Review and Discussion of Gonococcal Isolate Surveillance Project (GISP) Data Lizzi Torrone, MSPH, PhD Lead, Surveillance & Special Studies Team GISP Project Officer (acting) Division of STD Prevention SSS STAR STI Clinical Trials Group April 13, 2017

Caveats Not Bob Kirkcaldy, but he is here Presenting 2016 data which are preliminary—the numbers will change! Please do not distribute.

Gonococcal Isolate Surveillance Program (GISP) Established in 1986 to monitor trends in N. gonorrhoeae susceptibility to antimicrobials Collaboration between CDC, clinical sites, and laboratories Directly inform CDC STD Treatment Guidelines Data disseminated through routine surveillance reports

GISP isolate + data collection 27 participating STD clinics Urethral specimens and epi data obtained from first 25 men with gonococcal urethritis at clinical sites each month Isolates are sent to regional laboratories Susceptibility testing conducted by agar dilution Results provided to clinical sites (not for clinical decision making) Epi and susceptibility data transmitted to CDC and merged for analysis Alert isolates and archive isolates sent to CDC

Current GISP clinical sites Phoenix Albuquerque Dallas San Diego Orange Co. Las Vegas Portland New Orleans Honolulu San Francisco Minneapolis Philadelphia Columbus Chicago Erie Co. Boston Atlanta Birmingham Seattle Cleveland Tripler AMC Los Angeles Greensboro Pontiacit New York City Kansas Indianapolis

Antibiotic Resistance Lab Network (ARLN)

Gonorrhea trends in the U.S.

Gonorrhea — Rates of Reported Cases by Year, United States, 1941–2015 Rate per 100,000 1976: 1,013,436 cases 2010: 309,341 cases 2015: 395,216 cases *2016 data are preliminary as of 4/3/17

Gonorrhea — Rates of Reported Cases by Year, United States, 1941–2016* Rate per 100,000 1976: 1,013,436 cases 2016: 454,235 cases 15% increase 2010: 309,341 cases 2015: 395,216 cases *2016 data are preliminary as of 4/7/17

Gonorrhea — Rates of Reported Cases by Sex, United States, 2006–2015 Rate per 100,000 Males Females

Gonorrhea — Rates of Reported Cases by Sex, United States, 2006–2016* Rate per 100,000 19% increase Males Females 10% increase *2016 data are preliminary as of 4/7/17

Estimated Proportion* of MSM†, MSW†, and Women Among Gonorrhea Cases by Jurisdiction, STD Surveillance Network (SSuN), 2015 * Estimate based on weighted analysis of data obtained from interviews (n=2,278) conducted among a random sample of reported gonorrhea cases during June to December 2015. † MSM = Gay, bisexual, and other men who have sex with men (collectively referred to as MSM); MSW = Men who have sex with women only. ‡ California data excludes San Francisco (shown separately).

Proportion of MSM* Attending STD Clinics with Primary and Secondary Syphilis, Gonorrhea (GC) or Chlamydia (CT) by HIV Status†, STD Surveillance Network (SSuN), 2015 * MSM = Gay, bisexual, and other men who have sex with men (collectively referred to as MSM). † Excludes all persons for whom there was no laboratory documentation or self-report of HIV status. ‡ GC urethral and CT urethral include results from both urethral and urine specimens.

Proportion of MSM* Attending STD Clinics with Primary and Secondary Syphilis, Gonorrhea (GC) or Chlamydia (CT) by HIV Status†, STD Surveillance Network (SSuN), 2015 * MSM = Gay, bisexual, and other men who have sex with men (collectively referred to as MSM). † Excludes all persons for whom there was no laboratory documentation or self-report of HIV status. ‡ GC urethral and CT urethral include results from both urethral and urine specimens.

Gonorrhea: Estimated burden & cost 395,000 cases diagnosed and reported in 2015 Most diagnosed outside of the STD clinic Case reports underestimate burden of disease ~820,000 infections occur annually Estimated $162 million in direct medical costs https://www.cdc.gov/std/stats/sti-estimates-fact-sheet-feb-2013.pdf

GISP trends

Susceptibility criteria Antimicrobial Susceptibility criteria Ceftriaxone ≥0.125 μg/ml Elevated MICs Cefixime ≥0.25 μg/ml Azithromycin ≥2.0 μg/ml Reduced susceptibility Ciprofloxacin ≥1.0 μg/ml Resistance Penicillin ≥2.0 μg/ml or Beta lactamase + Tetracycline Gentamicin Not established

Neisseria gonorrhoeae — Distribution of Isolates with Penicillin, Tetracycline, and/or Ciprofloxacin Resistance, Gonococcal Isolate Surveillance Project (GISP), 2016* Data are preliminary as of 4/9/2017; NOTE: PenR = penicillinase-producing Neisseria gonorrhoeae and chromosomally-mediated penicillin-resistant N. gonorrhoeae; TetR = chromosomally- and plasmid-mediated tetracycline-resistant N. gonorrhoeae; and QRNG = quinolone-resistant N. gonorrhoeae.

