12/8/12. Overview. Optimizing STD Management in HIVinfected Individuals: What s new in 2012

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1 Optimizing STD Management in HIVinfected Individuals: What s new in 2012 Gail Bolan, M.D. Director, Division of STD Prevention National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention Centers for Disease Control and Prevention USCF December 6, 2012 No conflict of interest Overview Threat of untreatable gonorrhea Trends in GC antimicrobial susceptibility GC management challenges Treatment Options Detection of Treatment Failures GC clinical preventive efforts Concerning epidemiologic trends among young MSM National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of STD Prevention How have you learned about what s new in the CDC 2010 STD Treatment Guidelines? 1. I have reviewed an available 2010 STD Treatment Guideline table 2. I have been to at least one CDC webinar or podcast 3. I have been to an STD/HIV Prevention Training Center training on these 2010 guidelines 4. I have read the entire document 5. I have read the entire page document and listened to a webinar or podcast or attended a PTC training 6. I am not very familiar and am hoping to become more so at this session 7. Other CDC STD Treatment Guidelines Authoritative, evidence-based source for STD clinical management Recommended regimens preferred over alternative regimens Alphabetized unless there is a priority of choice Available at Wall charts, pocket guides To be updated in meeting to review evidence 5/13 1

2 What is the first line antimicrobial you currently use for your patients with rectal gonorrhea? 1. Azithromycin 2 gm po 2. Cefixime 400 mg po 3. Cefpodoxime 400 mg po 4. Ceftriaxone 250 mg IM 5. Ceftriaxone 500 mg IM 6. Other 7. I have not treated a rectal GC case recently Case 1 28 year- old HIV uninfected man states a partner told him to come and get checked for gonorrhea. He has no complaints, his physical exam is normal. He was treated for rectal gonorrhea 6 weeks ago with pills. He reports mostly protected recepbve anal intercourse, but unprotected oral sex with mulbple anonymous partners in the past 2 months. He reports a history of a mild erythematous rash, not hives when he took PCN over 20 years ago. How would you manage this patient? Case 1 How would you manage this patient? 1. Test for GC at all sites using NAAT & await results 2. Test using NAAT & treat with Azithromycin 2 gm 3. Test using NAAT & treat with Cefixime 400 mg/ Azithromycin 1 gm 4. Test using NAAT & treat with Ceftriaxone 250 mg 5. Test using NAAT & treat with Ceftriaxone 250 mg/ Azithromycin 1 gm 6. Test using culture & treat with Ceftriaxone 250 mg/ Azithromycin 1 gm 7. Other TRENDS IN GC ANTIMICROBIAL SUSCEPTIBILITY AND THE THREAT OF UNTREATABLE GC 2

3 Historical Perspective On Gonorrhea Antimicrobial Resistance 1936 Sulfanilimide Introduced 1945 Penicillin Late 1940s Sulfa Resistance Widespread Late 1940s Tetracycline s 1976 Penicillinase Producing N. gonorrhoeae Ceftriaxone Recommended Penicillin Dropped 1984 Plasmid Mediated Tetra Resistance Chromosomal PCN & Tetracycline resistance gradual increase MICs 1991 Quinolone Resistant NG in Hawaii 1993 Quinolones & Cefixime 2007 Quinolone No Longer Recommended Workowski K, Ann Int Med 2008;148: Gonococcal Isolate Surveillance Project (GISP): Sites and Regional Laboratories Orange Co. San Diego Seattle Portland San Francisco Las Vegas Los Angeles* Denver Phoenix Albuquerque United States, Tripler AMC* Honolulu Dallas Minneapolis Oklahoma City Kansas City* New Orleans Detroit Chicago Cleveland Cincinnati Birmingham Atlanta Philadelphia Baltimore Greensboro* Miami New York City Richmond Clinic site Lab Percentage of Gonorrhea Specimens with Reduced Cephalosporin Susceptibility Gonococcal Isolate Surveillance Project, United States, % of isolates with cefixime MICs 0.25µg/ml or ceftriaxone µg/ml Cefixime Ceftriaxone (preferred antibiotic) * 2008* Year Abbreviations: MICs = minimum inhibitory concentrations * Cefixime susceptibility not tested during Percentage of isolates Percentage of Neisseria gonorrhoeae isolates with elevated MICs of cefixime ( 0.25 µg/ml) by sex of sex partner and region, GISP, West Midwest 3.7 MSM= Men who have sex with men; MSW = Men who have sex only with women N= Northeast & South MS M MS W 3

