1. Monitoring Emerging Resistance in Neisseria gonorrhoeae in the United States Eileen L. Yee, MD 2008 National STD Prevention Conference March 11, 2008 Chicago, IL "The findings and conclusions in this presentation are those of the author and do not necessarily represent the views of the CDC/ATSDR."

2. Overview Background GISP antimicrobial susceptibility trends GC treatment among GISP participants Limitations Challenges Conclusions Recommendations

3. Why Monitor? High burden of disease Key to reducing burden is by effective prevention and control programs using prompt detection and effective treatment Effective treatment is complicated by N. gonorrhoeae’s ability to develop resistance to effective antimicrobials

4. History of ARG in US 1930’s : Sulfonamides used for treatment 1940’s : Resistance to sulfonamides; penicillin (PCN) recommended 1970’s : Resistance to PCN detected with treatment doses of PCN increasing 1980’s : Resistance to penicillin/tetracycline increasing; ceftriaxone recommended 1993: Fluoroquinolones (FQ) also recommended (Ex: ciprofloxacin, ofloxacin, levofloxacin) Early 1990’s : Fluoroquinolone-resistant N. gonorrhoeae (QRNG) sporadically detected in US; increasing in Asia and other parts of the world 2000: FQ no longer recommended in Hawaii, Pacific Islands, and those who acquired infections in these areas and in Asia 2002: FQ no longer recommended in California 2004: FQ no longer recommended among MSM in US 2007: FQ no longer recommended for treatment of GC infections and associated conditions

5. Gonococcal Isolate Surveillance Project (GISP) Established in 1986 Serves as national sentinel surveillance system: –To monitor trends in antimicrobial susceptibilities of Neisseria gonorrhoeae –To establish rational basis for the selection of antimicrobial treatment for gonococcal infections Collaborative effort: CDC, 25-30 publicly-funded STD clinics (GISP sentinel sites) and their respective local/state public health authorities, and 5 regional laboratories

6. GISP Sentinel Sites/Regional Labs Sentinel Sites –Submit first 25 male urethral gonococcal isolates to regional laboratory –Submit patient clinical/demographic data for all submitted isolates Regional Labs –Perform antimicrobial susceptibility testing (AST) using agar dilution method –Antibiotics tested are: Penicillin, Tetracycline, Spectinomycin, Ceftriaxone, Ciprofloxacin, Azithromycin, & Cefixime (discontinued in 2007),

7. Phoenix Albuquerque Dallas San Diego Orange Co. Las Vegas Portland New Orleans Honolulu San Francisco Long Beach Minneapolis Philadelphia Cincinnati Baltimore Chicago Miami Denver Atlanta Birmingham Seattle Cleveland Birmingham Regional Labs Atlanta Denver Seattle Cleveland Tripler AMC Los Angeles Greensboro Detroit Oklahoma City New York City Kansas City Richmond Locations of sites and regional laboratories: United States, 2007 (30 Sites)

8. Characteristics of GISP Participants, 2006 & 2007* 2006 N=6,089 2007* N=3,204 Median Age (Range)27 (13-85)27 (14-76) Race/Ethnicity %n=5,989n=2,949 White16.3 %15.5% Black70.2 %68.6% Hispanic 9.6 %12.3% Asian/Pacific Islander1.8 %1.6% American Indian0.3 %0.4% Other/Multiracial1.8 %1.7% Sexual Orientation %n=5,962n=2,946 MSM21.5 %24.6% Heterosexual78.5 %75.4% HIV Positive %n=4,014n=2,085 Positive7.8%9.5% * Preliminary 2007 Data (Jan-Jun)

