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Influence of inoculum size and marbofloxacin plasma exposure on the amplification of resistant subpopulations of Klebsiella pneumoniae in a rat lung infection model
- Source :
- Antimicrobial Agents and Chemotherapy, Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2009, 53 (11), pp.4740-8. ⟨10.1128/AAC.00608-09⟩
- Publication Year :
- 2009
- Publisher :
- HAL CCSD, 2009.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 00664804 and 10986596
- Database :
- OpenAIRE
- Journal :
- Antimicrobial Agents and Chemotherapy, Antimicrobial Agents and Chemotherapy, American Society for Microbiology, 2009, 53 (11), pp.4740-8. ⟨10.1128/AAC.00608-09⟩
- Accession number :
- edsair.doi.dedup.....570697d7df2cd2c9d91332f126111416