In light of the concept of the mutant selection window, i.e., the range between the MIC and the mutant prevention concentration (MPC), MPC-related pharmacokinetic indices should be more predictive of bacterial resistance than the respective MIC-related indices. However, experimental evidence of this hypothesis remains limited and contradictory. To examine the predictive power of the ratios of the area under the curve (AUC 24 ) to the MPC and the MIC, the selection of ciprofloxacin-resistant mutants of four Escherichia coli strains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC 24 /MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. Resistant E. coli was intensively enriched at AUC 24 T he concept of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC) (1), has contributed to an understanding of why antibiotic-resistant mutants are enriched in some but not all treatments. In light of this hypothesis, MPC-related pharmacokinetic indices should be more predictive of bacterial resistance than the respective MIC-related indices. However, the advantages of the former over the latter indices have been reported in only a few in vitro studies with ciprofloxacin-exposed (2) and levofloxacin-exposed(3) Staphylococcus aureus and with ciprofloxacin-exposed Escherichia coli (4). On the other hand, the predictive potentials of the MPC-and MIC-related indices were shown to be similar in an in vivo study of Streptococcus pneumoniae-infected rabbits treated with gatifloxacin using a human-like dosing regimen (5) and in an in vitro study with marbofloxacin-and enrofloxacin-exposed E. coli (6). In our in vitro study with S. aureus exposed to daptomycin and vancomycin, the ratio of the 24-h area under the concentration-time curve (AUC 24 ) to the MPC was less predictive of bacterial resistance than the AUC 24 /MIC ratio (7).To further examine the predictive power of AUC 24 /MPC and AUC 24 /MIC, the selection of ciprofloxacin-resistant mutants of four E. coli strains at various MPC/MIC ratios was studied over a wide range of simulated AUC 24 /MICs.
MATERIALS AND METHODSAntimicrobial agents, bacterial strains, and susceptibility testing. Ciprofloxacin powder was purchased from AppliChem Biochemica Chemical Synthesis Services, Darmstadt, Germany.E. coli ATCC 25922, E. coli clinical isolates 4300 and 4454, and E. coli laboratory strain mutator GM2995 (ES1578) (8) were selected for the study. The MICs were determined prior to and after 3-day simulated treatments with ciprofloxacin. Susceptibility testing was performed at least in duplicate by broth microdilution techniques at 24 h postexposure with organisms grown in Ca 2ϩ -and Mg 2ϩ -supplemented Mueller-Hinton broth (MHB) at an inoculum size of 10 6 CFU/ml. The MICs of ciprofloxacin were 0.008 g/ml with E. coli strains ATCC 25922, 4300, and 4454 and 0.016 g/ml with E. coli strain GM2995.Th...
To explore if combinations of linezolid (L) with rifampicin (R) are able to restrict Staphylococcus aureus resistance, the enrichment of L- and R-resistant mutants was studied in an in vitro dynamic model. L- and R-resistant mutants were enriched in all single drug treatments. In contrast, L-resistant mutants were not enriched and R-resistant mutants were similar to baseline amounts with only minimal regrowth at the end of the combination treatments. These effects appear to be explained by lowering the mutant prevention concentration (MPC) for L+R combinations (MPC) compared to the MPCs of L and R alone (MPC and MPC) and thereby the longer times above MPC (73-100% of the dosing interval for L and 42-58% for R) compared to the times above MPC (0-44%) and MPC (0%). These findings provide an opportunity to predict the selection of S. aureus resistance in L+R treatments using MPCs.
The bell-shaped pattern of AUC24/MIC and AUC24/MPC relationships with S. aureus resistance to linezolid is consistent with the MSW hypothesis. 'Antimutant' AUC24/MIC ratios were predicted based on the AUC24/MIC relationship with AUBCM.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.