceptible bacteria by 24 h for the 106 cfu/mL inoculum. The hypermutable PAOΔmutS showed the highest numbers of resistant bacteria. Total and resistant bacterial counts were described well by novel mechanism-based modelling.

CONCLUSIONS:

Extensive resistance emerged for 10 and 24 h durations of exposure, but not for shorter durations. The tobramycin concentration-time profile shape is vital for resistance prevention and should aid the introduction of optimized combination regimens.

PMID:
27521357
PMCID:
PMC5079302
DOI:
10.1093/jac/dkw297
[Indexed for MEDLINE]
Free PMC Article

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