Neisseria gonorrhoeae — Percentage of Isolates with Elevated Cefixime MICs and Elevated Ceftriaxone MICs, GISP, 2006–2016* Percentage * 2016 data are preliminary as of 4/9/2017; Isolates not tested for cefixime susceptibility in 2007 and 2008.

Neisseria gonorrhoeae — Percentage of Isolates with Elevated Cefixime MICs and Elevated Ceftriaxone MICs, GISP, 2006–2016* Percentage 0.25 μg/ml (n=17) 0.50 μg/ml (n=2) 0.125 μg/ml (n=18) * 2016 data are preliminary as of 4/9/2017; Isolates not tested for cefixime susceptibility in 2007 and 2008.

Neisseria gonorrhoeae — Percentage of Isolates with Elevated Cefixime MICs and Elevated Ceftriaxone MICs, GISP, 2006–2016* Percentage * 2016 data are preliminary as of 4/9/2017; Isolates not tested for cefixime susceptibility in 2007 and 2008.

Neisseria gonorrhoeae — Percentage of Isolates with Elevated Cefixime MICs, Elevated Ceftriaxone MICs, and Azithromycin Reduced Susceptibility, GISP, 2006–2013 Percentage *Isolates not tested for cefixime susceptibility in 2007 and 2008.

Neisseria gonorrhoeae — Percentage of Isolates with Elevated Cefixime MICs, Elevated Ceftriaxone MICs, and Azithromycin Reduced Susceptibility, GISP, 2006–2013 Percentage * 2016 data are preliminary as of 4/9/2017; Isolates not tested for cefixime susceptibility in 2007 and 2008.

Neisseria gonorrhoeae — Distribution of Isolates with Azithromycin Reduced Susceptibility by MIC and by Year, GISP, 2011–2016* Percentage MICs (μg/ml) * 2016 data are preliminary as of 4/9/2017

Percentage of Isolates with (A) Reduced Azithromycin Susceptibility and (B) Reduced Ceftriaxone Susceptibility with Other Resistance Phenotypes, 2015 A Azithromycin-RS† (n=133) B Ceftriaxone-RS† (n=14) Percentage † Azithromycin-RS=reduced azithromycin susceptibility (MIC ≥2 µg/ml); ceftriaxone-RS=reduced ceftriaxone susceptibility (MIC ≥0.125 µg/ml) NOTE: Resistance categories are not mutually exclusive

Percentage of Isolates with (A) Reduced Azithromycin Susceptibility and (B) Reduced Ceftriaxone Susceptibility with Other Resistance Phenotypes, 2016* A Azithromycin-RS† (n=200) 4 isolates from Hawaii B Ceftriaxone-RS† (n=18) Percentage † Azithromycin-RS=reduced azithromycin susceptibility (MIC ≥2 µg/ml); ceftriaxone-RS=reduced ceftriaxone susceptibility (MIC ≥0.125 µg/ml) 2016 data are preliminary as of 4/7/17; NOTE: Resistance categories are not mutually exclusive

Cluster of N. gonorrhoeae isolates with high-level azithromycin resistance AND reduced ceftriaxone susceptibility, April–May, 2016 High-level azithromycin resistance (MIC ≥256 µg/ml) in 8 specimens from 7 patients 4 isolates had reduced ceftriaxone susceptibility (MIC ≥0.125 µg/ml) All were resistant to penicillin, tetracycline, & ciprofloxacin Closely related by genomic analysis All cases and 4/9 partners interviewed All had sx resolution or tested negative Katz A et al. STD Prevention Conference, 2016

Neisseria gonorrhoeae — Distribution of Gentamicin MICs by Year, GISP, 2015–2016* Percentage MICs (μg/ml) * 2015 and 2016 data are preliminary as of 4/9/2017

(REALLY REALLY) preliminary 2017 data Only 648 isolates with AST data to CDC Similar patterns as 2016 To date: No isolates with reduced susceptibility to both AZI and CRO No isolates with CRO MIC >0.125 μg/ml 3 isolates with CFX MICs ≥0.25 μg/ml

Emergence of ceftriaxone-resistant N Emergence of ceftriaxone-resistant N. gonorrhoeae could impose direct medical costs of over $400 million over the next 10 years.

Conclusions GISP in the CARB era GISP is not going away! Continue to inform treatment guidelines

Conclusions GISP in the CARB era GISP is not going away! Continue to inform treatment guidelines eGISP funding

Conclusions (cont) Resistance is urgent threat Dual therapy still highly effective Declining cephalosporin and azithromycin susceptibility threatens last recommended gonorrhea treatment New antimicrobials & innovative prevention and control strategies are urgently needed

Acknowledgements Alesia Harvey Tremeka Sanders Bob Kirkcaldy John Papp Ellen Kersh Hillard Weinstock GISP clinical sites and regional laboratories

Lizzi Torrone igf0@cdc.gov 404-639-8948 Thank you! Lizzi Torrone igf0@cdc.gov 404-639-8948

Neisseria gonorrhoeae — Distribution of Azithromycin MICs by Year, GISP, 2011–2016* Percentage MICs (μg/ml) * 2016 data are preliminary as of 4/9/2017