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

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 ? ?

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

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

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

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

Decreased susceptibility to ESCs Cefixime Ceftriaxone penA mosaic Zhou et al. Mol Microbiol 2005 57: 1238-51

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.

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

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

Response to AMR GC Public Health Agencies Global Regional National

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.

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

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

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

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)

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

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

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