Testing the mutant selection window in rabbits infected with methicillin-resistant Staphylococcus aureus exposed to vancomycin

Yu, Zhao; Hu, Lifen; Mei, Qing; Cheng, Jun; Liu, Yanyan; Ying, Yun; Li, Jiabin

doi:10.1093/jac/dks280

Cited by 34 publications

(26 citation statements)

References 24 publications

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“…Our results differ from many in vitro studies and a few in vivo studies in which the evolution of resistance was reduced at higher doses [71][72][73]. The discordance between these studies and ours likely arises from the existence of the so-called inverted U, where resistance evolution is minimized at very low or very high doses and maximized somewhere in-between [3,4].…”

Section: Dose and The Emergence Of Resistancecontrasting

confidence: 99%

The effect of drug dose and timing of treatment on the emergence of drug resistancein vivoin a malaria model

Acosta

Sim

Bram

et al. 2020

Preprint

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Background and objectives:There is significant interest in identifying clinically effective drug treatment regimens that minimize the de novo evolution of antimicrobial resistance in pathogen populations. However, in vivo studies that vary treatment regimens and directly measure drug resistance evolution are rare. Here, we experimentally investigate the role of drug dose and treatment timing on resistance evolution in an animal model. Methodology: In a series of experiments, we measured the emergence of atovaquone-resistant mutants of Plasmodium chabaudi in laboratory mice, as a function of dose and timing of treatment with the antimalarial drug atovaquone. Results: Increasing the concentration of atovaquone increased the likelihood of high-level resistance emergence. Treating very early or late in infection reduced the risk of resistance, likely as a result of population size at time of treatment, but we were not able to exclude influence of the immune response in the latter. When we varied starting inoculum, resistance was more likely at intermediate inoculum sizes, but this did not correlate directly with population sizes at time of treatment. Conclusions and implications: (i) Higher doses do not always minimize resistance emergence and can result in competitive release of parasites with high-level resistance. (ii) Altering treatment timing affects the risk of resistance emergence, but not as a simple function of population size at the time of treatment. (iii) Finding the 'right' dose and 'right' time to maximize clinical gains and limit resistance emergence can vary depending on biological context and was non-trivial even in our simplified experiments.

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Section: Dose and The Emergence Of Resistancecontrasting

confidence: 99%

The effect of drug dose and timing of treatment on the emergence of drug resistancein vivoin a malaria model

Acosta

Sim

Bram

et al. 2020

Preprint

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“…Thus, resistance is thought to be promoted when antimicrobial concentrations fall within the MSW (11). This has been shown using in vitro studies and studies in animals (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23).…”

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confidence: 99%

In Vitro Resistance Selection in Shigella flexneri by Azithromycin, Ceftriaxone, Ciprofloxacin, Levofloxacin, and Moxifloxacin

Allen

Harris

2017

Antimicrob Agents Chemother

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Shigella flexneri continues to be a major cause of diarrhea-associated illness, and increasing resistance to first-line antimicrobials complicates the treatment of infections caused by this pathogen. We investigated the pharmacodynamics of current antimicrobial treatments for shigellosis to determine the likelihood of resistance promotion with continued global antimicrobial use. The mutant prevention concentration (MPC) and mutant selection window (MSW) were determined for azithromycin, ceftriaxone, ciprofloxacin, levofloxacin, and moxifloxacin against a wildtype strain of S. flexneri (ATCC 12022) and an isogenic gyrA mutant (m-12022). Timekill assays were performed to determine antimicrobial killing. Concentrations of approved doses of ciprofloxacin, levofloxacin, and moxifloxacin are predicted to surpass the MPC for a majority of the dosage interval against ATCC 12022. However, against m-12022, concentrations of all fluoroquinolones are predicted to fall below the MPC and remain in the MSW for a majority of the dosage interval. Concentrations of ceftriaxone fall within the MSW for the majority of the dosage interval for both strains. All agents other than azithromycin displayed bactericidal activity in time-kill assays. Results of pharmacodynamic analyses suggest that all tested fluoroquinolones would achieve a favorable area under the concentration-time curve (AUC)/MPC ratio for ATCC 12022 and would restrict selective enrichment of mutants but that mutant selection in m-12022 would be likely if ciprofloxacin were used. Based on pharmacodynamic analyses, azithromycin and ceftriaxone are predicted to promote mutant selection in both strains. Confirmation of these findings and examination of novel treatment regimens using in vivo studies are warranted.KEYWORDS Shigella flexneri, mutant prevention concentration, mutant selection window T he pathogenic bacterium Shigella flexneri is a major cause of dysentery and related morbidity and mortality worldwide, particularly in children less than 5 years of age in developing countries and travelers returning from tropical areas. In the 1990s, the number of annual cases of shigellosis worldwide was approximately 164.7 million, with 1.1 million resulting in death (1). Data from 2014 demonstrated an average of 5.81 cases per 100,000 individuals in the United States (2). The treatment of shigellosis has been complicated by the emergence of strains of S. flexneri that are resistant to many antimicrobials, including former first-line treatment options such as ampicillin, chloramphenicol, tetracyclines, and trimethoprim-sulfamethoxazole (SXT) (1). Current treatment guidelines for infectious diarrhea from the Infectious Diseases Society of America, published in 2001, recommend SXT, a fluoroquinolone (ofloxacin, norfloxacin, or ciprofloxacin), ceftriaxone, or azithromycin (3). In guidelines published by the WHO in 2005, ciprofloxacin was considered the first-line treatment for shigellosis, with ceftriaxone and azithromycin considered to be alternative therapies (4). Howe...

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“…8 MSW hypothesis has been validated with different antimicrobial-pathogen combinations in vitro and in vivo. [9][10][11][12] It is generally believed that this hypothesis may have broad applications for fighting the growing problem of antimicrobial resistance, and then the clinical applications of MSW were investigated quite intensively in recent years. [13][14][15][16] However, the applicability of the MSW to most of these antimicrobial-pathogen combinations was investigated only with in vitro model.…”

Section: Introductionmentioning

confidence: 99%

“…In previous studies, this concept has also been proven to be relevant for vancomycin, but our in silico simulation results truly questioned the anti-mutant pharmacokinetics/pharmacodynamics (PK/PD) index derived from in vitro experiments. 12,17 Thus, we believe that results obtained from in vitro experiments cannot usually be reliably extrapolated to in vivo behavior.…”

Section: Introductionmentioning

confidence: 99%

Validation of the mutant selection window hypothesis with fosfomycin against Escherichia coli and Pseudomonas aeruginosa: an in vitro and in vivo comparative study

Pan¹,

Mei²,

Ye³

et al. 2016

J Antibiot

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Testing the mutant selection window in rabbits infected with methicillin-resistant Staphylococcus aureus exposed to vancomycin

Abstract: These findings support the MSW hypothesis and the anti-mutant AUC/MIC ratio estimated in vivo is consistent with that reported in in vitro studies. Keeping vancomycin concentrations above the MPC or AUC(24)/MPC >15 h is a straightforward way to restrict the acquisition of resistance.

Cited by 34 publications

References 24 publications

The effect of drug dose and timing of treatment on the emergence of drug resistancein vivoin a malaria model

The effect of drug dose and timing of treatment on the emergence of drug resistancein vivoin a malaria model

In Vitro Resistance Selection in Shigella flexneri by Azithromycin, Ceftriaxone, Ciprofloxacin, Levofloxacin, and Moxifloxacin

Validation of the mutant selection window hypothesis with fosfomycin against Escherichia coli and Pseudomonas aeruginosa: an in vitro and in vivo comparative study

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