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...
The time inside the mutant selection window (MSW), T MSW , appears to be less predictive of the selection of fluoroquinolone-resistant Staphylococcus aureus than is the ratio of the area under the concentration-time curve (AUC) to the MIC. This observation might be attributed to the fact that T MSW does not consider the actual position of simulated antibiotic concentrations inside the MSW, which also might influence the amplification of resistant mutants. To test this hypothesis, the enrichment of ciprofloxacin-resistant S. aureus was studied at ciprofloxacin (CIP) concentrations that oscillate near the mutant prevention concentration (MPC), i.e., closer to the top of the MSW ("upper case"), and closer to the MIC, i.e., at the lower limit of the MSW ("lower case") at the same T MSW . Two methicillin-resistant strains of S. aureus, ATCC 6538 and ATCC 43300 (MICs of 0.25 and 0.5 mg/liter, respectively, and MPCs of 4 and 2 mg/liter, respectively), were exposed to twice-daily CIP treatments for three consecutive days. With S. aureus ATCC 6538, the simulated ratios of the AUC at 24 h (AUC 24 ) to the MIC were 50 and 260 h (T MSW 75% of the dosing interval). With S. aureus ATCC 43300, the simulated AUC 24 /MICs were 30 and 100 h (T MSW 56%). With each organism, mutants resistant to CIP were enriched in an AUC 24 /MIC-dependent manner: the higher the AUC 24 /MIC ratio, the lower the growth on CIP-containing plates. For example, the area under the time-kill curve of mutants resistant to 4؋ MIC of CIP in the upper case was three times smaller than that in the lower case for both S. aureus strains. Similar differences were seen at the higher (8؋ MIC) and lower (2؋ MIC) CIP concentrations. These data highlight differences in the selection of resistant S. aureus, depending on the position of simulated concentrations inside the MSW at a given T MSW . This explains why T MSW -based predictions of resistance are less accurate than those based on AUC/MIC and AUC/MPC.
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