The Unrecognized #Threat of Secondary #Bacterial #Infections with #COVID19 (mBio, abstract)

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

The Unrecognized Threat of Secondary Bacterial Infections with COVID-19

Mylene Vaillancourt, Peter Jorth

DOI: 10.1128/mBio.01806-20

 

ABSTRACT

Coronavirus disease 2019 (COVID-19) is the greatest pandemic of our generation, with 16 million people affected and 650,000 deaths worldwide so far. One of the risk factors associated with COVID-19 is secondary bacterial pneumonia. In recent studies on COVID-19 patients, secondary bacterial infections were significantly associated with worse outcomes and death despite antimicrobial therapies. In the past, the intensive use of antibiotics during the severe acute respiratory syndrome coronavirus (SARS-CoV) pandemic led to increases in the prevalence of multidrug-resistant bacteria. The rising number of antibiotic-resistant bacteria and our decreasing capacity to eradicate them not only render us more vulnerable to bacterial infections but also weaken us during viral pandemics. The COVID-19 pandemic reminds us of the great health challenges we are facing, especially regarding antibiotic-resistant bacteria.

The views expressed in this article do not necessarily reflect the views of the journal or of ASM.

Keywords: SARS-CoV-2; COVID-19; Bacterial coinfections; Antibiotics; Drugs Resistance.

——

#Functional #neuraminidase #inhibitor #resistance motifs in #avian #influenza A(#H5Nx) viruses (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 1 August 2020, 104886 | In Press, Journal Pre-proof | Research paper

Functional neuraminidase inhibitor resistance motifs in avian influenza A(H5Nx) viruses

Dagmara Bialy, Holly Shelton, The Pirbright Institute, Pirbright, United Kingdom

Received 24 March 2020, Revised 13 July 2020, Accepted 16 July 2020, Available online 1 August 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104886

 

Highlights

  • A R292K residue change in NA reduces susceptibility to NA inhibitor drugs (NAIs) in H5N6 and H5N2 avian influenza viruses.
  • All four mutations (E119V, H274Y, R292K and N294S) reducing susceptibility to NAIs in H5N6 viruses also reduced viral NA activity.
  • Reduced susceptibility to NA inhibitors in H5N6 did not attenuate virus replication efficiency in chicken cells or eggs.
  • A reduction of the viral HA affinity for sialic acid was observed in H5N6 viruses with reduced NA activity.

 

Abstract

Neuraminidase inhibitors (NAIs) are antiviral agents recommended worldwide to treat or prevent influenza virus infections in humans. Past influenza virus pandemics seeded by zoonotic infection by avian influenza viruses (AIV) as well as the increasing number of human infections with AIV have shown the importance of having information about resistance to NAIs by avian NAs that could cross the species barrier. In this study we introduced four NAI resistance-associated mutations (N2 numbering) previously found in human infections into the NA of three current AIV subtypes of the H5Nx genotype that threaten the poultry industry and human health: highly pathogenic H5N8, H5N6 and H5N2. Using the established MUNANA assay we showed that a R292K substitution in H5N6 and H5N2 viruses significantly reduced susceptibility to three licenced NAIs: oseltamivir, zanamivir and peramivir. In contrast the mutations E119V, H274Y and N294S had more variable effects with NAI susceptibility being drug- and strain-specific. We measured the replicative fitness of NAI resistant H5N6 viruses and found that they replicated to comparable or significantly higher titres in primary chicken cells and in embryonated hens’ eggs as compared to wild type – despite the NA activity of the viral neuraminidase proteins being reduced. The R292K and N294S drug resistant H5N6 viruses had single amino acid substitutions in their haemagglutinin (HA): Y98F and A189T, respectively (H3 numbering) which reduced receptor binding properties possibly balancing the reduced NA activity seen. Our results demonstrate that the H5Nx viruses can support drug resistance mutations that confer reduced susceptibility to licenced NAIs and that these H5N6 viruses did not show diminished replicative fitness in avian cell cultures. Our results support the requirement for on-going surveillance of these strains in bird populations to include motifs associated with human drug resistance.