9. Reported sexual orientation by race/ethnicity in GISP, 2006 Race % reported sexual orientation

10. GISP Antimicrobial Susceptibility Testing Trends

11. Criteria for Antimicrobial Resistance in N. gonorrhoeae Criteria recommended by the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS): - Penicillin, MIC ≥ 2.0 µg/ml -Tetracycline, MIC ≥ 2.0 µg/ml -Spectinomycin, MIC ≥ 128.0 µg/ml -Ciprofloxacin, MIC 0.125 - 0.5 µg/ml (intermediate resistance) -Ciprofloxacin, MIC ≥ 1.0 µg/ml (resistance) -Ceftriaxone, MIC ≥ 0.5 µg/ml (decreased susceptibility)* -Cefixime, MIC ≥ 0.5 µg/ml (decreased susceptibility)* * CLSI criteria for resistance to ceftriaxone, cefixime, and azithromycin and for susceptibility to azithromycin have not been established

12. Percentage of isolates from GISP with intermediate resistance or resistance to ciprofloxacin (QRNG), 1990-2007 * Intermediate (MIC 0.125 -0.50 µg/ml) Resistance (MIC ≥1.0 µg/ml) Year *Preliminary 2007 Data (Jan-Jun) 9.4% 13.8% 6.8% 4.1% 2.2% 15.4%

13. Percentage of GISP isolates with QRNG by sexual orientation (Exclude CA/HI), 2002-2007* Year % QRNG *Preliminary 2007 Data (Jan-Jun) MMWR

14. Distribution of MICs to Ciprofloxacin, 2003-2007* % isolates Resistant MICs MIC *Preliminary 2007 Data (Jan-Jun)

15. Distribution of Ciprofloxacin MICs ≥1.0 µg/ml 2003-2007* % isolates MIC *Preliminary 2007 Data (Jan-Jun)

16. Distribution of MICs to Ceftriaxone, 2003-2007* % isolates MIC *Preliminary 2007 Data (Jan-Jun)

17. Distribution of MICs to Azithromycin, 2003-2007* % isolates MIC *Preliminary 2007 Data (Jan-Jun)

18. Antimicrobial Susceptibility Trend for Other Antibiotics 2006 and 2007* Penicillin/Tetracycline or both: >20% Spectinomycin: All susceptible Cefixime: 1 isolate (2006) Ceftriaxone: None Azithromycin: – (2006) 14 isolates (0.2%) with MIC ≥ 2.0 µg/ml – (2007) 17 isolates (0.6%) with MIC ≥ 2.0 µg/ml

19. GC Treatment Used Among GISP Participants

20. Recommended Treatment § for GC from 2006 CDC STD Treatment Guidelines, MMWR RR, August 4, 2006 Ceftriaxone 125 mg IM x 1 (injection) Or Cefixime 400 mg po x 1 (oral) Or *Ciprofloxacin 500 mg po x 1 or Ofloxacin 400 mg po x 1 or Levofloxacin 250 mg po x 1 (oral) [plus, treatment for Chlamydia trachomatis infection, if chlamydial infection is not ruled out] * Quinolones should not be used for infections in MSM or in those with a history of recent foreign travel or partners’ travel, infection acquired in California or Hawaii, or infection acquired in other areas with increased QRNG prevalence. § Mainly for uncomplicated GC infections of Cervix, Urethra, & Rectum

21. Updated: Recommended Treatment § for GC from 2006 CDC STD Treatment Guidelines MMWR, April 13, 2007 Ceftriaxone 125 mg IM x 1 (injection) Or Cefixime 400 mg po x 1 (oral) [plus, treatment for Chlamydia trachomatis infection, if chlamydial infection is not ruled out] § Uncomplicated GC infections of Cervix, Urethra, & Rectum

22. Cephalosporins, 2002 -2007* *Preliminary 2007 Data (Jan-Jun)

23. Fluoroquinolones, 2002-2007* *Preliminary 2007 Data (Jan-Jun)

24. Macrolides & Spectinomycin, 2002-2007* *Preliminary 2007 Data (Jan-Jun)

25. Limitations of GISP Not representative of total population with GC –~ 3% of all men with GC infections –No isolates from women –No isolates from the non-public sector As >70% of GC cases from private sector Limited Sampling –Military population Difficult to define local prevalence of ARG

