Antiviral Drug Resistance: Mechanisms and Clinical Implications

Strasfeld, Lynne; Chou, Sunwen

doi:10.1016/j.idc.2010.07.001

Cited by 78 publications

(43 citation statements)

References 192 publications

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“…However, an increasing number of ganciclovir-resistant CMV infections has been reported in solid organ and especially pediatric bone marrow transplant recipients (Lurain and Chou, 2010;Strasfeld and Chou, 2010). Here we report a case of multidrug-resistant CMV infection in a severely immunocompromised pediatric patient.…”

Section: Discussionmentioning

confidence: 82%

Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

et al. 2016

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Section: Discussionmentioning

confidence: 82%

Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

et al. 2016

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“…Because of the continuous positive selection of resistant bacterial clones, whether pathogenic, commensal, or even environmental bacteria, the population structure of microbial communities is modified. AMR has become one of the main public health burdens of the last decades, and it is therefore extremely important to study and monitor the emergence of isolates with reduced susceptibility against antimicrobials [1,2]. This may be performed by determining the minimum inhibitory concentration (MIC), defined as the smallest concentration of a given antimicrobial substance that inhibits the visible growth of a microorganism.…”

Section: Introductionmentioning

confidence: 99%

Estimation of the wild‐type minimum inhibitory concentration value distribution

Jaspers

Aerts

Verbeke

et al. 2013

Statistics in Medicine

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Antimicrobial resistance has become one of the main public health burdens of the last decades, and monitoring the development and spread of non-wild-type isolates has therefore gained increased interest. Monitoring is performed based on the minimum inhibitory concentration (MIC) values, which are collected through the application of dilution experiments. In order to account for the unobserved population heterogeneity of wild-type and non-wild-type isolates, mixture models are extremely useful. Instead of estimating the entire mixture globally, it was our major aim to provide an estimate for the wild-type first component only. The characteristics of this first component are not expected to change over time, once the wild-type population has been confidently identified for a given antimicrobial. With this purpose, we developed a new method based on the multinomial distribution, and we carry out a simulation study to study the properties of the new estimator. Because the new approach fits within the likelihood framework, we can compare distinct distributional assumptions in order to determine the most suitable distribution for the wild-type population. We determine the optimal parameters based on the AIC criterion, and attention is also paid to the model-averaged approach using the Akaike weights. The latter is thought to be very suitable to derive specific characteristics of the wild-type distribution and to determine limits for the wild-type MIC range. In this way, the new method provides an elegant means to compare distinct distributional assumptions and to quantify the wild-type MIC distribution of specific antibiotic-bacterium combinations.

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“…Despite this drug development activity against EBOV, there remain significant needs for clinically proven anti-EBOV therapeutics and prophylactic agents. Also, combination therapies against multiple targets is an increasingly common antiviral therapeutic strategy to both enhance efficacy and minimize the emergence of mutation-based drug resistance (11), and this requires further studies.…”

mentioning

confidence: 99%

Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection

Ekins

Lingerfelt

Comer

et al. 2018

Antimicrob Agents Chemother

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Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside the United States. A machinelearning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate, and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9, and 1A2). Tilorone was shown to have 52% human plasma protein binding with excellent plasma stability and a mouse liver microsome half-life of 48 min. Dose range-finding studies in mice demonstrated a maximum tolerated single dose of 100 mg/kg of body weight. A pharmacokinetics study in mice at 2-and 10-mg/kg dose levels showed that the drug is rapidly absorbed, has dosedependent increases in maximum concentration of unbound drug in plasma and areas under the concentration-time curve, and has a half-life of approximately 18 h in both males and females, although the exposure was ϳ2.5-fold higher in male mice. Tilorone doses of 25 and 50 mg/kg proved efficacious in protecting 90% of mice from a lethal challenge with mouse-adapted with once-daily intraperitoneal (i.p.) dosing for 8 days. A subsequent study showed that 30 mg/kg/day of tilorone given i.p. starting 2 or 24 h postchallenge and continuing through day 7 postinfection was fully protective, indicating promising activity for the treatment of EVD.

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Antiviral Drug Resistance: Mechanisms and Clinical Implications

Cited by 78 publications

References 192 publications

Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

Multidrug-resistant cytomegalovirus infection in a pediatric stem cell transplantation patient

Estimation of the wild‐type minimum inhibitory concentration value distribution

Efficacy of Tilorone Dihydrochloride against Ebola Virus Infection

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