Case report
Oseltamivir-induced resistant pandemic A/H1N1 influenza virus in a child with cystic fibrosis and Pseudomonas aeruginosa infection

https://doi.org/10.1016/j.jcv.2010.02.019Get rights and content

Abstract

Background

Oseltamivir is considered the drug of choice for patients with pandemic influenza for whom drug treatment is recommended because adamantanes seem to be ineffective against pandemic A/H1N1 influenza virus and zanamivir is contraindicated in people with underlying respiratory conditions and difficult to administer in younger children.

Objectives

To increase knowledge on oseltamivir resistance emergence in pandemic A/H1N1 influenza.

Study design

Description of the case of an 8-year-old boy with cystic fibrosis and Pseudomonas aeruginosa infection in whom an oseltamivir-resistant pandemic A/H1N1 influenza virus was demonstrated.

Results

On the basis of clinical and virological failure (nasopharyngeal secretions remained positive for pandemic A/H1N1 influenza virus and appearance of 275Y mutation in 100% virus population) on fifth day of treatment, oseltamivir was replaced by zanamivir inhalation (5 mg to be inhaled twice a day). This change was associated with a rapid improvement in the patient's general condition, respiratory findings and laboratory data (including disappearance of pandemic A/H1N1 influenza virus) in the absence of any adverse event.

Conclusions

The emergence of oseltamivir-resistant strains is related to the administration of the drug, supporting the restriction of oseltamivir use to carefully defined high-risk groups. Infection due to pandemic virus with the H275Y mutation can be associated with a severe clinical course, supporting the systematic monitoring of antiviral susceptibility in pandemic influenza-positive high-risk patients whose influenza is not resolved by oseltamivir treatment. Zanamivir inhalation can be successfully used in patients with cystic fibrosis without causing adverse respiratory events, highlighting that the risks and benefits of this drug must be considered on a patient by patient basis.

Section snippets

Why this case is important

We describe the case of an 8-year-old boy with cystic fibrosis and Pseudomonas aeruginosa infection in whom pandemic A/H1N1 influenza occurred. Clinical and virological course may add useful data to increase knowledge on oseltamivir resistance emergence in pandemic A/H1N1 influenza.

Study patients

An 8-year-old boy with cystic fibrosis weighting 25 kg was seen at the outpatient clinic of the Cystic Fibrosis Center of the University of Milan's Department of Maternal and Pediatric Sciences because of mild fever and cough in the last week of October 2009, during a period in which the circulation of pandemic A/H1N1 influenza virus was widespread.

Because of reduced breath sounds with wheezing and crackles in the lower part of the right lung and chest radiography showed a significant worsening

Other similar and contrasting cases in the literature

Oseltamivir is considered the drug of choice for patients with pandemic influenza for whom drug treatment is recommended because adamantanes seem to be ineffective against pandemic A/H1N1 influenza virus and zanamivir (the other available neuraminidase inhibitor) is contraindicated in people with underlying respiratory conditions and difficult to administer in younger children.4

Unfortunately, the previously documented resistance to oseltamivir of seasonal influenza viruses5, 6 has now been

Discussion

Our case offers some insights into the problems related to the emergence of oseltamivir-resistant pandemic A/H1N1 influenza virus, the clinical significance of mutant strains, and the antiviral treatment of the resulting infections.

First of all, it supports the hypothesis that the emergence of oseltamivir-resistant strains is related to the administration of the drug as the mutation was not present before therapy but found after 5 days of oseltamivir treatment and the patient has no known

Competing interests

None declared.

Ethical approval

Diagnostic and therapeutic procedures for approach to influenza-like illness have been approved by Ethical Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico. Patient's parents signed the consent for influenza tests and antiviral therapy at patient's admission and then signed for consenting to the publication of this report.

Acknowledgments

The laboratory analyses were partially supported by a grant from the Italian Ministry of Health, Bando Giovani Ricercatori 2007.

References (12)

  • S. Esposito et al.

    Impact of human bocavirus on children and their families

    J Clin Microbiol

    (2008)
  • CDC. CDC protocol of real-time RT-PCR for swine influenza A (H1N1), 28 April 2009 revision 1 (30 April 2009). Available...
  • A. Lackenby et al.