Keywords: Avian Influenza; H5N2; H5N6; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

——

Successful #Treatment With #Baloxavir Marboxil of a Patient With #Peramivir #Resistant #Influenza A / #H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell #Transplantation: A Case Report (BMC Infect Dis., abstract)

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

BMC Infect Dis. 2020 Jul 6;20(1):478. doi: 10.1186/s12879-020-05205-1.

Successful Treatment With Baloxavir Marboxil of a Patient With Peramivir-Resistant Influenza A/H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell Transplantation: A Case Report

Naonori Harada 1, Wataru Shibata 2 3, Hideo Koh 4, Emi Takashita 5, Seiichiro Fujisaki 5, Hiroshi Okamura 1, Satoru Nanno 1, Koichi Yamada 2 3, Hirohisa Nakamae 1, Masayuki Hino 1, Hiroshi Kakeya 2 3

Affiliations: 1 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. 2 Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan. 3 Research Center for Infectious Disease Sciences (RCIDS), Graduate School of Medicine, Osaka City University, Osaka, Japan. 4 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. hide_koh@med.osaka-cu.ac.jp. 5 Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.

PMID: 32631240 DOI: 10.1186/s12879-020-05205-1

 

Abstract

Background:

Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir.

Case presentation:

A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/μL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2.

Conclusions:

In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.

Keywords: Allogeneic hematopoietic cell transplantation; Baloxavir marboxil; Dual E119D/R292K substitution; Immunocompromised host; Influenza A/H3N2; Neuraminidase mutation; Peramivir resistance.

Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; Hematology; H3N2; Cancer; Immunosuppression; Peramivir; Baloxavir.

—–

Characterization of #Neuraminidase #Inhibitor #Resistant #Influenza Virus Isolates From Immunocompromised Patients in the Republic of #Korea (Virol J., abstract)

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

Virol J. 2020 Jul 6;17(1):94. doi: 10.1186/s12985-020-01375-1.

Characterization of Neuraminidase Inhibitor-Resistant Influenza Virus Isolates From Immunocompromised Patients in the Republic of Korea

Heui Man Kim 1, Namjoo Lee 1, Mi-Seon Kim 1, Chun Kang 1, Yoon-Seok Chung 2

Affiliations: 1 Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Cheongju-si, South Korea. 2 Division of Viral Diseases, Center for Laboratory Control of Infectious Diseases, Korea Centers for Disease Control and Prevention, Cheongju-si, South Korea. rollstone93@korea.kr.

PMID: 32631440 DOI: 10.1186/s12985-020-01375-1

 

Abstract

Background:

The emergence of influenza viruses resistant to anti-influenza drugs is a threat to global public health. The Korea Centers for Disease Control and Prevention operates the Korea Influenza and Respiratory Viruses Surveillance System (KINRESS) to monitor epidemics of influenza and Severe Acute Respiratory Infection (SARI) to identify mutated influenza viruses affecting drug resistance, pathogenesis, and transmission.

Methods:

Oropharyngeal swab samples were collected from KINRESS and SARI during the 2018-2019 season. The specimens confirmed influenza virus using real-time RT-PCR on inoculated MDCK cells. HA and NA sequences of the influenza viruses were analyzed for phylogeny and mutations. Neuraminidase inhibition and hemagglutination inhibition assays were utilized to characterize the isolates.

Results:

Two A(H1N1)pdm09 isolates harboring an H275Y substitution in the neuraminidase sequence were detected in patients with acute hematologic cancer. They had prolonged respiratory symptoms, with the virus present in the respiratory tract despite oseltamivir and peramivir treatment. Through the neuraminidase inhibition assay, both viruses were found to be resistant to oseltamivir and peramivir, but not to zanamivir. Although hemagglutinin and neuraminidase phylogenetic analyses suggested that the 2 A(H1N1)pdm09 isolates were not identical, their antigenicity was similar to that of the 2018-19 influenza vaccine virus.

