Medical Director, Community & Behavioral Health Clinics Department of Health and Human Services

Transcription

1 Patrick F. Luedtke MD, MPH Senior Public Health Officer Medical Director, Community & Behavioral Health Clinics Department of Health and Human Services

2 I have no relevant financial disclosures

3 Review current Oregon-wide gonorrhea data Review historical & current Lane Co. STD data Discuss gonorrhea ABX resistance Discuss diagnostic challenges/experiences Discuss CDC treatment protocols

4 Gonorrhea rate in Lane Co. is climbing fast Extragenital gonorrhea cases occur commonly Abx resistance of GC not an issue at present STD rates are high enough to routinely include on your DDx list If you treat, please get sexual history & contact info---then share with Public Health! Consider extra screening for high risk pts.

5 Oregon-wide STDs: Gonorrhea

6 U.S. Oregon

7 Year Cases Rate* ** *Per 100,000 population per year **Projected

8 Female Male 0

9 1171, 67% 16% 84% Yes No Sex with other men? 565, 33% Male Female

10 Gonorrhea cases by county, Oregon 2012, >10 cases & ~ 100% increase,

11 County 2012 Cases 2013 Cases Percent increase Clatsop % Coos % Douglas ,050% Jackson % Josephine % Lane % Malheur % Umatilla %

12 County Male Cases Asked about sex with men Sex with men (%) Clatsop 5 (42%) 0 (0%) n/a Coos 7 (86%) 1 (14%) 0% Douglas 14 (61%) 7 (50%) 43% Jackson 72 (48%) 4 (6%) 75% Josephine 22 (59%) 0 (0%) n/a Lane 129 (60%) 25 (19%) 24% Malheur 5 (29%) 0 (0%) n/a Umatilla 4 (33%) 1 (14%) 0% State 1,171 (67%) 539 (46%) 84%

13 Top Age strata: = > Male Female Total *

14 Screening

15 Extra-genital Gonorrhea & Chlamydia Gonococcal Infections Anatomic Site Among PHSKC MSM, STD high Clinic rates 2011 of extra-genital GC & CT Pharyngeal GC: 9.2% 1 Rectal GC: 9.7% 3 Rectal CT: 12% 3 The majority 43% of infections are asymptomatic Rectum 92% of pharyngeal GC 2 & 57% 84-86% of rectal GC 2 Isolated to Pharynx and/or Urethral Infectious with or without EG Infections 1. Kent CK. CID Morris, CID Barbee, STD 2014 Barbee STD 2014

16 Gonorrhea: Abx Resistance?

17 Since its difficult to impact who has sex with whom; And its difficult to change how frequently people have sex; Perhaps the only way to pick up early STD cases is more frequent testing

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19 1936 Sulfonamides Introduced Historical Perspective on Neisseria gonorrhoeae Antimicrobial Resistance in the United States 1945 Penicillin Late 1940s Tetracycline 1989 Ceftriaxone Recommended Penicillin Dropped 1993 Quinolones & Cefixime 1 st line Late 1940s Sulfa Resistance Widespread Penicillinase Producing N. gonorrhoeae in U.S. Plasmid Mediated Tetra Resistance Quinolone Resistant NG in Hawaii Quinolone No Longer Recommended s Chromosomal PCN & Tetracycline resistance gradual increase MICs Slide courtesy of Matt Golden. Modified from Workowski K A et al. Ann Intern Med 2008;148:

20 Trends in the Prevalence of Quinolone Resistant Neisserria gonorrhoeae in China and the U.S China U.S. Honolulu San Diego Seattle QRNG= MIC>1mg/l Yue-Ping Yin, Chinese National STD Control Program CDC 2008 GISP Report Barbee, Marrazzo & Baeten STD Update October 7, 2013 slide 20

21 Percent Proportion of N. gonorrhoeae Isolates with Elevated MICs to Oral Cephalosporins, MSM Heterosexuals Hawaii San Diego LA San Portland Seattle Francisco Total number isolates tested Elevated MIC =cefixime MIC >0.25µg/ml Source: Kircaldy & GISP Collaborators

22 Cefixime and ceftriaxone alert * level MIC s by year, Portland, Oregon Percent 10 Ceftriaxone Cefixime 5 0 *Cefixime: 0.25 µg/ml; ceftriaxone µg/ml

23 Extensively Drug Resistant Neisseria gonorrhoeae: The Superbugs Author (Year) Country Population Ceftriaxone MIC (µg/ml) Cefixime MIC (µg/ml) Resistance to Other Abx Clinical Ohnishi (2011) Japan Sex Worker Penicillin, quinolone Pharyngeal GC Cured with IV ceftriaxone Unemo (2011) France MSM Quinolones, azithromycin penicillin, tetracycline Urethral GC Failed Cefixime 200mg x 2 Cured Gent 160mg IM Camara (2012) Spain 2 MSM Barbee, Marrazzo & Baeten STD Update Penicillin, quinolones, tetracycline, Urethral & Rectal GC (partners) One pt cured with 7 days doxy, one with Azithro October 7, 2013 slide 23

