Table 2.

Common infectious syndromes or pathogens that may be treated with azithromycin in the clinical setting

Syndrome or specific pathogen	Age group mostly affected	Serious consequences of untreated Infection	Evidence or guidelines supporting azithromycin use	Evidence from MDA studies supporting or refuting use of azithromycin for syndrome/ pathogen
Skin and soft tissue infection/ impetigo, most commonly caused by Staphylococcus aureus and Streptococcus pyogenes. Can occur as a secondary bacterial infection following scabies infection, a parasitic NTD for which MDA of the anti-parasitic ivermectin has been used	Children and adults	Bacteremia, glomerulonephritis, and potentially rheumatic heart disease	Macrolides can be used in the treatment of impetigo. The IDSA recommends erythromycin as an alternative to beta lactam-based therapies [70]	•In the Solomon Islands, a cluster RCT of ivermectin MDA only or ivermectin co-administered with azithromycin to all residents showed a similar decrease in impetigo prevalence in both arms at 12 months [57] •Ivermectin plus either oral azithromycin or topical tetracycline showed 74% reduction in impetigo prevalence at 12 months in azithromycin arm in the Solomon Islands [71]. Three years after the intervention, the prevalence of scabies had decreased by 74.9% and the prevalence of impetigo had decreased by 61.3% [72] •Among children £10 years in Nepal, MDA-azithromycin was associated with a 60% decrease in impetigo 10 days after treatment, but levels returned to baseline by 6 months [73]
Rheumatic heart disease caused by group A Streptococcus	Children	Long term disability or death	IDSA recommends azithromycin as an alternative to penicillin in treatment for group A streptococcal pharyngitis and secondary prophylaxis of acute rheumatic disease [74] Erythromycin is an alternative for penicillin-allergic patients for primary and secondary prophylaxis of rheumatic heart disease, but it should not be used in areas where S. pyogenes has high rates of macrolide resistance [75]	•The reduction of rheumatic heart disease has not been reported in the literature on MDA-azithromycin programs
Acute respiratory Infection	Children and geriatric populations	Respiratory failure or death	Single-dose azithromycin 1500 mg reduced risk of community-acquired pneumonia by 50% compared to no therapy in male Russian military recruits (10.3% developed pneumonia compared to 20.2% in the control group over 22 weeks) [76]	•The incidence of upper respiratory infection over three malaria seasons was 15% lower in children treated with MDA antimalarials and azithromycin compared to children treated with MDA antimalarials and placebo in a cluster RCT in Burkina Faso and Mali [26] •In a cohort of children < 5 years in Tanzania, a single round of MDA-azithromycin was associated with a short-term (1‒3 months after administration) decrease in ARI of 38% compared to untreated communities, but this difference was not sustained after 1 month [77] •In a cohort of children £10 years in Nepal, ARI symptoms did not decrease after MDA-azithromycin [73] •One cluster RCT that examined MDA-azithromycin in the Gambia among children < 14 years treated with 3 doses of azithromycin did not show a reduction in ARI following MDA-azithromycin [78]
Diarrheal illness	Children	Stunting, vitamin deficiencies, death	Azithromycin is one of the first-line agents for the treatment of Campylobacter spp, Shigella spp, non-typhoidal Salmonella spp, and enteric fever due to Salmonella typhi or Salmonella paratyphi [55]	•In a cluster RCT in the Gambia, there was an almost 50% reduction in diarrhea at 28 days in children < 14 years treated with 3 doses of azithromycin [78] •In a cluster RCT in Mali and Burkina Faso, there was a 15% reduction in diarrhea in the azithromycin-MDA arm compared to placebo arm, when given with SMC [26] •In a cohort study in Nepal, there was a 75% reduction in diarrheal illness following one round of MDA-azithromycin in children ≤ 10 years [73] •In a cohort study in Tanzania, there was no significant reduction in diarrheal illness among children < 5 years of age after one round of MDA-azithromycin.[79]
Malaria	Children and to a lesser extent adults in endemic areas		Azithromycin displays weak antimalarial activity [80]	•In a cohort of children < 5 years in Tanzania, a single round of MDA-azithromycin was associated with a short-term (only in first month), 73% reduction in Plasmodium falciparum infections in treatment versus control villages [81] •Cluster RCT in Mali and Burkina Faso of MDA-azithromycin versus placebo with malaria SMC showed no decrease in laboratory-confirmed malaria in children < 5 years of age [26]
Syphilis	Adults	Cardiovascular disease, tabes dorsalis	In the setting of a penicillin allergy, azithromycin is recommended by the WHO as an option for early syphilis treatment if local susceptibility is likely and 14 days of doxycycline cannot be used [82]	•In Rakai, Uganda, in a sub-analysis of a cluster-randomized trial assessing STD control, participants received either single-dose benzathine penicillin G, single-dose azithromycin 1 g, or combination of the two drugs for participants with positive syphilis serology. There was no difference in cure rates of syphilis by treatment group [83]
Chlamydia	Adults	Ectopic pregnancies, pelvic inflammatory disease, infertility	Azithromycin is recommended for treatment of chlamydia [84]	•A study of gonorrhea and chlamydia rates in the Solomon Islands after an MDA-azithromycin campaign for trachoma showed a 40% reduction in the age-adjusted prevalence of C. trachomatis. Gonorrhea rates did not change [85]

NTD neglected tropical disease, MDA mass drug administration, RCT randomized controlled trial, IDSA Infectious Diseases Society of America, WHO World Health Organization