Conclusions:

Our data indicate the utility of monitoring influenza-infected immunocompromised patients in general hospitals for the early detection of emerging neuraminidase inhibitor-resistant viruses and maintaining continuous laboratory surveillance of patients with influenza-like illness in sentinel clinics to monitor the spread of such new variants. Finally, characterization of the virus can inform the risk assessment for future epidemics and pandemics caused by drug-resistant influenza viruses.

Keywords: Drug resistance; H275Y; Immunocompromised patients; Influenza virus.

Keywords: Seasonal Influenza; H1N1pdm09; Cancer; Immunosuppression; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir; S. Korea.

——

#Influenza #H1N1pdm09 virus exhibiting reduced #susceptibility to #baloxavir due to a PA E23K #substitution detected from a #child without baloxavir #treatment (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 20 June 2020, 104828 | In Press, Journal Pre-proof | Short Communication

Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment

Emi Takashita 1, Takashi Abe 2, Hiroko Morita 1, Shiho Nagata 1, Seiichiro Fujisaki 1, Hideka Miura 1, Masayuki Shirakura 1, Noriko Kishida 1, Kazuya Nakamura 1, Tomoko Kuwahara 1, KeikoMitamura 3, Masataka Ichikawa 4, Masahiko Yamazaki 5, Shinji Watanabe 1, Hideki Hasegawa 1, The Influenza Virus Surveillance Group of Japan,  Rika Komagome 6, Asami Ohnishi 7, Rika Tsutsui 8, Masaki Takahashi 9, MieSasaki 10, Shiho Tamura 11, Chihiro Shibata 12, Kenichi Komabayashi 13, Nozomi Saito 14, Aoi Saito 15, Fuminori Mizukoshi 16, Akira Wakatsuki 17, Hiroyuki Tsukagoshi 18, Noriko Suzuki 19, Yuka Uno 20, Noriko Oitate 21, Wakako Nishikawa  22, Mami Nagashima 23, Sumi Watanabe 24, Chiharu Kawakami 25, Hideaki Shimizu 26, Hazime Amano 27, Satoko Kanazawa 28, Kaori Watanabe 29, Kazunari Yamamoto 30, Tetsuya Yoneda 31, Sachiko Nakamura 32, Kaori Sato 33, Masayuki Oonuma 34, Michiko Takeuchi 35, ErinaTanaka 36, Masahiro Nishioka 37, Yusuke Sato 38, Yukiko Sakai 39, Takaharu Maehata 40, Toshihiko Furuta 41, Yoshihiro Yasui 42, Takuya Yano 43, Asa Tanino 44, Sachi Hirata 45, Akiko Nagasao 46, Satoshi Hiroi 47, Hideyuki Kubo 47, Fumika Okayama 48, Tomohiro Oshibe 49, Ai Mori 50, Ryutaro Murayama 51, Shoko Chiba 52, Yuki Matsui 53, Yuko Kiguchi 54, Koji Takeuchi 55, Tetsuo Mita 56, Kayoko Nomiya 57, Yukie Shimazu 58, Yoshiki Fujii 59, Shoichi Toda 60, Yumiko Kawakami 61, Yukari Terajima 62, Mayumi Yamashita 63, Tomiyo Takahashi 64, Yuki Ashizuka 65, Chinami Wasano 66, Takashi Kimura 67, Sanae Moroishi 68, Miho Urakawa 69, Takashi Sakai 70, Kaori Nishizawa 71, Toru Hayashi 72, Yu Matsuura 73, Yuka Hamada 74, Yumani Kuba 75