24 Male Female Total

25 Male Female Total

26 Acute HBV Acute HCV Acute HIV

27 Gonorrhea: a.) Pharyngeal & rectal disease b.) Ceftriaxone 250mg (plus Azithromycin) c.) Alternative antibiotic regimens Syphilis a.) Failure to test: We are Here, We are here! b.) Diagnostic failures (e.g., rashes)

28 CDC guidelines for uncomplicated GC Recommended for urogenital infection: Ceftriaxone 250 mg injection x 1 best choice PLUS: Azithromycin 1g orally x 1 best choice Doxycycline 100mg orally BID x 7 days Alternatives: Cefixime 400mg orally plus Azithromycin* Azithromycin 2g orally x 1 penicillin allergy *Still available for heterosexual expedited partner therapy.

29 Key Learning Points Gonorrhea numbers in Lane Co. are climbing fast Extragenital gonorrhea cases occur commonly Abx resistance of GC not an issue at present STD rates are high enough to routinely include on your DDx list, where appropriate If you treat, please get sexual history & contact info---then share with Public Health! Don t forget CDC treatment guidelines for STDs

30 Questions?

31 Screening Focus on key population: MSM Focus on the key sites: anus and pharynx Treatment Dual therapy with ceftriaxone + azithromycin Partner treatment EPT for heterosexuals Not a GC control strategy, per se, but: We need to rethink the focus of STD partner services for MSM HIV testing of index case HIV testing of partner

32 It s time to sound the alarm - Gail Bolan, MD; CDC Director of the Division of STD Prevention ; NEJM 2012

33 Cefixime (oral ) treatment failures even with susceptible MICs 291 gonorrhea culture positive individuals 133 who returned for test of cure 13 were culture positive 9 patients were determined to have experienced cefixime treatment failure, involving urethral (n = 4), pharyngeal (n = 2), and rectal (n = 3) sites. The overall rate of clinical treatment failure among those who had a test of cure was 6.77% (95% CI, 3.14%-12.45%; 9/133). Allen VG et al. Neisseria gonorrhoeae treatment failure and susceptibility to cefixime in Toronto, Canada, JAMA 2013

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35 Neisseria gonorrhoeae Screening/Testing NAAT (most sensitive) FDA cleared for the widest variety of specimen types including endocervical swabs, vaginal swabs, urethral swabs (men), and urine (from both men and women). Limitation of NAAT: no drug resistance testing

36 NAAT for rectal and pharyngeal testing >2x sensitivity of culture for rectal and pharyngeal chlamydia and gonorrhea Not FDA-approved, but can be done if laboratory validation is complete (Lab Corp and Quest have done this) Can use vaginal swab for these sites

37 Self-obtained Testing Comparable to clinician-obtained testing Can do at home, non-clinic sites etc Examples CBOs HIV Clinic self-testing STD Clinic expedited care

38 Frequency of Screening for MSM? CDC guidelines Yearly for all sexually active MSM More frequent for higher risk (non-specific) King County recommendations: Q3 month screening for high-risk MSM Bacterial STD in past year Methamphetamine or popper use in past year 10 or more sex partners in past year Unprotected anal intercourse with HIV non-concordant partners

39 Treatment

40 Treatment Regimens Oral Combination Therapy with Azithromycin Oral Combination Therapy with Doxycycline Oral Cephalosporin Monotherapy Ceftriaxone Combination therapy Ceftriaxone Monotherapy Total days 7.0% (8/115) 33.3% (14/42) 29.8% (17/57) 11.3% (7/62) 9.1% (4/44) Adjusted Relative Risk* (95% Confidence Interval) Referent Group 4.18 ( ) 3.98 ( ) 1.20 ( ) 0.81 ( ) * Adjusted for time from treatment to TOC, year, sexual behavior, sexual orientation, age. Barbee et al. CID, 2013

41 Oral two-drug regimens with azithromycin are comparable to ceftriaxone-containing regimens Combination oral therapy with doxycycline performs poorly

42 The Pharynx Reservoir of infection Asymptomatic Underdiagnosed Transmissable to urethra through oral sex 27.8% of urethral infections attributable to oral sex in recent King County STD Clinic study Harder site to treat May foster the development of resistance

43 The pharynx may serve as a breeding ground for resistance Commensal Neisseria Species Gonococcus ability to scavenge DNA Sub-therapeutic Drug Levels

44 Treatment: Other Key Points 1) Counseling: No sex for 7 days after treatment 2) Treat partners presumptively 30-70% infected 4) Retest 3 months >10% infection

