Should a non-pregnant patient with uncomplicated Chlamydia (Chlamydia trachomatis) and potential concurrent gonorrhea (Neisseria gonorrhoeae) infection be given ceftriaxone (a cephalosporin antibiotic) in addition to azithromycin (a macrolide antibiotic)?

Should Ceftriaxone Be Added to Azithromycin?

Yes, ceftriaxone must be given in addition to azithromycin for any patient with suspected or confirmed gonorrhea, even when only chlamydia is documented, because co-infection rates are extremely high (40-50%) and treating gonorrhea inadequately risks treatment failure and antimicrobial resistance. 1

Primary Treatment Recommendation

The CDC recommends ceftriaxone 500 mg IM as a single dose PLUS treatment for chlamydia (either azithromycin 1 g orally once OR doxycycline 100 mg orally twice daily for 7 days) for all patients with uncomplicated gonorrhea or suspected co-infection. 1, 2

Why Dual Therapy Is Mandatory

• Co-infection is the rule, not the exception: 40-50% of patients with gonorrhea also have chlamydia, making presumptive treatment for both organisms essential when either infection is suspected. 1, 3

• Azithromycin alone is insufficient for gonorrhea: Single-dose azithromycin 1 g has only 93% efficacy against gonorrhea and should never be used as monotherapy. 1, 3

• Ceftriaxone has no activity against chlamydia: The FDA label explicitly states that ceftriaxone has no activity against Chlamydia trachomatis, requiring appropriate antichlamydial coverage when chlamydia is a suspected pathogen. 4

• Dual therapy prevents resistance emergence: Combination therapy with two antimicrobials having different mechanisms of action improves treatment efficacy and potentially delays emergence of cephalosporin resistance. 1

Specific Dosing Regimen

For uncomplicated urogenital, anorectal, or pharyngeal infections:

• Ceftriaxone 500 mg IM single dose 1, 2
• PLUS either:
  • Azithromycin 1 g orally single dose (preferred for compliance) 1, OR
  • Doxycycline 100 mg orally twice daily for 7 days 2

The 2020 CDC update increased the ceftriaxone dose from 250 mg to 500 mg to ensure adequate treatment, particularly for pharyngeal infections which are more difficult to eradicate. 2

Critical Site-Specific Considerations

• Pharyngeal gonorrhea is significantly harder to treat than urogenital or anorectal infections, requiring regimens with >90% cure rates. 1, 5

• Ceftriaxone 500 mg IM is the only reliably effective treatment for pharyngeal infections, with superior efficacy compared to oral alternatives. 1

• The higher 500 mg dose is particularly important for pharyngeal infections because extended-spectrum cephalosporins have marked variability in clearance and half-life within pharyngeal tissues. 1

Alternative Regimens (Only When Ceftriaxone Unavailable)

If ceftriaxone is not available:

• Cefixime 400 mg orally single dose PLUS azithromycin 1 g orally single dose 1
• Mandatory test-of-cure at 1 week is required with this regimen due to inferior efficacy 1

For severe cephalosporin allergy:

• Azithromycin 2 g orally single dose (monotherapy) 1
• This has lower efficacy (93%) and high gastrointestinal side effects (35%) 1, 6
• Mandatory test-of-cure at 1 week 1

Alternative non-cephalosporin regimen:

• Gentamicin 240 mg IM single dose PLUS azithromycin 2 g orally achieved 100% cure rate in clinical trials 1, 7
• However, gentamicin has poor pharyngeal efficacy (only 20% cure rate) 1

Critical Pitfalls to Avoid

• Never use fluoroquinolones (ciprofloxacin, ofloxacin) for gonorrhea treatment due to widespread resistance, despite their historical 99.8% cure rates. 1, 8

• Never use azithromycin 1 g alone for gonorrhea—it has insufficient efficacy at only 93%. 1, 3

• Never use spectinomycin for pharyngeal infections—it has only 52% efficacy at this site. 9, 1, 3

• Never assume chlamydia testing excludes gonorrhea—both infections frequently coexist and require different antimicrobials. 4

Special Populations

Pregnancy:

• Use ceftriaxone 500 mg IM single dose (safe in pregnancy) 1, 3
• For chlamydia coverage: azithromycin 1 g orally single dose OR amoxicillin 500 mg three times daily for 7 days 3
• Never use quinolones, tetracyclines, or doxycycline in pregnancy 9, 1, 3

Men who have sex with men (MSM):

• Ceftriaxone is the only recommended treatment due to higher prevalence of resistant strains 1
• Do not use quinolones in this population 1

Follow-Up Requirements

• No routine test-of-cure needed for patients treated with recommended ceftriaxone-based regimens unless symptoms persist. 1, 3

• Mandatory test-of-cure at 1 week for patients receiving cefixime or azithromycin monotherapy. 1

• If symptoms persist after treatment: obtain culture with antimicrobial susceptibility testing and report to public health officials within 24 hours. 1

• Retest all patients at 3 months due to high reinfection risk. 1

Partner Management

• All sexual partners from the preceding 60 days must be evaluated and treated for both gonorrhea and chlamydia with the same dual therapy regimen. 1, 3, 5

• Patients should avoid sexual intercourse until therapy is completed and both patient and partners are asymptomatic. 9, 3, 5

• Expedited partner therapy with oral combination therapy (cefixime 400 mg plus azithromycin 1 g) may be considered when partners cannot be linked to timely evaluation, but this is not recommended for MSM due to high risk of undiagnosed coexisting STDs or HIV. 1