6 Hokkaido Institute of Public Health; 7 Sapporo City Institute of Public Health; 8 Aomori Prefectural Public Health and Environment Center; 9 Iwate Prefectural Research Institute for Environmental Sciences and Public Health; 10 Miyagi Prefectural Institute of Public Health and Environment; 11 Sendai City Institute of Public Health; 12 Akita Prefectural Research Center for Public Health and Environment; 13 Yamagata Prefectural Institute of Public Health; 14 Fukushima Prefectural Institute of Public Health; 15 Ibaraki Prefectural Institute of Public Health; 16 Tochigi Prefectural Institute of Public Health and Environmental Sciences; 17 Utsunomiya City Institute of Public Health and Environment Science; 18 Gunma Prefectural Institute of Public Health and Environmental Sciences; 19 Saitama Institute of Public Health; 20 Saitama City Institute of Health Science and Research;  21 Chiba Prefectural Institute of Public Health; 22 Chiba City Institute of Health and Environment; 23 Tokyo Metropolitan Institute of Public Health; 24 Kanagawa Prefectural Institute of Public Health; 25 Yokohama City Institute of Public Health; 26 Kawasaki City Institute of Public Health; 27 Yokosuka Institute of Public Health; 28 Sagamihara City Institute of Public Health; 29 Niigata Prefectural Institute of Public Health and Environmental Sciences; 30 Niigata City Institute of Public Health and Environment; 31 Toyama Institute of Health; 32 Ishikawa Prefectural Institute of Public Health and Environmental Science; 33 Fukui Prefectural Institute of Public Health and Environmental Science; 34 Yamanashi Institute for Public Health; 35 Nagano Environmental Conservation Research Institute; 36 Nagano City Health Center; 37
Gifu Prefectural Research Institute for Health and Environmental Sciences; 38 Gifu Municipal Institute of Public Health; 39 Shizuoka Institute of Environment and Hygiene; 40 Shizuoka City Institute of Environmental Sciences and Public Health; 41 Hamamatsu City Health Environment Research Center; 42 Aichi Prefectural Institute of Public Health; 43 Mie Prefecture Health and Environment Research Institute; 44 Shiga Prefectural Institute of Public Health; 45 Kyoto Prefectural Institute of Public Health and Environment; 46 Kyoto City Institute of Health and Environmental Sciences; 47 Osaka Institute of Public Health; 48 Sakai City Institute of Public Health; 49 Hyogo Prefectural Institute of Public Health Science; 50 Kobe Institute of Health; 51 Amagasaki City Institute of Public Health; 52 Nara Prefecture Institute of Health; 53 Wakayama Prefectural Research Center of Environment and Public Health; 54 Wakayama City Institute of Public Health; 55 Tottori Prefectural Institute of Public Health and Environmental Science; 56 Shimane Prefectural Institute of Public Health and Environmental Science; 57 Okayama Prefectural Institute for Environmental Science and Public Health; 58 Hiroshima Prefectural Technology Research Institute; 59 Hiroshima City Institute of Public Health; 60 Yamaguchi Prefectural Institute of Public Health and Environment; 61 Tokushima Prefectural Public Health, Pharmaceutical and Environmental Sciences Center; 62 Kagawa Prefectural Research Institute for Environmental Sciences and Public Health; 63 Ehime Prefecture Institute of Public Health and Environmental Science; 64 Kochi Public Health and Environmental Science Research Institute; 65 Fukuoka Institute of Health and Environmental Sciences; 66 Fukuoka City Institute of Health and Environment; 67 Kitakyushu City Institute of Health and Environmental Sciences; 68 Saga Prefectural Institute of Public Health and Pharmaceutical Research; 69 Nagasaki Prefectural Institute for Environment Research and Public Health; 70 Kumamoto Prefectural Institute of Public-Health and Environmental Science; 71 Kumamoto City Environmental Research Center; 72 Oita Prefectural Institute of Health and Environment; 73 Miyazaki Prefectural Institute for Public Health and Environment; 74 Kagoshima Prefectural Institute for Environmental Research and Public Health; 75 Okinawa Prefectural Institute of Health and Environment; 1 Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan; 2 Abe Children’s Clinic, Minowa 2-15-22, Kohoku, Yokohama, Kanagawa, 223-0051, Japan; 3 Eiju General Hospital, Higashi Ueno 2-23-16, Taito, Tokyo, 110-8645, Japan; 4 Ichikawa Children’s Clinic, Higashi Odake 1544-3, Isehara, Kanagawa, 259-1133, Japan; 5 Zama Children’s Clinic, Tatsuno Dai 2-20-24, Zama, Kanagawa, 252-0023, Japan

Received 18 February 2020, Revised 14 May 2020, Accepted 28 May 2020, Available online 20 June 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104828

 

Highlights

  • Influenza A(H1N1)pdm09 virus carrying a PA E23K substitution was detected.
  • The PA E23K mutant virus showed reduced baloxavir susceptibility.
  • The PA E23K mutant virus was isolated from a child without baloxavir treatment.
  • Possible transmission of the PA E23K mutant virus among humans is suggested.
  • Baloxavir susceptibility monitoring of influenza viruses is essential.

