Mechanisms and Genes Involved in Neisseria gonorrhoeae Antimicrobial Resistance
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. 1
Key Resistance Mechanisms by Antimicrobial Class
Cephalosporin Resistance
- PenA gene modifications:
- Mosaic penA-60.001 allele encodes altered penicillin-binding protein 2 (PBP2), the target of extended-spectrum cephalosporins 2
- FC428 strain (first identified in Japan in 2015) carries this allele and has achieved sustained international transmission 2
- Diverse strains harboring the penA-60.001 allele show elevated ceftriaxone MICs 2
Fluoroquinolone Resistance
- Emerged in the United States during the 1990s-2000s, initially in Hawaii and California 2
- By 2007, fluoroquinolone-resistant N. gonorrhoeae was widespread, prompting CDC to no longer recommend fluoroquinolones 2
- Resistance mechanisms include:
- Mutations in gyrA and parC genes (encoding DNA gyrase and topoisomerase IV)
- Reduced drug accumulation through efflux pump overexpression
Penicillin Resistance
- Chromosomally-mediated resistance:
- Mutations in penA gene (encoding PBP2)
- Mutations in mtrR gene (increasing efflux)
- Mutations in ponA gene (encoding PBP1)
- Mutations in pilQ gene (altering outer membrane permeability)
- Plasmid-mediated resistance:
- Production of β-lactamase (penicillinase) via plasmid-borne blaTEM gene
Tetracycline Resistance
- Chromosomally-mediated:
- Mutations in rpsJ gene (encoding ribosomal protein S10)
- Overexpression of MtrCDE efflux pump
- Plasmid-mediated:
- tetM gene carried on conjugative plasmids
Macrolide Resistance (Azithromycin)
- Mutations in 23S rRNA genes
- Overexpression of MtrCDE efflux pump via mutations in mtrR promoter or coding region
- Presence of erm genes (encoding rRNA methylases)
Spectinomycin Resistance
- Mutations in 16S rRNA gene (specifically at position 1192)
- Mutations in rpsE gene (encoding ribosomal protein S5)
Geographical Distribution and Trends
- Ceftriaxone resistance prevalence in China estimated at nearly 9% 2
- Fluoroquinolone resistance initially emerged in Hawaii, California, and among men who have sex with men before spreading throughout the United States 2
- FC428 strain and related clones with reduced cephalosporin susceptibility are typically associated with travel from the Asia-Pacific region 2
Anatomical Site Considerations
- Pharyngeal infections:
- More difficult to eradicate than urogenital infections 1
- Play a pivotal role in the emergence and spread of antimicrobial resistance 2
- Lower cure rates due to unfavorable pharmacokinetics of cephalosporins in pharyngeal tissues 2
- Majority of treatment failures have involved asymptomatic pharyngeal infection 2
Clinical Implications
- Treatment failures are increasingly likely as resistance emerges 2
- Current first-line treatment recommendation is combination therapy with ceftriaxone 250 mg intramuscularly plus either azithromycin 1 g orally or doxycycline 100 mg orally twice daily for 7 days 2
- CDC no longer recommends cefixime at any dose as a first-line regimen due to declining susceptibility 2
- Test-of-cure is recommended, particularly for pharyngeal infections 2
Surveillance and Future Directions
- Enhanced surveillance of infection, antimicrobial resistance, and treatment failures is critical 1
- Development of rapid phenotypic and genetic point-of-care AMR tests is needed 3
- Novel antimicrobials under investigation include solithromycin, zoliflodacin, and gepotidacin 4
- Vaccine development represents a potential long-term solution to combat resistance 5
The evolution of antimicrobial resistance in N. gonorrhoeae represents a significant public health challenge that requires ongoing surveillance, appropriate antimicrobial stewardship, and development of new therapeutic options to prevent the emergence of truly untreatable gonorrhea.