Cefixime for Post-Exposure Prophylaxis Against Gonorrhea
Cefixime 400 mg orally can be used for post-exposure prophylaxis against gonorrhea in sexual assault victims when only genital penetration occurred, but it is no longer recommended as a first-line option and should only be used when ceftriaxone is unavailable. 1
Current Guideline Recommendations for Post-Exposure Prophylaxis
The American Academy of Pediatrics recommends prophylactic treatment for gonorrhea in adolescent sexual assault victims who have been vaginally or anally penetrated (with or without ejaculation) or orally penetrated (with ejaculation). 1 The first-line regimen is:
- Ceftriaxone 125 mg intramuscularly plus azithromycin 1 g orally or doxycycline 100 mg twice daily for 1 week 1
Cefixime 400 mg orally can substitute for ceftriaxone only if genital penetration occurred (not pharyngeal exposure) and ceftriaxone is unavailable. 1
Critical Limitations of Cefixime for Prophylaxis
Declining Susceptibility and Resistance Concerns
The CDC removed cefixime from routine first-line recommendations in 2012 due to rising minimum inhibitory concentrations (MICs) among Neisseria gonorrhoeae isolates, which increased from 0.2% to 1.4% nationally between 2006-2011. 1, 2, 3
Among men who have sex with men (MSM), elevated cefixime MICs increased from 0.2% to 3.8% during the same period, mirroring the pattern of fluoroquinolone resistance emergence in the 1990s. 1, 3, 4
Continued use of cefixime may accelerate resistance to ceftriaxone, the last highly effective single-dose antimicrobial for gonorrhea at all anatomic sites. 1, 3
Inferior Pharmacokinetic Profile
Cefixime 400 mg orally provides lower and less sustained bactericidal levels compared to ceftriaxone 125-250 mg intramuscularly. 2, 3, 4
While cefixime achieves 97.4% cure rates for urogenital and anorectal gonorrhea, it demonstrates only 91% efficacy for pharyngeal infections, which is below the 95% threshold required for first-line therapy. 2, 4, 5
When Cefixime May Be Considered
Use cefixime 400 mg orally plus azithromycin 1 g orally only when:
- Ceftriaxone is genuinely unavailable 1, 2
- The exposure involved only genital penetration (vaginal or anal), not oral penetration with ejaculation 1
- A test-of-cure at 1 week can be ensured 2, 4
Common Pitfalls to Avoid
Never use cefixime as monotherapy—always combine with azithromycin 1 g orally or doxycycline 100 mg twice daily for 7 days. 1, 2, 4
Never use cefixime for pharyngeal exposure prophylaxis given its suboptimal 91% efficacy at this anatomic site. 2, 3, 4
Do not assume cefixime and ceftriaxone are interchangeable—ceftriaxone provides superior pharmacodynamics with sustained bactericidal levels for 22-50 hours versus cefixime's shorter duration. 6
Be aware that resistance patterns are more prevalent in Western U.S. states and among MSM populations, making ceftriaxone even more critical in these contexts. 1, 2, 3
Evidence Quality Assessment
The recommendation for cefixime in post-exposure prophylaxis comes from a 2008 AAP guideline specifically addressing sexual assault victims. 1 However, this predates the 2012 CDC guidance that removed cefixime from first-line status due to resistance concerns. 1 The most recent high-quality evidence (CDC guidelines synthesized in 2025) emphasizes that cefixime should only serve as an alternative when ceftriaxone is unavailable, with mandatory combination therapy and test-of-cure. 2, 3, 4
Historical efficacy data from the early 1990s showed cefixime 400 mg achieved 96-98% cure rates comparable to ceftriaxone, 5, 7 but these studies preceded current resistance patterns and cannot be extrapolated to contemporary practice.