 

Abstract

Human-to-human transmission of PA I38 mutant influenza A(H3N2) viruses with reduced baloxavir susceptibility has been reported in Japan. In December 2019, we detected a PA E23K mutant A(H1N1)pdm09 virus from a child without baloxavir treatment. The PA E23K mutant virus exhibited reduced baloxavir susceptibility but remained susceptible to neuraminidase inhibitors. Epidemiological data suggest possible transmission of this PA E23K mutant virus among humans, although its growth capability relative to that of the wild-type virus was reduced. Therefore, baloxavir susceptibility monitoring of influenza viruses is essential.

Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir; Oseltamivir; Pediatrics; Japan.

——

#COVID19 and #Antimicrobial #Resistance: Parallel and Interacting #Health #Emergencies (Clin Infect Dis., abstract)

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

COVID-19 and Antimicrobial Resistance: Parallel and Interacting Health Emergencies

Robby Nieuwlaat, Lawrence Mbuagbaw, Dominik Mertz, Lori Burrows, Dawn M E Bowdish, Lorenzo Moja, Gerry D Wright, Holger J Schünemann

Clinical Infectious Diseases, ciaa773, https://doi.org/10.1093/cid/ciaa773

Published: 16 June 2020

 

Abstract

The COVID-19 pandemic and antimicrobial resistance are parallel and interacting health emergencies with opportunity for mutual learning. As their measures and consequences are comparable, the COVID-19 pandemic helps to illustrate the potential long-term impact of AMR, which is less acute but not less crucial. They may also impact each other as there is a push to resort to existing antimicrobials in critically ill COVID-19 patients in the absence of specific treatments, while attempts to manage the spread of COVID-19 may also lead to a slow down AMR. Understanding how COVID-19 affects AMR trends and what we can expect if these remain the same or worsen, will help us plan next steps to tackle AMR. Researchers should now start collecting data to measure the impact of current COVID-19 policies and programs on AMR.

COVID-19, SARS-CoV-2, antimicrobial resistance, antibiotic resistance

Issue Section: Viewpoints

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This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: SARS-CoV-2; COVID-19; Antibiotics; Drugs Resistance.

——-

Host-targeted #Nitazoxanide has a high barrier to #resistance but does not reduce the emergence or #proliferation of #oseltamivir-resistant #influenza viruses in vitro or in vivo when used in combination with oseltamivir (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 13 June 2020, 104851 | In Press, Journal Pre-proof | Research paper

Host-targeted Nitazoxanide has a high barrier to resistance but does not reduce the emergence or proliferation of oseltamivir-resistant influenza viruses in vitro or in vivo when used in combination with oseltamivir

Danielle Tilmanis 1, Paulina Koszalka 1, Ian G. Barr 1,3, Jean-Francois Rossignol 2, Edin Mifsud 1, Aeron C. Hurt 1,3

1 WHO Collaborating Centre for Reference and Research on Influenza, VIDRL, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, 3000, Australia; 2 Romark Laboratories, L.C., Tampa, Florida, USA; 3 The University of Melbourne, Department of Microbiology and Immunology, Parkville, Victoria, 3010, Australia

Received 1 January 2020, Revised 5 June 2020, Accepted 7 June 2020, Available online 13 June 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104851

 

Highlights

  • Serial passaging was used to determine the propensity for influenza viruses to develop resistance to tizoxanide.
  • Tizoxanide selective pressure up to 20 μM did not result in virus populations with altered drug susceptibility.
  • Host-targeted Nitazoxanide has a high barrier to antiviral resistance.
  • Tizoxanide/oseltamivir combination therapy did not prevent the emergence or selection of oseltamivir resistant virus.

