Mechanisms of Antibiotic Resistance in Neisseria gonorrhoeae
Neisseria gonorrhoeae has developed resistance to virtually all antibiotics used in its treatment through multiple mechanisms, with the most concerning being resistance to extended-spectrum cephalosporins which are currently the last reliable treatment option. 1
Key Resistance Mechanisms
1. Extended-Spectrum Cephalosporin Resistance
- Mosaic penA Alleles: The most significant mechanism involves mutations in the penA gene encoding penicillin-binding protein 2 (PBP2), the target of cephalosporins
- The mosaic penA-60.001 allele is particularly concerning, first identified in the FC428 strain from Japan in 2015 1
- This allele has achieved sustained international transmission, particularly from the Asia-Pacific region
- Diverse strains harboring this allele show elevated ceftriaxone MICs
2. Fluoroquinolone Resistance
- GyrA and ParC Mutations: Alterations in DNA gyrase and topoisomerase IV genes
3. Macrolide Resistance (Azithromycin)
- 23S rRNA Mutations: Alterations in the ribosomal target site
- mtrR Mutations: Overexpression of efflux pumps
- Rapid rise in azithromycin resistance with approximately 5% of isolates showing elevated MICs (≥2.0 mcg/mL) by 2018 2
4. Tetracycline Resistance
- tetM Gene: Ribosomal protection protein
- rpsJ Mutations: Alterations in ribosomal protein S10
- Higher prevalence of tetracycline resistance compared to azithromycin resistance 1
5. Penicillin Resistance
- Beta-lactamase Production: Plasmid-mediated resistance
- PBP2 Alterations: Chromosomal mutations reducing affinity for penicillins
- mtrR Mutations: Increased efflux
Anatomical Considerations in Resistance
Pharyngeal infections are particularly problematic:
- More difficult to eradicate than urogenital or anorectal infections 3
- Unfavorable pharmacokinetics of cephalosporins in pharyngeal tissues 1
- Play a pivotal role in the emergence and spread of antimicrobial resistance 1
- Many treatment failures with extended-spectrum cephalosporins involve pharyngeal infections 1
Horizontal Gene Transfer and Resistance Development
- Resistance often emerges first in commensal Neisseria species before transferring to N. gonorrhoeae via transformation 4
- Low-level antibiotic exposure in both N. gonorrhoeae and commensal Neisseria can select for resistance emergence 1
- This creates a "pan-Neisseria genome" consideration for treatment strategies 4
Current Treatment Approaches to Combat Resistance
- Dual Therapy: Ceftriaxone 250-500mg IM plus azithromycin 1-2g orally or doxycycline 100mg twice daily for 7 days 1, 3
- Increased ceftriaxone dosing (500mg) now recommended in recent guidelines 2
- Combination regimens appear more effective than monotherapy, particularly for pharyngeal infections 1
- Limited options for patients with cephalosporin allergies 2
Emerging Antimicrobials and Resistance Concerns
- Zoliflodacin: Shows promise but variable efficacy for pharyngeal infections (4/8 with 2g dose, 9/11 with 3g dose) 1
- Gepotidacin: Limited data for pharyngeal infections; concerns about rapid resistance development 1
- Both require further evaluation for pharmacokinetics in pharyngeal tissue 1
Surveillance and Prevention Strategies
- Molecular assays for rapid determination of resistance (e.g., ciprofloxacin susceptibility testing) 1
- Culture and antimicrobial susceptibility testing crucial for persistent infections 1
- Test-of-cure recommended for alternative treatment regimens 1
- Enhanced surveillance of infection, AMR, and treatment failures 5
The rapid evolution of resistance in N. gonorrhoeae represents an urgent global health threat, with limited treatment options remaining effective. Ongoing surveillance, antimicrobial stewardship, and development of novel antimicrobials are critical to address this challenge.