What are the main mutations conferring resistance to azithromycin (a macrolide antibiotic) and ciprofloxacin (a fluoroquinolone antibiotic) in gonorrhea?

Main Mutations Conferring Antibiotic Resistance in Neisseria gonorrhoeae

The most critical mutations conferring resistance to azithromycin in N. gonorrhoeae are A2059G and C2611T in the 23S rRNA gene, while the S91F mutation in the gyrase A gene is the primary determinant of ciprofloxacin resistance. These mutations significantly impact treatment outcomes and are driving the global crisis of antimicrobial resistance in gonorrhea.

Azithromycin Resistance Mutations

Key 23S rRNA Mutations

• A2059G mutation:

  • Causes high-level azithromycin resistance (MICs ≥256 μg/mL) 1, 2
  • Most critical mutation for azithromycin resistance
  • When present in 3-4 of the four 23S rRNA alleles, confers complete high-level resistance 1
  • Has been proven to be the only genetic determinant required for high-level resistance 2
  • Enhances biological fitness in vivo, making these resistant strains more successful at colonization 2

• C2611T mutation:

  • Associated with moderate azithromycin resistance (MICs 2-8 μg/mL) 1
  • Usually requires presence in at least 3 of 4 alleles to confer clinically significant resistance 1
  • Less potent than A2059G but still clinically important

Additional Resistance Mechanisms

• mtrR promoter mutations:

  • Mutations in the mtrR coding region or promoter lead to overexpression of efflux pumps 3
  • Contribute to reduced azithromycin susceptibility but typically not high-level resistance alone
  • Often work in combination with 23S rRNA mutations to enhance resistance

• erm genes:

  • Encode methylases that can modify the ribosomal target of azithromycin
  • Less common in N. gonorrhoeae compared to other bacterial species 1

Ciprofloxacin Resistance Mutations

Key Mutations

• S91F mutation in gyrA gene:

  • Primary determinant of quinolone resistance in N. gonorrhoeae
  • Alters DNA gyrase, preventing ciprofloxacin binding to its target
  • Has led to widespread fluoroquinolone resistance globally 4

• Additional quinolone resistance mutations:

  • D95G/A/N in gyrA
  • S87R and E91G in parC (topoisomerase IV)
  • These often occur alongside S91F to further increase resistance levels

Clinical Significance and Implications

Impact on Treatment

• The rising prevalence of these mutations has led to significant changes in treatment guidelines:
  • Fluoroquinolones are no longer recommended for empiric gonorrhea treatment due to widespread resistance 4, 5
  • Azithromycin is increasingly being removed from first-line treatment regimens 4
  • Current guidelines recommend ceftriaxone monotherapy in many regions due to concerns about azithromycin resistance 4

Geographical Distribution

• Azithromycin resistance mutations are increasingly common globally, with rates exceeding 19% in some studies 6
• High-level azithromycin resistance (A2059G mutation) has been reported in multiple countries 1, 2
• Quinolone resistance is now widespread, particularly in Asia and the Pacific regions 4

Surveillance Implications

• Molecular detection of these mutations is becoming crucial for surveillance and treatment decisions 5
• Whole genome sequencing has revealed that some resistant strains are spreading clonally, suggesting person-to-person transmission rather than de novo mutation 6

Treatment Considerations

• For patients with suspected or confirmed gonorrhea with these resistance mutations:

  • Avoid azithromycin monotherapy due to high resistance rates
  • Avoid ciprofloxacin unless susceptibility is confirmed by testing
  • Use ceftriaxone as the primary treatment agent 4, 5
  • Consider test of cure for all cases treated with alternative regimens 5

• Pharyngeal infections are particularly challenging to treat and may harbor resistant strains:

  • Higher treatment failures occur at this site
  • May require higher doses or extended treatment courses 4
  • Consider testing for pharyngeal infection in cases of treatment failure 4

The emergence and spread of these resistance mutations represent a critical public health threat, with N. gonorrhoeae evolving toward potential untreatable status. Understanding these specific mutations is essential for developing new treatment strategies and diagnostic approaches.