26. Challenges of Monitoring Gonococcal Resistance Decreased culture testing among public health laboratories –Non-culture tests such as nucleic acid amplification tests (NAATs) rapidly replacing culture –No organism to perform susceptibility testing Fewer public health laboratories performing antimicrobial susceptibility testing In addition, STD testing performed by many non- public laboratories

27. GC NAATS vs Culture among Public Health Laboratories Year# of Labs Performs any GC testing % of Labs that perform GC culture Total # of GC Tests Performed % of tests that were GC NAAT % of tests that were GC Culture 200010079%3.1 million11%18% Dicker, LW, Mosure, DJ, et al. Laboratory Tests Used in US Public Health Laboratories for STD, 2000. STD 31(5) pgs 259-264, 2004.

28. GC NAATS vs Culture among Public Health Laboratories Year# of Labs Performs any GC testing % of Labs that perform GC culture Total # of GC Tests Performed % of tests that were GC NAAT % of tests that were GC Culture 200010079%3.1 million11%18% 200410878%3.5 million61%8% Dicker, LW, Mosure, DJ, et al. Laboratory Tests Used in US Public Health Laboratories for STD, 2000. STD 31(5) pgs 259-264, 2004. Dicker, LW, Mosure, DJ, et al. Testing for STD in US Public Health Laboratories in 2004. STD 34(1) pgs 41-44, 2007.

29. GC NAATS vs Culture among California Laboratories (1996-2003) # of Labs Performs any GC Testing Proportion of Labs that Perform GC Culture Total # of GC Tests Performed % of tests that were GC NAAT % of tests that were GC Culture 384 - 73470% (1993) 59% (2003) 2 to 3 million 0.6% (1996) 59% (2003) 42% (1996) 10% (2003) Ahrens, K, Bradbury, J et al. Trends in the Use of STD Diagnostic Technologies in California, 1996-2003, STD 34(7), pgs 513-518, 2007.

30. GC NAATS vs Culture among California Laboratories (1996-2003) # of Labs Performs any GC Testing Proportion of Labs that Perform GC Culture Total # of GC Tests Performed % of tests that were GC NAAT % of tests that were GC Culture 384 - 73470% (1993) 59% (2003) 2 to 3 million 0.6% (1996) 59% (2003) 42% (1996) 10% (2003) 39 – 49 (Public Health only) 74% (1993) 52% (2003) 270,000 - 330,000 2% (1996) 85% (2003) 68% (1996) 8% (2003) Unpublished data. Personal communication with Hendlish, S, Samuel, M, Bolan, G. CA Dept of Public Health.2007

31. Conclusions GISP provides national ‘picture’ and provides crucial data to direct national treatment guidelines QRNG is endemic throughout the US and continues to increase; FQ not recommended for treatment Currently, no ceftriaxone isolates with decreased susceptibility detected and recommended for treatment Azithromycin as MICs seem to be slowly increasing and therefore is not recommended for treatment Continued decrease in GC culture testing and AST poses real threat to monitoring newly emerging resistance in Neisseria gonorrhoeae in the US

32. CDC Recommendations Strongly recommend all state & local health department labs maintain or develop capacity to perform culture Encourage labs to maintain capacity to perform AST or form partnership with experienced labs that can perform AST Report to CDC any cephalosporin-resistant isolate and case of clinical treatment failures after treatment with cephalosporins through local/state public health authorities

33. Summary Close and continuous monitoring for antimicrobial resistance in N. gonorrhoeae remain critical Need to remain vigilant for cephalosporin- resistance –Cephalosporins are the only class of antibiotics currently available

34. Lastly... Cefixime 400mg tablets (Lupin Pharmaceuticals Inc.) should be available in 2008 (mid-March) CDC is working with FDA and Pfizer to make spectinomycin available

