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Antibiotic resistance in Neisseria gonorrhoeae

Antibiotic resistance in Neisseria gonorrhoeae. Michelle Cole GUNA Summer Clinical Meeting 28 th June 2013. Today’s prese nta tion. Overview of gonorrhoea Disease UK surveillance data Antibiotic resistance Mechanisms Antibiotic resistance surveillance Public health response

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Antibiotic resistance in Neisseria gonorrhoeae

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  1. Antibiotic resistance in Neisseria gonorrhoeae Michelle Cole GUNA Summer Clinical Meeting 28th June 2013

  2. Today’s presentation • Overview of gonorrhoea • Disease • UK surveillance data • Antibiotic resistance • Mechanisms • Antibiotic resistance surveillance • Public health response • Emerging resistance • Treatment failures • Treatment guidelines • Action plans • Future challenges Antibiotic resistance in N. gonorrhoeae

  3. Gonorrhoea • Neisseria gonorrhoeae (gonococcus / GC) • Gram negative diplococci • Obligate human pathogen • Causes primarily a mucosal infection • Colonises the urogenital tract / pharynx / rectum = discharge / pain on urination • Is asymptomatic in many women = infertility / pelvic inflammatory disease • Conjunctivitis • Rarely invades to the blood = disseminated gonococcal infection • Facilitate transmission of HIV Antibiotic resistance in N. gonorrhoeae

  4. Number of new diagnoses of selected STIs, GUM clinics, England : 2011-12 Antibiotic resistance in N. gonorrhoeae

  5. New diagnoses of syphilis, gonorrhoea, genital herpes and genital warts at GUM clinics by gender, 2003-2012, England Antibiotic resistance in N. gonorrhoeae

  6. Resistance is common in N. gonorrhoeae • Individual patient management • Interrupt transmission • Single dose used to aid compliance • Often administered before lab results known • Co-treatment for chlamydial infection advised • National/international guidelines informed by surveillance data • To achieve >95% therapeutic success (WHO) Treatment of gonorrhoea Sulphonamides PBP, efflux pumps, pili, porins Penicillin Β-lactamase (PPNG) Ribosomes, efflux pumps, pili, porins, TET-M (TRNG) Tetracycline DNA topoisomerase & gyrase Ciprofloxacin Azithromycin 23S rRNA Cephalosporins PBP, efflux pumps, porins Antibiotic resistance in N. gonorrhoeae

  7. Incomplete course of therapy (including sex before cleared infection) Inadequate dosage OTC use What influences resistance Misuse of antimicrobial agents Correct / continual use Treatment with sub inhibitory dosage Long term use as treatment of choice Selective pressure Selection of mutants Antibiotic resistance in N. gonorrhoeae

  8. Mechanisms of antibiotic resistance Modification of target Impermeable to antibiotic Efflux of antibiotic Antibiotic resistance in N. gonorrhoeae

  9. Antibiotic resistance in N. gonorrhoeae • Versatile organism. • Highly competent for genetic exchange • Other Neisseria (e.g. in throat) • Mixed infection is thought to occur frequently. • Adept at developing mechanisms of resistance to therapeutic agents. Antibiotic resistance in N. gonorrhoeae

  10. Antibiotic resistance in N. gonorrhoeae • 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 (mutations in multiple genes) • Penicillin • Ciprofloxacin Antibiotic resistance in N. gonorrhoeae

  11. Sulphonamide 1930s 1940s N. gonorrhoeae treatments & resistance timeline Penicillin 1943 Resistance first document (year) Treatment available (year) Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

  12. Modification of target – penicillin binding proteins Penicillin - mechanisms of resistance • Enzymatic modification/ degradation of antibiotic • TEM-1 type β-lactamase plasmid • Penicillinase producing N. gonorrhoeae, high-level • Impermeable to antibiotic • Porins • Pili Efflux of antibiotic – Upregulation of efflux pump Antibiotic resistance in N. gonorrhoeae

  13. Sulphonamide 1930s 1940s N. gonorrhoeae treatments & resistance timeline PBP, efflux pumps , pili, porins 1950s 1943 Β-lactamase (PPNG) 1976 Tetracycline 1962 Resistance first document (year) Treatment available (year) Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

  14. Tetracycline - mechanisms of resistance Modification of target – High-level plasmid mediated resistance – streptococcal tetM determinant on a conjugative plasmid; reduced binding to ribosomes • Impermeable to antibiotic • Porins • Pili Efflux of antibiotic – Upregulation of efflux pump Antibiotic resistance in N. gonorrhoeae

