Effect of early #oseltamivir #treatment on #mortality in critically ill patients with different types of #influenza: a multi-season cohort study (Clin Infect Dis., abstract)

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

Clin Infect Dis. 2019 Feb 7. doi: 10.1093/cid/ciz101. [Epub ahead of print]

Effect of early oseltamivir treatment on mortality in critically ill patients with different types of influenza: a multi-season cohort study.

Lytras T1, Mouratidou E1,2, Andreopoulou A1, Bonovas S3,4, Tsiodras S1,5.

Author information: 1 Hellenic Centre for Disease Control and Prevention, Athens, Greece. 2 European Programme for Intervention Epidemiology Training (EPIET), European Centre for Disease Prevention and Control (ECDC), Stockholm, Sweden. 3 Department of Biomedical Sciences, Humanitas University, Milan, Italy. 4 Humanitas Clinical and Research Center, Milan, Italy. 5 4th Department of Internal Medicine, Attikon University Hospital, University of Athens Medical School, Athens, Greece.

 

Abstract

BACKGROUND:

The available evidence on whether neuraminidase inhibitors reduce mortality in patients with influenza is inconclusive, and focuses solely on influenza A/H1N1pdm09. We assessed whether early oseltamivir treatment (≤48 hours from symptom onset) decreases mortality compared to late treatment in a large cohort of critically ill patients with influenza of all types.

METHODS:

The study included all adults with laboratory-confirmed influenza hospitalized in intensive care units (ICU) in Greece over eight seasons (2010-2011 to 2017-2018) and treated with oseltamivir. The association of early oseltamivir with mortality was assessed with log-binomial models, and a competing risks analysis estimating cause-specific and subdistribution hazards for death and discharge. Effect estimates were stratified by influenza type and adjusted for multiple covariates.

RESULTS:

1330 patients were studied, of whom 622 (46.8%) died in the ICU. Among patients with influenza A/H3N2, early treatment was associated with significantly lower mortality (Relative Risk 0.69, 95% CrI 0.49-0.94; subdistribution Hazard Ratio 0.58, 95% CrI 0.37-0.88). This effect was purely due to an increased cause-specific hazard for discharge, while the cause-specific hazard for death was not increased. Among survivors, the median length of ICU stay was shorter with early treatment by 1.8 days (95% CrI 0.5-3.5). No effect on mortality was observed for A/H1N1 and influenza B patients.

CONCLUSIONS:

Severely ill patients with suspected influenza should be promptly treated with oseltamivir, particularly when A/H3N2 is circulating. The efficacy of oseltamivir should not be assumed to be equal against all types of influenza.

PMID: 30753349 DOI: 10.1093/cid/ciz101

Keywords: Seasonal Influenza; H1N1pdm09; H3N2; Antivirals; Oseltamivir.

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Preliminary results on the #uptake and #biochemical response to #water-exposure of Tamiflu® (#oseltamivir phosphate) in two marine #bivalves (J Toxicol Environ Health A., abstract)

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

J Toxicol Environ Health A. 2019 Jan 22:1-11. doi: 10.1080/15287394.2018.1562393. [Epub ahead of print]

Preliminary results on the uptake and biochemical response to water-exposure of Tamiflu® (oseltamivir phosphate) in two marine bivalves.

Dallarés S1, Montemurro N2, Pérez S2, Rodríguez-Sanchez N3, Solé M1.

Author information: 1a Institute of Marine Sciences (ICM-CSIC) , Barcelona , Spain. 2b Institute for Environmental Assessment and Water Research (IDAEA-CSIC) , Barcelona , Spain. 3c Chemicals Regulation Directorate , Bootle , UK.

 

Abstract

Tamiflu® (oseltamivir phosphate, OST) is an antiviral drug used for the pandemic treatment of avian influenza but few data are available regarding its toxicity. It should be noted that acute adverse responses are not likely to occur due to low environmental presence of this drug. Nonetheless, water concentration levels of this compound may reach the µg/L range under influenza episodes. Bivalves are reliable sentinels of chemical exposure due to their low metabolism; however, biotransformation of drugs does occur in these aquatic invertebrates. Two species of bivalves, namely mussels Mytilus galloprovincialis and clams Ruditapes philippinarum, were exposed for 48 h to 100 µg/L OST. Hemolymph from control and treated bivalves was withdrawn and the presence of OST and its metabolite oseltamivir carboxylate (OST-C) determined by LC-MS/MS. Gills and digestive gland were excised from control and exposed bivalves and carboxylesterase (CE) activities measured using different substrates. In addition, antioxidant defences and lipid peroxidation levels were determined. Higher metabolism of OST seemed to occur in mussels, since both OST and OST-C were found in hemolymph, whereas in clams only the parent compound was detected. In contrast, biomarker responses were more evident in exposed clams which indicate that this species may be considered as more sensitive to OST exposure. CE-related activities successfully reflected OST exposure, with substrates 1-naphthyl acetate (1NA) and 1-naphthyl butyrate (1NB) displaying the highest sensitivity in the two bivalve species. Data thus indicate the usefulness of CE-related activities as biomarkers for OST exposure in bivalves.