35. Acknowledgements CDC/GISP Atlanta Staff: Hillard Weinstock, Stuart Berman, John Papp, David Trees, Ron Ballard, Alesia Harvey, Katrina Kramer, Kevin Pettus, Samera Bowers, Manhar Parekh, Joan Knapp, & Michael Grabenstein GISP Principal Investigators & Regional Laboratories: Atlanta: Carlos del Rio, James Thomas, Bianca Humphrey, Tanisha Sullivan Birmingham: Ned Hook, Connie Lenderman, Paula Dixon Cleveland: Gerrie Hall, Laura Doyle, Gary Procop, Denver: Frank Judson, Jo Ehret Seattle: King Holmes, Wil Whittington, Karen Winterscheid 30 GISP Sentinel Sites and their respective local/state public health authorities in 2006 & 2007 (lab, clinic, program staff): Albuquerque, NM Atlanta, GA Baltimore, MD Chicago, IL Cincinnati, OH Cleveland, OH Dallas, TX Denver, CO Detroit, MI Greensboro, NC Honolulu, HI Kansas City, MO Las Vegas, NV Long Beach, CA Los Angeles, CA Miami, FL Minneapolis, MN New Orleans, LA New York City, NY Oklahoma City, OK Orange County, CA Philadelphia, PA Phoenix, AZ Portland, OR Richmond, VA San Diego, CA San Francisco, CA Seattle, WA Tripler Army Medical Center, HI

36. Additional Information For more information on GISP: http://www.cdc.gov/std/gisp/ Resource website for information on antimicrobial resistant Neisseria gonorrhoeae: http://www.cdc.gov/std/Gonorrhea/arg/default.htm

37. Additional Slides

38. Additional Characteristics of GISP Participants, 2006 & 2007* 2006 N=6,089 2007* N=3,204 Within Previous 60 Days: Injection Drug Use 1.8 % (n=3,783) 1.4% (n=1,802) Non-injection Drug Use 26.3 % (n=3,373) 27.9% (n=1,652) Travel Outside the State Where Sentinel Site Located 9.0% (n=3,521) 8.5% (n=1,589) Giving or Receiving Drugs/Money for Sex 2.1% (n=3,441) 2.0% (n=1,620) Antibiotic Use 4.9% (n=4,511) 5.4% (n=2,063) HIV Positive7.8 % (n=4,014) 9.5% (n=2,085) * Preliminary 2007 Data (Jan-Jun)

39. Percentage of GISP cases among men who have sex with men (MSM), 1988-2007* Year * Preliminary 2007 data (Jan-Jun)

40. Percent of Neisseria gonorrhoeae isolates obtained from MSM attending STD clinics, 2003–2006

41. Prevalence of QRNG among GISP isolates (Excluding CA & HI), 2003-2007* Year % QRNG 9.4% 6.1% 3.6% 1.2% 13.8% 9.4% 6.8% 4.1% *Preliminary 2007 Data (Jan-Jun) 11.8% 15.4% Key: CA= California GISP sites HI = Hawaii GISP sites

42. Percentage of GISP isolates with QRNG by sexual orientation (All sites), 2003-2007* Year % QRNG 35.4% 9.5% 15.0% 23.8% 1.5% 2.9% 29.0% 3.8% 39.0% 7.0% *Preliminary 2007 Data (Jan-Jun)

43. Percentage of GISP isolates with QRNG by sexual orientation (Exclude CA/HI), 2003-2007* Year % QRNG *Preliminary 2007 Data (Jan-Jun)

44. Proportion of GISP QRNG isolates by sexual orientation and demographics, 2006 Proportion of QRNG infections among men who have sex with men Proportion of QRNG infections among heterosexual men Race/Ethnicity White Black Asian/Native Hawaiian Hispanic American Indian Other Unknown 296 (44.6%) 56 (21%) 37 (51.4%) 83 (38.4%) 2 (40%) 21 (44.7%) 4 (40%) 69 (22.9%) 200 (5.1%) 7 (20%) 40 (11.2%) 1 (6.7%) 9 (15.3%) 2 (33.3%) Age Groups (years) 13-19 20-29 30-39 40-49 >50 15 (28.9%) 206 (37.7%) 142 (38.1%) 105 (44.1%) 31 (44.9%) 21 (3.4%) 113 (4.9%) 81 (8.6%) 80 (13.6%) 33 (13.9%) Region West South/East Midwest 422 (43.5%) 49 (26.9%) 28 (21.9%) 174 (11.8%) 145 (7.5%) 9 (0.7%)

