Efficacy and Safety of Azithromycin for the Treatment of COVID-19: A Systematic Review and Meta-analysis

Abstract

Background: The lack of effective medications for coronavirus disease 2019 (COVID-19) has led to a trend of drug repurposing such as the case of azithromycin which shows immunomodulatory and anti-viral effect. Several clinical trials have shown conflicting results. It is currently unclear whether the available evidence is in favor or against the use of azithromycin in COVID-19 patients. Thus, the aim of this study was to investigate the efficacy and safety of azithromycin in COVID-19 patients.

Methods: Four independent reviewers selected relevant studies from PubMed, ScienceDirect, EBSCO, and ProQuest published prior to March 2021. The protocol used in this study has been registered in PROSPERO (CRD42020224967).

Results: We included 17 studies and found that the mortality rate (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.76-1.19), need of respiratory support (OR, 1.30; 95% CI, 0.98-1.73), hospitalization rate (standardized mean difference, 0.12; 95% CI, -0.02 to 0.27), and intensive care unit transfer (OR, 1.21; 95% CI, 0.79-1.86) of azithromycin-treated group did not differ significantly (p>0.05) from those of the control group. Azithromycin treatment did not significantly increase the risk of getting secondary infection (OR, 1.23; 95% CI, 0.83-1.82), hypoglycemia (OR, 0.73; 95% CI, 0.38-1.40), gastrointestinal problems (OR, 1.03; 95% CI, 0.73-1.45) or electrocardiogram abnormalities (OR, 1.16; 95% CI, 0.94-1.42). The overall quality of evidence ranged from low to very low.

Conclusion: Azithromycin did not result in a superior clinical improvement in COVID-19 patients, although it was well-tolerated and safe to use.

Keywords: Azithromycin; COVID-19; Meta-analysis; Systematic Review; Treatment.

Figure 1

PRISMA Flow Diagram showing the search strategy and the selection process applied to include articles eligible for this meta-analysis.

Figure 2

Methodological quality: randomized controlled trials.

Figure 3

(A–D) Efficacy of azithromycin. The horizontal line indicates 95% CI of the study. The square represents the result of each individual study. The size of the square varies according to the weight of a particular study. The diamond at the bottom of the plot represents pooled analysis of all included studies. Outer edges of the diamond indicate CIs. CI: confidence interval; df: degree of freedom; I²: test of heterogeneity; M-H: Mantel-Haenszel.

Figure 4

(A–D) Safety of azithromycin. The square represents the result of each individual study. The size of the square varies according to the weight of a particular study. The diamond at the bottom of the plot represents pooled analysis of all included studies. Outer edges of the diamond indicate CIs. CI: confidence interval; df: degree of freedom; I²: test of heterogeneity; M-H: Mantel-Haenszel.

Figure 5

(A–H) Publication bias. Funnel plot presented the distribution of included studies. Asymmetrical plot indicated that publication bias was present. This was confirmed by Begg and Mazumdar rank correlation test and Egger’s test of the intercept to determine the presence of publication bias statistically (p<0.1). ICU: intensive care unit.

Figure 6

(A–H) Trial sequential analysis. Findings are represented by cumulative Z-curves. When Z-curves surpass the futility boundary, the level of evidence is adequate and further trials will be judged as futile. The level of evidence was judged to be adequate and conclusive if the Z-curves surpassed the conventional and trial sequential significance boundaries. On the contrary, when Z-curves did not cross any boundaries or only surpassed the conventional boundary, the level of evidence was inadequate and more trials would be needed to clarify the conclusion. The blue line represents the cumulative Z-curve. The horizontal red line at Z=+1.96 and Z=−1.96 indicates the conventional meta-analysis boundary. The diagonal red line at the top and the bottom of the plot indicates the trial sequential significance boundary. The triangular red line on the right represents the trial sequential futility boundary. The vertical red line on the right indicates the required sample size for the meta-analysis.