What are the first and second line treatments for gonorrhea?

Gonorrhea Treatment: First and Second Line Regimens

First-Line Treatment

The current first-line treatment for uncomplicated gonorrhea is ceftriaxone 500 mg intramuscularly as a single dose, plus doxycycline 100 mg orally twice daily for 7 days if chlamydial coinfection has not been excluded. 1

Primary Regimen Components

• Ceftriaxone 500 mg IM single dose is the cornerstone of gonorrhea treatment, providing sustained bactericidal levels with a 99.1% cure rate for uncomplicated urogenital and anorectal infections 2, 3
• Add doxycycline 100 mg orally twice daily for 7 days for presumptive chlamydia coverage when coinfection has not been ruled out 1
• This represents an evolution from the previous dual therapy recommendation of ceftriaxone 250 mg plus azithromycin 1 g, driven by antimicrobial stewardship concerns and increasing azithromycin resistance 1

Critical Dosing Considerations

• The 500 mg dose (rather than 250 mg) is particularly important for pharyngeal infections, which are more difficult to eradicate due to marked variability in cephalosporin clearance and half-life within pharyngeal tissues 2
• Ceftriaxone must be administered over 60 minutes in neonates to reduce risk of bilirubin encephalopathy 4
• In adults, intramuscular injection should be deep into a large muscle mass with aspiration to avoid intravascular injection 4

Alternative to Doxycycline for Chlamydia Coverage

• Azithromycin 1 g orally single dose may be substituted for doxycycline when single-dose therapy is preferred for compliance reasons 2
• Azithromycin offers convenience advantages but should not be used as monotherapy for gonorrhea (only 93% efficacy) 2

Second-Line Treatment Options

When Ceftriaxone is Unavailable

Cefixime 400 mg orally single dose PLUS azithromycin 1 g orally single dose is the recommended alternative when ceftriaxone cannot be administered 2, 5

• Mandatory test-of-cure at 1 week is required with this regimen due to inferior efficacy compared to ceftriaxone 2, 5
• Cefixime has documented treatment failures in Europe and provides lower, less sustained bactericidal levels than ceftriaxone 2
• This regimen has only 97.4% cure rate for urogenital/anorectal infections versus 99.1% for ceftriaxone 6

For Severe Cephalosporin Allergy

Azithromycin 2 g orally single dose is recommended for patients with documented severe cephalosporin allergy 2, 5

• Mandatory test-of-cure at 1 week is required 2
• This regimen has lower efficacy (93%) and high gastrointestinal side effects 2
• Should be reserved only for true severe allergies, not minor reactions 2

Alternative Salvage Regimens

Gentamicin 240 mg IM single dose PLUS azithromycin 2 g orally single dose has shown 100% cure rates in clinical trials 2, 3

• However, gentamicin has poor efficacy for pharyngeal infections (only 20% cure rate) 2
• Should not be used when pharyngeal infection is suspected 2

Special Population Considerations

Men Who Have Sex with Men (MSM)

• Only ceftriaxone-based regimens should be used due to higher prevalence of resistant strains in this population 2, 5
• Quinolones are absolutely contraindicated 6, 2
• Patient-delivered partner therapy is not recommended for MSM due to high risk of undiagnosed coexisting STDs or HIV 2

Pregnant Women

• Ceftriaxone 500 mg IM plus azithromycin 1 g orally is the recommended regimen 2, 7
• Quinolones and tetracyclines (including doxycycline) are contraindicated in pregnancy 2, 5
• Retest in third trimester unless recently treated 7

Pharyngeal Gonorrhea

• Ceftriaxone 500 mg IM is the only reliably effective treatment for pharyngeal infections 2
• Oral alternatives including cefixime have substantially lower efficacy 2
• Spectinomycin has only 52% efficacy for pharyngeal infections and should be avoided 2

Critical Pitfalls to Avoid

Never Use Quinolones

• Fluoroquinolones (ciprofloxacin, ofloxacin) are no longer recommended due to widespread resistance, despite historical cure rates of 99.8% 2, 1
• Resistance emerged rapidly after 2006, with 6.8% of isolates resistant by 2004 and 23.9% among MSM 6

Never Use Azithromycin Monotherapy

• Azithromycin 1 g alone is insufficient for gonorrhea treatment with only 93% efficacy 2
• Monotherapy risks rapid resistance emergence 2

Avoid Calcium-Containing Solutions

• Do not mix ceftriaxone with calcium-containing IV solutions (Ringer's, Hartmann's) as precipitation can occur 4
• In neonates, ceftriaxone is contraindicated if calcium-containing IV solutions are required 4

Concurrent Management Requirements

Chlamydia Coinfection

• Coinfection occurs in 10-50% of gonorrhea cases, making presumptive treatment essential 2, 8
• If chlamydia has been excluded by testing, doxycycline may be omitted from the regimen 1

Partner Management

• All sexual partners from preceding 60 days must be evaluated and treated with the same dual therapy regimen 2, 5
• If last sexual contact was >60 days before diagnosis, treat the most recent partner 5
• Expedited partner therapy with oral combination (cefixime 400 mg plus azithromycin 1 g) may be considered when partners cannot access timely evaluation, except in MSM 2

Additional Testing

• Screen for syphilis with serology at time of gonorrhea diagnosis 2, 5
• HIV testing should be performed given gonorrhea's facilitation of HIV transmission 2

Follow-Up and Test-of-Cure

Routine Follow-Up

• Patients treated with recommended ceftriaxone-based regimens do not need routine test-of-cure unless symptoms persist 2
• Retest all patients at 3 months due to high reinfection risk (9.9% retreatment rate within 2 years) 9, 1

Mandatory Test-of-Cure Situations

• Test-of-cure at 1 week is mandatory for patients receiving cefixime or azithromycin monotherapy 2, 5
• If symptoms persist after treatment, obtain culture with antimicrobial susceptibility testing 2, 5

Treatment Failure Management

• If treatment failure occurs, obtain specimens for culture and antimicrobial susceptibility testing immediately 2
• Report the case to local public health officials within 24 hours 2
• Consult an infectious disease specialist 2
• Recommended salvage regimens include gentamicin 240 mg IM plus azithromycin 2 g orally, or ertapenem 1 g IM for 3 days 2

Resistance Surveillance Context

The evolution from ceftriaxone 250 mg plus azithromycin 1 g (2010-2020) to ceftriaxone 500 mg plus doxycycline (2020-present) reflects the ongoing challenge of antimicrobial resistance 1. While ceftriaxone resistance remains rare, increasing azithromycin resistance and antimicrobial stewardship concerns prompted this change 1. The higher ceftriaxone dose provides additional therapeutic reserve, particularly for pharyngeal infections where treatment failures are most likely to occur 2.