4 GC Azithromycin Susceptibility, * Current GISP alert breakpoint is MIC 2 µg/ml GISP Alerts , 87 (0.4%) isolates had MICs 2 µg/ml *, 45 (0.3%) isolates had MICs 2 µg/ml No clear trend in azithromycin susceptibility in GISP Cluster of 9 cases from MSM in West with MICs to azithromycin of 8 16 µg ( ) Hawaii identified case with MIC > 512 µg/ml (2011) Azithromycin 2 g treatment failure in MSM in Oregon confirmed by molecular typing (2011) Higher MICs tend to be from the West and MSM Antimicrobial Susceptibility Among GC Isolates with Elevated Cefixime MICs ( 0.25), PenR/QRNG PenR/TetR 1% 1% TetR/QRNG 7% QRNG 3% Susceptible 20% Azithromycin 99% susceptible 1 had MIC of 2 µg/ml Spectinomycin 100% susceptible Resistance to Penicillin, Tetracycline & Quinolones 69% (n=106) Source: Gonococcal Isolate Surveillance Project * (Jan-June) August 9, 2012 Releases 4

5 STD Treatment Guidelines, 2010 Uncomplicated Gonococcal Infections of Cervix, Urethra & Rectum Ceftriaxone 250 mg as a single intramuscular dose (Or if not an option, Cefixime 400 mg orally in a single dose) PLUS Azithromycin 1 g orally or Doxycycline 100 mg twice daily for 7 days STD Treatment Guidelines, 2012 Uncomplicated Gonococcal Infections of Cervix, Urethra & Rectum Recommended Regimen Ceftriaxone 250 mg as a single intramuscular dose PLUS Azithromycin 1 g orally or Doxycycline 100 mg twice daily for 7 days Source: MMWR Aug 9, 2012 STD Treatment Guidelines, 2012 Uncomplicated Gonococcal Infections of Cervix, Urethra & Rectum Alternative Regimens Cefixime 400 mg orally in a single dose plus Azithromycin 1 g orally If Ceftriaxone is not readily available For Expedited Partner Therapy (EPT) Azithromycin 2 g orally If cephalosporin allergy TOC at one week if alternative regimen is used Gonorrhea Management Challenges Low awareness of problem Declining STD control resources for assessment and assurance of adequate treatment and partner services Limited treatment options Challenges in detecting treatment failures Role of EPT Source: MMWR Aug 9,

6 GONORRHEA MANAGEMENT CHALLENGES: LIMITED TREATMENT OPTIONS Evolution of Criteria for GC Treatment Recommendations Antimicrobial resistance surveillance has guided treatment decisions (GISP, GASP) Change in antimicrobial if resistance prevalence >5% (MMWR 1987) GC treatment efficacy >95% and 95% CI lower bound 90% (HHH,1992) >95% and 95% CI lower bound 95% (Moran, 1995) Other factors Serum concentration at least 4x MIC90 x 10 hr after peak (Jaffe1987) At least twice the minimum efficacious dose Should criteria be modified post QRNG? (Newman 2007) Recommended regimens >95% and 95% CI lower bound 95% Alternative regimens >95% and 95% CI lower bound 90% Alternative Treatment Approaches Consider: in vitro studies, pharmacokinetic/ pharmacodynamic aspects, treatment efficacy, mechanisms of action, side-effects and safety, and cost Increase dose or duration of cephalosporin Efficacy of beta lactams based on 4 x MIC90 x 10 hrs (Jaffe 1979) Dose limit dependent on MIC (short term solution) Ceftriaxone 1 gm may fail if MIC >0.125 (modeling) Alternative cephalosporin regimen IM followed by oral therapy or oral bid (modeling) Dual therapy Ceftriaxone + azithromycin preferred (TetM) Azithromycin 1 vs 2 gm Combination Therapy as an Alternative Urogenital GC Regimen NIH sponsored non-comparative randomized trial investigating two antimicrobial regimens 1. gentamicin (240mg IM or 5 mg/kg IM) + azithromycin 2 gm PO 2. gemifloxacin 320 mg PO + azithromycin 2 gm PO Rationale for regimens Additive effect between gentamicin and azithromicin (in vitro ) Gemifloxacin more active against GC with known cipro resistance or mutations in the GyrA and ParC regions (in vitro) Drugs already available in U.S. 6

