1. Challenges to IPP: Emerging Gonococcal Antimicrobial Resistance and Skepticism That Screening in Its Current Form Can Reduce Chlamydial Morbidity Edward W. Hook, III, M.D. Professor, Medicine, Microbiology and Epidemiology University of Alabama at Birmingham

2. Emerging Gonococcal Antimicrobial Resistance

4. Emerging Gonococcal Antimicrobial Resistance – Deja Vu Pre-1937Antiseptic Irrigation With Potassium Permanganate, Silver Salts, Mercurochrome 1937Sulfonamide Therapy 1943Penicillin Therapy (Mahoney et al) 194435%Treatment Failure With Sulfonamides 1972Penicillin Regimen Increased to 4.8 Million Units Plus Probenecid

5. Emerging Gonococcal Antimicrobial Resistance – Deja Vu 1976Recognition of PPNG (AFRICA, S.E. ASIA) 1984 High Level Chromosomal Penicillin Resistance, (Durham, N.C.) 1985 Recognition of Plasmid Mediated Tetracycline Resistance 1987High Level Spectinomycin Resistance, (Korea) 1989 Penicillin No Longer Drug of Choice for G.C. 2002Concern Regarding Rising Quinolone MICs

6. Gonococcal Isolate Surveillance Project (GISP) — Location of participating clinics and regional laboratories: United States

7. Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseria gonorrhoeae isolates with resistance to ciprofloxacin by sexual behavior, 2001–2006

8. Gonococcal Isolate Surveillance Project (GISP) — Percent of Neisseria gonorrhoeae isolates with resistance or intermediate resistance to ciprofloxacin, 1990–2008 Note: Resistant isolates have ciprofloxacin MICs ≥1 µg/ml. Isolates with intermediate resistance have ciprofloxacin MICs of 0.125 - 0.5 µg/ml. Susceptibility to ciprofloxacin was first measured in GISP in 1990.

9. Ceftriaxone 250 125 mg IM or Cefixime 400 mg PO or Ciprofloxacin 500 mg PO* or Ofloxacin 400 mg PO* or Levofloxacin 250 mg PO* Plus, IF CHLAMYDIAL INFECTION IS NOT RULED OUT Azithromycin 1.0 g Single Dose Or Doxycycline 100 BID x 7d 200610 CDC STD TREATMENT GUIDELINES Uncomplicated Gonorrhea

10. Ceftriaxone 250 mg IM or Cefixime 400 mg PO PLUS Azithromycin 1.0 g Single Dose or Doxycycline 100 BID x 7d 2010 CDC STD TREATMENT GUIDELINES Uncomplicated Gonorrhea

11. "Those who cannot remember the past are condemned to repeat it." George Santayana

12. 2008-2009 Decreased Cephalosporin Susceptibility 2003 2007 Hong Kong: 4 treatment failures with cefixime Increasing MICs to cephalosporins reported in Australia, Europe, and US Japan: isolate with Ceftriaxone MIC of 2 µg/ml (female CSW) 1999 2001 2002 Japan: Possible treatment failure with cefdinir Japan: 30% isolates have MICs to cefixime ≥ 0.5 μg/ml Japan: 0% isolates have MICs to cefixime ≥ 0.5 μg/ml Japan: 8 (12%) of men with GC in study unsuccessfully treated with cefixime 2010 Norway: 2 treatment failures with cefixime Sweden: 1 pharyngeal GC treatment failure with ceftriaxone 250 mg

13. Distribution of MICs to Cefixime, 2005–2010* Percentage of isolates Minimum Inhibitory Concentrations (MICs), µg/ml * Preliminary (Jan-Sept)

14. Distribution of MICs to Cefixime, 2005–2010* Percentage of isolates Minimum Inhibitory Concentrations (MICs), µg/ml 1.3% (n=58) 0.2% (n=8) * Preliminary (Jan-Sept)

15. Proportion of GISP isolates with MICs to Cefixime ≥ 0.25 μg/ml, 2000–2010* Cefixime AST not conducted Percentage of isolates 1.5% (n=66) * Preliminary (Jan-Sept)

