ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model

Firsov, Alexander A.; Vostrov, Sergey N.; Lubenko, Irene Yu; Арзамасцев, А. П.; Portnoy, Yury A.; Zinner, Stephen H.

doi:10.1093/jac/dkh242

Cited by 46 publications

(32 citation statements)

References 15 publications

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“…With each of three clinical isolates, the maximal amplification of mutants resistant to 4ϫ, 8ϫ, and 16ϫ MIC of ciprofloxacin was observed when antibiotic concentrations fell into the MSW for most of the dosing interval, and both AUC 24 /MIC and AUC 24 /MPC relationships with resistance expressed by the population analysis data (AUBC M ) or susceptibility testing (ratio of the postexposure MIC to preexposure MIC) were bell shaped. These observations are consistent with earlier findings reported in studies with fluoroquinolones (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Discussionsupporting

confidence: 93%

“…Using these models, bell-shaped relationships have been established between the emergence of resistance to fluoroquinolones and the ratios of 24-hour area under the concentration-time curve (AUC 24 ) to the MIC (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Such relationships have been reported with moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, the investigational fluoroquinolone ABÒ492, pazufloxacin, tosufloxacin, and garenoxacin against Staphylococcus aureus (6)(7)(8)(14)(15)(16); moxifloxacin against Streptococcus pneumoniae (12,13); garenoxacin against Klebsiella pneumoniae (15); ciprofloxacin and moxifloxacin against Pseudomonas aeruginosa (11,12); and ciprofloxacin, marbofloxacin, and enrofloxacin against Escherichia coli (9,10,17). In some of these studies (6-15, 17, 18), changes in susceptibility of antibiotic-exposed bacteria and/or their enrichment with resistant mutants was observed at fluoroquinolone concentrations above the MIC but below the mutant prevention concentration (MPC), i.e., inside the mutant selection window (MSW) but not outside the MSW, in accordance with the MSW hypothesis (19,20).…”

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confidence: 99%

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Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models

Strukova

Portnoy

Romanov

et al. 2016

Antimicrob Agents Chemother

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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.A n increasing number of reports on the isolation of resistant pathogens (1, 2) combined with a weak antibiotic pipeline suggests that optimization of antibiotic therapy should be aimed at the suppression of resistance (3, 4). In this regard, dynamic models that mimic antimicrobial pharmacokinetics in vitro have been proven to be a useful tool in predicting the amplification of resistant mutants at clinically achievable antibiotic concentrations (5). Using these models, bell-shaped relationships have been established between the emergence of resistance to fluoroquinolones and the ratios of 24-hour area under the concentration-time curve (AUC 24 ) to the MIC (6-17). Such relationships have been reported with moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin, the investigational fluoroquinolone ABÒ492, pazufloxacin, tosufloxacin, and garenoxacin against Staphylococcus aureus (6-8, 14-16); moxifloxacin against Streptococcus pneumoniae (12, 13); garenoxacin against Klebsiella pneumoniae (15); ciprofloxacin and moxifloxacin against Pseudomonas aeruginosa (11, 12); and ciprofloxacin, marbofloxacin, and enrofloxacin against Escherichia coli (9,10,17). In some of these studies (6-15, 17, 18), changes in susceptibility of antibiotic-exposed bacteria and/or their enrichment with resistant mutants was observed at fluoroquinolone concentrations above the MIC but below the mutant prevention concentration (MPC), i.e., inside the mutant selection window (MSW) but not outside the MSW, in accordance with the MSW hypo...

