Treatment of Immunocompromised, Critically Ill Patients with Influenza A H1N1 Infection with a Combination of Oseltamivir, Amantadine, and Zanamivir

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Abstract

Immunocompromised patients are at increased risk of complications of influenza virus infection. We report on two critically ill patients on immunosuppressive medication with influenza pneumonia. In both patients, oseltamivir monotherapy did not result in clearance of the virus after 18 and five days, respectively. After adding zanamivir and amantadine to the treatment, PCRs on pharyngeal and/or plasma specimens turned negative in both patients after four and three days, respectively. We suggest, that in critically ill patients with influenza A H1N1 infection, treatment efficacy should be monitored closely and treatment with a combination of antiviral drugs should be considered.

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Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses.

Ken Kunisaki, Edward Janoff (2009)

Patients that are immunosuppressed might be at risk of serious influenza-associated complications. As a result, multiple guidelines recommend influenza vaccination for patients infected with HIV, who have received solid-organ transplants, who have received haemopoietic stem-cell transplants, and patients on haemodialysis. However, immunosuppression might also limit vaccine responses. To better inform policy, we reviewed the published work relevant to incidence, outcomes, and prevention of influenza infection in these patients, and in patients being treated chemotherapy and with systemic corticosteroids. Available data suggest that most immunosuppressed populations are indeed at higher risk of influenza-associated complications, have a general trend toward impaired humoral vaccine responses (although these data are mixed), and can be safely vaccinated--although longitudinal data are largely lacking. Randomised clinical trial data were limited to one study of HIV-infected patients with high vaccine efficacy. Better trial data would inform vaccination recommendations on the basis of efficacy and cost in these at-risk populations.

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Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.

G He, J Massarella, P Ward (1999)

Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. Oral administration of oseltamivir delivers the active antiviral Ro 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible. The pharmacokinetic profile of oseltamivir is simple and predictable, and twice daily treatment results in effective antiviral plasma concentrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours. Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway. Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases. The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions. Neither paracetamol (acetaminophen) nor cimetidine altered the pharmacokinetics of Ro 64-0802. Coadministration of probenecid resulted in a 2.5-fold increase in exposure to Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects. These properties make oseltamivir a suitable candidate for use in the prevention and treatment of influenza.

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Antiviral combinations for severe influenza

Jake Dunning, J Baillie, Bin Cao … (2014)

Summary Observational data suggest that the treatment of influenza infection with neuraminidase inhibitors decreases progression to more severe illness, especially when treatment is started soon after symptom onset. However, even early treatment might fail to prevent complications in some patients, particularly those infected with novel viruses such as the 2009 pandemic influenza A H1N1, avian influenza A H5N1 virus subtype, or the avian influenza A H7N9 virus subtype. Furthermore, treatment with one antiviral drug might promote the development of antiviral resistance, especially in immunocompromised hosts and critically ill patients. An obvious strategy to optimise antiviral therapy is to combine drugs with different modes of action. Because host immune responses to infection might also contribute to illness pathogenesis, improved outcomes might be gained from the combination of antiviral therapy with drugs that modulate the immune response in an infected individual. We review available data from preclinical and clinical studies of combination antiviral therapy and of combined antiviral-immunomodulator therapy for influenza. Early-stage data draw attention to several promising antiviral combinations with therapeutic potential in severe infections, but there remains a need to substantiate clinical benefit. Combination therapies with favourable experimental data need to be tested in carefully designed aclinical trials to assess their efficacy.

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Author and article information

Journal

Journal ID (nlm-ta): Case Rep Infect Dis

Journal ID (iso-abbrev): Case Rep Infect Dis

Journal ID (publisher-id): CRIID

Title: Case Reports in Infectious Diseases

Publisher: Hindawi Publishing Corporation

ISSN (Print): 2090-6625

ISSN (Electronic): 2090-6633

Publication date (Print): 2015

Publication date (Electronic): 9 August 2015

Volume: 2015

Electronic Location Identifier: 504975

Affiliations

¹Wilhelmina Children's Hospital, University Medical Center Utrecht, Lundlaan 6, P.O. Box 85090, Utrecht, Netherlands

²Department of Pharmacy & Pharmacology, Slotervaart Hospital, 1066 EC Amsterdam, Netherlands

³Department of Clinical Pharmacy, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands

⁴Department of Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands

⁵Department of Hematology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands

⁶Department of Virology, Erasmus Medical Center, 3015 CE Rotterdam, Netherlands

⁷Department of Intensive Care, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands

⁸Department of Virology, Medical Microbiology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands

Author notes

*Wouter J. Meijer: woutermeijer@ 123456hotmail.com

Academic Editor: Ian Barr

Article

DOI: 10.1155/2015/504975

PMC ID: 4546743

SO-VID: 4b00fd1c-b37f-47a9-b8f7-148bdec631eb

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 30 May 2015

Date revision received : 21 July 2015

Date accepted : 28 July 2015

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Treatment of Immunocompromised, Critically Ill Patients with Influenza A H1N1 Infection with a Combination of Oseltamivir, Amantadine, and Zanamivir

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Karger: Coronavirus / COVID-19

Most cited references 14

Influenza in immunosuppressed populations: a review of infection frequency, morbidity, mortality, and vaccine responses.

Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.

Antiviral combinations for severe influenza

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