Characterization of Multidrug-Resistant Influenza A/H3N2 Viruses Shed during 1 Year by an Immunocompromised Child
Open Access
- 15 December 2006
- journal article
- Published by Oxford University Press (OUP) in Clinical Infectious Diseases
- Vol. 43 (12), 1555-1561
- https://doi.org/10.1086/508777
Abstract
Background. Development of influenza drug resistance is an important problem in immunocompromised children that could result in treatment failure and viral transmission to others. Methods.A total of 17 influenza A/H3N2 isolates were recovered over a period of 1 year from an immunocompromised child who was initially treated with oseltamivir and then with amantadine and zanamivir for viral pneumonitis. Drug susceptibility phenotypes to oseltamivir, zanamivir, and peramivir were evaluated by neuraminidase (NA) inhibition assays, and sequence analysis of key viral genes (i.e., M2, NA, and hemagglutinin [HA]) was performed. The impact of NA mutations identified in oseltamivir-resistant isolates was analyzed using recombinant NA proteins. Results. An influenza A variant with NA mutations E59G, E119V, and I222V was first detected after 38 days of oseltamivir treatment. In an NA inhibition assay, this variant was 274 times more resistant to oseltamivir than the original isolate but was susceptible to zanamivir. The I222V substitution enhanced the level of oseltamivir resistance that was primarily conferred by the E119V mutation in recombinant NA proteins. Remarkably, the E119V mutation persisted for 8 months after cessation of oseltamivir. Amantadine therapy led to rapid emergence of the M2 mutation S31N, which is known to confer amantadine resistance. The patient shed the virus intermittently while receiving nebulized zanamivir therapy despite the absence of a resistance phenotype, which could be the result of nonoptimal drug delivery and impaired host immunity. Conclusions. This study highlights the potential for emergence and persistence of multidrug-resistant influenza isolates in immunocompromised subjects even after cessation of treatment, reinforcing the need for development of new anti-influenza compounds.Keywords
This publication has 35 references indexed in Scilit:
- Neuraminidase Inhibitor-Resistant and -Sensitive Influenza B Viruses Isolated from an Untreated Human PatientAntimicrobial Agents and Chemotherapy, 2006
- Isolation of drug-resistant H5N1 virusNature, 2005
- Molecular mechanisms of influenza virus resistance to neuraminidase inhibitorsVirus Research, 2004
- Avian Influenza: A New Pandemic Threat?Mayo Clinic Proceedings, 2004
- Chimeric Influenza A Viruses with a Functional Influenza B Virus Neuraminidase or HemagglutininJournal of Virology, 2003
- Low mortality rates related to respiratory virus infections after bone marrow transplantationBone Marrow Transplantation, 2003
- Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factorsBlood, 2002
- Treatment of influenza with neuraminidase inhibitors: virological implicationsPhilosophical Transactions Of The Royal Society B-Biological Sciences, 2001
- Selection of Influenza Virus Mutants in Experimentally Infected Volunteers Treated with OseltamivirThe Journal of Infectious Diseases, 2001
- Emergence and Apparent Transmission of Rimantadine-Resistant Influenza A Virus in FamiliesNew England Journal of Medicine, 1989