7 Alternative Treatment Approaches Antimicrobial susceptibility profile directed therapy 68% of isolates are susceptible to all antimicrobials Less acceptable for symptomatic infection Most infections diagnosed with NAAT (no susceptibility data) Antibiotic cycling Treat index patient different than contacts Rotate first line agents every couple of months Alternative Treatment Approaches Promote identification of new treatments Use NIH clinical trials network for other promising new regimens Solithromycin (CEM 101) a fluoroketolide that is active against bacteria resistant to macrolides Mine DOD stockpiles for possible new agents Antibacterial drug pipeline solutions through incentives and regulatory change GC has been added as qualifying pathogen in incentives legislation- GAIN act (IDSA) Limited Population Antibacterial Development (LPAD) mechanism (IDSA) Novel agents Pleuromutilins, bicyclolide, ketolides non quinolone topisomerase inhibitors MUT (inhibitor of fatty acid biosynthesis enzyme) BASHH Treatment Guidelines Uncomplicated Gonococcal Infections of Cervix, Urethra & Rectum Ceftriaxone 500 mg as a single intramuscular dose TOC at 2 weeks Source: BASHH GC Treatment Guidelines 2011 PLUS Azithromycin 1 g orally MIC Simulation of Time Periods of Free Drug Concentrations Above MIC (Chisholm et al, 2010) Cefixime po Ceftriaxone IM 200 mg 400 mg 125 mg 250 mg 500 mg 1 g 2 g Light blue shading < 10 hrs above MIC; Dark blue shading hrs above MIC; No shading > 20 hrs above MIC 7

8 Clinician Response to the Threat of Cephalosporin Resistant GC GONORRHEA MANAGEMENT CHALLENGES: CHALLENGES IN DETECTING TREATMENT FAILURES Maintain vigilance for treatment failures If suspected culture with AST If symptoms don t resolve or recur after treatment do not assume refection Lower threshold for TOC NAAT could be used one week after treatment Proportion of Patients with Gonorrhea in Urine by NAATs Following Treatment, by Gender Clinical Management of Suspected GC Treatment Failure Cases Report immediately to health department & CDC Cefixime treatment failure Ceftriaxone 250 mg IM & Azithromycin 2 gm po Ceftriaxone treatment failure STD infectious disease expert consultation Test-of-cure in one week with culture/ast after re-treatment Ensure partner follow-up, including culture and treat according to treatment of the index case Source: Bachmann, et al J. Clin. Microbiol. 2002, 40(10):

9 If you have access to gonorrhea culture, what transport media do you use? GC Culture Candle Jar 1. Liquid Amies 2. Blue Amies 3. Culture plates 4. I don t know what media we use 5. I don t have access to GC culture 6. Other STD Atlas, 1997 What is the most common method you use to treat partners of your GC patients? GONORRHEA MANAGEMENT CHALLENGES: ROLE OF EPT 1. Encourage the patient to bring their partner(s) in with them when they return for treatment 2. Give the patient extra medication to give to their partner(s) 3. Give the patient a prescription for their partner(s) 4. Counsel the patient about the need to self refer their partner(s) for treatment 5. Call the Health Department for assistance with partner services 6. None of the above because that is a Health Department responsibility 9