16. Proportion of GISP isolates with MICs to Cefixime ≥ 0.25 μg/ml by Region, 2000–2010* Cefixime AST not conducted Percentage of isolates West Midwest N’east & South 3.7% (n=57) * Preliminary (Jan-Sept)

17. Proportion of GISP isolates with MICs to Cefixime ≥ 0.25 μg/ml by Sex of Sex Partner, 2000–2010* Cefixime AST not conducted Percentage of isolates 4.7% (n=56) MSM MSW * Preliminary (Jan-Sept)

18. Distribution of MICs to Ceftriaxone, 2006–2010* Percentage of isolates Minimum Inhibitory Concentrations (MICs), µg/ml * Preliminary (Jan-Sept)

19. Distribution of MICs to Ceftriaxone, 2006–2010* Percentage of isolates Minimum Inhibitory Concentrations (MICs), µg/ml * Preliminary (Jan-Sept) Pre

20. Gonorrhea — Rates by state: United States and outlying areas, 2008 Note: The total rate of gonorrhea for the United States and outlying areas (Guam, Puerto Rico, and Virgin Islands) was 110.3 per 100,000 population.

22. Emerging Resistance of C. trachomatis to Azithromycin, 2010?? Cured (%)/ Treated Doxycycline +/-55 (95%)/58 Tinidazole Azithromycin +/- 41 (77%)/53 Tinidazole p= 0.01 Schwebke JS et al. CIC 2011;52: 163-170

23. Skepticism That Screening in Its Current Form Can Reduce Chlamydial Morbidity Or Is IPP Working and Why Are U.S. Chlamydial Rates Increasing

28. IPP Logic Model 1. Association of CT and GC with PID 2. Association of tubal factor infertility with PID 3. Evidence that CT screening reduces PID

29. IPP Logic Model- Arguments 1. Association of CT and GC with PID Old data, association of other organisms (anaerobes, M. genitalium) with PID 2. Association of tubal factor infertility with PID 3. Evidence that CT screening reduces PID

30. Etiologic Agents of Pelvic Inflamatory Disease 1. Neisseria Gonorrhoeae 2. Chlamydia trachomatis 3. Mycoplasma genitalium (proposed) 4. Anaerobic Bacteria 5. Non-STD pathogens Actinomycosis Mycobacterium tuberculosis Other

31. IPP Logic Model- Arguments 1. Association of CT and GC with PID Old data, association of other organisms (anaerobes, M. genitalium) with PID 2. Association of tubal factor infertility with PID Declining PID rates, increasing CT rates 3. Evidence that CT screening reduces PID

33. Sources of Imprecision in PID Diagnosis 1. Non-specificity of clinical PID diagnosis 2. Decreasing emphasis on hospitalization for PID management 3. Declining gonorrhea rates – milder PID signs an symptoms?

34. Pelvic Inflammatory Disease: Accuracy of Clinical Diagnosis Sensitivity Lower Abdominal Pain 94% Adnexal Tenderness 92% Increased Vaginal D/C 55% Fever > 38° 41% Specificity Laporoscopic Confirmation in 529/814 (65%) Clinically Diagnosed Cases

35. Prevention of Pelvic Inflammatory Disease by Screening for Chlamydia 2607 at risk women randomized to screening (N=1009) or usual care (N=1598) 645 (64%) were screened of whom 44 (7%) were infected and treated Pelvic Inflammatory Disease Incidence Screening 9/1009 (8 per 10,000 women months) Usual Care 33/1598 (18 per 10,000 women months) Relative Risk for Screening Group = 0.44 Scholes D, et al. NEJM 1996;334-1362-6.

