Characterization of viral #genomic #mutations in novel #influenza A (#H7N9)-infected #patients: the association between #oseltamivir-resistant variants and viral shedding duration (Virus Genes., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Virus Genes. 2019 Jul 13. doi: 10.1007/s11262-019-01678-8. [Epub ahead of print]

Characterization of viral genomic mutations in novel influenza A (H7N9)-infected patients: the association between oseltamivir-resistant variants and viral shedding duration.

Chen R1, Zou Q2,3, Xie G2,3, Yu F2,3, Yang X2,3, Cao L1, Huo Z4, Zheng S5,6.

Author information: 1 Zhejiang Chinese Medical University, Hangzhou, People’s Republic of China. 2 Center of Clinical Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China. 3 Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China. 4 Experimental Teaching Center, School of Basic Medical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, People’s Republic of China. zxhuo@zju.edu.cn. 5 Center of Clinical Laboratory, First Affiliated Hospital, School of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China. zsfzheng@zju.edu.cn. 6 Key Laboratory of Clinical In Vitro Diagnostic Techniques of Zhejiang Province, Hangzhou, People’s Republic of China. zsfzheng@zju.edu.cn.

 

Abstract

Since February 2013, human infections with the novel influenza A H7N9 virus have occurred in eastern China. It is important to detect mutations in viral genes and analyze the clinical features of patients and viral shedding duration related to neuraminidase inhibitor (NAI) resistance. We collected clinical specimens from 31 hospitalized H7N9 patients and sequenced NA, PB2, HA, and M gene fragments. Of the 31 identified patients, 7 (22.6%) carried the R292K substitution in NA, 30 (96.8%), 3 (9.7%), and 5 (16.1%) carried E627K, Q591K, and D701N mutations in PB2, respectively, and 2 (6.5%) carried both E627K and D701N mutations in PB2. All 26 identified patients harbored Q226L mutations and possessed only a single arginine (R) at cleavage sites in the HA and a S31N mutation in M2. Among 7 NA-R292K mutated patients, 3 died and 4 were discharged. There was no significant difference in the days that patients started oseltamivir treatment after symptom onset between NA-R292K mutant and NA-R292 wild-type patients (median days, 7 vs 6, P = 0.374). NA-R292K mutant patients had a significantly longer duration of viral shedding than NA-R292 wild-type patients after oseltamivir treatment (median days, 10 vs 5, P = 0.022). The mutation of R292K in NA conferring the potential ability of oseltamivir resistance resulted in prolonged viral duration and poor outcome and should be taken into consideration in the clinical management of infected patients.

KEYWORDS: Influenza A (H7N9); Mutation; Neuraminidase (NA); Oseltamivir resistance; Viral duration

PMID: 31302878 DOI: 10.1007/s11262-019-01678-8

Keywords: Avian Influenza; H7N9; Antivirals; Drugs Resistance; Oseltamivir; China; Human.

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#Baloxavir and #Treatment-Emergent #Resistance: #PublicHealth Insights and Next Steps (J Infect Dis., summary)

[Source: Journal of Infectious Diseases, full page: (LINK). Summary, edited.]

Baloxavir and Treatment-Emergent Resistance: Public Health Insights and Next Steps

Larisa V Gubareva, Alicia M Fry

The Journal of Infectious Diseases, jiz245, https://doi.org/10.1093/infdis/jiz245

Published: 16 July 2019

Issue Section: Editorial Commentary

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Summary

Drug resistance is a topic of significant concern in the treatment of infectious diseases caused by rapidly evolving RNA viruses that can persist (eg, human immunodeficiency virus and hepatitis C virus) or reinfect (eg, influenza virus). Combination drug therapy is standard of care for the treatment of infections by rapidly mutating RNA viruses [1, 2]. However, it is not a common approach for treating influenza virus infections, partly because of the limited number of anti-influenza drugs and drug targets. We now know that all of the classes of anti-influenza drugs—M2 blockers, neuraminidase inhibitors (NAIs), and the newly licensed cap-dependent endonuclease inhibitor (baloxavir marboxil)—have low genetic barriers to resistance: 1 or 2 amino acid substitutions are sufficient to gain resistance [3, 4].

(…)

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Notes

Disclaimer.

The statements and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Financial support.

This work was supported by the Centers for Disease Control and Prevention.

Potential conflicts of interest.

Both authors: No reported conflicts. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Baloxavir; Seasonal Influenza.