 

Abstract

A major limitation of the currently available influenza antivirals is the potential development of drug resistance. The adamantanes, neuraminidase inhibitors, and more recently polymerase inhibitors, have all been associated with the emergence of viral resistance in preclinical, clinical studies or in clinical use. As a result, host-targeted drugs that act on cellular proteins or functions have become an attractive option for influenza treatment as they are less likely to select for resistance. Nitazoxanide (NTZ) is a host-targeted antiviral that is currently in Phase III clinical trials for the treatment of influenza. In this study, we investigated the propensity for circulating influenza viruses to develop resistance to nitazoxanide in vitro by serially passaging viruses under selective pressure. Phenotypic and genotypic analysis of viruses passaged ten times in the presence of up to 20 μM tizoxanide (TIZ; the active metabolite of nitazoxanide) showed that none had a significant change in TIZ susceptibility, and amino acid substitutions arising that were unique to TIZ passaged viruses, did not alter TIZ susceptibility.

Combination therapy, particularly utilising drugs with different mechanisms of action, is another option for combatting antiviral resistance, and while combination therapy has been shown to improve antiviral effects, the effect of reducing the emergence and selection of drug-resistant virus has been less widely investigated. Here we examined the use of TIZ in combination with oseltamivir, both in vitro and using the ferret model for influenza infection and found that the combination of the two drugs did not provide significant benefit in reducing the emergence or selection of oseltamivir-resistant virus.

These in vitro findings suggest that clinical use of NTZ may be significantly less likely to select for resistance in circulating influenza viruses compared to virus-targeted antivirals, and although the combination of NTZ with oseltamivir did not reduce the emergence of oseltamivir-resistant virus in vitro or in vivo, combination therapy with NTZ and other newer classes of influenza antiviral drugs should be considered due to NTZ’s higher host-based barrier to resistance.

View full text© 2020 Elsevier B.V. All rights reserved.

Keywords: Influenza A; Antivirals; Drugs Resistance; Nitazoxamide, Oseltamivir; Animal models.

—–

#Genotyping and #Reassortment #Analysis of Highly Pathogenic #Avian #Influenza Viruses #H5N8 and #H5N2 From #Egypt Reveals Successive Annual #Replacement of Genotypes (Infect Genet Evol., abstract)

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

Infect Genet Evol. 2020 May 23;104375. doi: 10.1016/j.meegid.2020.104375. Online ahead of print.

Genotyping and Reassortment Analysis of Highly Pathogenic Avian Influenza Viruses H5N8 and H5N2 From Egypt Reveals Successive Annual Replacement of Genotypes

Kareem E Hassan 1, Noha Saad 2, Hassanein H Abozeid 3, Salama Shany 4, Magdy F El-Kady 4, Abdelsatar Arafa 2, Azza A A El-Sawah 4, Florian Pfaff 5, Hafez M Hafez 6, Martin Beer 5, Timm Harder 7

Affiliations: 1 Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, Greifswald, Riems, Germany; Department of Poultry Diseases, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt. 2 National Laboratory for Veterinary Quality Control on Poultry Production, Animal Health Research Institute, 12618, Dokki, Giza, Egypt. 3 Department of Poultry Diseases, Faculty of Veterinary Medicine, Cairo University, Egypt. 4 Department of Poultry Diseases, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt. 5 Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, Greifswald, Riems, Germany. 6 Institute of Poultry Diseases, Free University Berlin, Berlin, Germany. 7 Institute of Diagnostic Virology, Friedrich-Loeffler-Institute, Greifswald, Riems, Germany. Electronic address: Timm.Harder@fli.de.

