Correspondence
Intravenous Zanamivir for Oseltamivir-Resistant 2009 H1N1 Influenza
N Engl J Med 2010; 362:88-89January 7, 2010
- Article
To the Editor:
A 10-year-old girl with acute lymphoblastic leukemia was transferred to our hospital on August 31. The patient required mechanical ventilation for worsening lobar pneumonia, despite the administration of broad-spectrum antibiotics (for details, see the Supplementary Appendix, available with the full text of this letter at NEJM.org). Two weeks earlier, she had completed 5 days of oseltamivir for an upper respiratory tract infection caused by influenza A virus (with positive results on rapid antigen testing). On August 27, she had presented with lobar pneumonia (with negative results on rapid antigen testing).
On admission to our hospital, infection with 2009 pandemic influenza A (H1N1) virus was confirmed from a tracheal aspirate sample on direct fluorescence and polymerase-chain-reaction (PCR) assays. Despite the administration of oseltamivir (75 mg through a nasogastric tube every 12 hours, starting September 1) and broad-spectrum antibiotics, the infection progressed to bilateral diffuse airspace disease with severe hypoxemia during the next 7 days (Figure 1Figure 1
Timeline of 2009 H1N1 Influenza in a 10-Year-Old Girl with Acute Lymphoblastic Leukemia.). The frequency of oseltamivir was increased to every 6 hours, starting on September 6, given the concern regarding drug bioavailability in this patient, who required nasogastric suction. The presence of oseltamivir-resistant virus with the H275Y neuraminidase mutation was detected in a nasal-wash specimen that was obtained on September 7 (with results reported on September 9). In retrospect, both oseltamivir-sensitive and oseltamivir-resistant subpopulations were detectable in a tracheal aspirate sample collected on September 1 (Fig. S1 in the Supplementary Appendix). The H275Y mutation confers resistance to oseltamivir and reduced in vitro susceptibility to peramivir, although zanamivir susceptibility is retained.A request for intravenous zanamivir was granted under an emergency investigational-new-drug application. On September 10, oseltamivir was stopped, and with approval of the local institutional review board and parental consent, the patient received 600 mg of zanamivir every 12 hours intravenously for 15 days. Serial PCR cycle threshold values in tracheal aspirate samples suggested a substantial decrease in the viral load, with a final negative value on October 3 (Figure 1). No zanamivir-related adverse effects were observed, and the patient was weaned off the ventilator on October 5.
Although the majority of 2009 H1N1 viruses are susceptible to oseltamivir, at least 39 cases of oseltamivir-resistant H1N1 influenza have been reported worldwide.1 This case highlights the importance of testing for oseltamivir resistance in patients with persistent 2009 H1N1 virus infection. Such resistance may have developed in our patient with the initial 5-day oseltamivir treatment, and this mutation may have persisted for 2 weeks after stopping the drug. These findings have infection-control implications.
The poor sensitivity of rapid antigen testing for the detection of 2009 H1N1 virus has been shown previously.2 In the absence of real-time access to testing for oseltamivir resistance, clinicians who are treating immunocompromised patients with suspected or proven 2009 H1N1 influenza who have persistent respiratory symptoms should have a high index of suspicion for drug resistance and consider zanamivir for treatment. For critically ill patients, the choice is limited, since aerosolized zanamivir that is delivered through the ventilatory circuit is not recommended,3 and the intravenous preparation4 is not commercially available.5
Aditya H. Gaur, M.D.
Bindiya Bagga, M.D.
Subrata Barman, Ph.D.
Randall Hayden, M.D.
Aubrey Lamptey, M.D.
James M. Hoffman, Pharm.D.
Deepa Bhojwani, M.D.
Patricia M. Flynn, M.D.
Elaine Tuomanen, M.D.
Richard Webby, Ph.D.
St. Jude Children's Research Hospital, Memphis, TN
aditya.gaur@stjude. org Supported in part by a contract with the National Institute of Allergy and Infectious Diseases (HHSN266200700005C), a grant from the National Institutes of Health (CA21765), and the American Lebanese Syrian Associated Charities.
Financial and other disclosures provided by the authors are available with the full text of this letter at NEJM.org.
This letter (10.1056/NEJMc0910893) was published on December 23, 2009, at NEJM.org.
5 References1
WHO pandemic (H1N1) weekly update. Geneva: World Health Organization, October 30, 2009. (Accessed December 15, 2009, at http://www.who.int/csr/disease/swineflu/laboratory30_10_2009/en/index.html.)
2
Vasoo S ,Stevens J ,Singh K . Rapid antigen tests for diagnosis of pandemic (swine) influenza A/H1N1. Clin Infect Dis 2009;49:1090-1093
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Safety letter from GlaxoSmithKline regarding Relenza (zanamivir). Silver Spring, MD: Food and Drug Administration, October 8, 2009. (Accessed December 15, 2009, at http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM186224.pdf.)
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Calfee DP ,Peng AW ,Cass LM ,Lobo M ,Hayden FG . Safety and efficacy of intravenous zanamivir in preventing experimental human influenza A virus infection. Antimicrob Agents Chemother 1999;43:1616-1620
Web of Science | Medline5
Kidd IM ,Down J ,Nastouli E , et al. H1N1 pneumonitis treated with intravenous zanamivir. Lancet 2009;374:1036-1036
CrossRef | Web of Science | Medline
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