1. Alternative Cephalosporin Treatment Options for Gonorrhea Christopher S. Hall, MD, MS 1 Michael Samuel, DrPH, 1 Michael McElroy, MPH, 1 Jessica Frasure, BA, 1 Heidi Bauer, MD, 1 Henry Chambers, MD, 2 and Gail Bolan, MD 1 1 California Department of Health Services (CDHS) STD Control Branch and the California STD/HIV Prevention Training Center 2 University of California, San Francisco Division of Infectious Diseases 2006 CDC National STD Prevention Conference, May 7-11, 2006

2. Neisseria gonorrhoeae (GC) Infection Gonorrhea is second most common reportable communicable disease in California and U.S. California rates increased to 92.6 cases per 100,000 persons in 2005, compared to 54.8 in 1999 3/2006 Provisional Data - CA DHS STD Control Branch

3. California United States 2004=113.5 (2005 n/a) 92.6 GC Rates in California and U.S. 2010 Objective (19.0) 1941–2005 3/2006 Provisional Data - CA DHS STD Control Branch

4. Gonococcal Isolate Surveillance Project (GISP), Percent of GC Isolates with Decreased Susceptibility or Resistance to Ciprofloxacin in Four California STD Clinics, 1990–2004 Note:Resistant isolates have MICs ≥ 1 μg ciprofloxacin/mL. Isolates with decreased susceptibility have MICs of 0.125 – 0.5 μg ciprofloxacin/mL 8/2005 Provisional Data - CA DHS STD Control Branch STD Clinic Sites: Long Beach, Orange, San Diego, San Francisco

5. GC Resistance in California In California, 20.3% of 1,082 specimens analyzed in 2004 were resistant to ciprofloxacin (minimum inhibitory concentration (MIC)  1.0  g/ml), and 1.7% had decreased susceptibility to ciprofloxacin (MIC 0.125 – 0.50  g/ml) No specimens exhibited decreased susceptibility or resistance to ceftriaxone 3/04 Provisional Data - CA DHS STD Control Branch

6. Fewer Alternatives for Treating GC Infection Factors leading to fewer antimicrobial alternatives for GC: –Decreased susceptibility of GC to some agents –Production and distribution changes by drug manufacturers Improved detection of pharyngeal site infection, with few agents effective (and/or well studied)

7. GC Treatment Recommendations Uncomplicated GC of the Cervix, Urethra, Rectum Recommended regimens: Cefixime 400 mg orally in a single dose, OR Ceftriaxone 125 mg IM in a single dose, OR Ciprofloxacin 500 mg orally in a single dose, OR Ofloxacin 400 mg orally in a single dose, OR Levofloxacin 250 mg orally in a single dose Alternative regimens: Spectinomycin 2 g in a single, IM dose, OR A single-dose (IM) cephalosporin regimen, OR An alternative single-dose quinolone regimen 2002 CDC STD Treatment Guidelines

8. Cefixime…Now you see it, now you don’t, or do you? Cefixime (Suprax), previously marketed by Wyeth, no longer available in the U.S. as of November 2002 –In February 2004, FDA granted Abbreviated NDA to Lupin Ltd. (India) for cefixime –Lupin re-launch product under Suprax trademark with exclusive license in the U.S. –To date, only Suprax suspension has become available, packaged as 50ml bottle, equivalent to 1000mg cefixime

9. Provider Practices re: Antimicrobial Treatment for Gonorrhea Web-based survey of provider practices and acceptance of alternative drug formulations Clinicians surveyed in 38 local health jurisdictions in California: –64 STD Controllers and STD clinic directors –143 infectious disease experts –382 HIV care providers –30 family planning clinicians –350 attendees of recent STD clinical trainings

10. Provider Practices re: Antimicrobial Treatment for Gonorrhea Preferred GC Treatment Option n = 26 STD Clinicians (46% physicians; 41% response rate) 5/06 Provisional Analysis - CA DHS STD Control Branch Most (%)Next Most (%) Azithromycin 1 grams orally03.1 Azithromycin 2 grams orally4.723.4 Cefixime suspension04.7 Cefpodoxime 200mg orally1.60 Cefpodoxime 400mg orally26.69.4 Ceftriaxone 125mg intramuscularly40.626.6 Ceftriaxone 250mg intramuscularly23.4 Fluoroquinolone (e.g., ciprofloxacin, etc.)1.6 Spectinomycin00

11. Provider Practices re: Antimicrobial Treatment for Gonorrhea Preferred GC Treatment Option n = 26 STD Clinicians (46% physicians; 41% response rate) 5/06 Provisional Analysis - CA DHS STD Control Branch Most (%)Next Most (%) Azithromycin 1 grams orally03.1 Azithromycin 2 grams orally4.723.4 Cefixime suspension04.7 Cefpodoxime 200mg orally1.60 Cefpodoxime 400mg orally26.69.4 Ceftriaxone 125mg intramuscularly40.626.6 Ceftriaxone 250mg intramuscularly23.4 Fluoroquinolone (e.g., ciprofloxacin, etc.)1.6 Spectinomycin00

12. Provider Practices re: Antimicrobial Treatment for Gonorrhea Is Cefpodoxime Available on Your Formulary? Are You Aware Cefixime Suspension Is Available? 5/06 Provisional Analysis - CA DHS STD Control Branch n = 26 STD Clinicians (46% physicians; 41% response rate)

13. Provider Practices re: Antimicrobial Treatment for Gonorrhea Would You Use Cefixime Tablets if Available? Would You Use Cefixime Sachet if Available? 5/06 Provisional Analysis - CA DHS STD Control Branch n = 26 STD Clinicians (46% physicians; 41% response rate)

