#Effectiveness of the #Neuraminidase #Inhibitors: The Supporting #Evidence Increases (J Infect Dis., summary)

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

Effectiveness of the Neuraminidase Inhibitors: The Supporting Evidence Increases

Arnold S Monto

The Journal of Infectious Diseases, jiz157, https://doi.org/10.1093/infdis/jiz157

Published: 20 May 2019

Issue Section: Editorial Commentary

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The neuraminidase inhibitors (NAIs) zanamivir and oseltamivir were the first in that class of influenza antivirals to receive approval by the Food and Drug Administration, with both approved at the turn of the last century [1, 2] The regulatory approvals, for both prophylaxis and treatment of uncomplicated influenza, occurred after standard review of studies. The 2 drugs target nearby sites in the enzymatically active pocket of the virus but are very different in their route of administration and pharmacokinetics [1, 2]. Despite these differences, the results of the clinical trials of both were remarkably similar in terms of the characteristics of prophylactic efficacy and of treatment effects. Recruitment of cases to the treatment studies was based on clinical criteria but was limited to the influenza season; these cases were the intent-to-treat population [3–5]. The studies were done before use of polymerase chain reaction analysis had become accepted for influenza diagnosis, so the standard method of detecting the infecting virus was by cell culture.

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Notes

Potential conflicts of interest.

A. S. M. reports personal fees from Roche outside the submitted work. The author has 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; Oseltamivir; Zanamivir; Peramivir; Influenza A; Pandemic Influenza.

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In vitro #neuraminidase inhibitory concentration (#IC50) of four neuraminidase inhibitors in the #Japanese 2017-18 #season: Comparison with the 2010-11 to 2016-17 seasons (J Infect Chemother., abstract)

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

J Infect Chemother. 2019 May 14. pii: S1341-321X(19)30099-6. doi: 10.1016/j.jiac.2019.04.007. [Epub ahead of print]

In vitro neuraminidase inhibitory concentration (IC50) of four neuraminidase inhibitors in the Japanese 2017-18 season: Comparison with the 2010-11 to 2016-17 seasons.

Ikematsu H1, Kawai N2, Chong Y3, Bando T2, Iwaki N2, Kashiwagi S2.

Author information: 1 Japan Physicians Association, Tokyo, Japan; Ricerca Clinica Co., Fukuoka, Japan. Electronic address: ikematsu@gray.plala.or.jp. 2 Japan Physicians Association, Tokyo, Japan. 3 Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.

 

Abstract

To assess the extent of susceptibility to the four most commonly used neuraminidase inhibitors (NAIs) of the viruses epidemic in the 2017-18 Japanese influenza season, we measured the 50% inhibitory concentration (IC50) for influenza virus isolates from patients and compared them with the results from the 2010-11 to 2016-17 seasons. Viral isolation was done with specimens obtained prior to treatment, and the type and subtype was determined by RT-PCR using type- and subtype-specific primers. The IC50 was determined by a neuraminidase inhibition assay using a fluorescent substrate. A total of 237 virus isolates, 50 A(H1N1)pdm09, 92 A(H3N2), and 95 B were measured. No A(H1N1)pdm09 with highly reduced sensitivity for oseltamivir was found in the 2017-18 season. No isolates with highly reduced sensitivity to the four NAIs have been found for A(H3N2) or B from the 2010-11 to 2017-18 seasons. The geometric mean IC50s of the four NAIs were quite consistent during the eight studied seasons. These results indicate that the sensitivity to the four commonly used NAIs has been maintained.

Copyright © 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

KEYWORDS: 50% inhibitory concentration; Influenza virus; Neuraminidase inhibitor; Resistance; Surveillance

PMID: 31101530 DOI: 10.1016/j.jiac.2019.04.007

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir; Laninamivir; Japan; Seasonal Influenza; H1N1pdm09; H3N2; Influenza B.

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#Oseltamivir induced Stevens-Johnson #syndrome/toxic #epidermal #necrolysis-case report (Medicine (Baltimore), abstract)

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

Medicine (Baltimore). 2019 May;98(19):e15553. doi: 10.1097/MD.0000000000015553.

Oseltamivir induced Stevens-Johnson syndrome/toxic epidermal necrolysis-case report.

Zuo W1,2, Wen LP1, Li J1, Mei D1, Fu Q1, Zhang B1.

Author information: 1 Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing. 2 Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education”, Yantai University, Yantai, China.