PMID: 32454245 DOI: 10.1016/j.meegid.2020.104375

 

Abstract

Highly pathogenic (HP) H5N1, clade 2.2.1, and low pathogenic avian influenza (LPAI) H9N2 viruses, G1-B lineage, are endemic in poultry in Egypt and have co-circulated for almost a decade. Surprisingly, no inter-subtypic reassortment events have been reported from the field during that time. After the introduction of HPAIV H5N8, clade 2.3.4.4b, in Egyptian poultry in 2016, suddenly HP H5N2 reassortants with H9N2 viruses emerged. The current analyses focussed on studying 32 duck flocks, 4 broiler chicken flocks, and 1 turkey flock, suffering from respiratory manifestations with moderate to high mortality reared in two Egyptian governorates during 2019. Real-time RT-PCR substantiated the presence of HP H5N8 in 21 of the 37 investigated flocks with mixed infection of H9N2 in two of them. HP H5N1 was not detected. Full hemagglutinin (HA) sequencing of 10 samples with full-genome sequencing of three of them revealed presence of a single genotype. Very few substituting mutations in the HA protein were detected versus previous Egyptian HA sequences of that clade. Interestingly, amino acid substitutions in the Matrix (M2) and the Neuraminidase (NA) proteins associated with conferring both Amantadine and Oseltamivir resistance were present. Systematic reassortment analysis of all publicly available Egyptian whole genome sequences of HP H5N8 (n = 23), reassortant HP H5N2 (n = 2) and LP H9N2 (n = 53) viruses revealed presence of at least seven different genotypes of HPAI H5Nx viruses of clade 2.3.4.4b in Egypt since 2016. For H9N2 viruses, at least three genotypes were distinguishable. Heat mapping and tanglegram analyses suggested that several internal gene segments in both HP H5Nx and H9N2 viruses originated from avian influenza viruses circulating in wild bird species in Egypt. Based on the limited set of whole genome sequences available, annual replacement patterns of HP H5Nx genotypes emerged and suggested selective advantages of certain genotypes since 2016.

Keywords: Beast analysis; Egypt; Genotyping; H5N2; H9N2; Highly pathogenic avian influenza; Phylogenetic analysis; Reassortment; Subtype H5N8; Tanglegram.

Copyright © 2019. Published by Elsevier B.V.

Conflict of interest statement. Declaration of Competing Interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Keywords: Avian Influenza; H5N2; H5N8; H9N2; Reassortant strain; Poultry; Wild Birds; Egypt; Antivirals; Drugs Resistance; Amantadine; Oseltamivir.

——

#Laninamivir – #Interferon-λ1 #Combination #Treatment Promotes #Resistance by #Influenza A Virus More Rapidly Than Laninamivir Alone (Antimicrob Agents Chemother., abstract)

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

Laninamivir–Interferon-λ1 Combination Treatment Promotes Resistance by Influenza A Virus More Rapidly Than Laninamivir Alone

Simone E. Adams, Vladimir Y. Lugovtsev, Anastasia Kan, Nicolai V. Bovin, Raymond P. Donnelly, Natalia A. Ilyushina

DOI: 10.1128/AAC.00301-20

 

ABSTRACT

Each year, 5-20% of the population of the United States becomes infected with influenza A virus. Combination therapy with two or more antiviral agents has been considered as a potential treatment option for influenza virus infection. However, the clinical results derived from combination treatment with two or more antiviral drugs have been variable. We examined the effectiveness of co-treatment with two distinct classes of anti-influenza drugs, i.e., neuraminidase (NA) inhibitor, laninamivir, and interferon (IFN)-λ1, against the emergence of drug-resistant virus variants in vitro. We serially passaged pandemic A/California/04/09 (A(H1N1)pdm09) influenza virus in a human lung epithelial cell line (Calu-3) in the presence or absence of increasing concentrations of laninamivir or laninamivir plus IFN-λ1. Surprisingly, laninamivir used in combination with IFN-λ1 promoted the emergence of the E119G NA mutation five passages earlier than laninamivir alone (passage 2 vs passage 7, respectively). Acquisition of this mutation resulted in significantly reduced sensitivity to NA inhibitors, laninamivir (∼284-fold↓) and zanamivir (∼1024-fold↓), and decreased NA enzyme catalytic activity (∼5-fold↓) compared to the parental virus. Moreover, the E119G NA mutation emerged together with concomitant hemagglutinin (HA) mutations (T197A and D222G), which were selected more rapidly by combination treatment with laninamivir plus IFN-λ1 (passage 2 and 3, respectively) than by laninamivir alone (passage 10). Our results show that treatment with laninamivir alone or in combination with IFN-λ1 can lead to the emergence of drug-resistant influenza virus variants. Addition of IFN-λ1 in combination with laninamivir may promote acquisition of drug resistance more rapidly than treatment with laninamivir alone.

