Update on Gonococcal Resistance in the United States Susan A. Wang, MD, MPH Division of STD Prevention National Center for HIV, STD, and TB Prevention March 2004

The continuing saga: history of antimicrobial resistance in Neisseria gonorrhoeae in the United States 1936: sulfanilamide introduced 1945: 1/3 of gonorrhea sulfanilamide-resistant; 50,000 units of penicillin becomes therapy of choice 1972: therapeutic penicillin dose reaches 4.8 million units 1976: PPNG first identified in U.S. patient with recent travel to Southeast Asia

History - Part II early 1980s: PPNG strains spread in the U.S.; beta-lactamase testing commonplace 1985: widespread tetracycline-resistance among gonococci; CDC recommends that tetracycline not be used for gonorrhea therapy 1987: penicillin abandoned; ceftriaxone becomes primary treatment 1989: ciprofloxacin (FQ) recommended by CDC 1991: QRNG identified in Hawaii

History - Part III 1998: marked QRNG increase in Hawaii 2000: CDC recommends that FQs no longer be used to treat gonorrhea acquired in Hawaii, Pacific Islands, or Asia; need travel hx for all GC pts 2002: CDC recommends that use of FQs in California and in other areas with increased QRNG may be inadvisable : local QRNG alerts and treatment recommendation changes

Quinolone Resistance Among Gonococci Elsewhere in the World Australia – 8.1%England & Wales – 9.8% China – 92.5% (GRASP, 2002) Japan – 73.4% Norway - 15% Korea – 63.3% (Aavitsland, et al 2002) Phillippines – 57.5%Canada – 2.1% Singapore – 46.5% (Sarwal, et al, 2001) Vietnam – 46.0%Israel – 61% (WHO WPR GASP, 2002) (Dan, et al, 2000)

Surveillance for gonococcal resistance in the United States National sentinel surveillance Local susceptibility surveillance

The Gonococcal Isolate Surveillance Project (GISP) National sentinel surveillance established in 1986 by CDC to monitor trends in antimicrobial susceptibilities of N. gonorrhoeae Consists of public STD clinics in cities and 5 Regional Laboratories Every month each clinic submits first 25 male urethral gonococcal isolates to a Regional Laboratory Each Regional Lab performs antimicrobial susceptibility testing by agar dilution Each clinic also submits patient demographic and clinical data for all submitted isolates  allows us to monitor characteristics of patients with gonorrhea

Gonococcal Isolate Surveillance Project (GISP) Locations of clinics and regional laboratories: United States, 2003 Phoenix Albuquerque Dallas San Diego Orange Co. Las Vegas Portland Anchorage New Orleans Honolulu San Francisco Long Beach Minneapolis Philadelphia Cincinnati Baltimore St. Louis Chicago Miami Denver Atlanta Birmingham Seattle Cleveland Birmingham Regional Labs Atlanta Denver Seattle Cleveland Tripler AMC Los Angeles Greensboro Detroit Salt Lake City Oklahoma City

Gonorrhea treatment for GISP participants, * *2003 data are preliminary. ceftriaxone 125 mg ceftriaxone 250 mg cefixime penicillins spectinomycin ciprofloxacin ofloxacin other * Percent of GISP patients other cephalosporins tetracyclines

Percentage of GISP isolates with intermediate resistance or resistance to ciprofloxacin, * *2003 data are preliminary * Percent of isolates ResistanceIntermediate resistance

Ciprofloxacin-resistant GISP isolates in the U.S. Year Sentinel Sites Isolates 1991 Honolulu Honolulu Honolulu, San Francisco Honolulu, San Francisco, Seattle, Denver Seattle Honolulu, San Diego, Portland, Atlanta Honolulu, San Francisco, Cincinnati Honolulu, San Francisco, San Diego, Orange Co, Seattle, Anchorage, Denver, Cincinnati, New Orleans, Fort Bragg Honolulu, San Francisco, San Diego, Orange Co, Seattle, Anchorage Honolulu, San Francisco, San Diego, Orange Co, Long Beach, Denver Honolulu, San Francisco, San Diego, Orange Co, Long Beach, Anchorage, Portland, Seattle, Phoenix, Minneapolis, Cincinnati, Philadelphia, Miami * Honolulu, Tripler, San Francisco, Los Angeles, San Diego, prelim Orange Co, Long Beach, Portland, Seattle, Las Vegas, Phoenix, Denver, Minneapolis, Chicago, Cincinnati, Cleveland, Philadelphia, Baltimore, Dallas, New Orleans, Miami 259*

Prevalence of ciprofloxacin-resistant Neisseria gonorrhoeae among tested gonococcal isolates,* and gonorrhea rate, Hawaii, ** *Includes GISP and non-GISP isolates for every year except **2003 data are preliminary and only GISP data.

Prevalence of ciprofloxacin-resistant GISP isolates and gonorrhea rate, California, * *2003 data are preliminary

Percent ciprofloxacin-resistant isolates in GISP, excluding Hawaii and California, * *2003 data are preliminary * Percent of isolates

Preliminary 2003 GISP Data – QRNG (incomplete) QRNG (all sites)4.1% (243/5936) Orange Co32.5% (49/151) Long Beach21.5% (17/79) San Francisco19.0% (51/268) Los Angeles13.3% (22/165) Honolulu13.3% (16/120) San Diego 12.1% (26/215) Seattle 7.0% (18/258) Tripler 4.2% (1/24) Portland 3.0% (4/132) Las Vegas 2.4% (7/287)

