Placebo Not Non-Inferior to Azithromycin for Lower Respiratory Tract Infection

Azithromycin lowers cytokine responses, most notably interleukin 8, which is elevated in respiratory viral infections.

Placebo is not non-inferior to azithromycin in regards to symptom improvement in adults with a low procalcitonin levels and lower respiratory tract infection. These study results were published in Lancet Infectious Disease.

Researchers conducted a randomized, placebo-controlled, double-blind, non-inferiority trial was conducted at 5 health centers in the United States between December 8, 2017, and March 9, 2020. A total of 499 adults with non-pneumonia lower respiratory tract infection were enrolled in the study. Those with a procalcitonin concentration of 0.25 ng/mL or lower were randomly assigned in a 1:1 ratio in 4 blocks and stratified by site. Oral azithromycin 250 mg was administered daily for 4 days to 249 participants and placebo was administered to 250 participants.

A post-hoc analysis was used to monitor the effect of azithromycin and patient outcomes. All analyses used SAS (version 9.4) or R (version 3.2 or newer). The primary outcome was the efficacy of azithromycin versus placebo regarding symptom improvement on day 5.

The azithromycin cohort was 68% male (n=169), 64% Black (n=159), and 92% non-Hispanic (n=228). The placebo cohort was 61% male (n=154), 58% Black (n=246), and 93% non-Hispanic (n=233). Pre-existing conditions were prevalent in both groups, affecting 90% (n=225) of participants in the azithromycin cohort and 92% (n=230) in the placebo cohort.

Inappropriate prescribing of antibiotics for viral acute respiratory infection contributes to increased health-care costs and unnecessary drug-related adverse effects, and is a major contributor to antimicrobial resistance.

Placebo was shown to be non-inferior to azithromycin on day 11 and day 28, but not on day 5. Clinical improvement at 5 days was seen in 155 (95% CI, 61-77) of 227 participants in the azithromycin group and in 148 (95% CI, 54-71) of 238 participants in the placebo group. On day 11, clinical improvement was observed in 187 (95% CI, 74-87) of 226 participants in the azithromycin group and in 184 (95% CI, 70-83) of 235 participants in the placebo group. On day 28, a total of 202 participants in the azithromycin group and 194 participants the placebo group showed clinical improvement.

The study was limited by the inability to attain the target enrollment. The primary outcome was also based on clinical improvement at day 5. Participants had low levels of procalcitonin and bacterial infections were minimal.

According to the researchers, “Inappropriate prescribing of antibiotics for viral acute respiratory infection contributes to increased health-care costs and unnecessary drug-related adverse effects, and is a major contributor to antimicrobial resistance.”

Disclosure: Some study authors declared affiliations with biotech and pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.

References:

Tsalik EL, Rouphael NG, Sadikot RT, et al. Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: A randomised, placebo-controlled, double-blind, non-inferiority trial. The Lanc Infect Dis. 2022. doi:10.1016/s1473-3099(22)00735-6