36. IPP Logic Model- Arguments 1. Association of CT and GC with PID Old data, association of other organisms (anaerobes, M. genitalium) with PID 2. Association of tubal factor infertility with PID Declining PID rates, increasing CT rates 3. Evidence that CT screening reduces PID Studies conducted in high risk women generalized to general population; occurrence of PID in women following screening

37. U.S. Chlamydial Prevalence (NHANES), 14-39 YO Women, 1999-2008 Data From Johnson and Berman in Modern Infectious Disease Epidemiology, Kraemer and Kretzschmar Eds. 2010

38. IPP Logic Model- Arguments 1. Association of CT and GC with PID Old data, association of other organisms (anaerobes, M. genitalium) with PID 2. Association of tubal factor infertility with PID Declining PID rates, increasing CT rates 3. Evidence that CT screening reduces PID Studies conducted in high risk women generalized to general population; occurrence of PID in women following screening

39. Suggested Steps To Enhance IPP 1. Measure PID and infertility, the outcomes of interest. 2. Efforts to expand testing 3. Consider new metrics to encourage continuous quality improvement (CQI)

40. Accelerating Infertility Prevention With Small Steps: CQI – Doing It Better Optimizing Chlamydia Screening Targeting those who need screening Improving the process of chlamydial screening Assuring Timely Treatment

41. Time To Treatment Following STD Screening, JCHD STD Clinic No Treatment Within 30 Days Treatment Within 14-30 Days of Screening Treatment Within 13 Days of Screening 18% 28% 54% 35% 20% 45%

42. Chlamydial Culture Performance in Women Without Other Indications for Therapy Patients with positive screening cultures 81 Patients referred elsewhere for therapy 3 Patients without documented F/U or therapy20/78 (26%) PID at F/U 2/58 (4%) Interval to treatment (N=58) 7 days24% 14 days50% 21 days60% 28 days 81% Hook et al. JAMA 1994; 272; 867-70

43. Pelvic Inflammatory Incidence Following STD Screening Baltimore STD Clinic – 2 (4%) of 58 UAB Emergency Dept.- 3 (4.5%) of 67 Birmingham STD Clinic – 2 (2%) of 115 Hook et al. JAMA 1994; 272: 867-70. Bachmann et al.. Sex Transm Dis. 1999;26(9):496-499. Geisler et al. Sex Trans Dis. 2008

44. Improving Chlamydial Screening Through CQI: Potential Metrics Optimization of time from screening to treatment -Specimen transit time to lab -TAT in the lab -Time to recording of test results -Time to notification of infected persons -Mechanisms for facilitating treatment of persons with positive screening tests Evaluation and characterization of those who either do not get test results or fail to return

45. Improving Chlamydial Screening Through CQI: Potential Metrics Infections diagnosed treated Time from screening to treatment Asymptomatic persons returning for re- screening at 6 months

46. APTIMA Combo 2 Sensitivity C. TrachomatisN. Gonorrhoeae Endocervical Swab 94%99% Initial Void Urine 95%91% Clinician Collected Vaginal Swab 97%96% Patient Collected Vaginal Swab 97%99%

47. Changing Paradigms For Urogenital Specimen Collection Pre-NAAT’s: Specimen Quality Critical - Endocervical Or Urethral Swabs - Swab Order Impacts Test Results : Culture > Non-Amplified Nucleic Acid Detection > Antigen Detection NAAT’s: More Forgiving Specimen Collection - Vaginal Swab = Endocervical Swab > Endocervical Swab > Initial Void Urine

48. Arguments For Non-Invasive STD Testing Patient: Faster : Less Uncomfortable Provider: Faster : Fewer Resources Personnel Specula Examination Table System: Testing At Sites Of Opportunity : Patient Satisfaction

49. Populations for Whom Non-Invasive STD Testing Have Been Used Non-Health Care Settings School Based Clinics Incarcerated Youth and Adults Military Recruits Homeless Persons - Street Outreach - Shelters Long Haul Truck Drivers

52. STD Incidence R = BcD R=Reproductive Rate B=Infectivity C=Sexual Partner Selection Parameters (rate and variability) D=Duration of Infectivity Anderson, RM and May RM; Nature 1988;333:323-320

53. THE NEXT GREAT PLAGUE TO GO Thomas Parran’s 5-Point Program For Syphilis Control – 1936 1.Case Finding – Serologic Screening Programs 2.Prompt Therapy 3.Contact Identification, Testing, and Therapy 4.Mandatory Serological Evaluations – Premarital and Early Pregnancy 5.Public Education = Symptoms, Complications, Treatment

54. Insanity is doing the same thing over and over again and expecting a different result. Albert Einstein