 

Abstract

RATIONALE:

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are 2 rare but life-threatening diseases characterized by detachment of epidermis, bullous skin lesions, and mucous membrane erosions. Drugs are highly suspected to be the causative agents. We report a case of SJS/TEN induced by oseltamivir, which is a very rare event.

PATIENT CONCERNS:

A 9-year-old girl with upper respiratory tract infections presented with generalized maculopapular rash the second day after taking oseltamivir.

DIAGNOSIS:

The diagnosis of SJS/TEN was made based on cytotoxic skin lesions and mucous membrane involvement.

INTERVENTIONS:

After discontinuing of the drug and combination therapy of corticosteroid and human immunoglobulin initiation, the lesions were improved. Human leukocyte antigen (HLA) gene sequencing was done.

OUTCOMES:

The girl was followed-up for 1 year. The skin and mucous membranes symptoms were relieved.

LESSONS:

We report this case to attract attention to the rare but serious side effect of this antiviral drug.

PMID: 31083216 DOI: 10.1097/MD.0000000000015553

Keywords: Seasonal Influenza; Antivirals; Oseltamivir; Drugs safety; Steven-Johnson Syndrome.

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Efficacy and Safety of #Danirixin (GSK1325756) Co-administered With Standard-of-Care Antiviral (#Oseltamivir): A Phase 2b, Global, Randomized Study of Adults Hospitalized With #Influenza (Open Forum Infect Dis., abstract)

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

Open Forum Infect Dis. 2019 Apr 3;6(4):ofz163. doi: 10.1093/ofid/ofz163. eCollection 2019 Apr.

Efficacy and Safety of Danirixin (GSK1325756) Co-administered With Standard-of-Care Antiviral (Oseltamivir): A Phase 2b, Global, Randomized Study of Adults Hospitalized With Influenza.

Madan A1, Chen S1, Yates P2, Washburn ML1, Roberts G3, Peat AJ1, Tao Y1, Parry MF4, Barnum O5, McClain MT6, Roy-Ghanta S1.

Author information: 1 GlaxoSmithKline, Upper Providence, Pennsylvania. 2 GlaxoSmithKline, Stevenage, United Kingdom.  3 GlaxoSmithKline, Research Triangle Park, North Carolina. 4 Stamford Hospital, Stamford, Connecticut. 5 Natchitoches Regional Medical Center, Natchitoches, Louisiana. 6 Duke University Center for Applied Genomics and Precision Medicine, Durham, North Carolina.

 

Abstract

BACKGROUND:

Excessive neutrophil migration has been correlated with influenza symptom severity. Danirixin (GSK1325756), a selective and reversible antagonist of C-X-C chemokine receptor 2, decreases neutrophil activation and transmigration to areas of inflammation. This study evaluated the efficacy and safety of intravenous (IV) danirixin co-administered with oseltamivir for the treatment of adults hospitalized with influenza.

METHODS:

In this phase 2b, double-blind, 3-arm study (NCT02927431), influenza-positive participants were randomized 2:2:1 to receive danirixin 15mg intravenously (IV) twice daily (bid) + oral oseltamivir 75mg bid (OSV), danirixin 50mg IV bid + OSV, or placebo IV bid + OSV, for up to 5 days. The primary endpoint was time to clinical response (TTCR).

RESULTS:

In total, 10 participants received study treatment (danirixin 15mg + OSV, n = 4; danirixin 50mg + OSV, n = 4; placebo + OSV, n = 2) before the study was terminated early due to low enrollment. All participants achieved a clinical response. Median (95% confidence interval) TTCR was 4.53 days (2.95, 5.71) for danirixin 15mg + OSV, 4.76 days (2.71, 5.25) for danirixin 50mg + OSV, and 1.33 days (0.71, 1.95) for placebo + OSV. Adverse events (AEs) were generally of mild or moderate intensity; no serious AEs were considered treatment-related. Interleukin-8 levels increased in nasal samples (using synthetic absorptive matrix strips) and decreased serum neutrophil-elastase-mediated degradation of elastin decreased in danirixin-treated participants, suggesting effective target engagement.

CONCLUSIONS:

Interpretation of efficacy results is restricted by the low participant numbers. The safety and tolerability profile of danirixin was consistent with previous studies.

CLINICAL TRIAL INFORMATION:

The registration data for the trial are in the ClinicalTrials.gov database, number NCT02927431, and in the EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/) as GSK study 201023, EudraCT 2016-002512-40. Anonymized individual participant data and study documents can be requested for further research from http://www.clinicalstudydatarequest.com.