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#Treatment-Emergent #Influenza Variant Viruses With Reduced #Baloxavir Susceptibility: Impact on #Clinical and Virologic #Outcomes in Uncomplicated Influenza (J Infect Dis., abstract)

[Source: Journal of Infectious Diseases, full page: (LINK). Abstract, edited.]

Treatment-Emergent Influenza Variant Viruses With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in Uncomplicated Influenza

Takeki Uehara, Frederick G Hayden, Keiko Kawaguchi, Shinya Omoto, Aeron C Hurt, Menno D De Jong, Nobuo Hirotsu, Norio Sugaya, Nelson Lee, Keiko Baba, Takao Shishido, Kenji Tsuchiya, Simon Portsmouth, Hiroshi Kida

The Journal of Infectious Diseases, jiz244, https://doi.org/10.1093/infdis/jiz244

Published: 16 July 2019

 

Abstract

Background

Single-dose baloxavir rapidly reduces influenza virus titers and symptoms in patients with uncomplicated influenza, but viruses with reduced in vitro susceptibility due to amino acid substitutions at position 38 of polymerase acidic protein (PA/I38X) sometimes emerge.

Methods

We evaluated the kinetics, risk factors, and effects on clinical and virologic outcomes of emergence of PA/I38X-substituted viruses.

Results

Viruses containing PA/I38X substitutions were identified 3–9 days after baloxavir treatment in 9.7% (36/370) of patients, of whom 85.3% had transient virus titer rises. Median time to sustained cessation of infectious virus detection was 192, 48, and 96 hours in the baloxavir recipients with PA/I38X-substituted viruses, without PA/I38X-substituted viruses, and placebo recipients, respectively. The corresponding median times to alleviation of symptoms were 63.1, 51.0, and 80.2 hours, respectively. After day 5, symptom increases occurred in 11.5%, 8.0%, and 13.0%, respectively, and in 8.9% of oseltamivir recipients. Variant virus emergence was associated with lower baseline neutralizing antibody titers.

Conclusions

The emergence of viruses with PA/I38X substitutions following baloxavir treatment was associated with transient rises in infectious virus titers, prolongation of virus detectability, initial delay in symptom alleviation, and uncommonly with symptom rebound. The potential transmissibility of PA/I38X-substituted viruses requires careful study.

Clinical Trial Registration NCT02954354.

antiviral susceptibility, baloxavir marboxil, cap-dependent endonuclease, influenza, polymerase acidic protein

Issue Section: Major Article

Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir Marboxil.

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#Plasmid-Mediated #mcr-1 #Colistin #Resistance in #Escherichia coli from a Black Kite in #Russia (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Plasmid-Mediated mcr-1 Colistin Resistance in Escherichia coli from a Black Kite in Russia

Hassan Tarabai, Adam Valcek, Ivana Jamborova, Sergey V. Vazhov, Igor V. Karyakin, Rainer Raab, Ivan Literak, Monika Dolejska

DOI: 10.1128/AAC.01266-19

 

ABSTRACT

The gene mcr-1 conferring resistance to last-line antibiotic colistin has been reported globally. Here we describe the first detection of plasmid-mediated colistin resistance in Russian wildlife, an isolate of Escherichia coli sequence type 2280 from a black kite (Milvus migrans), scavenging raptor. Whole genome sequencing and plasmid transferability experiments revealed that mcr-1.1 was located on a conjugative IncI2 plasmid pDR164 (59891 bp). Migratory Black Kites may contribute to the global spread of mobile colistin resistance.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Colistin; MCR1; E. Coli; Wild Birds; Russia.

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#Synergistic #combinations and repurposed #antibiotics active against the #pandrug #resistant #Klebsiella pneumoniae #Nevada strain (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Synergistic combinations and repurposed antibiotics active against the pandrug-resistant Klebsiella pneumoniae Nevada strain

Thea Brennan-Krohn [MD], James E. Kirby [MD]

DOI: 10.1128/AAC.01374-19

 

ABSTRACT

In early 2017, the Centers for Disease Control and Prevention issued an alarming report describing a woman in Nevada who died in the setting of infection with a pan-resistant Klebsiella pneumoniae isolate that harbored an NDM-1 enzyme (AR-0636) and was colistin resistant as a result of inactivation of the mgrB regulator gene (1, 2).…

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Klebsiella pneumoniae; USA; Nevada.