KEYWORDS: Bivalves; antiviral drug; carboxylesterases; oseltamivir carboxylate; oxidative stress

PMID: 30669952 DOI: 10.1080/15287394.2018.1562393

Keywords: Antivirals; Toxic chemicals; Environmental pollution; Wildlife; Oseltamivir.

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Suspected #Oseltamivir-induced #bradycardia in a #pediatric patient: A case report from King Abdullah Specialist Children’s Hospital, Riyadh, #Saudi Arabia (Clin Pract., abstract)

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

Clin Pract. 2018 Nov 28;8(4):1094. doi: 10.4081/cp.2018.1094. eCollection 2018 Oct 26.

Suspected Oseltamivir-induced bradycardia in a pediatric patient: A case report from King Abdullah Specialist Children’s Hospital, Riyadh, Saudi Arabia.

Arabi H1, Zaid AA1, Alreefi M2, Alahmed S2.

Author information: 1 King Abdullah Specialist Children’s Hospital, National Guard Health Affairs. 2 College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.

 

Abstract

In recent years, influenza infection in the pediatric population has been a widescale issue that physicians face during the winter season. Medications used to treat and prevent such infections include Oseltamivir, an anti-viral neuraminidase inhibitor developed for both influenzas A and B. The most commonly well-known and manifesting adverse effects are nausea, vomiting and gastrointestinal upset. There is paucity of reports on other potential serious side effects of Oseltamivir in the pediatric population. One of the rarely reported adverse reactions in adult population is sinus bradycardia. This case reports the development of sinus bradycardia in a pediatric patient after administration of Oseltamivir. The previously healthy five-year-old patient was started on Oseltamivir after a positive polymerase chain reaction for influenza. The patient developed sinus bradycardia but remained hemodynamically stable. This finding led to consultations and investigations to determine the cause of bradycardia. It is pivotal to increase the awareness of the potential link between Oseltamivir and bradycardia in pediatric and adult populations to avoid unnecessary clinical investigations and to enhance physician decisionmaking. A prospective cohort study on Oseltamivir is needed for better understanding of its adverse effects in the pediatric population.

KEYWORDS: Bradycardia; Influenza; Oseltamvir; Pediatrics

PMID: 30595829 PMCID: PMC6280064 DOI: 10.4081/cp.2018.1094

Keywords: Seasonal Influenza; Antivirals; Oseltamivir; Bradycardia; Drugs safety.

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Detection of #NAI-#resistant #influenza A (#H1N1)pdm09 viruses obtained from influenza #surveillance in #Indonesia (SAGE Open Med., abstract)

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

SAGE Open Med. 2018 Dec 10;6:2050312118818293. doi: 10.1177/2050312118818293. eCollection 2018.

Detection of neuraminidase inhibitor-resistant influenza A (H1N1)pdm09 viruses obtained from influenza surveillance in Indonesia.

Pawestri HA1, Nugraha AA1, Hariastuti NI1, Setiawaty V1.

Author information: 1 National Institute of Health Research Development, Ministry of Health, Jakarta, Republic of Indonesia.

 

Abstract

BACKGROUND:

Influenza antiviral resistance has been shown to occur in many countries and is commonly found in influenza A(H1N1)pdm09 and A(H3N2). In this study, we monitored and investigated the neuraminidase inhibitor resistance of influenza A(H1N1)pdm09 viruses through the influenza surveillance system in Indonesia.

METHODS:

A total of 4752 clinical specimens were collected from patients with influenza-like illness and severe acute respiratory infection during the year 2016. An allelic discrimination assay was conducted by a single base substitution or a single-nucleotide polymorphism that is specific to the H275 wild-type and Y275 mutant. Sequencing was performed to confirm the H275Y mutations, and we analysed the phylogenetic relationship.

