In Vitro Dynamic Models as Tools to Predict Antibiotic Pharmacodynamics

Firsov, Alexander A.; Zinner, Stephen H.; Lubenko, Irene Yu

doi:10.3109/9781420017137.003

Cited by 7 publications

(4 citation statements)

References 114 publications

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“…With the two strains of S. aureus that exhibit four-fold different MPC/MIC ratios, this enrichment was concentration-dependent: the higher the AUC 24 /MIC, the later [5,8,16]. It is very likely that with both S. aureus ATCC 43300 and ATCC 6538 the lowest simulated AUC 24 /MIC relates to the end of the ascending portion (close to the top of the bell) and the two higher AUC 24 /MICs to the descending portion of the bell curve.…”

Section: Discussionmentioning

confidence: 95%

Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion

Firsov

Smirnova

Strukova

et al. 2008

International Journal of Antimicrobial Agents

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Section: Discussionmentioning

confidence: 95%

Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion

Firsov

Smirnova

Strukova

et al. 2008

International Journal of Antimicrobial Agents

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“…Over the last 5 years, this phenomenon has been studied intensively in vitro by using dynamic models; the results of these studies have recently been reviewed and discussed in detail elsewhere (9). Previously reported complex relationships between the enrichment of resistant mutants and in vitro-simulated pharmacokinetics of fluoroquinolones (5)(6)(7)16) and glycopeptides (8) support the hypothesis of the mutant selection window (MSW) (14).…”

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confidence: 88%

Enrichment of Fluoroquinolone-Resistant Staphylococcus aureus : Oscillating Ciprofloxacin Concentrations Simulated at the Upper and Lower Portions of the Mutant Selection Window

Firsov

Lubenko

Smirnova

et al. 2008

Antimicrob Agents Chemother

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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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“…Given a growing number of clinical reports on the isolation of resistant pathogens combined with a weak antibiotic pipeline [2], the development of new compounds is currently aimed at the suppression and/or restriction of resistance [3,4]. Given that the enrichment of resistant mutants with concomitant loss in pathogen susceptibility should be concentration-dependent, concentration-resistance relationships are the methodological basis on which so-called "anti-mutant" antibiotic dosing regimens can be designed [5]. Such a relationship was first established in an in vitro study with fluoroquinolone-exposed Staphylococcus aureus using a dynamic model that simulates human antibiotic pharmacokinetics [6].…”

Section: Introductionmentioning

confidence: 99%

Time inside the mutant selection window as a predictor of staphylococcal resistance to linezolid

et al. 2018

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To explore if the time inside the mutant selection window (T) is a reliable predictor of emergence of bacterial resistance to linezolid, mixed inocula of each of three methicillin-resistant Staphylococcus aureus strains (MIC of linezolid 2 μg ml) and their previously selected resistant mutants (MIC 8 μg ml) were exposed to linezolid pharmacokinetics using an in vitro dynamic model. In five-day treatments simulated over a wide range of the 24-h area under the concentration-time curve (AUC) to the MIC ratio, mutants resistant to 4 × MIC of antibiotic were enriched in a T-dependent manner. With each strain, T relationships with the area under the bacterial mutant concentration-time curve (AUBC) exhibited a hysteresis loop, with the upper portion corresponding to the time above the mutant prevention concentration (MPC; T) of 0 and the lower portion-to the T > 0. Using AUBC related to the maximal value observed with a given strain (normalized AUBC) at T > 0, a strain-independent sigmoid relationship was established between AUBC and T, as well as T (r 0.99 for both). AUC/MIC and AUC/MPC relationships with normalized AUBC for combined data on the three studied S. aureus strains were bell-shaped (r 0.85 and 0.80, respectively). These findings suggest that T at T > 0, T, AUC/MIC and AUC/MPC are useful bacterial strain-independent predictors of the emergence of staphylococcal resistance to linezolid.

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In Vitro Dynamic Models as Tools to Predict Antibiotic Pharmacodynamics

Cited by 7 publications

References 114 publications

Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion

Enrichment of resistant Staphylococcus aureus at ciprofloxacin concentrations simulated within the mutant selection window: bolus versus continuous infusion

Enrichment of Fluoroquinolone-Resistant Staphylococcus aureus : Oscillating Ciprofloxacin Concentrations Simulated at the Upper and Lower Portions of the Mutant Selection Window

Time inside the mutant selection window as a predictor of staphylococcal resistance to linezolid

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