  15. Sulphonamide 1930s 1940s N. gonorrhoeae treatments & resistance timeline PBP, efflux pumps, pili, porins 1950s 1943 Β-lactamase (PPNG) 1976 Ribosomes, efflux pumps, pili, porins, TET-M (TRNG) Tetracycline 1962 1985 Resistance first document (year) 1987 Ciprofloxacin Treatment available (year) Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

  16. Ciprofloxacin - mechanisms of resistance • Modification of target • DNA topoisomerase • DNA gyrase • Both essential for cell division and growth. Antibiotic resistance in N. gonorrhoeae

  17. Sulphonamide 1930s 1940s N. gonorrhoeae treatments & resistance timeline PBP, efflux pumps, pili, porins 1950s 1943 Β-lactamase (PPNG) 1976 Ribosomes, efflux pumps, pili, porins, TET-M (TRNG) Tetracycline 1962 1985 Resistance first document (year) DNA topoisomerase / gyrase 1991 1987 Ciprofloxacin Treatment available (year) 1983 Azithromycin Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

  18. Azithromycin not recommended first line therapy but 2g is effective. Use for co-treatment (1g) for chlamydia (40% co-infected) Azithromycin - mechanisms of resistance • Modification of ribosomal target • 23S RNA methylases • Mutations in 23S rRNA alleles • High-level >256 mg/L from mutations in at least 3 / 4 alleles. Sporadic worldwide detection Crystal violet tolerant Efflux of antibiotic – Upregulation of efflux pump Antibiotic resistance in N. gonorrhoeae

  19. Sulphonamide 1930s 1940s N. gonorrhoeae treatments & resistance timeline PBP, efflux pumps, pili, porins 1950s 1943 Β-lactamase (PPNG) 1976 Ribosomes, efflux pumps, pili, porins, TET-M (TRNG) Tetracycline 1962 1985 Resistance first document (year) DNA topoisomerase / gyrase 1991 1987 Ciprofloxacin Treatment available (year) 23S rRNA 1999 1983 Azithromycin 1983 Cefixime Ceftriaxone 1980 Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

  20. Modification of target – penicillin binding protein encoded by penA. • Mosaic penA gene fragments from other commensal Neisseria spp • Usually found in the throat • Naturally less susceptible to cephalosporins Cephalosporins - mechanisms of resistance Impermeable to antibiotic - Porins Efflux of antibiotic – Upregulation of efflux pump Antibiotic resistance in N. gonorrhoeae

  21. Sulphonamide 1930s 1940s N. gonorrhoeae treatments & resistance timeline PBP, efflux pumps, pili, porins 1950s 1943 Β-lactamase (PPNG) 1976 Ribosomes, efflux pumps, pili, porins, TET-M (TRNG) Tetracycline 1962 1985 Resistance first document (year) DNA topoisomerase / gyrase 1991 1987 Ciprofloxacin Treatment available (year) 23S rRNA 1999 1983 Azithromycin 1983 2001 Cefixime PBP, efflux pumps, porins 2011 Ceftriaxone 1980 Super bug?? Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

  22. Neisseria gonorrhoeae: Susceptibility testing • Susceptibility testing • E-Test • Disk Diffusion • To predict therapeutic failure • Categorise strains into : • Sensitive • Intermediate • Resistance • Category relates to chance of therapeutic failure Antibiotic resistance in N. gonorrhoeae

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

  24. Began in 2000 26 participating GUM clinics and laboratories Regional representation 3 month collection each year One isolate from consecutive patients Monitors resistance to: Penicillin Tetracycline Ciprofloxacin Azithromycin Spectinomycin Ceftriaxone and cefixime Newcastle Leeds Liverpool Sheffield Manchester Nottingham Wolverhampton Cambridge Birmingham Newport Northampton Luton Gloucester Cardiff London (9) Bristol Reading Brighton Gonococcal resistance to antimicrobials surveillance programme (GRASP) Antibiotic resistance in N. gonorrhoeae

  25. 1480 samples were collected from patients attending GRASP GUM clinics in 2011 Almost half of which were from the London region (49.3%) 48.8% (665) of patients were men who have sex with men (MSM), 28.4 (387) were heterosexual men and 22.9% (312) were women. Retrieval rate was 88.5% Data completeness varied slightly >85% GRASP 2011 Antibiotic resistance in N. gonorrhoeae