RESULTS:

The first occurrence of oseltamivir-resistant influenza A(H1N1)pdm09 was observed in the samples from the influenza-like illness surveillance. Two H275Y oseltamivir-resistant viruses (0.74%) out of 272 influenza A(H1N1)pdm09 positives were found. Both of them were collected from untreated patients.

CONCLUSION:

The number of oseltamivir-resistant influenza A(H1N1)pdm09 viruses in Indonesia is very low. However, it is necessary to continue with active surveillance for oseltamivir resistance in severe and mild cases.

KEYWORDS: Neuraminidase inhibitor resistant; influenza A(H1N1)pdm09; surveillance

PMID: 30574303 PMCID: PMC6295675 DOI: 10.1177/2050312118818293

Keywords: Influenza A; H1N1pdm09; Indonesia; Antivirals; Drugs Resistance; Oseltamivir.

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In vitro and in vivo characterization of novel #neuraminidase #substitutions in #influenza A #H1N1pdm09 identified using #Laninamivir-mediated in vitro selection (J Virol., abstract)

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

In vitro and in vivo characterization of novel neuraminidase substitutions in influenza A(H1N1)pdm09 identified using Laninamivir-mediated in vitroselection

Khristine Kaith S. Lloren, Jin Jung Kwon, Won-Suk Choi, Ju Hwan Jeong, Su Jeong Ahn, Young Ki Choi, Yun Hee Baek, Min-Suk Song

DOI: 10.1128/JVI.01825-18

 

ABSTRACT

Neuraminidase inhibitors (NAIs) are widely used antiviral drugs for the treatment of humans with influenza virus infections. There have been widespread reports of NAI resistance among seasonal A(H1N1) viruses, and most have been identified in oseltamivir-exposed patients or those treated with other NAIs. Thus, monitoring and identifying NA markers conferring resistance to NAIs—particularly newly introduced treatments—is critical to manage viral infections. Therefore, we screened and identified substitutions conferring resistance to laninamivir by enriching random mutations in the NA gene of the 2009 pandemic influenza [A(H1N1)pdm09] followed by deep sequencing of the laninamivir-selected variants. After the generation of single mutants possessing each identified mutation, two A(H1N1)pdm09 recombinants possessing novel NA gene substitutions (ie, D199E and P458T) were shown to confer resistance to more than one NAI. Of note, mutants possessing P458T—which is located outside of the catalytic or framework residue of the NA active site—exhibited highly reduced inhibition by all four approved NAIs. Using MDCK cells, we observed that the in vitro viral replication of the two recombinants was lower compared with WT. Additionally, in infected mice, decreased mortality and/or mean lung viral titers were observed in mutants compared with WT. Reverse mutations to WT were observed in the lung homogenate samples from D199E-infected mice after 3 serial passages. Overall, the novel NA substitutions identified which could possibly emerge in influenza A(H1N1)pdm09 during laninamivir therapy and have altered NAI susceptibility, but the compromised in vitro/in vivo viral fitness may limit viral spreading.

 

IMPORTANCE

With the widespread emergence of NAI-resistant influenza virus strains, continuous monitoring of mutations that confer antiviral resistance is needed. Laninamivir is the most recently approved NAIs in several countries; little data exists related to the in vitro selection of viral mutations conferring resistance to laninamivir. Thus, we screened and identified substitutions conferring resistance to laninamivir by random mutagenesis in the NA gene of the 2009 pandemic influenza [A(H1N1)pdm09] strain followed by deep sequencing of the laninamivir-selected variants. We found several novel substitutions in NA (D199E and P458T) in an A(H1N1)pdm09 background which demonstrated resistance to NAIs and which have an impact on viral fitness. Our study highlights the importance of continued surveillance for potential antiviral-resistant variants and the development of alternative therapeutics.

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

Keywords: Influenza A; H1N1pdm09; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir; Laninamivir.

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In Vitro Properties and #Virulence of Contemporary #Recombinant #Influenza B Viruses Harboring #Mutations of Cross- #Resistance to #Neuraminidase Inhibitors (Viruses, abstract)

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

Viruses. 2018 Dec 22;11(1). pii: E6. doi: 10.3390/v11010006.

In Vitro Properties and Virulence of Contemporary Recombinant Influenza B Viruses Harboring Mutations of Cross-Resistance to Neuraminidase Inhibitors.

Fage C1, Abed Y2, Checkmahomed L3, Venable MC4, Boivin G5.