45 Treatment Back-up Plan? Ertapenem Works in the lab; no human trial Increase dose and dosing frequency? Cefixime Phase I study currently enrolling Combinations of older drugs CDC study on-going Azithromycin plus either gentamicin or gemifloxacin New agents Solithromycin, Novel quinolone Phase 2 & 3 human studies underway

46 Partner Treatment

47 Terminology Refresher 1) Provider referral Health department attempts to contact all or almost all patients & to contact all partners 2) Contact referral Health department attempts to interview all or almost all patients & to contact only partners that are not examined within a specified period of time 3) Patient referral - No routine public health assistance with PN provided. 1) Simple referral no assistance offered 2) Supported patient referral may involve interview, counseling, offer of assistance,

48 GC & CT PN: RCTs Population: 1898 Dade Co. Florida STD clinic pt (94% men) -? dates Design & Intervention: RCT 3 arms: patient referral, pamphlet & motivational self-interview, conditional referral Outcomes: new cases treated, reinfection 4 weeks Measure Pt referral No. partners examine/index 0.37 No. new cases treated 154 % index cases infected at f/u* 7.6 Pamphlet SR Conditional R * 54% returned for f/u testing Source: Cleveland, unpublished

49 Percent Interviewed for PN Percentage of Cases of STD/HIV Interviewed for PN in High STD/HIV Morbidity Areas of U.S., & Syphilis HIV Gonorrhea Chlamydia Sources: Golden, STD 2003:30:490; Golden, STD 2004;31:709

50 Expedited Partner Therapy (EPT) Global term for process of treating partners without their mandatory prior examination Patient delivered partner therapy (PDPT) index patient gives meds to partners Most common form of EPT

51 Effect of PDPT on Partner Notification or Treatment Effect of PDPT on Partner Notification/Treatment Study name Statistics for each study Risk ratio and 95% CI Risk Lower Upper ratio limit limit Z-Value p-value Schillinger Golden Kissinger (urethritis) Kissinger (TV) Cameron Fav ours Control Fav ours PDPT Meta Analysis All outcomes based on index patient report of partner notification or treatment Outcomes varied across studies (e.g. delivery study intervention [Schillinger], all partners notified or treated [Golden, Cameron], partners treated [Kissinger]) One study excluded due to use of different methods for ascertaining outcomes in two study arms

52 Effect of PDPT on Persistent/Recurrent Gonorrhea & Chlamydia Study name Statistics for each study Risk ratio and 95% CI Risk Lower Upper ratio limit limit p-value Schillinger Golden Kissinger Cameron Fav ours PDPT Fav ours Control Meta Analysis Source: Golden, work in progress

53 Cost Effectiveness of EPT (Male Index Patients) Costs (per 100 index pts)* QALYs Lost (per 100 index pts) Cost-effectiveness Ratio ($/QALY saved)* Payer perspective (includes costs borne by an individual payer) Standard $24, EPT $23, $2351 (cost-saving) Health care system (includes all direct medical costs, regardless of who pays) Standard $45, EPT $39, $14,803 (costsaving) Societal perspective (includes all medical and lost productivity costs) Standard $59, EPT $48, $28,914 (costsaving) *All costs in 2008 dollars Source: Gift T. Sex Transm Dis 2011;38:1067

54 Is PDPT Safe? Passive ascertainment of adverse drug reactions WA & CA PDPT instructions advise to call hotline for drug reaction. No instances of anaphylaxis ascertained Azithromycin cardiac toxicity NEJM - ~350,000 5-days courses azithro vs. amox, cipro and no abx 47 (63-576) extra deaths per 1 million doses 245 extra deaths (vs. Amox) in persons in highest decile CV risk 9 (2-21) extra deaths (vs. Amox) in persons in lowest 50% CV risk Seattle-Oregon collaboration: 64,956 cases GC/CT treated azithro vs. 38,126 cases other drugs 46.2 vs deaths/1 million, AZM vs. other abx - no CV deaths Estimated risk CV death risk =0 (95% CI ) per million

55 Legal Status of EPT in the United States WA ME MT ND MN CA OR NV ID AZ UT WY CO NM SD NE KS OK TX WI IA IL MO AR MS LA MI IN KY TN AL OH WV GA NY PA VA NC SC AK FL Source: Adapted from Hodge JG. AJPH 2008;98:236 HI EPT Permissible EPT Prohibited EPT legal status uncertain

56 PDPT in WA State Free PDPT packs available to all providers Stocked in high-volume clinics and in 157 pharmacies, statewide Preprinted prescriptions on case-report form and on faxable forms Medication prepackaged to meet requirements of state pharmacy board Allergy warning (English & Spanish) Azithromycin 1g Cefixime 400mg (gonorrhea only) Condoms Information