10 Expedited Partner Therapy Legal Status as of October 2011 WA OR ID MT WY ND SD MN WI MI VT NY ME NH CA NV UT CO NE KS IA MO IL PA IN OH WV VA KY MA RI CT AK AZ NM OK AR TN NC SC NJ DE HI EPT is Permissible EPT is Likely Prohibited TX LA MS AL GA FL MD DC (Baltimore only) GONORRHEA CLINICAL PREVENTIVE EFFORTS: BACK TO BASICS EPT is Potentially Allowable Legislation Introduced Scale Up Provider GC Clinical Preventive Efforts Timely diagnosis and treatment Screen per STD Treatment Guidelines Females less than 25 years old annually MSM at site of exposure annually or every 3-6 months if higher risk Promote condom use and link to risk reduction counseling Seek care for symptoms and return if symptoms don t resolve or recur after treatment Repeat testing at 3 months after treatment STD Screening for MSM STD Site Type of Sex HIV blood oral, anal Syphilis blood oral, anal GC/CT urethra or urine oral, anal GC/CT rectum receptive anal GC pharynx receptive oral HSV-2* blood * Some experts recommend FREQUENCY: At least at the initial visit then annually or more frequently based on risk 10

11 Proportion of Unidentified CT and GC Infections if only Urine/Urethral Screening Performed among MSM: San Francisco 2003 Do you using NAATs for rectal and pharyngeal gonorrhea and chlamydia screening in your clinical practice? Chlamydia n = 574 Gonorrhea n = Yes 2. No 3. Don t know 4. I am not screening extragenital sites Kent, CK et al. ISSTDR, July 2005 Rectal Gonorrhea & Chlamydia Reinfection: Markers for Increased HIV Risk San Francisco municipal STD Clinic Retrospective cohort: 541 HIV(-) MSM with rectal GC or CT Follow-up: at least 12 months after entry to determine HIV seroconversion Estimated annual HIV incidence of 2.25% (1198 person years of f/u) MSM with 2 prior CT or GC rectal infections in past 2 years, HIV incidence 15% Subpopulation of MSM in critical need of innovative prevention (? PrEP) CONCERNING EPIDEMIOLOGIC TRENDS AMONG YOUNG MSM (Kyle Bernstein et al. JAIDS 2010; 53: ) 11

12 HIV Among Youth in the US Who's At Risk? Number of new HIV Infections among youth by sex and race/ethnicity United States, 2010 CDC. Vital Signs: HIV Infection, Testing, and Risk Behaviors Among Youths - United States. MMWR 2012:61 Increases in P&S syphilis among young men having sex with men, 27 states* MSM with P&S syphilis per 100,000 males ** % increase since % increase since % increase since 2005 * States reporting sex of partner data for at least 70% of cases of P&S syphilis each year during ** Calculated using population data from 2009 (Su, JR et al, Ann Intern Med Aug 2;155(3):145-51) BLACK HISPANIC WHITE Race/ethnicity and age group (years) Gonorrhea Positivity* among MSM, by Age and Quarter, STD Surveillance Network (SSuN), Posi%vity (%) q2009 2q2009 3q2009 4q2009 1q2010 2q2010 3q2010 4q2010 1q2011 2q2011 3q2011 4q2011 1q2012 2q *GC+ at any anatomic site among 56,847 MSM with 1 or more visit 2009 through 2 nd quarter 2012 Conclusions Cephalosporin-resistant GC is likely to occur in US and significant challenges exist Need to decrease GC morbidity Need to develop infrastructure to Detect treatment failures and resistant strains Slow their spread and limit complications Increase antimicrobial pipeline Rebuilding our defenses against GC will require public and private sector partnerships GC is an important risk marker or risk factor for HIV transmission Stay tuned for STD Treatment Guidelines updates: STD Atlas,

13 Acknowledgements Thank you! CDC Bob Kirkcaldy Sarah Kidd Kevin O Connor John Papp Tom Peterman David Trees Hillard Weinstock Kim Workowski GISP PIs and Laboratories GISP Clinic Sites CDC Division of STD Prevention Questions? gyb2@cdc.gov For more information please contact Centers for Disease Control and Prevention 1600 Clifton Road NE, Atlanta, GA Telephone, CDC-INFO ( )/TTY: cdcinfo@cdc.gov Web: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention Division of STD Prevention 13