Copyright © 2020 American Society for Microbiology. All Rights Reserved.

Keywords: Influenza A; H1N1pdm09; Antivirals; Drugs Resistance; Laninamivir; Interferons.

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Historical #Origins and #Zoonotic #Potential of #Avian #Influenza Virus #H9N2 in #Tunisia Revealed by Bayesian Analysis and Molecular Characterization (Arch Virol., abstract)

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

Arch Virol. 2020 Apr 25. doi: 10.1007/s00705-020-04624-4. Online ahead of print.

Historical Origins and Zoonotic Potential of Avian Influenza Virus H9N2 in Tunisia Revealed by Bayesian Analysis and Molecular Characterization

Marwa Arbi 1, Oussema Souiai 2, Natalia Rego 3, Imen Larbi 1, Hugo Naya 3 4, Abdeljelil Ghram 1, Mehdi Houimel 5

Affiliations: 1 Laboratory of Epidemiology and Veterinary Microbiology, LR19IPT03, Institut Pasteur de Tunis, University Tunis El Manar, 13, Place Pasteur, BP74, 1002, Tunis, Belvedere, Tunisia. 2 Laboratory of Bioinformatics, Biomathematics and Biostatistics, LR16IPT09, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia. 3 Bioinformatics Unit, Institut Pasteur de Montevideo, Mataojo 2020, 11400, Montevideo, Uruguay. 4 Departmento de Producción Animal y Pasturas, Facultad de Agronomía, Universidad de la República, Av. Gral. Eugenio Garzón 780, 12900, Montevideo, Uruguay. 5 Laboratory of Epidemiology and Veterinary Microbiology, LR19IPT03, Institut Pasteur de Tunis, University Tunis El Manar, 13, Place Pasteur, BP74, 1002, Tunis, Belvedere, Tunisia. mehdi.houimel@pasteur.rns.tn.

PMID: 32335769 DOI: 10.1007/s00705-020-04624-4

 

Abstract

During 2009-2012, several outbreaks of avian influenza virus H9N2 were reported in Tunisian poultry. The circulating strains carried in their hemagglutinins the human-like marker 226L, which is known to be important for avian-to-human viral transmission. To investigate the origins and zoonotic potential of the Tunisian H9N2 viruses, five new isolates were identified during 2012-2016 and their whole genomes were sequenced. Bayesian-based phylogeny showed that the HA, NA, M and NP segments belong to the G1-like lineage. The PB1, PB2, PA and NS segments appeared to have undergone multiple intersubtype reassortments and to be only distantly related to all of the Eurasian lineages (G1-like, Y280-like and Korean-like). The spatiotemporal dynamic of virus spread revealed that the H9N2 virus was transferred to Tunisia from the UAE through Asian and European pathways. As indicated by Bayesian analysis of host traits, ducks and terrestrial birds played an important role in virus transmission to Tunisia. The subtype phylodynamics showed that the history of the PB1 and PB2 segments was marked by intersubtype reassortments with H4N6, H10N4 and H2N2 subtypes. Most of these transitions between locations, hosts and subtypes were statistically supported (BF > 3) and not influenced by sampling bias. Evidence of genetic evolution was observed in the predicted amino acid sequences of the viral proteins of recent Tunisian H9N2 viruses, which were characterized by the acquisition of new mutations involved in virus adaptation to avian and mammalian hosts and amantadine resistance. This study is the first comprehensive analysis of the evolutionary history of Tunisian H9N2 viruses and highlights the zoonotic risk associated with their circulation in poultry, indicating the need for continuous surveillance of their molecular evolution.

Grant support LR19IPT06/Tunisian Ministry for Research and Technology

Keywords: Avian Influenza; H9N2; Poultry; Reassortant strain; Tunisia; Antivirals; Drugs resistance; Amantadine.

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