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Neisseria gonorrhoeae Antimicrobial Resistance

Neisseria gonorrhoeae Antimicrobial Resistance. Robert D. Kirkcaldy, MD, MPH Division of STD Prevention NCHHSTP/CDC. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention. Division of STD Prevention. Disclosures: No Relevant Relationships. Objectives.

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Neisseria gonorrhoeae Antimicrobial Resistance

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  1. Neisseria gonorrhoeae Antimicrobial Resistance Robert D. Kirkcaldy, MD, MPH Division of STD Prevention NCHHSTP/CDC National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of STD Prevention Disclosures: No Relevant Relationships

  2. Objectives • Participants will be able to describe: • recommended gonorrhea treatment • epidemiological patterns of gonococcal resistance • potential consequences of cephalosporin resistance

  3. Overview • Gonorrhea • Overview of resistance • Emerging cephalosporin resistance • Molecular epidemiology & resistance determinants • Treatment update • Conclusions

  4. Gonorrhea • One of the oldest known human diseases • Named by Galen (2nd century) ~ “flow of semen” • Caused by Neisseria gonorrhoeae • Described in 1879 by Albert Neisser • Can cause • pelvic inflammatory disease (PID) • ectopic pregnancy • infertility • Prompt antimicrobial treatment limits sequelae & transmission

  5. Gonorrhea Rates, United States, 1941–2012 Rate (100,000 population) Source: Centers for Disease Control and Prevention

  6. Gonorrhea Rates, United States, 1941–2012 Rate (100,000 population) 107.5 98.1 Source: Centers for Disease Control and Prevention

  7. Gonorrhea Rates by State, United States, 2012 Rate per 100,000 population ≤45 45–78 79–99.1 99.2–141 142–400 Source: Centers for Disease Control and Prevention

  8. Gonorrhea Rates by State, United States, 2012 112.6 Rate per 100,000 population ≤45 45–78 79–99.1 99.2–141 142–400 Source: Centers for Disease Control and Prevention

  9. 0.0 – 6.7 6.8 – 20.8 20.9 – 43.8 43.9 – 102.6 102.7 – 360.3 Gonorrhea rate per 100,000 by County, Indiana, 2012

  10. 0.0 – 6.7 6.8 – 20.8 20.9 – 43.8 43.9 – 102.6 102.7 – 360.3 360.3 3,311 cases Gonorrhea rate per 100,000 by County, Indiana, 2012

  11. Treatment of Uncomplicated Gonorrhea • Recommended regimen • Ceftriaxone 250 mg IM PLUS • Azithromycin 1 g orally or doxycycline 100 mg twice daily x 1wk (azithromycin is preferred) • Alternatives • Cefixime 400 mg PLUS either azithromycin 1 g or doxycycline • Test of cure OR • Azithromycin 2 g • Test of cure CDC. Update to CDC’s Sexually Transmitted Diseases Treatment Guidelines, 2010. Oral cephalosporins no longer a recommended treatment for gonococcal infections. MMWR 2012;61(31):590-594.

  12. Neisseria gonorrhoeae (NG)Antimicrobial Resistance • Undermines treatment success • Heightens risk of complications • Facilitates transmission (by lengthening infectious period)

  13. Treatment of Gonorrheain the Pre-Antibiotic Era • Patent Medicines • Intraurethral irrigation • Mercurochrome • Nitric acid • Silver nitrate • Mechanical removal of strictures • Sounds • Dilators • injectors Baumann F. Gonorrhea: Its Diagnosis and Treatment. D. Appleton & Co. 1910

  14. Timeline of Introduction of Antimicrobials and Emergence of Resistance Ciprofloxacin (Fluoroquinolones) Tetracycline PPNG Penicillin (chromosomal) Sulphonamides 1940 1950 1960 2000 1970 1980 1990 PPNG = penicillinase-producing N. gonorrhoeae Adapted from: Goire N et al. Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance. Nature Reviews Microbiology 2012

  15. Ciprofloxacin Resistance in N. gonorrhoeae, United States, 1990–2007 California Hawaii Prevalence, % Rest of the US Year GISP, Gonococcal Isolate Surveillance Project, 1990–2007 Resistant isolates have ciprofloxacin MICs ≥1 µg/ml 15

  16. Ciprofloxacin Resistance in N. gonorrhoeae, by Gender of Sex Partner, United States, 1999-2007 MSM Prevalence, % MSW Year GISP, Gonococcal Isolate Surveillance Project, 1990–2007 Resistant isolates have ciprofloxacin MICs ≥1 µg/ml MSM, men who have sex with men MSW, men who have sex exclusively with women 16

  17. emerging cephalosporin resistance

  18. Global Emergence of Cephalosporin Resistance • Increasing N. gonorrhoeaecephalosporin minimum inhibitory concentrations (MICs) • East Asia & Western Pacific Region • Europe • Canada • US • Treatment failures ~ oral cephalosporins • East Asia • Europe • Canada (Toronto) • Ceftriaxone-resistant strains (MICs 1–2 µg/ml) identified in Japan, Spain & France

  19. Global Emergence of Cephalosporin Resistance • Increasing cephalosporin minimum inhibitory concentrations (MICs) • East Asia & Western Pacific Region • Europe • Canada • US • Treatment failures ~ oral cephalosporins • East Asia • Europe • Canada (Toronto) • Ceftriaxone-resistant strains (MICs 1–2 µg/ml) identified in Japan, Spain & France What are MICs??

