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Is Gonorrhoea untreatable?

Is Gonorrhoea untreatable?. Catherine Ison Health Protection Agency, London, UK. 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:

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Is Gonorrhoea untreatable?

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

  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. 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 Antimicrobial resistance in GC

  4. 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 • Monitor trends in resistance • Monitor drift in susceptibility • Detect emergence of resistance • Inform treatment guidelines Surveillance programmes Local National Regional Global

  6. Ciprofloxacin (MIC≥1mg/l) resistance by gender and sexual orientation, 2000-2009 Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

  7. EuroGASP – informing guidelines 5% • 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)

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

  12. Ceftriaxone susceptibility

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

  14. Appropriate diagnostic tests Molecular detection • 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 • 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

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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 0.125-0.25mg/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

  20. 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

  21. Test of cure • Why? • 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

  22. 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

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