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  • 1
    Online Resource
    Online Resource
    Bacterial Resistance Studies Using In Vitro Dynamic Models: the Predictive Power of the Mutant Prevention and Minimum Inhibitory Antibiotic Concentrations
    American Society for Microbiology ; 2013
    In:  Antimicrobial Agents and Chemotherapy Vol. 57, No. 10 ( 2013-10), p. 4956-4962
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 57, No. 10 ( 2013-10), p. 4956-4962
    Abstract: 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 /MPCs from 1 to 10 h (AUC 24 /MIC from 60 to 360 h) but not at the lower or higher AUC 24 /MPC and AUC 24 /MIC ratios. AUC 24 /MPC and AUC 24 /MIC relationships of the areas under the time courses of ciprofloxacin-resistant E. coli (AUBC M ) were bell-shaped. A Gaussian-like function fits the AUBC M -AUC 24 /MPC and AUBC M -AUC 24 /MIC data combined for all organisms ( r 2 = 0.69 and 0.86, respectively). The predicted anti-mutant AUC 24 /MPC ratio was 58 ± 35 h, and the respective AUC 24 /MIC ratio was 1,080 ± 416 h. Although AUC 24 /MPC was less predictive of strain-independent E. coli resistance than AUC 24 /MIC, the established anti-mutant AUC 24 /MPC ratio was closer to values reported for Staphylococcus aureus (60 to 69 h) than the respective AUC 24 /MIC ratio (1,080 versus 200 to 240 h). This implies that AUC 24 /MPC might be a better interspecies predictor of bacterial resistance than AUC 24 /MIC.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00578-13
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2013
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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  • 2
    Online Resource
    Online Resource
    Enrichment of Fluoroquinolone-Resistant Staphylococcus aureus : Oscillating Ciprofloxacin Concentrations Simulated at the Upper and Lower Portions of the Mutant Selection Window
    American Society for Microbiology ; 2008
    In:  Antimicrobial Agents and Chemotherapy Vol. 52, No. 6 ( 2008-06), p. 1924-1928
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 52, No. 6 ( 2008-06), p. 1924-1928
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01371-07
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2008
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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    Online Resource
  • 3
    Online Resource
    Online Resource
    In Vitro Resistance Studies with Bacteria That Exhibit Low Mutation Frequencies: Prediction of “Antimutant” Linezolid Concentrations Using a Mixed Inoculum Containing both Susceptible and Resistant Staphylococcus aureus
    American Society for Microbiology ; 2015
    In:  Antimicrobial Agents and Chemotherapy Vol. 59, No. 2 ( 2015-02), p. 1014-1019
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 59, No. 2 ( 2015-02), p. 1014-1019
    Abstract: Bacterial resistance studies using in vitro dynamic models are highly dependent on the starting inoculum that might or might not contain spontaneously resistant mutants (RMs). To delineate concentration-resistance relationships with linezolid-exposed Staphylococcus aureus , a mixed inoculum containing both susceptible cells and RMs was used. An RM selected after the 9th passage of the parent strain (MIC, 2 μg/ml) on antibiotic-containing media (RM9; MIC, 8 μg/ml) was chosen for the pharmacodynamic studies, because the mutant prevention concentration (MPC) of linezolid against the parent strain in the presence of RM9 at 10 2 (but not at 10 4 ) CFU/ml did not differ from the MPC value determined in the absence of the RMs. Five-day treatments with twice-daily linezolid doses were simulated at concentrations either between the MIC and MPC or above the MPC. S. aureus RMs (resistant to 2× and 4× MIC but not 8× and 16× MIC) were enriched at ratios of the 24-h area under the concentration-time curve (AUC 24 ) to the MIC that provide linezolid concentrations between the MIC and MPC for 100% (AUC 24 /MIC, 60 h) and 86% (AUC 24 /MIC, 120 h) of the dosing interval. No such enrichment occurred when linezolid concentrations were above the MIC and below the MPC for a shorter time (37% of the dosing interval; AUC 24 /MIC, 240 h) or when concentrations were consistently above the MPC (AUC 24 /MIC, 480 h). These findings obtained using linezolid-susceptible staphylococci supplemented with RMs support the mutant selection window hypothesis. This method provides an option to delineate antibiotic concentration-resistance relationships with bacteria that exhibit low mutation frequencies.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.04214-14
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2015
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models
    American Society for Microbiology ; 2016
    In:  Antimicrobial Agents and Chemotherapy Vol. 60, No. 3 ( 2016-03), p. 1208-1215
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 60, No. 3 ( 2016-03), p. 1208-1215
    Abstract: There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC 24 ) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of three Klebsiella pneumoniae 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 K. pneumoniae mutants were intensively enriched at an AUC 24 /MIC ratio of 60 to 360 h (AUC 24 /MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC 24 /MIC and AUC 24 /MPC ratios, in accordance with the MSW hypothesis. AUC 24 /MPC and AUC 24 /MIC relationships with areas under the time courses of ciprofloxacin-resistant K. pneumoniae (AUBC M ) were bell shaped. These relationships predict highly variable “antimutant” AUC 24 /MPC ratios (20 to 290 h) compared to AUC 24 /MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC 24 /MPC ratio as an interstrain predictor of K. pneumoniae resistance is lower than that of the AUC 24 /MIC ratio.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.02334-15
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2016
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
    Location Call Number Limitation Availability
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    Online Resource
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