Alternative Cephalosporin Treatment Options for Gonorrhea Christopher S. Hall, MD, MS 1 Michael Samuel, DrPH, 1 Michael McElroy, MPH, 1 Jessica Frasure,

Alternative Cephalosporin Treatment Options for

Gonorrhea

Christopher S. Hall, MD, MS1

Michael Samuel, DrPH,1 Michael McElroy, MPH,1

Jessica Frasure, BA,1 Heidi Bauer, MD,1

Henry Chambers, MD,2 and Gail Bolan, MD1

1California Department of Health Services (CDHS) STD Control Branch and the California STD/HIV Prevention Training Center

2University of California, San Francisco Division of Infectious Diseases

2006 CDC National STD Prevention Conference, May 7-11, 2006

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

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400

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1941 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005

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(2005 n/a)

92.6

GC Rates in California and U.S.

2010 Objective (19.0)

1941–2005


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

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1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

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Resistant Decreased Susceptibility


STD Clinic Sites: Long Beach, Orange, San Diego, San Francisco

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


Fewer Alternativesfor 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)

GC Treatment RecommendationsUncomplicated 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

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

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


Preferred GC Treatment Optionn = 26 STD Clinicians (46% physicians; 41% response rate)

5/06 Provisional Analysis - CA DHS STD Control Branch

Most (%) Next Most (%)

Azithromycin 1 grams orally 0 3.1

Azithromycin 2 grams orally 4.7 23.4

Cefixime suspension 0 4.7

Cefpodoxime 200mg orally 1.6 0

Cefpodoxime 400mg orally 26.6 9.4

Ceftriaxone 125mg intramuscularly 40.6 26.6


Fluoroquinolone (e.g., ciprofloxacin, etc.) 1.6 1.6

Spectinomycin 0 0


Preferred GC Treatment Optionn = 26 STD Clinicians (46% physicians; 41% response rate)


Most (%) Next Most (%)

Azithromycin 1 grams orally 0 3.1

Azithromycin 2 grams orally 4.7 23.4

Cefixime suspension 0 4.7

Cefpodoxime 200mg orally 1.6 0

Cefpodoxime 400mg orally 26.6 9.4



Fluoroquinolone (e.g., ciprofloxacin, etc.) 1.6 1.6

Spectinomycin 0 0


Yes48%

No/Unsure52%

Is Cefpodoxime Availableon Your Formulary?

No59%

Yes41%

Are You AwareCefixime Suspension

Is Available?


n = 26 STD Clinicians (46% physicians; 41% response rate)


Yes83%

No/Unsure17%

Would You UseCefixime Tablets

if Available?Would You Use

Cefixime Sachet if Available?

Yes72%

No/Unsure28%


n = 26 STD Clinicians (46% physicians; 41% response rate)

General Guidelines for EvaluatingDrugs 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 MIC90 for at least 10 hours

Handsfield HH et al., CID 1992; 15 (Suppl 1): S123-30John Moran, William Levine. CID 1995; 20 (Suppl 1): S47-65

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

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

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

Agent, dose, route Site Studied Cured % Cure (95%CI)

Ceftriaxone 125 IM SS 442 438 99.1 (98.7, 99.8)

PH 63 59 93.7 (84.5, 98.2)

Cefixime 400mg PO SS 344 336 97.7 (96.1, 99.3)

Cefpodoxime 200 PO (*) SS 284 274 96.5 (94.3, 98.6)

PH 19 15 78.9 (54.5, 94.0)

Cefpodoxime 400 PO (*) SS 10 10 100 (69.1, 100)

Cefuroxime 1 gm PO SS 469 454 96.8 (95.2, 98.4)

MS 104 102 98.1 (93.2, 99.8)

SS - single urogenital or rectal sitePH - pharynx; MS - multiple or unspecified site

Why Further EvaluateCefpodoxime 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”)

Cefuroxime vs. Cefpodoxime• More current usage in

lieu of cefixime

• Smaller dose; dose-ranging suggests better tolerability

• Based on MIC90 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.

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

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

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

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

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

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

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)

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

Documents

Alternative Cephalosporin Treatment Options for Gonorrhea Christopher S. Hall, MD, MS 1 Michael Samuel, DrPH, 1 Michael McElroy, MPH, 1 Jessica Frasure,