45. QRNG Prevalence by Site in West, 2005-2007* 200520062007* Region%% WestAlbuquerque---7.2822.06 Denver10.9215.7018.75 Honolulu19.3235.7920.51 Las Vegas 5.42 8.6716.98 Long Beach23.4728.3627.03 Los Angeles14.5122.7126.67 Orange County27.5034.5950.00 Phoenix 7.0711.85 9.70 Portland23.1127.2219.67 San Diego26.1935.1140.45 San Francisco31.3344.4834.48 Seattle11.5731.8235.45 Tripler--- ^ *Preliminary 2007 data (Jan-June) ^ Tripler collected <10 isolates

46. QRNG Prevalence by Site in South, 2005-2007* 200520062007* Region%% SouthAtlanta3.805.692.56 Baltimore3.031.442.67 Birmingham1.051.0910.79 Dallas3.206.0810.14 Greensboro0.561.735.63 Miami9.0619.8121.00 New Orleans6.25^10.20*18.10 Oklahoma City2.334.337.09 *Preliminary 2007 data (Jan-June) ^ Isolate Collection only from Jan-May 2005, * GISP restarted in Oct 2006

47. QRNG Prevalence by Site in Midwest/Northeast, 2005-2007* 200520062007* Region%% MidwestChicago4.664.056.87 Cincinnati1.000.67 --- Cleveland2.833.061.4 Detroit0.340.330.67 Minneapolis8.035.659.40 NortheastNew York City Philadelphia ---^ 14.33 7.55 30.33 12.00 32.77 *Preliminary 2007 data (Jan-June) ^ New York City joined GISP in 2006

48. Penicillin and tetracycline resistance among GISP isolates, 2006

49. Chromosomally mediated resistance to penicillin and tetracycline among GISP isolates, 1988-2007* *Preliminary 2007 Data (Jan-Jun)

50. Plasmid-mediated resistance to penicillin and tetracycline among GISP isolates, 1988-2007* *Preliminary 2007 Data (Jan-Jun)

51. Distribution of MICs to Cefixime, 2003-2007* % isolates MIC *Preliminary 2007 Data (Jan-Jun)

52. Drugs used to treat gonorrhea in GISP participants, 1988-2006 Year

53. Current Chlamydia Treatment among GISP sites, 2002-2007* Tetracyclines & Macrolides *Preliminary 2007 Data (Jan-Jun)

54. Fluoroquinolone use by sexual orientation among GISP sites (All Sites), 2004-2007* Heterosexual MSM Percent Month 2004 2005 2006 MMWR 2007* *Preliminary 2007 Data (Jan-Jun) MMWR

55. Antimicrobials tested in GISP Antibiotic Tested Recommended for treatment Currently available Penicillin X. Tetracycline X. Spectinomycin. X Ceftriaxone.. Cefixime (testing discontinued in 2007). X Ciprofloxacin X. Azithromycin X. Slide provided by Dowell, D (2007)

56. APHL labs performing GC culture and AST (2006) 94 APHL Labs surveyed 81 (86.2%) Responded to survey 61 (75.3%) Performed GC culture 22 (36.1%) Performed AST Unpublished data: Kramer, KP, 2007

57. Quinolone Resistance Among Gonococci Elsewhere in the World China – 99.2% Japan – 80.8% Korea – 91.7% Philippines – 39.3% Singapore – 67.5% Vietnam – 80.4% (WHO WPR GASP, 2005) England & Wales – 26.5% (GRASP, 2006) Australia – 37.8% (AGSP, 2006) Canada – 15.7% Europe – 30.9% (ESSTI, 2006 -comprised of 12 countries in Western Europe )