Characterization of Multiple Cytomegalovirus Drug Resistance Mutations Detected in a Hematopoietic Stem Cell Transplant Recipient by Recombinant Phenotyping

Drouot, Emilien; Piret, Jocelyne; LeBel, Marc; Boivin, Guy

doi:10.1128/jcm.02205-14

Cited by 27 publications

(22 citation statements)

References 18 publications

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“…Unlike UL97, there is no compact list of canonical resistance mutations; instead diverse mutations cluster in certain functional domains with characteristic associated resistance phenotypes [1,2,4,5]. New UL54 mutations affecting drug susceptibility continue to be reported regularly (Table 2) [13,18–21]. In most cases they are close to known mutations of similar phenotype but are sometimes in unexpected locations, e.g.…”

Section: Genetic Mechanisms Of CMV Drug Resistancementioning

confidence: 99%

“…Instead, the drug susceptibility phenotypes of newly encountered mutations are determined by mutagenesis of cloned baseline CMV laboratory strains followed by quantitative growth assays, often using reporter genes under increasing drug concentrations, a process known as recombinant phenotyping [1,13,27]. Newly introduced phenotyping assays need to be calibrated using mutations conferring known levels of drug susceptibility.…”

Section: Laboratory Diagnosis Of CMV Drug Resistancementioning

confidence: 99%

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Approach to drug-resistant cytomegalovirus in transplant recipients

Chou

2015

Current Opinion in Infectious Diseases

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Purpose of review updated information on diagnosis of CMV drug resistance, treatments for drug-resistant infection and potential uses of experimental antiviral compounds. Recent findings For established CMV antivirals, uncommon viral UL97 kinase and UL54 DNA polymerase drug resistance mutations are sporadically described that expand an extensive existing database. Some novel mutations reported from treated patients have no drug resistant phenotype and may be genotyping artifacts. Next generation sequencing technology may enable earlier detection of emerging resistance mutations in treated patients. Management options for drug-resistant infection include optimization of host defenses, antiviral dose escalation, substitutions or combinations of standard or experimental antivirals. Maribavir and letermovir have antiviral targets distinct from the classic DNA polymerase. UL97 mutations elicited by ganciclovir and maribavir are different, although a single p-loop mutation can confer significant cross-resistance. High-grade resistance mutations in the UL56 terminase gene are readily selected in vitro under letermovir and await clinical correlation. Summary Technical advancements can enhance the accurate and timely genotypic detection of drug resistance. Antivirals undergoing clinical trial offer the prospect of new viral targets and drug combinations, but unresolved issues exist with regard to their therapeutic potential for drug-resistant CMV and their genetic barriers to resistance.

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Section: Genetic Mechanisms Of CMV Drug Resistancementioning

confidence: 99%

Section: Laboratory Diagnosis Of CMV Drug Resistancementioning

confidence: 99%

Approach to drug-resistant cytomegalovirus in transplant recipients

Chou

2015

Current Opinion in Infectious Diseases

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“…However, in some cases, multiple UL97 and UL54 (DNA polymerase) mutations that conferred resistance to ganciclovir and foscarnet (Choi et al, 2014) or to all three currently available anti-CMV drugs (i.e. ganciclovir, cidofovir and foscarnet) have been described (Blackman et al, 2004;Drouot et al, 2014;Springer et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…The sequences were then analyzed by using an online mutational resistance analyzer (MRA) available from the University of Ulm, https://www.informatik.uni-ulm.de/ni/mitarbeiter/HKestler/mra/app/index.php?plugin=form [5]. Ganciclovir resistance was confirmed by the presence of the A594V mutation in UL97 [6] What was unique in our patient compared to other reported CMV-associated HLH cases was the overwhelming infection with MDROs. On hospital admission, the patient was found to be colonized with multiple MDROs including VRE, and carbapenamase-producing Enterobacteriaceae, which may have been acquired during his previous hospital course in India.…”

Section: Discussionmentioning

confidence: 83%

Unusual accumulation of a wide array of antimicrobial resistance mechanisms in a patient with cytomegalovirus-associated hemophagocytic lymphohistiocytosis: a case report

et al. 2020

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Background: Infections with multidrug-resistant organisms (MDRO) pose a serious threat to patients with dysregulated immunity such as in hemophagocytic lymphohistiocytosis (HLH), but such infections have rarely been comprehensively characterized. Here, we present a fatal case of HLH secondary to cytomegalovirus (CMV) infection complicated by both anti-viral drug resistance and sepsis from multiple MDROs including pandrug-resistant superbug bacteria. Case presentation: A previously healthy, six-year-old boy presented with a 45-day history of fever prior to a diagnosis of hemophagocytic lymphohistiocytosis and hemorrhagic colitis, both associated with CMV. On hospital admission, the patient was found to be colonized with multiple, multidrug-resistant (MDR) bacteria including vancomycin-resistant enterococci (VRE) and carbapenamase-producing organisms (CPO). He eventually developed respiratory, urine and bloodstream infections with highly drug-resistant, including pandrug-resistant bacteria, which could not be controlled by antibiotic treatment. Antiviral therapy also failed to contain his CMV infection and the patient succumbed to overwhelming bacterial and viral infection. Whole genome sequencing (WGS) of the MDR bacteria and metagenomic analysis of his blood sample revealed an unusual accumulation of a wide range of antimicrobial resistance mechanisms in a single patient, including antiviral resistance to ganciclovir, and resistance mechanisms to all currently available antibiotics. Conclusions: The case highlights both the risk of acquiring MDR superbugs and the severity of these infections in HLH patients.

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Characterization of Multiple Cytomegalovirus Drug Resistance Mutations Detected in a Hematopoietic Stem Cell Transplant Recipient by Recombinant Phenotyping

Cited by 27 publications

References 18 publications

Approach to drug-resistant cytomegalovirus in transplant recipients

Approach to drug-resistant cytomegalovirus in transplant recipients

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

Unusual accumulation of a wide array of antimicrobial resistance mechanisms in a patient with cytomegalovirus-associated hemophagocytic lymphohistiocytosis: a case report

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