1. Neisseria gonorrhoeae: the first untreatable infection
Catherine Ison
Sexually Transmitted Bacteria Reference Unit
(STBRU), HPA, London, UK
31 December 2018

2. Treatment of gonorrhoea
Syndromic management often used
Administered before lab results available
Single dose used to aid compliance
Co-treatment for dual infections often given
Test of cure – seldom used
National/international guidelines inform choice of therapy
Aim 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. GRASP: Cefixime DS GC (MIC = >0.125mg/L)
Newcastle
Leeds
Liverpool
Manchester
Sheffield
Nottingham
Wolverhampton
Birmingham
Cambridge
Northampton
Newport
Gloucester
Luton
Cardiff
Bristol
Reading
GRASP :Initiated in 2000
Sentinel study: 26 sites
Consecutive isolates over 3 month period
London (9)
Brighton

5. Euro-GASP: Cefixime DS GC (MIC = >0.125mg/L)
2009
2010

6. Prevalence of Genogroup 1407
<5%
31-40%
* Low numbers of isolates tested
11-20%
5-10%
21-30%
41-50%
Non-participating countries *

7. Decreased susceptibility to ESCs
Cefixime
Ceftriaxone
penA mosaic
Zhou et al. Mol Microbiol :

8. When to change therapy? Recommendations
In response to rise in resistance levels;
WHO >5% of general population
CDC >3% in high risk groups
Change to agent with no known resistance
Current situation
Treatment failure is documented but still uncommon
Emergence of true treatment failure – high level resistance
True level of treatment failure probably unknown
New alternative therapies lacking
Resistance exists to all previously used agents.

9. 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

10. Treatment guidelines BASHH guidelines 2011 IUSTI guideline 2012
First-line:
Ceftriaxone – 500mgs IM + Azithromycin 1g
Second-line:
Cefixime 400mgs + Azithromycin, 1g
IUSTI guideline 2012
Ceftriaxone – 500mgs IM + Azithromycin 2g
Cefixime 400mgs + Azithromycin, 2g

11. Response to AMR GC
Public Health Agencies
Global
Regional
National

12. GRASP Action Plan
Provision of robust and timely surveillance data on antimicrobial resistant gonorrhoea in England & Wales.
Advising on appropriate changes to the national guidelines for the management of gonorrhoea.
Giving technical advice to clinical microbiologists on appropriate methods for detection of decreased susceptibility or resistant gonococcal isolates in the laboratory.
Providing support to allow rapid detection of treatment failures to cefixime, ceftriaxone and azithromycin.
Communication to all healthcare professionals and at risk groups to raise awareness of the threat of untreatable gonorrhoea.
Promote prevention messages to enhance public health control of gonorrhoea.

13. Case definition for confirmed/probable treatment failure
Online report tool available through GUMCAD portal or GRASP webpage
Monthly alerts to GUM physicians. Need to improve link to microbiologists

14. Technical advice to laboratories
Antimicrobial susceptibility testing
Determination of MIC by Etest is the recommended method of choice
Screening of gonococcal isolates can be achieved using cefuroxime discs (5μg) and azithromycin discs (15μg) but must be confirmed using Etest
Referral and archiving of potential failures or resistant isolates to STBRU.
Cefixime
Cefuroxime

15. Measurable outcomes Quarterly and/or annual reports on:
Treatment failures reported
Number of isolates referred to STBRU for confirmation of decreased susceptibility to cefixime and/or ceftriaxone and/or azithromycin resistance
Number of isolates referred to GRASP from sentinel sites
Number of patients participating in GRASP receiving the recommended antimicrobial treatment
Publications or communications to healthcare professionals regarding the threat of antimicrobial resistant gonorrhoea

16. Prescribing practice and resistance trends, GRASP 2001-2011
In May 2011, new guidelines for the treatment of gonorrhoea were issued by BASHH in the UK.
Recommending a single dose of ceftriaxone at 500mg IM combined with a azithromycin 1gm (orally) as first line treatment
Left axis shows the prescribing data for cefixime, ceftriaxone and ciprofloxacin
right axis shows the resistant and decreased susceptibility for ciprofloxacin and cefixime respectively.
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

17. Geometric mean MICS (mg/L) of cefixime and ceftriaxone, 2007 -2011
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

18. Euro-GASP: Cefixime DS GC (MIC = >0.125mg/L)
2010
2011

19. 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
Strengthen prevention messages
Be vigilant for emerging resistance