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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.

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



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.


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.


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.


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.

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