Shape does matter: short high-concentration exposure minimizes resistance emergence for fluoroquinolones in Pseudomonas aeruginosa.
OBJECTIVE
For fluoroquinolones, the area under the free plasma concentration-time curve divided by the MIC (fAUC/MIC) best predicts bacterial killing in mice and outcomes in patients. However, it is unknown whether the shape of the antibiotic concentration profile affects resistance emergence. Our objective was to compare killing and resistance between ciprofloxacin concentration profiles with different shapes at the same fAUC/MIC and identify the durations of ciprofloxacin exposure that minimize resistance emergence.


METHODS
Static time-kill studies over 24 h using Pseudomonas aeruginosa ATCC 27853 assessed fAUC/MIC of 44 and 132 of ciprofloxacin (MICCIP = 0.25 mg/L) and fAUC/MIC of 22, 44 and 132 of ciprofloxacin plus an efflux pump inhibitor (MICCIP+EPI = 0.031 mg/L) at initial inocula of 10(4), 10(5) and 10(6) cfu/mL. Ciprofloxacin was added at 0 h and rapidly removed at 1, 4, 10, 16 or 24 h. Mutant frequencies and MICs were determined at 24 h.


RESULTS
High ciprofloxacin concentrations over 1-10 h yielded more rapid and extensive initial killing compared with 16 and 24 h exposures at the same fAUC/MIC. No resistance emerged for 1-10 h exposures, although regrowth of susceptible bacteria was extensive. Ciprofloxacin exposure over 24 h yielded less regrowth, but ciprofloxacin-resistant bacteria at 5× MIC amplified by over 5 log10 and almost completely replaced the susceptible bacteria by 24 h; MICs increased 4- to 8-fold. Resistance also emerged on 3× MIC, but not 5× MIC, plates when efflux was inhibited.


CONCLUSIONS
Pre-existing resistant subpopulations amplified extensively with 24 and 16 h exposures, but not with shorter durations. The shape of the ciprofloxacin concentration profile was critical to minimize resistance emergence.
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.
Vanessa E
VE
Rees
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Jürgen B
JB
Bulitta
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia.
Roger L
RL
Nation
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Brian T
BT
Tsuji
IBMP-Institute for Biomedical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, Nürnberg-Heroldsberg, Germany Institute of Pharmacology, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany.
Fritz
F
Sörgel
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), Parkville, Victoria 3052, Australia School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA cornelia.landersdorfer@monash.edu.
Cornelia B
CB
Landersdorfer
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D024841:Fluoroquinolones / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects*; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D012641:Selection, Genetic; D013997:Time Factors
D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones
P. aeruginosa; antibiotic resistance; ciprofloxacin; pharmacokinetic/pharmacodynamic relationships