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Sex and the Superbug: Next Steps in Dealing with Multi-drug Resistant Gonorrhea in Maryland

Learn about the rising rates of multi-drug resistant gonorrhea in Maryland and the steps being taken to address this public health concern. Explore screening and diagnostic methods, as well as the efficacy of antibiotics for treatment.

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Sex and the Superbug: Next Steps in Dealing with Multi-drug Resistant Gonorrhea in Maryland

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  1. Sex and the Superbug:Next Steps in Dealing with Multi-drug Resistant Gonorrhea in Maryland Jafar H. Razeq, PhD, HCLD(ABB) Chief, Public Health MicrobiologyLaboratories AdministrationMaryland Department of Health and Mental Hygiene Khalil Ghanem, MD, PhD Associate Professor of MedicineJohns Hopkins University School of MedicineDirector, STD/HIV/TB Clinical Services Baltimore City Health Department October 4, 2012

  2. E-mail your questions for the presenters to: maphtc@jhsph.edu

  3. KhalilGhanem, MD, PhDPart 1

  4. Disclosures No relevant financial disclosures

  5. Gonorrhea Rates, United States 1941-2007

  6. Gonorrhea Prevalence by Geographic Region

  7. Gonorrhea Prevalence by Race/Ethnicity

  8. Gonorrhea Prevalence by Age

  9. Gonorrhea Incidence Rates in Maryland, 2007-2011 Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene

  10. Gonorrhea Incidence Rates by Gender Maryland, 2007-2011 Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene

  11. Gonorrhea by Age (10–25) Maryland, 2010-2011 Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene

  12. The Percent of Asymptomatic STDs

  13. Screening for Gonorrhea in Women • Targeted screening is recommended for high-risk women (e.g. previous gonorrhea infection, other STIs, new or multiple sex partners, and inconsistent condom use; CSW and drug use; area of high prevalence) • Screening is recommended at the first prenatal visit for pregnant women who are in a high-risk group for gonorrhea infection. Those who are at continued risk, and for those who acquire a new risk factor, a second screening should be conducted during the third trimester • Repeat testing (i.e. retesting or rescreening) of GC+ patients recommended 3 months after treatment

  14. Screening for Gonorrhea in Men • The USPSTF found insufficient evidence to recommend for or against routine screening for gonorrhea infection in men at increased risk for infection, but CDC recommends annual gonorrhea screening for all sexually active MSM by testing for urethral infection in men who have had insertive intercourse in past year, rectal infection in men who have had receptive anal intercourse in past year, and pharyngeal infection in men who have had receptive oral intercourse in past year • Repeat testing (i.e. retesting or rescreening) of GC+ patients recommended 3 months after treatment

  15. Prevalence of Extragenital Sexual Behaviors ORAL SEX ANAL SEX • Young MSM: 50% • Young heterosexual men and women: 14-49% Ekstrand M, et al. AIDS 1999; 13 (12): 1525-33 Halperin D, et al. AIDS Patient Care STDs 1999; 13(12); 717-30 Michael RT, et al. Sex in America: A Definitive Survey. Little, Brown and Co. UK. 1994

  16. Extragenital Gonorrhea and Chlamydia Infections • Studies suggest that up to 65% of cases of gonorrhea and 50% of cases of chlamydia among MSM may be missed if genital-only testing were performed Sex Transm Dis. 2008;35(10):845 Clin Infect Dis. 2005;41(1):67 • In women, 10% of CT and 31% of GC infections would have been missed if extragenital testing were not done Sex Transm Dis. 2011;38(9):783 • The majority of rectal and pharyngeal GC & CT infections are ASYMPTOMATIC • Rectal and pharyngeal infections are of public health significance Clin Infect Dis. 2009;49(12):1793

  17. Extragenital STI Diagnostics • All persons should be tested for rectal and pharyngeal gonorrhea if they report pharyngeal or rectal exposures • Sensitivity of culture <50% to detect rectal and pharyngeal GC vs. >90% sensitivity for Nucleic Acid Amplification Tests (NAATs) Sex Transm Infect. 2009 Jun;85(3):182-6 • The CDC recommends that NAATs be used to detect these extragenital infections MMWR Recomm Rep. 2011 ;60(1):18 • If NAATs for extragenital testing of GC are not feasible in your setting, use culture to detect these infections. It is an acceptable alternative

  18. Extragenital NAATs • Although none of the NAATs are FDA cleared to use with extragenital specimens, most large laboratories have conducted in-house validation assays and they are able to provide this service • Check with your local laboratory to see if they can provide extragenital NAATs testing • See slide on ‘CPT Codes and Laboratory Test Codes’ at the end of my presentation for additional details