Preliminary 2003 GISP Data - QRNG Minneapolis2.3% (5/215) Phoenix 2.2% (4/183) Chicago2.1% (6/285) Dallas2.1% (6/288) Philadelphia1.3% (4/316) Miami1.2% (2/164) New Orleans 0.7% (1/152) Cincinnati 0.4% (1/276) Denver0.4% (1/250) Baltimore0.4% (1/289) Cleveland0.3% (1/292)

GISP QRNG by Sexual Orientation, 2002 and 2003* All sites Excluding Hawaii and California *2003 data are preliminary * * Percent of isolates MSW MSM all

Preliminary Non-GISP QRNG in 2003 incomplete New Hampshire – 28.6% (6/21) Massachusetts – 13.9% (56/402) Michigan – 2.9% (17/582) New York City – 2.9% (30/1026) Indianapolis – 0.4 (2/491) Other places where QRNG have been identified: Kansas (1), Maine (1), New Jersey (2), New York (1), Ohio (1), Utah (1) In 2002, no health dept susceptibility testing data for 72% of STD programs and limited susceptibility data available for the other 28%

QRNG clusters in 2003 New York City (Reddy, P013): ~8% GC cases tested; 13% QRNG among MSM, 2% among MSW and among women Massachusetts (Ratelle, P014): ~12% GC cases tested; 11% QRNG among MSM and 2% among MSW Michigan (Macomber, LB10): ~4% GC cases tested; 12% QRNG among MSM, 9% among MSW, 2% among women Seattle (Whittington, Tues LB): 22% QRNG among MSM and 3% among MSW and women Cost-effectiveness model to identify threshold for changing treatment (Roy, P068)

Factors Associated with Acquisition of QRNG (in areas where QRNG is not endemic) Residence in or history of recent travel to Asia or the Pacific Islands, Hawaii, California, or other areas with increased QRNG prevalence or sex partner with such history Asian and White races Heterosexual transmission (England, Norway, Australia, U.S.) In , MSM transmission in the U.S.

GISP Trends for Other Antimicrobials In 2002, prevalence of resistance for penicillin was 8.2% and for tetracycline was 14.7% No isolates resistant to spectinomycin since 1994 Proportion of isolates with azithromycin Minimum Inhibitory Concentrations (MICs)  1.0 mg/L increased from 0 in 1992 to 0.6% in 2002 No isolates with decreased susceptibility to ceftriaxone since 1997 (but trend toward higher MICs).

GISP Trends for Other Antimicrobials, Multi-drug resistant isolates identified in 2001 in Hawaii and again in 2003 in Los Angeles: resistant to penicillin, tetracycline, ciprofloxacin; decreased susceptible to cefixime and azithromycin –these types of isolates identified since 1999 in Japan where cefixime treatment failures have also been reported

The Challenges of Monitoring Gonococcal Resistance Few laboratories performing susceptibility testing –primarily public health laboratories, yet >60% of GC reported from private sector Absence of culture testing so no organism to susceptibility test –non-culture tests (NAATs) rapidly replacing culture; some health depts no longer have GC culture capacity at all

The Challenges of Monitoring Gonococcal Resistance Bias toward over representation of data from rectal and pharyngeal isolates since only culture has FDA indication for those anatomic sites –fewer data from urethral and endocervical isolates Extremely limited sampling or no sampling of certain populations –e.g., military, women, private patients

Summary Antimicrobial resistance remains a key consideration in the treatment and control of gonorrhea Preliminary 2003 data show QRNG remained endemic in Hawaii and California. Significant QRNG increases were noted in Seattle, New Hampshire, Massachusetts, New York City, and Michigan, and were identified with increasing frequency elsewhere in the U.S. QRNG increases among MSM are a concern Significant challenges exist in 2004 for monitoring resistance

Acknowledgements The many GISP collaborators: –GISP Regional Laboratories (Atlanta, Birmingham, Cleveland, Denver, Seattle): Laura Doyle, Josephine Ehret, Connie Lenderman, James Thomas, Wil Whittington, Karen Winterscheid, Carlos del Rio, King Holmes, Ned Hook, Frank Judson, Gary Procop –the 30 GISP Sentinel Sites: lab, clinic, program staff –Alesia Harvey, Susan Conner Health departments performing local susceptibility testing: Massachusetts, Michigan, New York City, New Hampshire, Hawaii, Indianapolis, Wisconsin, and more…

Resource website for information on antimicrobial resistant Neisseria gonorrhoeae. Please report GC treatment failures or identification of resistant GC to CDC (via program consultant or or

Gonorrhea Treatment (from CDC STD Treatment Guidelines, May 10, 2002 MMWR) Cefixime 400 mg or Ceftriaxone 125 mg IM or Ciprofloxacin 500 mg or Ofloxacin 400 mg or Levofloxacin 250 mg [plus, treatment for Chlamydia trachomatis infection] * Need to obtain travel history from patients suspected to have gonorrhea. A patient who may have acquired gonorrhea in Asia or Hawaii or the Pacific Islands or whose sex partner(s) may have acquired gonorrhea in those places should NOT be treated with quinolones! Use of quinolones is probably inadvisable for infections acquired in California and in other areas with increased prevalence of quinolone resistance.

Treatment of Chlamydia trachomatis infection in GISP participants, * For each year, “other” accounted for < 1% and erythromycin accounted for no more than 1% of treatment. *2003 data are preliminary. azithromcyin or erythromycin doxycycline or tetracycline none or other 0% 20% 40% 60% 80% 100% * Percent of GISP patients

Observations on QRNG surveillance Most QRNG patients have NOT been identified as a result of recognition of treatment failures but through susceptibility testing Where QRNG surveillance is taking place, susceptibility data generally represent <15% of GC cases