Neisseria gonorrhoeae Antimicrobial Resistance Robert D. Kirkcaldy, MD, MPH Division of STD Prevention NCHHSTP/CDC National Center for HIV/AIDS, Viral.

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  Participants will be able to describe:  recommended gonorrhea treatment  epidemiological patterns of gonococcal resistance  potential consequences of cephalosporin resistance

Overview  Gonorrhea  Overview of resistance  Emerging cephalosporin resistance  Molecular epidemiology & resistance determinants  Treatment update  Conclusions

Gonorrhea  One of the oldest known human diseases  Named by Galen (2 nd 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

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

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

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

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

Gonorrhea rate per 100,000 by County, Indiana, 2012 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 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

 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 Treatment of Uncomplicated Gonorrhea 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.

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

Treatment of Gonorrhea in 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

Timeline of Introduction of Antimicrobials and Emergence of Resistance 194019501960 197019801990 2000 Sulphonamides Penicillin (chromosomal) PPNG Tetracycline Ciprofloxacin (Fluoroquinolones) PPNG = penicillinase-producing N. gonorrhoeae Adapted from: Goire N et al. Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance. Nature Reviews Microbiology 2012

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

Ciprofloxacin Resistance in N. gonorrhoeae, by Gender of Sex Partner, United States, 1999-2007 MSM 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 Prevalence, % MSW Year 16

EMERGING CEPHALOSPORIN RESISTANCE

Global Emergence of Cephalosporin Resistance  Increasing N. gonorrhoeae 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

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??

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

Measuring Antimicrobial 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

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

Agar Dilution & MICs 1.000.500.250.0600.030 Antimicrobial concentrations 2.00 0.125

Agar Dilution & MICs 1.000.500.250.0600.030 Antimicrobial concentrations 2.00 0.125 MIC

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

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

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

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

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

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

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

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

Percentage of N. gonorrhoeae Isolates with Cefixime MICs ≥0.125 µg/ml, United Kingdom (GRASP), 2007–2011 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 Percentage

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

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

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

MOLECULAR EPIDEMIOLOGY & RESISTANCE DETERMINANTS

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

Phylogenetic reconstruction of cluster 1 with inferred location and sexual orientation MSM Honolulu California MSW Grad YH et al. Genomic epidemiology of Neisseria gonorrhoeae with reduced susceptibility to cefixime in the USA: a retrospective observational study. Lancet ID 2014

Neisseria gonorrhoeae Resistance Mutations & Antibiotic Targets Goire N et al. Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance. Nature Reviews Microbiology 2012

Neisseria gonorrhoeae Resistance Mutations & Antibiotic Targets Goire N et al. Molecular approaches to enhance surveillance of gonococcal antimicrobial resistance. Nature Reviews Microbiology 2012 Penicillin-binding proteins (PBPs) Involved in final stages of creating peptidoglycan Peptidoglycan major part of bacterial cell wall Cell walls needed for bacterial growth, cell division, and maintaining structure of bacteria Bind β-lactam antibiotics

Mosaic penA and PBP2 Unemo M, Nicholas RA. Emergence of multidrug-resistant, extensively drug-resistant and untreatable gonorrhea. Future Microbiol 2012 Mosaic-type penA gene Includes DNA from other Neisseria spp mosaic penA XXXIV encodes Mutated PBP2: antibiotics cannot bind well

Molecular Tests for Detecting N. gonorrhoeae Resistance  Hold promise for patient care and surveillance  Especially with widespread use of NAATs, declining use of culture  None currently commercially available that have been rigorously evaluated  Determinants of cephalosporin resistance (esp. ceftriaxone) not fully understood  Promising avenues  San Francisco real-time PCR for mosaic penA Of 59 RTPCR (+) samples: o 36% elevated cefixime MICs o 25% elevated ceftriaxone MICs  Assays for pan-sensitive strains  Whole genome sequencing Gose S et al. Neisseria gonorrhoeae and extended-spectrum cephalosporins in California: surveillance and molecular detection of mosaic penA. BMC Infect Dis 2013

Medical Diagnostics Laboratories, LLC (MDL)  Offers RT PCR for Ng with reflex antibiotic resistance by Bio- Plex Analysis  Use with caution  Not FDA approved  Results have not been compared to phenotypic AST  Unknown how results correlate with resistance  At this time, not recommended to guide therapy http://www.mdlab.com/testing-menu/