  19. Efficacy of Antibiotics for GC Cephalosporins Macrolides • Ceftriaxone 250mg IM X 1 • >98% anogenital • >98% pharyngeal • Cefixime 400mg PO X 1 • >97% anogenital • 90% pharyngeal • Azithromycin 1g PO X 1 • 97% anogenital • ? Pharyngeal • Azithromycin 2g PO X 1* • 99% anogenital • 99% pharyngeal * 20% vomiting within 1h

  20. History of Antibiotic Resistance Unemo M, Shafer WM. Antibiotic resistance in Neisseria gonorrhoeae: origin, evolution, and lessons learned for the future. Ann N Y Acad Sci. 2011;1230:E19-28

  21. GC Macrolide Resistance U.S. • 126 GISP isolates with reduced susceptibility to azithromycin (at MIC ≥2 μg per milliliter) have been reported in the United States since 2005, including 27(0.5% of GISP isolates) in 2010 • The first strain with high-level resistance to azithromycin(MIC ≥512 μg per milliliter) identified in the United States was detected in Hawaii in 2011 and several strains have now been detected in Hawaii and California MMWR;60(18):579-81 Clin Infect Dis2012; 54:841

  22. Reduced Susceptibility to Cephalosporins Worldwide

  23. Cephalosporin MICs in the US:2000-2011 Although the MIC breakpoints for resistance to cephalosporin have not been defined, the CLSI defines susceptibility to cefixime and ceftriaxone as MICs of 0.25 μg per milliliter or below, and 0.125 μg per milliliter or below, respectively MMWR 2011 Jul 8;60(26):873-7 N Engl J Med. 2012;366(6):485-7

  24. GC Cephalosporin Resistance in Baltimore • In November 2011, the Baltimore GISP Program identified the first cephalosporin resistant strain. • The Baltimore strain was resistant to cefixime and cefpodoxime (MIC of 0.5), sensitive to ceftriaxone (MIC of 0.06) and sensitive to ciprofloxacin

  25. Mechanisms of Resistance to Cephalosporins • Combined effects of several chromosomal mutations: • PenA (PBP2) • PenB (PorB1b) • MtrR (MTRCDE- encoded pump repressor) • Mosaic PenA • Novel mutation resulting in cefixime resistance • Acquired via horizontal transfer from oral commensal bacteria N Engl J Med. 2012;366(6):485-7

  26. Importance of Maintaining GC Culture Capacity • Culture is currently the only reliable method for determining antibiotic susceptibility • Maryland is one of the few states that has maintained culture capacity GISP analyses are based on (a) demographic and clinical data from the first 25-30 male patients attending the sentinel clinics each month who have been identified to have a positive urethral culture for N. gonorrhoeae, and (b) antimicrobial susceptibility data from these urethral isolates.

  27. Updated CDC Treatment Recommendations for Gonorrhea • First-Line (preferred) • Ceftriaxone 250 mg IM X1 +Azithromycin 1g PO X 1 or Doxycycline 100mg PO BID X 7 days • Azithromycin is preferred over doxycycline but both are acceptable • Use dual therapy even if C. trachomatis is ruled out! • Alternate • Cefixime 400mg PO X1 + Azithromycin1gPO X1or Doxycycline 100mg PO BID X 7 days • Azithromycin 2g PO X 1 (single therapy single dose) • Azithromycin 2g PO X1 is the only regimen currently available to treat a patient who has an allergy to cephalosporins MMWR 2012 ;61(31):590-4

  28. Test of Cure • If an alternate regimen is used to treat GC, patient should return 1 week after treatmentfor a TEST OF CURE (culture is preferred but NAAT is also acceptable) • If a NAAT is performed as the test of cure and the follow-up NAAT result is positive, a specimen for culture should be obtained so that susceptibility testing can be performed

  29. Treatment Failure with Cefixime-Based Regimen or Single-Dose Azithromycin Regimen • Culturerelevant clinical sites and perform antimicrobial susceptibility testingusing disk diffusion, Etest, or agar dilution • Treat withCeftriaxone 250 mg IM X 1 PLUS azithromycin 2g orally as a single dose • TEST OF CURE: culture (≥72 hours after re-treatment), if culture is not available, with NAAT (≥7 days after re-treatment). If the test of cure NAAT is positive, a specimen for culture should be obtained to both ensure that the NAAT result is reliable and to allow for antimicrobial susceptibility testing • Evaluate sex partners from the preceding 60 days with culture from all exposed sites and treat with ceftriaxone 250 mg IM X 1 PLUS azithromycin 2g orally as a single dose • The laboratory should retain the isolate for possible further testing MMWR 2012 ;61(31):590-4