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models

Strukova

Portnoy

Romanov

et al. 2016

Antimicrob Agents Chemother

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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). Based on these studies, both mutant selection and the concomitant loss in susceptibility depend on the simulated ratio of area under the curve (AUC) to the MIC in a bell-shaped manner.…”

mentioning

confidence: 99%

“…Based on these studies, both mutant selection and the concomitant loss in susceptibility depend on the simulated ratio of area under the curve (AUC) to the MIC in a bell-shaped manner. Together with AUC/MIC, the time inside MSW (T MSW ) has been proposed as a predictor of resistance (5), although it appeared to be less predictive of the selection of fluoroquinolone-resistant and, especially, glycopeptide-resistant Staphylococcus aureus than was the AUC/ MIC ratio (1,(6)(7)(8)12). This observation might be attributed to the fact that T MSW does not consider the position of simulated antibiotic concentrations within the MSW, which also might influence the amplification of resistant mutants (15).…”

mentioning

confidence: 99%

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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“…The argument has been mostly tested in in vitro studies for fluoroquinolones where the mutant-restrictive thresholds of AUC0-24/MPC were approximately one-third of those AUC0-24/MIC values [436,460].…”

Section: Mutant Prevention Concentrationmentioning

confidence: 99%

Optimizing beta-lactam antibiotic dosing in critically ill patients: Prolonged infusion versus intermittent bolus administration

Abdul‐Aziz¹,

Mohd²

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Severe sepsis is a major burden in the intensive care unit (ICU) with persistently high mortality rates. Optimization of antibiotic dosing has been suggested as an intervention to improve clinical outcomes for critically ill patients with severe sepsis. However, current antibiotic dosing guidelines may not be appropriate for these patients, as they rarely consider the altered physiology and illness severity associated with this population. Optimizing antibiotic dosing using pharmacokinetic (PK) and pharmacodynamic (PD) principles can address these critical illness-related changes and promote therapeutic success. Due to their wide spectrum of antibiotic activity and excellent safety profile, beta-lactam antibiotics are commonly used for severe infections in the ICU. Two alternative dosing approaches to traditional intermittent bolus (IB) dosing, namely continuous infusion (CI) and extended infusion (EI), have been suggested to maximize the therapeutic potential of these antibiotics in critically ill patients. Collectively, the two dosing approaches can also be referred as prolonged infusion (PI).This Thesis aims to better characterize the pharmacokinetics/pharmacodynamics (PK/PD) of betalactam antibiotics to determine whether there is any therapeutic advantage associated with PI dosing (CI and/or EI) as compared to IB dosing. This Thesis comprises of eight chapters. Chapter 1 is an introductory chapter which provides an overview of the published literature on the area of research. The discussion in Chapter 1 presents a theoretical framework behind the Thesis objectives. Chapter 1 concludes with the specific aims of this Thesis.Chapter 2 reports the findings of a prospective PK study which aimed to describe the population PK of doripenem in critically ill patients with sepsis and perform dosing simulations to develop clinically relevant dosing guidelines for these patients. Twelve critically ill participants receiving 500 mg of doripenem 8-hourly as a 1-hr infusion were enrolled. The volume of distribution (Vd) and clearance (CL) of doripenem in this patient cohort were substantially different than those usually described in non-critically patients. As current dosing guidelines were mostly derived from the non-critically ill, findings from this study suggest that the licensed "one-dose-fits-all" dosing for doripenem is unlikely to achieve optimal exposures in critically ill patients. Empirical use of PI dosing should be considered to account for PK and illness severity differences, particularly when less-susceptible pathogens are involved.ii Chapter 3 incorporates a published systematic review which compares the PK/PD data and clinical outcomes between CI and IB dosing to describe any potential merits supporting either of the two dosing approaches for critically ill patients. The findings suggest that beta-lactam CI may not be advantageous for all critically ill patients and may be beneficial in patients with severe infections.Chapter 4 describes the findings of a post hoc analysis on the Defining...

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ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model

Abstract: Overall, these findings predict greater efficacy of clinically achievable AUC/MIC (or AUC24/MIC) of ABT492 both in terms of the anti-staphylococcal effect and prevention of the selection of resistant mutants.

Cited by 46 publications

References 15 publications

Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models

Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by Using In Vitro Dynamic Models

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

Optimizing beta-lactam antibiotic dosing in critically ill patients: Prolonged infusion versus intermittent bolus administration

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