57 WA State Community-level Randomized Trial of EPT Objectives 1) To determine if a program to promote the use of EPT can be brought to scale in a state with 6.5 million inhabitants 2) To determine if an EPT program can decrease the prevalence of chlamydia and incidence of gonorrhea in women Methods Stepped-wedge community-level randomized trial Local health jurisdictions (LHJ) unit of randomization and analysis 23 of 25 LHJs in WA state participated Primary Outcomes: Chlamydia positivity among women age tested in Infertility Prevention Project (IPP) Clinics Gonorrhea Incidence in women

58 Number of PDPT Packets Distributed in WA State and Dispensed via Pharmacies Doses PDPT per 6 Months Dispensed via Pharmacies Sent to Clinics & Pharmacies 2010 = 9,921 doses = 3548 doses ,344 cases of GC/CT diagnosed in WA heterosexuals in 2010

59 Percent Cases/100,000 P<.001 for both chlamydial positivity and gonorrhea incidence Trends in Chlamydia Positivity Among Women Age Tested Through IPP Clinics and Gonorrhea Incidence in WA State Women 10 Chlamydia Positivity Gonorrhea Incidence Time Time

60 Cases/100,000 Cases/100,000 Gonorrhea Incidence in Women, by Study Wave Wave 1 Wave Cases/100,000 Cases/100, Wave 3 Wave

61 Effect of EPT on Chlamydial Positivity and Gonorrhea Incidence in Women, Randomized Trial ITT Analysis Chlamydial positivity in women Gonorrhea incidence in women Risk Ratio 95% CI Combined GC/CT in women * Analysis controls for secular trend that may have been ongoing independent of the study intervention. Combined outcome is post-hoc analysis (p=.064) Source: Matthew Golden, in progress

62 Conclusions of the Community Trial EPT intervention is scalable >50% of heterosexuals with GC or CT in WA State are offered EPT Less use for GC than CT opposite of what makes sense Uncertain if intervention decreased rates of STI No intervention for an STI has been shown to reduce population prevalence Intervention has proven sustainable in the posttrial period

63 Is PDPT still safe in the era of emerging resistance? YES! In fact, it is crucial Key points: Not all partners infected Decreased susceptibility extremely uncommon in heterosexuals Evidence that dual therapy with oral azithromycin is as effective as ceftriaxone If PDPT use decreases or % of cases decreases even slightly overall rates of GC and rates of decreased susceptibility GC could increase Source: Golden et al, in press

64 STD Diagnoses in Persons Presenting as Contacts to Bacterial STD* in Two Studies Women Hetero Men MSM US Australia US Australia US Australia N=2507 N=195 N=3511 N=243 N=460 N=188 Gonorrhea 3.9% 1% 3.1% 0 6.1% 8% PID 3.7% 3.1% NA NA NA NA HIV % 0 5.5% 5.1% Syphilis <0.1% % 0.5% * U.S. Study include contacts to CT, GC and NGU. Australian study includes only contacts to CT Sources: Stekler J. CID 2005;40:787. McNulty A. STD 2008;35:834

65 HIV Testing

66 Rethinking STD Partner Services Need a system that varies the cost & intensity of intervention based on the population and infection EPT is a scalable, low-cost approach to partner services for gonorrhea and chlamydial infection in heterosexuals Decreases reinfection, increases partner treatment Uncertain population-level effect Partner services in MSM have remained a challenge HIV is the priority STD Have we focused on the right outcomes in MSM?

67 Percent Percent of MSM with Bacterial STIs Newly Diagnosed with HIV (among those tested for HIV), Washington State, USA * Number Tested * Excludes persons with previously diagnosed HIV infection

68 Percent Percent of MSM with Bacterial STIs Tested for HIV Infection at Time of STI Diagnosis or Treatment, WA Pre-intervention (5/10-4/12) Intervention (5/12-4/13) STD-HIV Specialty STD-HIV Provide Specialty Provide Non-Specialty Non-Specialty King King County County * Excludes persons with previously diagnosed HIV infection STD-HIV Specialty STD-HIV Provider Specialty Provider Non-Specialty Non-Specialty Outside of King Outside County King P<.0001 for intervention effect controlling for clinical source of diagnosis and STI diagnosis

69 Number of New HIV Diagnoses New HIV Diagnoses Per Year Among MSM with Bacterial STIs Before and After Intervention Pre-intervention (5/10-4/12) Intervention (5/12-4/13) P=.17 for intervention effect controlling for clinical source of diagnosis and STI diagnosis

70 Summary of Key Points Need to improve extragenital screening in MSM Ceftriaxone remains a highly effective therapy EPT is the key intervention for GC in heterosexuals Cefixime + AZM remains appropriate for EPT Getting partners treated is the primary goal Partner services for MSM with GC should ensure HIV testing

71 Acknowledgements Matthew Golden Lindley Barbee Jeanne Marrazzo Julie Simon Roxanne Kerani David Katz Christine Khosropour