Intravenous Zanamivir for Oseltamivir-Resistant 2009 H1N1 Influenza

Gaur, Aditya H.; Bagga, Bindiya; Barman, Subrata; Hayden, Randall T.; Lamptey, Aubrey; Hoffman, James M.; Bhojwani, Deepa; Flynn, Patricia M.; Tuomanen, Elaine; Webby, R

doi:10.1056/nejmc0910893

Cited by 119 publications

(86 citation statements)

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“…Oseltamivir is available only for oral intake (1), whereas zanamivir may be inhaled or given intravenously (2,3). While oseltamivir resistance has been studied extensively in seasonal H1N1 (sH1N1) (4-7) and pandemic H1N1 (pH1N1) (7-11) FLUAV strains, there are only a few reports of zanamivir resistance.…”

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confidence: 99%

“…Moreover, oseltamivir has been associated with neuropsychiatric side effects in pediatric settings primarily in Japan, emphasizing the need for alternative antiviral agents (29). To date, the intravenous formulation of zanamivir, which is in phase III clinical development, has been used in cases of oseltamivir resistance in pediatric and intensive care patients (3,30,31). In order to optimize therapy in the future, detection and characterization of mutations that confer zanamivir resistance is important.…”

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confidence: 99%

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Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Kaminski

Ohnemus

Staeheli

et al. 2013

J Virol

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Resistance of influenza A viruses to neuraminidase inhibitors can arise through mutations in the neuraminidase (NA) gene. We show here that a Q136K mutation in the NA of the 2009 pandemic H1N1 virus confers a high degree of resistance to zanamivir. Resistance is accompanied by reduced numbers of NA molecules in viral particles and reduced intrinsic enzymatic activity of mutant NA. Interestingly, the Q136K mutation strongly impairs viral fitness in the guinea pig transmission model. N euraminidase (NA) inhibitors, such as oseltamivir and zanamivir, are the most commonly used antiviral drugs for the treatment of severe infections with influenza A virus (FLUAV). Oseltamivir is available only for oral intake (1), whereas zanamivir may be inhaled or given intravenously (2, 3). While oseltamivir resistance has been studied extensively in seasonal H1N1 (sH1N1) (4-7) and pandemic H1N1 (pH1N1) (7-11) FLUAV strains, there are only a few reports of zanamivir resistance. A Q136K mutation in the viral neuraminidase was shown to confer zanamivir resistance in seasonal H1N1 virus strains (12,13). An I223R mutation in the NA of a clinical pH1N1 isolate was reported to confer resistance to both oseltamivir and zanamivir (14,15). Both mutant viruses retained good transmissibility in the ferret transmission model (12, 15). Further, E119G or E119V mutations introduced by reverse genetics into the NA of a Canadian pH1N1 virus isolate were shown to confer multidrug resistance. However, both mutants exhibited severely compromised fitness (16). To date, there are no reports on NA mutations in the background of pH1N1 which would solely confer a high degree of resistance to zanamivir. Here, we investigated the potential of the pH1N1 strain A/Hansa Hamburg/01/2009 (identical to A/Hamburg/05/2009; GenBank accession numbers HQ111361 to HQ111368) to acquire zanamivir resistance.The virus was subjected to 11 serial passages on Madin-Darby canine kidney (MDCK) cells in the presence of escalating concentrations of zanamivir starting from 1 nM up to 2 mM in the final passage. Zanamivir resistance of the passaged viruses was determined by the NA-Star assay (Applied Biosystems) which measures neuraminidase activity with a defined substrate (17). The 50% inhibitory concentration (IC 50 ) values of zanamivir started to rise at passage 8 and reached a value of ϳ5 nM at passage 11 (Fig. 1A). Sequencing of plaque-purified viruses from passage 11 revealed a glutamine-to-lysine mutation at amino acid position 136 of NA (Q136K). This mutation, as well as the well-described H275Y oseltamivir resistance mutation in NA, was introduced into the wild-type virus using reverse genetics. We found that the virus carrying the Q136K mutation exhibited an 86-fold increase in the IC 50 for zanamivir compared to the wild-type virus (Fig. 1B) but remained sensitive to oseltamivir carboxylic acid (TRC Inc., North York, Canada). In agreement with previous results (11), the H275Y mutant virus exhibited a high degree of resistance to oseltamivir but remained susceptible to ...

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confidence: 99%

Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Kaminski

Ohnemus

Staeheli

et al. 2013

J Virol

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“…Prompt use of neuraminidase inhibitors has been recommended for the treatment of patients with influenza (18); however, administration of anti-influenza drugs via conventional routes (tablets, suspension, or oral inhalation) may not be practical or appropriate for hospitalized patients, as a result of impaired absorption (of oral agents) from the gut or inability to administer these drugs to patients requiring mechanical ventilation. Furthermore, recent reports of resistance to oseltamivir further highlight the critical need for additional treatment options (4,5,6,13,17).…”

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Zanamivir Pharmacokinetics and Pulmonary Penetration into Epithelial Lining Fluid following Intravenous or Oral Inhaled Administration to Healthy Adult Subjects

