Azithromycin Alone Does NOT Adequately Treat Gonorrhea
Azithromycin should never be used as monotherapy for gonorrhea—it must be combined with ceftriaxone 250 mg IM as dual therapy, which is the CDC's recommended first-line treatment. 1, 2
Why Azithromycin Alone Is Insufficient
Azithromycin 1 g as monotherapy has only 93% efficacy against gonorrhea, which is unacceptably low for a curable infection with serious sequelae including pelvic inflammatory disease, ectopic pregnancy, and infertility 2
The FDA label for azithromycin lists gonorrhea (urethritis and cervicitis due to Neisseria gonorrhoeae) as an indication, but this does not reflect current resistance patterns and CDC guidance supersedes this older labeling 3
Resistance to azithromycin develops rapidly when used alone, with isolated outbreaks showing up to 9.1% of isolates having reduced susceptibility (MIC ≥8 μg/mL) in certain geographic areas 4
Current Standard of Care: Dual Therapy
CDC recommends ceftriaxone 250 mg IM PLUS azithromycin 1 g orally as a single dose for all uncomplicated gonococcal infections of the cervix, urethra, rectum, and pharynx 1, 2
Azithromycin is preferred over doxycycline as the second agent due to single-dose convenience, better compliance, and substantially lower gonococcal resistance to azithromycin compared to tetracycline 1, 2
Dual therapy serves two critical purposes: (1) treats common chlamydial co-infection (present in 40-50% of gonorrhea cases), and (2) delays emergence of cephalosporin resistance through combination antimicrobial mechanisms 1, 2
When Azithromycin 2 g Can Be Used (Severe Cephalosporin Allergy Only)
For patients with severe cephalosporin allergy, azithromycin 2 g orally as a single dose is the CDC's recommended alternative regimen 1, 5, 2
Mandatory test-of-cure at 1 week is required when using this alternative regimen, preferably with culture to allow antimicrobial susceptibility testing 1, 5
This 2 g dose showed 98.9% efficacy in clinical trials, comparable to ceftriaxone, but was associated with gastrointestinal side effects in 35.3% of patients (moderate in 10.1%, severe in 2.9%) 6
Consultation with an infectious disease specialist is recommended when treating patients with severe cephalosporin allergy due to limited data on alternative regimens 5
Critical Pitfalls to Avoid
Never use azithromycin 1 g as monotherapy—this suboptimal dosing accelerates resistance development and has inadequate cure rates 2
Pharyngeal gonorrhea is particularly difficult to eradicate and requires the full dual therapy regimen; ceftriaxone has superior efficacy at this site compared to oral alternatives 1, 2
In areas with documented azithromycin resistance (such as San Diego County in 2009), even the 2 g dose may be unreliable, necessitating test-of-cure 3 weeks after treatment and sexual abstinence until negative results 4
Surveillance Data Supporting Current Recommendations
National surveillance (2005-2013) shows overall low prevalence of reduced azithromycin susceptibility (0.4%), with MIC₅₀ of 0.25 μg/mL and MIC₉₀ of 0.5 μg/mL, supporting continued use in combination therapy 7
No clear temporal trend in rising azithromycin MICs has been observed nationally, unlike the concerning trends seen with cefixime that led to its removal as first-line therapy 1, 7
Men who have sex with men (MSM) have significantly higher azithromycin MICs than heterosexual men, emphasizing the importance of dual therapy in this population 7