title: Relationship between ceftolozane-tazobactam exposure and selection for Pseudomonas aeruginosa resistance in a hollow-fiber infection model.
abstract: It is important to understand the relationship between antibiotic exposure and the selection of drug resistance in the context of therapy exposure. We sought to identify the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. Two Pseudomonas aeruginosa challenge isolates were selected for study, a wild-type ATCC strain (ceftolozane-tazobactam MIC, 0.5 mg/liter) and a clinical isolate (ceftolozane-tazobactam MIC, 4 mg/liter). The experiment duration was 10 days, and the ceftolozane-tazobactam dose ratio (2:1) and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The studied ceftolozane-tazobactam dosing regimens ranged from 62.5/31.25 to 2,000/1,000 mg per dose in step fold dilutions. Negative-control arms included no treatment and tazobactam at 500 mg every 8 h. Positive-control arms included ceftolozane at 1 g every 8 h and piperacillin-tazobactam dosed at 4.5 g every 6 h. For the wild-type ATCC strain, resistance was not selected by any ceftolozane-tazobactam regimen evaluated. For the clinical isolate, an inverted-U-shaped function best described the relationship between the amplification of a drug-resistant subpopulation and drug exposure. The least (62.5/31.25 mg) and most (2,000/1,000 mg) intensive ceftolozane-tazobactam dosing regimens did not select for drug resistance. Drug resistance selection was observed with intermediately intensive dosing regimens (125/62.5 through 1,000/500 mg). For the intermediately intensive ceftolozane-tazobactam dosing regimens, the duration until the selection for drug resistance increased with dose regimen intensity. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance selection.
authors: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors: Brian D
authors: BD
authors: VanScoy
authors: JMI Laboratories, North Liberty, Iowa, USA.
authors: Rodrigo E
authors: RE
authors: Mendes
authors: JMI Laboratories, North Liberty, Iowa, USA.
authors: Mariana
authors: M
authors: Castanheira
authors: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors: Jennifer
authors: J
authors: McCauley
authors: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors: Sujata M
authors: SM
authors: Bhavnani
authors: JMI Laboratories, North Liberty, Iowa, USA.
authors: Ronald N
authors: RN
authors: Jones
authors: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors: Lawrence V
authors: LV
authors: Friedrich
authors: Cubist Pharmaceuticals, Lexington, Massachusetts, USA.
authors: Judith N
authors: JN
authors: Steenbergen
authors: Institute for Clinical Pharmacodynamics, Latham, New York, USA University of Oxford, Oxford, United Kingdom PAmbrose@ICPD.com.
authors: Paul G
authors: PG
authors: Ambrose
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002511:Cephalosporins / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D000078142:Tazobactam
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C519491:ceftolozane; D010397:Penicillanic Acid; D000078142:Tazobactam