Pharmacodynamic Profiling of a Siderophore-Conjugated Monocarbam in Pseudomonas aeruginosa: Assessing the Risk for Resistance and Attenuated Efficacy
| Autor: | Robert E. McLaughlin, Elise Gorseth, Michael T. Rooney, Ann E. Eakin, Aryun Kim, Asha S. Nayar, Andy S. Tsai, Kerry E. Murphy-Benenato, Alita A. Miller, Jared L. Crandon, David P. Nicolau, Christina M. Blinn, April Chen, David E. Ehmann, Amy Kutschke, Brian Dangel, Sara A. Patey |
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| Rok vydání: | 2015 |
| Předmět: |
Siderophore
Iron Siderophores Microbial Sensitivity Tests Drug resistance Biology medicine.disease_cause beta-Lactamases Bacterial genetics Microbiology Mice Pharmacokinetics In vivo Drug Resistance Bacterial medicine Animals Experimental Therapeutics Pseudomonas Infections Pharmacology (medical) Whole blood Pharmacology Mice Inbred ICR Sulfonamides Pseudomonas aeruginosa Anti-Bacterial Agents Infectious Diseases Pharmacodynamics Azetidines Female Oligopeptides |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 59:7743-7752 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC ( fT >MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA , piuC , pirR , fecI , and pvdS . Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT >MIC using the MIC in CDMHB ( R 2 = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT >MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa . |
| Databáze: | OpenAIRE |
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