Influence of inoculum size and marbofloxacin plasma exposure on the amplification of resistant subpopulations of Klebsiella pneumoniae in a rat lung infection model
| Autor: | Michel Laurentie, Agnès Perrin-Guyomard, Alain Bousquet-Mélou, Aude A. Ferran, Pascal Sanders, Pierre-Louis Toutain, Anne-Sylvie Kesteman |
|---|---|
| Přispěvatelé: | Physiologie et Toxicologie Expérimentales, Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Laboratoire d'études et de recherches sur les médicaments vétérinaires et les désinfectants, Agence Française de Sécurité Sanitaire des Aliments (AFSSA), AFSSA |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Male
Klebsiella pneumoniae Antibiotics MESH: Klebsiella pneumoniae infection respiratoire Drug resistance modèle MESH: Dose-Response Relationship Drug 0403 veterinary science Anti-Infective Agents Pharmacology (medical) MESH: Animals résistance Lung Antibacterial agent bactérie 0303 health sciences MESH: Microbial Sensitivity Tests biology 04 agricultural and veterinary sciences 3. Good health Dose–response relationship Infectious Diseases MESH: Klebsiella Infections Area Under Curve Fluoroquinolones medicine.drug agent pathogène MESH: Rats 040301 veterinary sciences medicine.drug_class pneumonie MESH: Anti-Infective Agents Microbial Sensitivity Tests Microbiology 03 medical and health sciences Marbofloxacin Pharmacokinetics Drug Resistance Bacterial MESH: Drug Resistance Bacterial medicine Animals Experimental Therapeutics MESH: Lung Pharmacology microorganisme Dose-Response Relationship Drug 030306 microbiology marbofloxacine MESH: Fluoroquinolones biology.organism_classification infection MESH: Male Klebsiella Infections Rats klebsiella pneumoniae Pharmacodynamics poumon [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology MESH: Area Under Curve enterobacteriaceae |
| Zdroj: | Antimicrobial Agents and Chemotherapy Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2009, 53 (11), pp.4740-8. ⟨10.1128/AAC.00608-09⟩ |
| ISSN: | 0066-4804 1098-6596 |
| DOI: | 10.1128/AAC.00608-09⟩ |
| Popis: | We tested the hypothesis that the bacterial load at the infection site could impact considerably on the pharmacokinetic/pharmacodynamic (PK/PD) parameters of fluoroquinolones. Using a rat lung infection model, we measured the influence of different marbofloxacin dosage regimens on selection of resistant bacteria after infection with a low (10 5 CFU) or a high (10 9 CFU) inoculum of Klebsiella pneumoniae . For daily fractionated doses of marbofloxacin, prevention of resistance occurred for an area-under-the-concentration-time-curve (AUC)/MIC ratio of 189 h for the low inoculum, whereas for the high inoculum, resistant-subpopulation enrichment occurred for AUC/MIC ratios up to 756 h. For the high-inoculum-infected rats, the AUC/MIC ratio, C max /MIC ratio, and time within the mutant selection window ( T MSW ) were not found to be effective predictors of resistance prevention upon comparison of fractionated and single administrations. An index corresponding to the ratio of the time that the drug concentrations were above the mutant prevention concentration (MPC) over the time that the drug concentrations were within the MSW ( T > MPC / T MSW ) was the best predictor of the emergence of resistance: a T > MPC / T MSW ratio of 0.54 was associated with prevention of resistance for both fractionated and single administrations. These results suggest that the enrichment of resistant bacteria depends heavily on the inoculum size at the start of an antimicrobial treatment and that classical PK/PD parameters cannot adequately describe the impact of different dosage regimens on enrichment of resistant bacteria. We propose an original index, the T > MPC / T MSW ratio, which reflects the ratio of the time that the less susceptible bacterial subpopulation is killed over the time that it is selected, as a potentially powerful indicator of prevention of enrichment of resistant bacteria. This ratio is valid only if plasma concentrations achieve the MPC. |
| Databáze: | OpenAIRE |
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