  26. Ciprofloxacin resistance (MIC≥1mg/L) by gender and sexual orientation, 2000 - 2011 • Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP) Antibiotic resistance in N. gonorrhoeae Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

  27. Cefixime MIC (mg/L) by gender and sexual orientation, GRASP 2011 • Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP) Antibiotic resistance in N. gonorrhoeae Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

  28. Cefixime(MIC≥0.125mg/l) decreased susceptibility by gender and sexual orientation, 2004 - 2011 Source:Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP) Antibiotic resistance in N. gonorrhoeae Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

  29. Ciprofloxacin by cefixime MIC (mg/L) Source:Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP) Antibiotic resistance in N. gonorrhoeae Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

  30. Ceftriaxone MIC (mg/L) by gender and sexual orientation, GRASP 2011 Source:Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP) Antibiotic resistance in N. gonorrhoeae Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

  31. Countries with strains that exhibit decreased-susceptibility to cefixime (≥5%) Countries with strains that exhibit decreased-susceptibility to cefixime (<5%) Countries with no strains that exhibit decreased-susceptibility to cefixime Decreased susceptibility to cefixime (≥0.25mg/L) – Euro-GASP 2011 2010 2009 Location of published cefixime/ceftriaxone treatment failures • All ST1407 or closely related • Pre / post treatment isolate not always available

  32. Global surveillance • WHO Western Pacific Region GASP. • WHO South-East Asia Region • Gonococcal Isolate Surveillance Program (GISP) – USA. • Americas and the Caribbean. • Euro-GASP / WHO Europe (53 countries). • National programmes, i.e GRASP (E&W), Sweden, Denmark, Belgium, the Netherlands, Australia, Russia. Antibiotic resistance in N. gonorrhoeae

  33. Response to emerging and increasing resistance AND treatment failures • Update treatment guidelines • In response to rise in resistance levels; • WHO >5% of general population • CDC >3% in high risk groups • Monitor for treatment failures • European / WHO / CDC / GRASP response plans Antibiotic resistance in N. gonorrhoeae

  34. Treatment guidelines • 2004-2011 • First-line • Cefixime, 400mg (Cefotaxime). • Ceftriaxone, 125 or 250mg. • Spectinomycin 2g. • Since 2011 • First-line: • Ceftriaxone – 500mgs IM + Azithromycin 1g • Second-line: • Cefixime 400mgs + Azithromycin, 1g Antibiotic resistance in N. gonorrhoeae

  35. Ceftriaxone increased dose Prescribing practice and resistance trends, GRASP 2001-2011 Ciprofloxacin prescribed Introduction of cefixime/ceftriaxone Source:Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP) Antibiotic resistance in N. gonorrhoeae Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

  36. Future treatment options • 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 Antibiotic resistance in N. gonorrhoeae

  37. Response to AMR GC Public Health Agencies WHO Global Action Plan ECDC Response Plan Global Regional GRASP and CDC Action Plan National Antibiotic resistance in N. gonorrhoeae

  38. 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. Antibiotic resistance in N. gonorrhoeae

  39. Case definition for confirmed/probable treatment failure Antibiotic resistance in N. gonorrhoeae

  40. Monitoring treatment failure • Launched in May 2011 • On line submission, through GUMCAD portal • In first year:12 cases reported, 10 from MSM, 4/12 cases seen before guideline change • Reporting of failures retrospective, needs to be real-time • Plan to modify form and send monthly alert to GUM clinics • Lack of isolates data to obtain laboratory confirmation – archiving of isolates • Need to link more effectively to microbiologists • ?Reporting mechanism for microbiologists Antibiotic resistance in N. gonorrhoeae

  41. Technical advice to laboratories • Retain skills in GC isolation • Provides viable culture for GC sensitivity testing • Essential for emerging resistance/treatment failure • Issues • Requires significant resources • Requires invasively taken specimen • Availability of chaperone • Intolerant to delays in transportation to lab Antibiotic resistance in N. gonorrhoeae

  42. What is the Challenge? To maintain gonorrhoea as a treatable infection! • Use new diagnostic tests appropriately • Retain expertise for culture • Timely, representative and global surveillance data • Be vigilant for emerging resistance / treatment failures • Use appropriate treatment and consider alternatives: • Higher and multiple doses • New / old / combination therapies • Anti-infectives / vaccines Antibiotic resistance in N. gonorrhoeae

  43. Thanks……… • For listening! • To Cathy Ison and the GRASP team for additional slides • To the GRASP and Euro-GASP collaborators Antibiotic resistance in N. gonorrhoeae

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