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#Repurposing of #ribavirin as an adjunct #therapy against invasive #Candida strains: In vitro study (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Repurposing of ribavirin as an adjunct therapy against invasive Candidastrains: In vitro study

Hanane Yousfi, Carole Cassagne, Stéphane Ranque, Jean-marc Rolain, Fadi Bittar

DOI: 10.1128/AAC.00263-19

 

ABSTRACT

The use of antifungal agents in clinical settings is limited by the appearance of drug resistance and adverse side effects. There is, therefore, an urgent need to develop new drugs to strengthen the treatment of invasive fungal diseases. The aim of this study is to describe the potential repurposing of ribavirin as an adjunct therapy against Candida spp.

Primary screening of Prestwick chemical library against Candida albicans ATCC 90028 and fluconazole-resistant Candida albicans was performed. Subsequently, we evaluated the response of 100 Candida spp strains to ribavirin, an antiviral agent, using the broth microdilution method as recommended by CLSI. We checked the involvement of efflux pump activity in the development of ribavirin-resistance. We studied time-kill curves and performed a checkerboard assay for ribavirin-antifungals combinations study.

Twenty-one nonstandard antifungal compounds were identified, including ribavirin. Ribavirin had, in vitro, an antifungal activity against 63 Candida strains including C. albicans, C. parapsilosis and C. tropicalis, with a minimum inhibitory concentrations (MICs) ranging from 0.37 to 3.02 μg/ml, while MICs for C. krusei, C. glabrata, C. lusitaniae and some C. albicans remain high (≥ 24.16 μg/ml). No relation was observed between efflux pump activity and ribavirin-resistance. Ribavirin exhibited a fungistatic activity against multidrug-resistant (MDR) C. albicans and a fungicidal activity against C. parapsilosis strain. In addition, ribavirin acted synergistically with azoles against Candida strains for which ribavirin MICs were < 24.4 μg/ml.

This study highlights the potential clinical application of ribavirin, alone or in association with other antifungal agents, as an adjunct anti-Candida drug.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Candida spp.; Ribavirin.

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A #MDR #Plasmid pIMP26, Carrying blaIMP-26, fosA5, blaDHA-1, and qnrB4 in #Enterobacter cloacae (Sci Rep., abstract)

[Source: Scientific Reports, full page: (LINK). Abstract, edited.]

Article | OPEN | Published: 15 July 2019

A Multidrug Resistance Plasmid pIMP26, Carrying blaIMP-26, fosA5, blaDHA-1, and qnrB4 in Enterobacter cloacae

Su Wang,  Kaixin Zhou, Shuzhen Xiao, Lianyan Xie, Feifei Gu, Xinxin Li, Yuxing Ni, Jingyong Sun & Lizhong Han

Scientific Reports, volume 9, Article number: 10212 (2019)

 

Abstract

IMP-26 was a rare IMP variant with more carbapenem-hydrolyzing activities, which was increasingly reported now in China. This study characterized a transferable multidrug resistance plasmid harboring blaIMP-26 from one Enterobacter cloacae bloodstream isolate in Shanghai and investigated the genetic environment of resistance genes. The isolate was subjected to antimicrobial susceptibility testing and multilocus sequence typing using broth microdilution method, Etest and PCR. The plasmid was analyzed through conjugation experiments, S1-nuclease pulsed-field gel electrophoresis and hybridization. Whole genome sequencing and sequence analysis was conducted for further investigation of the plasmid. E. cloacae RJ702, belonging to ST528 and carrying blaIMP-26, blaDHA-1, qnrB4 and fosA5, was resistant to almost all β-lactams, but susceptible to quinolones and tigecycline. The transconjugant inherited the multidrug resistance. The resistance genes were located on a 329,420-bp IncHI2 conjugative plasmid pIMP26 (ST1 subtype), which contained trhK/trhV, tra, parA and stbA family operon. The blaIMP-26 was arranged following intI1. The blaDHA-1 and qnrB4cluster was the downstream of ISCR1, same as that in p505108-MDR. The fosA5 cassette was mediated by IS4. This was the first report on complete nucleotide of a blaIMP-26-carrying plasmid in E. cloacae in China. Plasmid pIMP26 hosted high phylogenetic mosaicism, transferability and plasticity.

Keywords: Antibiotics; Drugs Resistance; Carbapenem; Beta-lactams; Enterobacter cloacae; Shanghai; China; Quinolones; Tigecycline.

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