  20. MeasuringAntimicrobial Susceptibility • Disk Diffusion (Kirby-Bauer) • E-test* • Agar Dilution* • * Provide minimum inhibitory concentration (MIC): lowest antibiotic concentration that inhibits visible growth bioMérieux Clinical Diagnostics

  21. MeasuringAntimicrobial Susceptibility • Disk Diffusion (Kirby-Bauer) • E-test* • Agar Dilution* • * Provide minimum inhibitory concentration (MIC): lowest antibiotic concentration that inhibits visible growth Dead bacteria Live bacteria

  22. MeasuringAntimicrobial Susceptibility • Disk Diffusion (Kirby-Bauer) • E-test* • Agar Dilution* • * Provide minimum inhibitory concentration (MIC): lowest antibiotic concentration that inhibits visible growth bioMérieux Clinical Diagnostics

  23. Agar Dilution & MICs 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  24. Agar Dilution & MICs 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  25. Agar Dilution & MICs 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  26. Agar Dilution & MICs 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  27. Agar Dilution & MICs 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  28. Agar Dilution & MICs 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  29. Agar Dilution & MICs 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  30. Agar Dilution & MICs MIC 0.030 0.060 0.125 0.25 0.50 1.00 2.00 Antimicrobial concentrations

  31. Global Emergence of Cephalosporin Resistance • Elevated or increasing cephalosporin minimum inhibitory concentrations (MICs) • East Asia & Western Pacific Region • Europe • Canada • US • Treatment failures ~ oral cephalosporins • East Asia • Europe • Canada (Toronto) • Ceftriaxone-resistant strains (MICs 1–2 µg/ml) identified in Japan, Spain & France

  32. Gonococcal Isolate Surveillance Project —United States, 2014 Regional Labs Clinical sites Source: Gonococcal Isolate Surveillance Project

  33. Proportion of Isolates with Elevated Cefixime MICs (≥0.25 μg/ml), United States, 2000–2011 Percentage of isolates Cefixime AST not conducted Source: Gonococcal Isolate Surveillance Project

  34. Proportion of Isolates with Elevated Cefixime MICs (≥0.25 μg/ml), United States, 2000–2012 Percentage of isolates Cefixime AST not conducted Source: Gonococcal Isolate Surveillance Project

  35. Proportion of Isolates with Elevated Cefixime MICs (≥0.25 μg/ml), United States, 2000–2012 • Changes in Treatment Recs • 2010 • Ceftriaxone preferred • Increased ceftriaxone dose • Combination therapy • 2012 • First-line: Combination therapy with ceftriaxone Percentage of isolates Source: Gonococcal Isolate Surveillance Project

  36. Proportion of GISP Isolates with Elevated Cefixime MICs (≥0.25 μg/ml) by Gender of Sex Partner, US, 2006–2012 MSM Percentage of isolates Cefixime AST not conducted MSW • MSM = Men who have sex with men; MSW = Men who have sex exclusively with women Source: Gonococcal Isolate Surveillance Project

  37. Proportion of GISP Isolates with Elevated Cefixime MICs (≥0.25 μg/ml) by Region, US, 2006–2012 Percentage Year Source: Gonococcal Isolate Surveillance Project

  38. Percentage of Isolates with Elevated Ceftriaxone MICs (≥0.125 µg/ml), 2008–2012 Percentage of isolates Year Source: Gonococcal Isolate Surveillance Project

  39. Percentage of N. gonorrhoeae Isolates with Cefixime MICs ≥0.125 µg/ml, United Kingdom (GRASP), 2007–2011 Percentage Ison CA et al. Decreased susceptibility to cephalosporins among gonococci:: data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales, 2007-2011. Lancet ID. 2013;13:762-68

  40. Cefixime and Ceftriaxone MIC Distribution, Indianapolis, 2013* (n=299) Percentage ceftriaxone cefixime 0.3% MIC (µg/ml) * preliminary

  41. Percentage of isolates with elevated azithromycin MICs (≥2 µg/ml) and geometric mean MIC, GISP, 2008–2012 Geometric mean Percentage Percentage Year Source: Gonococcal Isolate Surveillance Project

  42. Azithromycin MIC Distribution, Indianapolis, 2013* (n=299) Percentage * Preliminary data

  43. Molecular Epidemiology & resistance determinants

  44. Genome Sequencing and Phylogenetic Analysis of 2009–2010 GISP Isolates (n=236) Grad YH et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet ID 2014

  45. Genome Sequencing and Phylogenetic Analysis of 2009–2010 GISP Isolates (n=236) Grad YH et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet ID 2014

  46. Genome Sequencing and Phylogenetic Analysis of 2009–2010 GISP Isolates (n=236) Grad YH et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet ID 2014

  47. Genome Sequencing and Phylogenetic Analysis of 2009–2010 GISP Isolates (n=236) Grad YH et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet ID 2014

  48. Genome Sequencing and Phylogenetic Analysis of 2009–2010 GISP Isolates (n=236) Grad YH et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet ID 2014

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