14. General Guidelines for Evaluating Drugs Active Against GC Bacterial culture is standard (diagnosis and test of cure); problem with NAATs for assessing cure based on residual nucleic acid following successful eradication Male urethritis, female cervicitis; other sites depending on sexual behavior history Appropriate testing of other STDs at enrollment Goal: drug plasma concentration should remain 10- times above the MIC 90 for at least 10 hours Handsfield HH et al., CID 1992; 15 (Suppl 1): S123-30 John Moran, William Levine. CID 1995; 20 (Suppl 1): S47-65

15. Factors in Antimicrobial Selection for Treatment of Gonorrhea Efficacy considerations: –Efficacy > 95% –Lower 95%CI of efficacy > 95% –Therapeutic reserve (dose twice that meeting above criteria) –Susceptibility not lower in organisms recovered after treatment Other considerations: –Tolerability –Efficacy against incubating syphilis –Cost of treatment John Moran, William Levine. CID 1995; 20 (Suppl 1): S47-65

16. CDC Recommended Antimicrobials for Treatment of Gonorrhea CDC “recommendation” criteria: –Regimen should cure > 95% of urogenital infections –Lower limit of the 95% confidence interval for cure should exceed 95% No new agents recommended by CDC since 1993 STD Treatment Guidelines CDC. STD guidelines 2002. MMWR 2002:51 (No. RR-6) CDC. Oral Alternatives to Cefixime for the Treatment of Uncomplicated Neisseria Gonorrhoeae Urogenital Infections. MMWR November 22, 2002 / 51(46);1052

17. Efficacy Data for Agents with Activity Against GC Infection John Moran, William Levine. CID 1995; 20 (Suppl 1): S47-65 * Novak et al., Antimicrob Agents Chemother 1992; 36: 1764-5 SS - single urogenital or rectal site PH - pharynx; MS - multiple or unspecified site

18. Why Further Evaluate Cefpodoxime Now? Cefpodoxime (Vantin ® ) is an oral third-generation cephalosporin Cefpodoxime 200 mg is FDA-approved for treatment of uncomplicated male urethritis, cervicitis, and female rectal infections Lower-limit of the 95% confidence interval for cefpodoxime only slightly less than 95% (CDC standard for recommendation of agent) Pharmacologic properties of cefpodoxime 400 mg better approximate cefixime, compared to cefixime Cefpodoxime 400 mg might provide enhanced margin of efficacy compared to lower, approved dose (“therapeutic reserve”)

19. Cefuroxime vs. Cefpodoxime More current usage in lieu of cefixime Smaller dose; dose- ranging suggests better tolerability Based on MIC 90 of 0.06, the 400mg dose is over the MIC for 16 hours; 200mg for ~ 13 hours (vs. cefixime 400mg ~ 24 hours) 400 mg = $9.86 Larger dose Cefuroxime 1g is above the MIC for less than 5 hours Cure rate for pharyngeal GC unacceptably low 56.9% (43-70) 1 gm = $16.69 Pricing: Lexi-Comp, Inc.

20. General Scope of Evaluation Recruitment from STD clinics in three California counties, Denver, CO, and Honolulu, Hawaii Evaluation of efficacy for treatment of urethritis and cervicitis, as well as pharyngeal/rectal co-infection Target enrollment: 1,300 participants One-time 400 mg oral dose Endpoint: Bacterial culture result at test-of cure (4 to 9 days following treatment) Projected Accrual Completion: June 2006

21. Cefpodoxime Study Challenges Decreasing availability of GC culture at clinics Unable to use GC NAATs to assess biologic cure in short (4-9 day) follow-up time-frame Participant aversion to urethral meatus culture since availability of urine-based testing

22. Cefpodoxime Study Challenges “Intention to treat”-type analysis requires categorization of all positive tests of cure as possible drug failures, irrespective of subjective participant report of sexual activity since baseline Statistically, few positive tests of cure – due either to drug failure or sexual re-exposure – are allowed to demonstrate the high level of efficacy required More conservative confidence interval calculation raises bar for determination of efficacy Uncertain effect of evolving cephalosporins MICs since era of prior drug studies

23. Limitations  California Gonorrhea Antimicrobial Survey  Low response rate  Experience bias of STD clinicians & ID specialists may overestimate knowledge of CA clinicians  GC-Cefpodoxime Study  Convenience sample of STD clinic attendees  Treatment failure group includes persons re- exposed from untreated partners

24. Conclusions  Few oral cephalosporin alternatives for GC treatment are available  Provider awareness of available forms of cephalosporin agents for GC is low, thus limiting use of some products  Ever fewer agents are available that meet CDC’s strict efficacy criteria for “recommended” agents

25. Recommendations  Agencies and the CDC should advocate for production and distribution of approved cephalosporin agents (i.e., Lupin’s Suprax)  Further evaluation of alternative cephalosporin (and other antimicrobial class) agents for efficacy at genital and non-genital sites infected by GC  Provider training on GC treatment guidelines and appropriate use of alternative antimicrobials

26. Acknowledgements  Local Co-investigators and Study Sites:  Denver Public Health (Dr. Kees Rietmeijer)  Hawaii Department of Public Health (Dr. Alan Katz)  Los Angeles DPH / Ruth Temple Clinic (Drs. Sarah Guerry & Peter Kerndt)  Orange County DPH (Dr. Chris Ried)  San Francisco DPH / SF City Clinic (Drs. Susan Philip & Jeffrey Klausner)

27. Acknowledgements, continued  Centers for Disease Control and Prevention  Stuart Berman  Susan Wang  John Moran  Kimberly Workowski  Lori Newman  David Trees  GC-Cefpodoxime Study Advisory Group  Emily Erbelding  Jeffrey Klausner  William M. Geisler  David Martin  Matthew Golden  Stephanie Taylor  Hunter Handsfield  Wil Whittington  Edward Hook