1. Is Gonorrhoea untreatable?
Catherine Ison
Health Protection Agency, London, UK
22 April 2017

2. Treatment of gonorrhoea
Empirical:
Single dose used to aid compliance
Often syndromic, administered before lab results known
Co-treatment for chlamydial infection can be given
Choice:
National/international guidelines informed by surveillance data
Outcome:
To achieve >95% therapeutic success (WHO)
Sulphonamides
penA, penB, mtr, penC, ponA
Penicillin
penicillinase
tet, mtr
Tetracycline
TETM
gyrA, parC
Quinolones
23S rRNA
Azithromycin
penA
mosaic
Cephalosporins ? ?

3. Antimicrobial resistance in GC
Acquisition
Plasmids
Penicillin (PPNG): tem-1 (Haemophilus)
Tetracycline (TRNG): tetM (Streptococci)
Chromosomal
Penicillin/Cephalosporin
(Commensal Neisseriae)
Selection
High-level, single step
Spectinomycin
Azithromycin
Additive, multiple steps
Penicillin
Ciprofloxacin

4. Inadequate dosage or incomplete course Long term use of a single agent
How does it happen?
Misuse or overuse of antimicrobial agents
Inadequate dosage or incomplete course
OTC use
Long term use of a single agent
Selection of mutants

5. First-line therapy Surveillance programmes
Monitor trends in resistance
Monitor drift in susceptibility
Detect emergence of resistance
Inform treatment guidelines
Local
National
Regional
Global

6. Ciprofloxacin (MIC≥1mg/l) resistance by gender and sexual orientation, 2000-2009
Ciprofloxacin resistance continues to be high among MSM between 2008 and 2009, resistance increased significantly from 45.9% to 54.0%. Ciprofloxacin resistance among heterosexual men and women was considerably lower. In 2009, 28.7% of heterosexual men and 15.1% of women had ciprofloxacin resistant gonococcal isolates.
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

7. EuroGASP – informing guidelines5%
EuroGASP – European Gonococcal Surveillance Programme
Part of European STI surveillance network coordinated by ECDC
Initiated by ESSTI, now funded by ECDC
Sentinel study, 110 consecutive isolates over 3 months

8. Gonorrhoea management guidelines
BASHH guideline 2005
Cefixime, 400mg (Cefotaxime).
Ceftriaxone, 125 or 250mg.
Spectinomycin 2g.
Where susceptibility known:
Ciprofloxacin, 500mg (Ofloxacin, Levofloxacin)
Azithromycin, 1g or 2g.
Ampicillin 2g (+ 3g probenecid).
IUSTI guideline 2009
Cefixime, 400mg oral
Ceftriaxone, 250mg IM
Spectinomycin 2g IM
Alternative therapies
Other single dose cephalosporin regimens;
Cefotaxime (500mg or 1gIM)
Cefodizime (500mg IM

9. Antimicrobial prescribing practice 2000-2010 in GRASP clinics

10. Prevalence of cases with gonococcal isolates exhibiting decreased cefixime susceptibility (MIC >0.125mg/L) by gender and sexual orientation. GRASP 2010 (GUM Cases)

12. Cefixime DS GC (MIC = >0.125mg/L)
2009
2010

13. Ceftriaxone susceptibility

14. Challenges for treatment
Use diagnostic tests appropriately
Retain expertise for culture
When to change?
What is treatment failure?
What treatment?
Test of cure?

15. Appropriate diagnostic tests
Molecular detection
Poor PPV in low prevalence populations
May require confirmation especially pharyngeal samples
No Molecular test for AMR in routine use
Does not provide a viable organism
Highly sensitive and specific
More sensitive than culture at extragenital sites
Uses non-invasively taken specimens, urines, SVS
Easier for screening or testing in primary care
CT/GC result from same test

16. Retain expertise for culture
Provides viable culture for GC sensitivity testing
Essential for emerging resistance
Disadvantages
Requires significant resources
Requires invasively taken specimen
Availability of chaperone
Intolerant to delays in transportation to lab

17. When to change therapy? Recommendations
In response to rise in resistance levels;
WHO >5% of general population
CDC >3% in high risk groups
Current situation
Treatment failure emerging –high-level resistance to ceftriaxone in Japan and France documented
True level of treatment failure probably unknown
New alternative therapies lacking
Resistance exists to all previously used agents.

18. Treatment failure Why important?
To establish link between dosage given, susceptibility data and failure to respond
What is definition?
Verified clinical failure; Detailed clinical history, exclusion of re-exposure and re-infection and isolates from pre- and post treatment indistinguishable
Challenge?
Definition in the absence of an isolate
Tapsall JW et al. Expert Rev Anti Ther. 2009;7:821-34

19. Clinical failures in England
Cefixime (3 cases)
Swindon in 2008, MSM, MIC 0.25mg/l
Newcastle in 2010 – bisexual, MIC 0.25mg/l
Newcastle – verified case – hetero, MIC 0.12mg/l
Isolates resistant to ciprofloxacin and penicillin
NG-MAST ST 1407 or related types (tbpB 110)
Ceftriaxone
None documented
Ison et al, Euro Surveill 2011;16(14):pii:19833
Forsyth et al, Int J STD AIDS 2011,22,296-7

20. Treatment failures in Europe
Cefixime
Small number of cases identified
MICs 0.125mg/L-0.25mg/L
NG-MAST ST1407 or related type
Likely many more cases unidentified
Ceftriaxone
Verified failure, pharyngeal gonorrhoea in Sweden (MIC mg/L)
High-level resistant strain from France (MIC 1-2mg/L)
ST1407, also cefixime MIC 4mg/L
No others documented
Unemo et al, Euro Surveill 2010;15(47):pii=19721 Unemo et al. Euro Surveill 2011;16(6):pii=19792U
Unemo et al. Antimicrob Agents Chemother, 2011

21. Options for treatment Single dose therapy
Ceftriaxone – same or higher dosage (?500mg or 1g)
Gentamicin 240mg
Combination therapy
Ceftriaxone + azithromycin 1g
Gentamicin + azithromycin 1g
Multiple doses
Ceftriaxone followed by cefixime
Alternative agents? – no clinical trials

22. Test of cure Why? When? How?
To confirm compliance and ensure resolution of symptoms
Prevent spread of antimicrobial resistant gonorrhoea
When?
Persisting symptoms or signs
Pharyngeal infection
Treatment with anything other than first-line recommendations
How?
Culture performed at least 72 hours after completion of therapy
Test with NAATs 2weeks after completion of therapy followed by culture if positive

23. What is the Challenge?
To maintain gonorrhoea as a treatable infection!
Use new diagnostic tests appropriately
Retain expertise for culture
Collect a representative sample of viable isolates
Maintain timely surveillance data
Be vigilant for emerging resistance.
Be prepared, responsive and innovative