For patients with confirmed influenza and an infiltrate consistent with pneumonia, does adding clarithromycin and naproxen to oseltamivir improve outcomes?

Adding clarithromycin and naproxen to oseltamivir significantly lowered all-cause mortality at 30 days and 90 days. This study was limited by its open-label design and a failure to conceal allocation. The outcome of mortality would not be subject to observer bias, though, and the groups were balanced. These findings are consistent with other studies of hospitalized patients with community-acquired pneumonia that concluded that adding a macrolide to amoxiclav or a cephalosporin improves outcomes. (LOE = 1b)

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: An open-label randomized, controlled, phase iib/iii trial. Chest 2017;151(5):1069-1080.  [PMID:27884765]

Randomized controlled trial (nonblinded)

Government

Concealed

Inpatient (any location)

These researchers recruited adults hospitalized with laboratory-confirmed influenza A (H3N2) within 72 hours of the onset of symptoms. All patients had an infiltrate on chest radiographs, fever, and at least one typical symptom of influenza. Of 334 patients screened for inclusion, 217 were randomized to receive either oseltamivir 75 mg twice daily, or oseltamivir plus clarithromycin 500 mg twice daily and naproxen 200 mg twice daily. The oseltamivir was given for 5 days, while the naproxen and clarithromycin were given for 3 days. Allocation does not appear to have been concealed, which is a flaw that would potentially allow manipulation of group assignment. However, groups were balanced at baseline. All patients also received amoxicillin-clavulanate and esomeprazole. The mean age of patients was 80 years and 57% were men. Approximately 50% were previously in good health, and despite extensive testing, only approximately 5% in each group had a bacterial co-infection. All-cause mortality was significantly lower at 30 days in the group who received clarithromycin and naproxen (0.9% vs 8.2%; P = .01; number needed to treat [NNT] = 14); it was also lower at 90 days (1.9% vs 10%; P = .01; NNT = 13). The researchers hypothesized based on in vitro studies that naproxen and clarithromycin both have antiviral properties, and they indeed found that viral titers and the pneumonia severity index scores also declined faster in the combination therapy group. The median length of hospitalization was shorter for those in the combination therapy group (2 vs 3 days; P < .001) as was the likelihood of admission to the "high dependency unit," which is apparently something between a regular ward and intensive care.