Shelton

Lovern

Ng-Cashin

et al. 2011

Antimicrob Agents Chemother

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Zanamivir serum and pulmonary pharmacokinetics were characterized following intravenous (i.v.) or oral inhaled administration. I.v. zanamivir was given as intermittent doses of 100 mg, 200 mg, and 600 mg every 12 h (q12h) for two doses or as a continuous infusion (6-mg loading dose followed by 3 mg/h for 12 h). Oral inhaled zanamivir (two 5-mg inhalations q12h for two doses) was evaluated as well. Each zanamivir regimen was administered to six healthy subjects with serial pharmacokinetic sampling. In addition, a single bronchoalveolar lavage (BAL) fluid sample was collected at various time points and used to calculate epithelial lining fluid (ELF) drug concentrations for each subject. For intermittent i.v. administration of 100 mg, 200 mg, and 600 mg zanamivir, the median zanamivir concentrations in ELF collected 12 h after dosing were 74, 146, and 419 ng/ml, respectively, each higher than the historic mean 50% inhibitory concentrations for the neuraminidases of wild-type strains of influenza A and B viruses. Median ELF/serum zanamivir concentration ratios ranged from 55 to 79% for intermittent i.v. administration (when sampled 12 h after the last dose) and 43 to 45% for continuous infusion (when sampled 6 to 12 h after the start of the infusion). For oral inhaled zanamivir, the median zanamivir concentrations in ELF were 891 ng/ml for the first BAL fluid collection and 326 ng/ml for subsequent BAL fluid collections (when sampled 12 h after the last dose); corresponding serum drug concentrations were undetectable. This study demonstrates zanamivir's penetration into the human pulmonary compartment and supports the doses selected for the continuing development of i.v. zanamivir in clinical studies of influenza.

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“…Declining or persistently low C T values during therapy, as in our patients, correlated with clinical worsening and the development of oseltamivir resistance long before confirmatory resistance testing results were available. Likewise, rising C T values corresponding to clinical improvement of oseltamivir-resistant H1N1 infection treated with zanamivir have been reported (5,6). Such data can also help discern the pathogenic role of H1N1 virus in immunosuppressed patients with multiple potential copathogens.…”

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confidence: 89%

Detection of Oseltamivir Resistance during Treatment of 2009 H1N1 Influenza Virus Infection in Immunocompromised Patients: Utility of Cycle Threshold Values of Qualitative Real-Time Reverse Transcriptase PCR

et al. 2010

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Two immunocompromised patients with 2009 H1N1 influenza pneumonia had viral shedding for over 5 weeks despite therapy with oseltamivir. Declining or persistently low cycle threshold values noted on serial qualitative real-time reverse transcriptase PCR (rRT-PCR) of respiratory specimens implied increasing viral load and probable drug resistance. Oseltamivir resistance was later confirmed by pyrosequencing. CASE REPORTSCase report 1. A 52-year-old male with myelodysplastic syndrome underwent an allogeneic hematopoietic stem cell transplantation (HSCT) complicated by graft-versus-host disease (GVHD) and bronchiolitis obliterans of his lungs. On day 864 post-HSCT, he developed cough and pleuritic chest pain. Nodular cavitary infiltrates were identified by computed tomography scan (CT) of his thorax. Aspergillus fumigatus was isolated from bronchoalveolar lavage (BAL) fluid, and the BAL fluid Aspergillus galactomannan assay was positive. Voriconazole therapy was initiated for probable pulmonary aspergillosis. Rhinovirus was detected on PCR assay of BAL fluid. Mycobacterium avium complex was also isolated from BAL fluid and was considered to represent colonization.On day 990 post-HSCT, in November 2009, he was hospitalized with fever, progressive dyspnea, and nonproductive cough. In addition to voriconazole, he was receiving methylprednisone, tacrolimus, sirolimus, imatinib mesylate, and extracorporeal photopheresis as therapy for GVHD. His oxygen saturation was 83% when he was breathing ambient air, and he had crackles at both lung bases. A computed tomography (CT) scan of the thorax demonstrated new bilateral lung infiltrates. The rapid influenza diagnostic test (RIDT) of the nasal wash was positive for influenza A virus, which was also isolated on viral culture. Oseltamivir (75 mg twice daily [BID] for 10 days) as well as empirical broad-spectrum antibiotic therapy was initiated. His symptoms improved within 7 days, and he was discharged to a rehabilitation facility. The patient was not retested for influenza virus at time of discharge.One week later he was admitted to the intensive care unit (ICU) with acute shortness of breath. A CT scan revealed interval improvement of the prior lung infiltrates. Empirical therapy with meropenem and vancomycin was begun for possible nosocomial lower respiratory tract infection. The methylprednisone dose was increased to 2 mg/kg/day for suspected worsening of bronchiolitis obliterans. On ICU day 8, he required mechanical ventilation. Bronchoscopy was performed; the BAL fluid tested positive for influenza A virus on RIDT, the novel 2009 H1N1 influenza virus (H1N1) was detected by real-time reverse transcriptase PCR (rRT-PCR), the cycle threshold (C T ) was 29, and influenza A virus was isolated from viral culture. Therapy with high-dose oseltamavir (150 mg BID) was initiated, the steroid dose was tapered, and antibiotics were discontinued. Therapy was switched to intravenous (i.v.) peramivir on day 10. Aerosolized zanamivir could not be administered, as the patient was being mech...

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Intravenous Zanamivir for Oseltamivir-Resistant 2009 H1N1 Influenza

Abstract: T h e ne w e ngl a nd jou r na l o f m e dic i ne n engl j med 362;1 nejm.org

Cited by 119 publications

References 3 publications

Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Pandemic 2009 H1N1 Influenza A Virus Carrying a Q136K Mutation in the Neuraminidase Gene Is Resistant to Zanamivir but Exhibits Reduced Fitness in the Guinea Pig Transmission Model

Zanamivir Pharmacokinetics and Pulmonary Penetration into Epithelial Lining Fluid following Intravenous or Oral Inhaled Administration to Healthy Adult Subjects

Detection of Oseltamivir Resistance during Treatment of 2009 H1N1 Influenza Virus Infection in Immunocompromised Patients: Utility of Cycle Threshold Values of Qualitative Real-Time Reverse Transcriptase PCR

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