Efficacy of combination therapy with oseltamivir phosphate and azithromycin for influenza: a multicenter, open-label, randomized study

Abstract

Background: Macrolides have antibiotic and immunomodulatory activities, which may have a favorable effect on the clinical outcome of patients with infections, including influenza. This study aimed to evaluate the effects of combination therapy with an anti-influenza agent, oseltamivir, and a single-dose formulation of azithromycin (AZM), which has been used for influenza-related secondary pneumonia, on influenza patients. The primary endpoint was a change in the expression levels of inflammatory cytokines. Secondary endpoints were the time required for resolution of influenza-related symptoms, incidence of complications, and adverse reactions.

Methods: Patients with seasonal influenza were enrolled in this multicenter, open-label, randomized study. Patients were stratified according to the presence of a high risk factor and were randomized to receive combination therapy with oseltamivir plus an extended-release formulation of AZM (combo-group) or oseltamivir monotherapy (mono-group).

Results: We enrolled 107 patients and randomized them into the mono-group (56 patients) or the combo-group (51 patients). All patients were diagnosed with influenza A infection, and none of the patients had comorbid pneumonia. Statistically significant differences were not observed in the expression levels of inflammatory cytokines and chemokines between the 2 groups. The maximum temperature in the combo-group was lower than that in the mono-group on day 3 through day 5 (p = 0.048), particularly on day 4 (p = 0.037).

Conclusion: To our knowledge, this is the first prospective, randomized, clinical trial of oseltamivir and AZM combination therapy for influenza. Although the difference in inflammatory cytokine expression level was not statistically significant, combination therapy showed an early resolution of some symptoms.

Name of registry: University hospital Medical Information Network (UMIN).

Trial registration no: UMIN000005371.

Figure 1. Trial Profile.

Figure 2. Comparison of inflammatory marker levels in the azithromycin-oseltamivir combination therapy and oseltamivir monotherapy groups.

Serial test results (on days 0, 2, and 5) for the 8 inflammatory markers were compared between the groups with and without AZM. The horizontal and vertical lines depicted in the scattergram represent the central 50% range (25–75 percentiles) and the median, respectively. In the graphs for interleukin 8 (IL-8), IL-12, and tumor necrosis factor α (TNF-α), missing central boxes or concordance of the left end of the box with the median indicate that the majority of the test results were lower than the limit of detection.

Figure 3. Comparisons of maximum temperature in the azithromycin-oseltamivir combination therapy and oseltamivir monotherapy groups.

The maximum temperatures on day 1 through day 5 were compared between groups. No significant differences were detected between the groups on days 1, 2, 3, and 5. However, our analysis revealed a significant decrease in the maximum temperature on day 4 in the combo-group compared to that in the mono-group (p = 0.037). In addition, a mixed-design ANOVA indicated that the maximum temperature on days 3 through 5 was significantly lower in the combo-group than in the mono-group (p = 0.048).