KEYWORDS: CXCR2 antagonist; danirixin; hospitalization; influenza; neutrophils

PMID: 31041358 PMCID: PMC6483311 DOI: 10.1093/ofid/ofz163

Keywords: Seasonal Influenza; Antivirals; Oseltamivir; Danirixin.

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More #targeted use of #oseltamivir and in-hospital #isolation facilities after implementation of a multifaceted strategy including a rapid molecular diagnostic panel for respiratory viruses in immunocompromised adult patients (J Clin Virol., abstract)

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

J Clin Virol. 2019 Apr 7;116:11-17. doi: 10.1016/j.jcv.2019.04.003. [Epub ahead of print]

More targeted use of oseltamivir and in-hospital isolation facilities after implementation of a multifaceted strategy including a rapid molecular diagnostic panel for respiratory viruses in immunocompromised adult patients.

Vos LM1, Weehuizen JM2, Hoepelman AIM2, Kaasjager KHAH3, Riezebos-Brilman A4, Oosterheert JJ2.

Author information: 1 Department of Infectious Diseases, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. Electronic address: l.m.vos-6@umcutrecht.nl. 2 Department of Infectious Diseases, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 3 Department of Acute Internal Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands. 4 Department of Microbiology and Virology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

 

Abstract

BACKGROUND:

Immunocompromised adults are more vulnerable to a complicated course of viral respiratory tract infections (RTI).

OBJECTIVES:

Provide evidence on the effect of implementation of rapid molecular diagnostics for viruses on use of in-hospital isolation facilities, oseltamivir and antibiotic usage, and other clinical outcomes in immunocompromised patients.

STUDY DESIGN:

A before-after study during two consecutive respiratory viral seasons, including immunocompromised adult patients presenting at a tertiary care emergency department with clinical suspicion of RTI. During the first season (2016/2017), respiratory viruses were detected using inhouse real-time PCR. The second season (2017/2018), we implemented a diagnostic flowchart including a rapid molecular test for 15 respiratory viruses (FilmArray®). We assessed the effect of this implementation on need for isolation, antivirals and empirical antibiotics.

RESULTS:

We included 192 immunocompromised adult patients during the first and 378 during the second season. Respiratory viral testing was performed in 135 patients (70%) during the first and 284 (75%) during the second season (p = 0.218) of which 213 (75%) using the rapid test. After implementation, use of in-hospital isolation facilities was reduced (adjusted odds ratio 0.35, 95%CI 0.19-0.64). Furthermore, adequate use of oseltamivir improved, with fewer prescriptions in influenza negative patients (0.15, 95%CI 0.08-0.28) and more in influenza positive patients (11.13, 95%CI 1.75-70.86). No effect was observed on empirical antibiotic use, hospital admissions, length of hospital stay or safety outcomes.

CONCLUSIONS:

Implementation of rapid molecular testing for respiratory viruses in adult immunocompromised patients results in more adequate use of oseltamivir and in-hospital isolation facilities without compromising safety.

Copyright © 2019 Elsevier B.V. All rights reserved.

KEYWORDS: Clinical impact; Immunocompromised; Rapid molecular diagnostics; Respiratory viruses

PMID: 30999234 DOI: 10.1016/j.jcv.2019.04.003

Keywords: Seasonal Influenza; Antivirals; Antibiotics; Oseltamivir.

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More targeted use of #oseltamivir and in-hospital #isolation #facilities after implementation of a multifaceted strategy … (J Clin Virol., abstract)

[Source: Journal of Clinical Virology, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 7 April 2019 / In Press, Accepted Manuscript

More targeted use of oseltamivir and in-hospital isolation facilities after implementation of a multifaceted strategy including a rapid molecular diagnostic panel for respiratory viruses in immunocompromised adult patients

Laura M Vos a, Jesper M Weehuizen a, Andy IM Hoepelman a, Karin HAH Kaasjager b, Annelies Riezebos-Brilman c, Jan Jelrik Oosterheert a

{a} Department of Infectious Diseases, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; {b} Department of Acute Internal Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; {c}
Department of Microbiology and Virology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands

Received 2 January 2019, Revised 4 April 2019, Accepted 6 April 2019, Available online 7 April 2019. DOI: https://doi.org/10.1016/j.jcv.2019.04.003

 

Highlights

  • The implementation of a rapid molecular test for the detection of respiratory viral pathogens in immunocompromised adult patients presenting with acute respiratory illness in a hospital emergency department setting results in more targeted use of oseltamivir and a reduction in the use of in-hospital isolation facilities.
  • No effect was seen on antibiotic use, antibiotic duration, hospital admissions and length of hospital stay.