    Rapid quantitation of neuraminidase inhibitor drug resistance in influenza virus quasispecies

    Antivir Ther

    (2008)
  • CDC. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza...
  • I. Stephenson et al.

    Neuraminidase inhibitor resistance after oseltamivir treatment of acute influenza A and B in children

    Clin Infect Dis

    (2009)
  • A. Meijer et al.

    Oseltamivir-resistant influenza virus A (H1N1), Europe, 2007–08 season

    Emerg Infect Dis

    (2009)
There are more references available in the full text version of this article.

Cited by (28)

  • Next-generation direct-acting influenza therapeutics

    2020, Translational Research
    Citation Excerpt :

    Major resistance mutations to zanamivir are NA substitutions Q136K and I223R (H1N1 viruses) and Q136K (H3N2 viruses), respectively.41 Whereas resistance to the NAIs is relatively rare in currently endemic influenza virus strains,42,43 the prevalence of escape mutations increased rapidly in the 2007/2008 influenza season44 and approximately 90% of strains circulating during the 2008/2009 season were resistant to NAIs,45-47 generating concern that this drug class could also be lost to resistance in the future.48 Although no biologics have been approved for influenza therapy so far, neutralizing antibodies (nAbs) in particular have been extensively tested.

  • Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model

    2020, Translational Research
    Citation Excerpt :

    Moreover, meta-analyses of the 2009/2010 influenza season suggested that NAI treatment provides little benefit to hospitalized patients suffering from complicated influenza and enhances the risk of progression to severe disease such as viral pneumonia.11 Resistance to NAI inhibitors is well documented, and even though it is relatively rare in the currently circulating influenza strains,12 up to 90% of the circulating strains exhibited resistance to NAIs during the 2007/2008, and 2008/2009 influenza seasons.13-15 Baloxavir marboxil, the founding member of the novel PA endonuclease inhibitor class, was recently licensed in Japan and the United States for the treatment of uncomplicated influenza in patients greater than 12 years of age.

  • Impact of pandemic A/H1N1/2009 influenza on children and their families: Comparison with seasonal A/H1N1 and A/H3N2 influenza viruses

    2011, Journal of Infection
    Citation Excerpt :

    No. 360c, Copan Italia, Brescia, Italy). Viral RNA was extracted by means of a Nuclisens EasyMAG automated extraction system (bioMeriéux, Bagno a Ripoli, Florence, Italy) using a generic protocol, a 190 μl sample input and 10 μL of cultured phocine distemper virus (PDV) (the extraction/PCR inhibition control was kindly provided by Prof. H.G.M. Niesters, UMCG, Groningen, The Netherland).15,19,20 Samples were first screened for the universal detection of type A influenza, as previously described.20,21

  • Pandemic influenza A/H1N1 vaccine administered sequentially or simultaneously with seasonal influenza vaccine to HIV-infected children and adolescents

    2011, Vaccine
    Citation Excerpt :

    Adverse reactions were defined as any reaction that persisted for longer than seven days after the vaccination, and serious adverse reactions as any reaction that required medical attention or hospitalisation during the study period. The subjects and their parents were asked to pay particular attention to the development of symptoms resembling influenza-like illness throughout the study period and, if these appeared, had to return immediately to the study centre for a clinical evaluation and the laboratory testing of nasal swabs for influenza viruses [14]. Further data regarding the clinical events that occurred between vaccine administrations were collected during the visits made for vaccine administration and/or blood collection.

  • Mixtures of oseltamivir-sensitive and -resistant pandemic influenza A/H1N1/2009 viruses in immunocompromised hospitalized children

    2011, Pediatric Infectious Disease Journal
    Citation Excerpt :

    Subsequently, even longer after the end of the 5-day oseltamivir course, wild-type and mutant viruses coexisted as a mixture (July 30, 2010), after which the virus became nondetectable (August 1, 2010). As reported previously, these pediatric cases have demonstrated that oseltamivir resistance can arise within the normal, recommended 5-day course of treatment,3 as well as when receiving longer treatment regimens.2,4 However, while all these previous cases describe an evolution of the virus population from a susceptible to a resistant phenotype, one of our patients (C.Y.Z.) showed a reversible change from susceptible-to-resistant-to-susceptible viral populations, despite receiving only the conventional 5-day course of oseltamivir treatment.

View all citing articles on Scopus
View full text