TREATMENT UPDATE

 Recommended regimen  Ceftriaxone 250 mg IM PLUS  Azithromycin 1 g orally or Doxycycline 100 mg twice daily x 1wk  Alternatives  Cefixime 400 mg PLUS either azithromycin 1 g or doxycycline  Test of cure OR  Azithromycin 2 g  Test of cure Updated GC Treatment Guidelines, 2012

Prevalence of Penicillin, Tetracycline and Fluoroquinolone Resistance, US, 1987–2010 Source: Gonococcal Isolate Surveillance Project (GISP) Penicillin Resistance QRNG Percent

New Systemic Antibacterial Agents Approved by the FDA, 1983–2007 Number of New Antimicrobial Agents Approved Spellberg B, Guidos R, Gilbert D et al. Clin Infect Dis 2008

Slide courtesy of C. Deal, NIAID Manufacturing and Post- Licensure Evaluation Safety Evaluation Basic Research Target Identification & Preclinical Development Clinical Evaluation Variable ~ 6 Years~ 9 Years Total cost: $3.7B to $11.8B per new drug Total time: 15 or more years Antimicrobial Pipeline

Novel potential treatment options  Solithromycin (CEM-101)  Fluoroketolide  41/41 cured with 1000 mg or 1200 mg  Delafloxacin  Novel fluoroquinolone  Currently under clinical investigation  VT12-008911  Aminobenzimidazole  Inhibits DNA replication (targets GyrB/ParE) Hook EW III et al. STI & AIDS World Congress 2013, July 14-17, Vienna, Austria Roberts MC et al. STI & AIDS World Congress 2013, July 14-17, Vienna, Austria Jeverica S et al. JAC 2014

NIAID/CDC GC Dual Therapy Clinical Trial: Percentage of Per Protocol Participants with Microbiological Cure at 10–17 days Gentamicin/ AzithromycinGemifloxacin/Azithromycin n/N% (L 95% CI)n/N% (L 95% CI) Urethra/Cervi x 202/202100% (98.5%)198/19999.5% (97.6%) Kirkcaldy RD et al. STI & AIDS World Congress 2013, July 14-17, Vienna, Austria.

Percentage of Per Protocol Participants Reporting Adverse Events (AEs) Gentamicin/ Azithromycin n=202 (%) Gemifloxacin/ Azithromycin n=199 (%) Nausea56 (27.7)74 (37.2) Vomiting15 (7.4)10 (5.0) Diarrhea39 (18.9)46 (23.2) Abdominal Discomfort 15 (7.5)21 (10.5) Any GI AE95 (47)109 (54.7) Nearly all were mild-moderate No serious adverse events occurred Kirkcaldy RD et al. STI & AIDS World Congress 2013, July 14-17, Vienna, Austria.

Coming later this year… 2014

Conclusions  Emerging cephalosporin resistance threatens gonorrhea treatment and control  Trends in the the United States  Cephalosporin (cefixime) MICs increased 2006–2010, decreased in 2012  No recent treatment failures identified  Molecular tests hold promise for enhancing treatment and surveillance  Treatment  Combination of ceftriaxone & azithromycin highly effective  But only one remaining first-line therapy  New treatment options and prevention strategies urgently needed

rkirkcaldy@cdc.gov rkirkcaldy@cdc.gov (404) 639-8659 For more information please contact Centers for Disease Control and Prevention 1600 Clifton Road NE, Atlanta, GA 30333 Telephone: 1-800-CDC-INFO (232-4636)/TTY: 1-888-232-6348 E-mail: cdcinfo@cdc.gov Web: http://www.cdc.gov The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of STD Prevention

Neisseria gonorrhoeae Antimicrobial Resistance Robert D. Kirkcaldy, MD, MPH Division of STD Prevention NCHHSTP/CDC National Center for HIV/AIDS, Viral.

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Neisseria gonorrhoeae Antimicrobial Resistance Robert D. Kirkcaldy, MD, MPH Division of STD Prevention NCHHSTP/CDC National Center for HIV/AIDS, Viral.

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Presentation on theme: "Neisseria gonorrhoeae Antimicrobial Resistance Robert D. Kirkcaldy, MD, MPH Division of STD Prevention NCHHSTP/CDC National Center for HIV/AIDS, Viral."— Presentation transcript:

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