Azithromycin Pulse Therapy Matches Doxycycline Efficacy for Acne with Fewer Adverse Effects

A new systematic review and meta-analysis suggests that oral azithromycin pulse therapy may provide efficacy comparable to daily doxycycline for patients with moderate to severe acne vulgaris, while offering a more favorable tolerability profile.¹

Background and Study Design

Doxycycline remains a widely recommended first-line systemic antibiotic for inflammatory acne because of its antimicrobial and anti-inflammatory effects. However, its use can be limited by gastrointestinal adverse events, photosensitivity, and contraindications in pregnancy and young children. Azithromycin has been used off-label in situations where tetracyclines are not tolerated or are contraindicated. It also shows fewer gastrointestinal symptoms compared to doxycycline.²

The analysis, which followed PRISMA guidelines and was prospectively registered in PROSPERO, included 23 comparative studies encompassing 2,769 patients with moderate to severe disease. Investigators evaluated efficacy outcomes, clinical response measures, acne severity scores, lesion counts, and treatment-related adverse events associated with oral azithromycin pulse regimens and daily doxycycline therapy.

Efficacy Findings

Across the pooled studies, investigators found that overall treatment effectiveness was largely similar between the 2 antibiotics. Analysis of 3 studies involving 406 participants demonstrated a statistically significant reduction in Global Acne Grading System (GAGS) scores favoring azithromycin, with a mean difference of 1.81 points. No heterogeneity was observed across these studies.

Azithromycin was also associated with a significantly greater reduction in non-inflammatory lesion counts. Based on 2 studies including 105 participants, treatment with azithromycin resulted in a mean reduction of 7.56 additional non-inflammatory lesions compared with doxycycline. In contrast, reductions in inflammatory lesion counts were similar between groups. Pooled data from 2 studies showed no statistically significant difference between azithromycin and doxycycline for inflammatory lesion reduction.

Several other clinical response measures likewise showed little separation between therapies. In 8 studies involving more than 1,200 patients, no significant difference in rates of “excellent” response between treatment groups was found. Similarly, pooled data from 8 studies showed no significant difference in combined good-to-excellent improvement outcomes. One outcome favored doxycycline. In 7 studies including 1,122 participants, doxycycline was associated with a higher likelihood of achieving a “good” clinical response. However, investigators noted that variability in response definitions across studies may have contributed to this finding.

The review also evaluated Michaelson Acne Severity Index (MASI) outcomes. Results across severity grades were mixed, with some analyses favoring one treatment over the other. The authors cautioned that these findings should be interpreted carefully because of heterogeneity among studies and potential variability in grading methods.

Safety and Tolerability Profile

The most consistent differences emerged in safety outcomes. Azithromycin was associated with significantly fewer gastrointestinal adverse events than doxycycline. Patients receiving azithromycin experienced lower risks of diarrhea and nausea, and pooled analysis showed an overall gastrointestinal adverse-event risk ratio of 0.43 compared with doxycycline.

Photosensitivity reactions were also markedly less common with azithromycin. Across 10 studies involving 815 participants, the risk of photosensitivity was substantially lower with azithromycin, with a pooled risk ratio of 0.17. Dermatologic adverse events were likewise less frequent among patients treated with azithromycin, with a pooled risk ratio of 0.29.

Other adverse events, including vomiting, gastritis, abdominal pain, and superinfection, did not demonstrate statistically significant differences between treatment groups. The authors noted that azithromycin’s pulse-dosing schedules and prolonged tissue half-life may improve adherence by reducing pill burden while maintaining therapeutic drug concentrations in the skin.

“These benefits support adherence, though they must be weighed against antibiotic stewardship considerations and the need for correct pulse dosing to avoid sub-therapeutic exposure,” the investigators noted.

Clinical Implications

The investigators concluded that oral azithromycin pulse therapy represents a viable alternative to daily doxycycline for moderate to severe acne. Although some efficacy measures showed small differences between treatments, overall acne improvement appeared comparable. The findings suggest that azithromycin may be particularly useful for patients who cannot tolerate tetracyclines, those with significant sun exposure, pregnant patients, or younger individuals for whom tetracyclines are not appropriate.

At the same time, the authors emphasized the importance of antibiotic stewardship. Current acne guidelines continue to favor tetracyclines as first-line systemic therapy, in part because of concerns regarding macrolide resistance. As a result, azithromycin should be reserved for appropriate clinical situations and used alongside topical agents such as benzoyl peroxide or retinoids rather than as monotherapy.

References

1. Batool A, Abbas MS, Ali Akbar M, et al. Comparative efficacy and safety of oral azithromycin versus doxycycline in moderate-to-severe Acne vulgaris: a systematic review and meta-analysis. J Dermatolog Treat. 2026;37(1):2648406. doi:10.1080/09546634.2026.2648406

2. Kardeh S, Saki N, Jowkar F, Kardeh B, Moein SA, Khorraminejad-Shirazi MH. Efficacy of Azithromycin in Treatment of Acne Vulgaris: A Mini Review. World J Plast Surg. 2019;8(2):127-134. doi:10.29252/wjps.8.2.127