Author information: 1 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. Clement.Fage2@crchudequebec.ulaval.ca. 2 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. yacine.abed@crchudequebec.ulaval.ca. 3 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. liva.checkmahomed@crchudequebec.ulaval.ca. 4 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. marie-christine.venable@crchudequebec.ulaval.ca. 5 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. guy.boivin@crchudequebec.ulaval.ca.

 

Abstract

Three neuraminidase inhibitors (NAIs: Oseltamivir, zanamivir and peramivir) are currently approved in many countries for the treatment of influenza A and B infections. The emergence of influenza B viruses (IBVs) containing mutations of cross-resistance to these NAIs constitutes a serious clinical threat. Herein, we used a reverse genetics system for the current B/Phuket/3073/2013 vaccine strain to investigate the impact on in vitro properties and virulence of H136N, R152K, D198E/N, I222T and N294S NA substitutions (N2 numbering), reported by the World Health Organization (WHO) as clinical markers of reduced or highly-reduced inhibition (RI/HRI) to multiple NAIs. Recombinant viruses were tested by NA inhibition assays. Their replicative capacity and virulence were evaluated in ST6GalI-MDCK cells and BALB/c mice, respectively. All NA mutants (excepted D198E/N) showed RI/HRI phenotypes against ≥ 2 NAIs. These mutants grew to comparable titers of the recombinant wild-type (WT) IBV in vitro, and some of them (H136N, I222T and N294S mutants) induced more weight loss and mortality in BALB/c mice in comparison to the recombinant WT IBV. These results demonstrate that, in contemporary IBVs, some NA mutations may confer RI/HRI phenotypes to existing NAIs without altering the viral fitness. This reinforces the need for development of novel antiviral strategies with different mechanisms of action.

KEYWORDS: fitness; influenza B; mouse model and neuraminidase mutation; resistance

PMID: 30583488 DOI: 10.3390/v11010006

Keywords: Influenza B; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

——

In Vitro #Properties and #Virulence of Contemporary Recombinant #Influenza B Viruses Harboring Mutations of Cross- #Resistance to #Neuraminidase Inhibitors (Viruses, abstract)

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

Viruses. 2018 Dec 22;11(1). pii: E6. doi: 10.3390/v11010006.

In Vitro Properties and Virulence of Contemporary Recombinant Influenza B Viruses Harboring Mutations of Cross-Resistance to Neuraminidase Inhibitors.

Fage C1, Abed Y2, Checkmahomed L3, Venable MC4, Boivin G5.

Author information: 1 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. Clement.Fage2@crchudequebec.ulaval.ca. 2 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. yacine.abed@crchudequebec.ulaval.ca. 3 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. liva.checkmahomed@crchudequebec.ulaval.ca. 4 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. marie-christine.venable@crchudequebec.ulaval.ca. 5 Research Center in Infectious Diseases of the CHUQ-CHUL and Laval University, 2705 Boulevard Laurier, Québec City, QC G1V 4G2, Canada. guy.boivin@crchudequebec.ulaval.ca.

 

Abstract

Three neuraminidase inhibitors (NAIs: Oseltamivir, zanamivir and peramivir) are currently approved in many countries for the treatment of influenza A and B infections. The emergence of influenza B viruses (IBVs) containing mutations of cross-resistance to these NAIs constitutes a serious clinical threat. Herein, we used a reverse genetics system for the current B/Phuket/3073/2013 vaccine strain to investigate the impact on in vitro properties and virulence of H136N, R152K, D198E/N, I222T and N294S NA substitutions (N2 numbering), reported by the World Health Organization (WHO) as clinical markers of reduced or highly-reduced inhibition (RI/HRI) to multiple NAIs. Recombinant viruses were tested by NA inhibition assays. Their replicative capacity and virulence were evaluated in ST6GalI-MDCK cells and BALB/c mice, respectively. All NA mutants (excepted D198E/N) showed RI/HRI phenotypes against ≥ 2 NAIs. These mutants grew to comparable titers of the recombinant wild-type (WT) IBV in vitro, and some of them (H136N, I222T and N294S mutants) induced more weight loss and mortality in BALB/c mice in comparison to the recombinant WT IBV. These results demonstrate that, in contemporary IBVs, some NA mutations may confer RI/HRI phenotypes to existing NAIs without altering the viral fitness. This reinforces the need for development of novel antiviral strategies with different mechanisms of action.

KEYWORDS: fitness; influenza B; mouse model and neuraminidase mutation; resistance

PMID: 30583488 DOI: 10.3390/v11010006

Keywords: Influenza B; Antivirals; Drugs Resistance; Oseltamivir; Zanamivir; Peramivir.

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