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NSAID-Macrolide-Antiviral Combination Improves Mortality in Flu

Amesh A. Adalja, MD, FACP, FACEP, FIDSA, June 9, 2017

Optimization of the treatment of influenza is important for clinical care as well as pandemic preparedness. In addition to standard antiviral treatment, there has been interest in augmented treatment with immune modulating drugs. A new study from Hong Kong, published in Chest, reports on the results of a phase IIb/III clinical trial that combined the nonsteroidal anti-inflammatory drug (NSAID) naproxen and the macrolide antibiotic clarithromycin—both of which are known to possess both antiviral and immunomodulating activity—with oseltamivir and broad spectrum antibiotics in the treatment of H3N2 influenza A pneumonia.


More than 200 Hospitalized Patients Studied; Mortality Benefit Seen

In this open-label randomized clinical trial, 217 patients hospitalized with PCR-positive H3N2 influenza in 2015 at the Queen Mary Hospital in Hong Kong were enrolled. All patients had radiographic infiltrates on imaging. Clarithromycin and naproxen were dosed at 500 mg twice daily and 200 mg twice daily, respectively, along with oseltamivir and amoxicillin-clavulanate. The controls received only the oseltamivir and amoxicillin-clavulanate. The primary outcome was 30-day mortality. 

The combination group achieved lower 30-day and 90-day mortality as well as shorter lengths of stay than the controls. Multivariate analysis demonstrated that receipt of combination therapy was the only independent factor associated with lower 30-day mortality. Those in the combination group also had greater decrements in viral titers by day 1 of treatment and lower pneumonia severity index (PSI) scores in that same period. Lower rates of antiviral-resistant quasi-species were also seen in the combination group. 


Important Proof-of-Concept

Though limited by its single center, open-label status, this study nonetheless provides important proof-of-concept that antiviral therapy for hospitalized influenza patients can be supplemented with clarithromycin and naproxen to achieve better clinical outcomes. Whether this outcome is being achieved by enhanced antiviral activity or immune modulation or some combination of both effects is unclear, and further work to untangle the effect as well as replicate the findings in other populations is needed. Additionally, assessing whether these effects are robust with H1N1, H7N9, and H5N1 will be very important.

The treatment of severe influenza is an important component of pandemic preparedness. The use of strategies such as this should be studied in depth to enhance influenza resiliency for both pandemics and routine care of seasonal influenza cases, as well as avian influenza cases caused by H5N1 and H7N9. 



Hung IFN, To KKW, Chan JFW, et al. Efficacy of clarithromycin-naproxen-oseltamivir combination in the treatment of patients hospitalized for influenza A(H3N2) infection. Chest 2017;151:1069-1080.