 

Abstract

Background

Immunocompromised adults are more vulnerable to a complicated course of viral respiratory tract infections (RTI).

Objectives

Provide evidence on the effect of implementation of rapid molecular diagnostics for viruses on use of in-hospital isolation facilities, oseltamivir and antibiotic usage, and other clinical outcomes in immunocompromised patients.

Study design

A before-after study during two consecutive respiratory viral seasons, including immunocompromised adult patients presenting at a tertiary care emergency department with clinical suspicion of RTI. During the first season (2016/2017), respiratory viruses were detected using inhouse real-time PCR. The second season (2017/2018), we implemented a diagnostic flowchart including a rapid molecular test for 15 respiratory viruses (FilmArray®). We assessed the effect of this implementation on need for isolation, antivirals and empirical antibiotics.

Results

We included 192 immunocompromised adult patients during the first and 378 during the second season. Respiratory viral testing was performed in 135 patients (70%) during the first and 284 (75%) during the second season (p = 0.218) of which 213 (75%) using the rapid test. After implementation, use of in-hospital isolation facilities was reduced (adjusted odds ratio 0.35, 95%CI 0.19-0.64). Furthermore, adequate use of oseltamivir improved, with fewer prescriptions in influenza negative patients (0.15, 95%CI 0.08-0.28) and more in influenza positive patients (11.13, 95%CI 1.75-70.86). No effect was observed on empirical antibiotic use, hospital admissions, length of hospital stay or safety outcomes.

Conclusions

Implementation of rapid molecular testing for respiratory viruses in adult immunocompromised patients results in more adequate use of oseltamivir and in-hospital isolation facilities without compromising safety.

Keywords: Rapid molecular diagnostics – clinical impact – respiratory viruses – immunocompromised

© 2019 Elsevier B.V. All rights reserved.

Keywords: Seasonal Influenza; Antivirals; Oseltamivir.

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Selection of #avian #influenza A (#H9N2) virus with reduced susceptibility to #neuraminidase #inhibitors #oseltamivir and #zanamivir (Virus Res., abstract)

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

Virus Res. 2019 Mar 22. pii: S0168-1702(18)30554-9. doi: 10.1016/j.virusres.2019.03.019. [Epub ahead of print]

Selection of avian influenza A (H9N2) virus with reduced susceptibility to neuraminidase inhibitors oseltamivir and zanamivir.

Kode SS1, Pawar SD2, Cherian SS3, Tare DS1, Bhoye D3, Keng SS1, Mullick J1.

Author information: 1 Avian Influenza Group, Microbial Containment Complex, ICMR-National Institute of Virology, Pune, India. 2 Avian Influenza Group, Microbial Containment Complex, ICMR-National Institute of Virology, Pune, India. Electronic address: shaileshpawarniv@gmail.com. 3 Bioinformatics Group, ICMR-National Institute of Virology, Pune, India.

 

Abstract

Identification of amino-acid substitutions in the neuraminidase (NA) of low-pathogenic avian influenza (AI) H9N2 viruses is important to study the susceptibility to NA inhibitors (NAI). To identify mutations under NAI selective pressure, the virus was serially passaged with increasing levels of either oseltamivir or zanamivir in ovo, and the growth of the viruses in the presence and absence of NAI’s compared. Mutations R292 K in the presence of oseltamivir and E119D in presence of zanamivir were observed within passage one and two respectively. The R292 K mutation reduced oseltamivir susceptibility significantly (2,523-fold) and moderately reduced susceptibility to zanamivir. The E119D mutation significantly reduced susceptibility to zanamivir (415-fold) and remained susceptible to oseltamivir. Genetic stability of the mutations assessed by serial passages of the mutant viruses in eggs without drug pressure resulted in the loss of these mutations, making the virus susceptible to both the drugs. Molecular modeling and dynamics simulations revealed that the R292 K mutation disrupted oseltamivir binding similar to other group 2 NAs, while a different mechanism was noted for zanamivir binding for both R292 K and E119D mutations. The study highlights the need for regular susceptibility screening of circulating AI viruses.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS: Antiviral resistance; Avian influenza; H9N2; Molecular dynamics; Oseltamivir; Zanamivir

PMID: 30910698 DOI: 10.1016/j.virusres.2019.03.019

Keywords: Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Avian Influenza; H9N2.

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