  30. Treatment Failure with Ceftriaxone-Based Regimen • Culture relevant clinical specimens and perform antimicrobial susceptibility testing using disk diffusion, Etest, or agar dilution • Consult an ID specialist, an STD/HIV Prevention Training Center (http://www.nnptc.org), or CDC (404-639-8659 )for treatment advice, and report the case to CDC through the local or state health department within 24 h of diagnosis • A test-of-cure should be conducted 1 week after re-treatment • Evaluate sex partners from the preceding 60 days and treat with the same antimicrobial regimen with which the index patient was re-treated MMWR 2012 ;61(31):590-4

  31. Suspected Treatment Failure: Evaluating and Treating Sex Partners • If you suspect treatment failure, assure treatment for both patient and sex partner(s) • In Maryland, local health departments can help assure that sex partners of patients with suspected treatment failure get treated

  32. Case Reporting: It’s the Law! • All Maryland providers are obligated by law to report all gonococcal infections and treatment information to local or State health officials • http://baltimorehealth.org/std.html • http://ideha.dhmh.maryland.gov/SitePages/reportable-diseases.aspx

  33. Cephalosporin-Resistant Case Classification Clinical Criteria Laboratory Criteria • Patient had laboratory-confirmed N. gonorrhoeae infection, and • Patient received CDC-recommended cephalosporin-based antimicrobial regimen as treatment, and • Patient subsequently had a positive N. gonorrhoeae test result (positive culture ≥72 hours after treatment or positive NAAT ≥7 days after treatment), and • Patient did not engage in sexual activity after treatment • Antimicrobial susceptibility testing of pre-treatment or post-treatment isolate of N. gonorrhoeae demonstrates: • Cefixime MIC ≥0.25 μg/ml, or • Ceftriaxone MIC ≥0.125 μg/ml www.cdc.gov/std/treatment/Ceph-R-ResponsePlanJuly30-2012.pdf

  34. Test-of-Cure vs. Re-screening Test of Cure (TOC) Rescreening • All persons who are treated with an alternate regimen for GC, or who have laboratory-evidence of cephalosporin resistance, or who are suspected of GC treatment failure should undergo a TOC • If culture is used for TOC, it can be done ≥72h after initial therapy • If NAATs are used for TOC, they can be performed ≥7d after initial therapy. The possibility of false-positivity with NAAT as early as 7 days after treatment is a concern, but is likely to be low* • The goal of TOC is to rule out TREATMENT FAILURE • All persons who are treated for gonorrhea, chlamydia, or trichomoniasis should be rescreened 3 months after treatment • For GC, rescreening can be done with either culture or NAATs (NAATs are more sensitive) • The goal of rescreening is to rule out REINFECTION *J Clin Microbiol2002;40(10):3596-601

  35. Expedited Partner Therapy (EPT) • At this time, Baltimore City Health Department (BCHD) is providing EPT services for gonorrhea and chlamydia • EPT may be expanded beyond BCHD in the not too distant future • If a heterosexual partner of a patient cannot be linked to evaluation and treatment in a timely fashion, then expedited partner therapy should be considered, using oral combination antimicrobial therapy for gonorrhea (cefixime 400 mg and azithromycin 1 g) delivered to the partner by the patient, a disease investigation specialist, or through a collaborating pharmacy • Emergence of resistance is threatening the viability of EPT for gonorrhea MMWR 2012 ;61(31):590-4

  36. Future Antimicrobial Options • Gentamicin • Has been used as first-line treatment in Malawi during the past 15 years without any observed emergence of resistance • ? Efficacy in pharynx • Carbapenems • Depends on the ceftriaxone resistance mechanisms and the penA alterations, of which most of them substantially also affect the carbapenem MICs

  37. CPT Codes and Laboratory Test Codes *If culture is positive, identification will be performed using separate CPT code(s): 87077 or 87140 or 87143 or 87147 or 87149. Antibiotic susceptibilities are only performed when appropriate (CPT code(s): 87181 or 87184 or 87185 or 87186) ** Several Lab Test Codes exist depending on the specimen source (urethral, urine, cervical) NAA=nucleic acid amplification test; GC= gonorrhea; CT= chlamydia

  38. Injectable Ceftriaxone • 250mg, 500mg, 1g, and 2g vials • Stored at 20°C to 25°C (68°F to 77°F) unopened • Once powder is diluted (usually with 1% lidocaine), may be stored in refrigerator and used within 72 hours of reconstitution • Cost: $5-$12 for each 250mg dose

  39. Jafar H. Razeq,PhDPart 2

  40. Disclosures No relevant financial disclosures

  41. The “Superbug” David B. Fankhauser University of Cincinnati Claremont College

  42. Neisseria gonorrhoeae (NG) is not considered part of human normal flora and the isolation of this organism is considered to be always significant. • NG is an exclusive human pathogen. • The organism is fastidious and environmentally sensitive pathogen; • The ideal and best way to recover the organism is to use Dacron or Rayon swabs to collect patient specimens. Inoculate immediately onto selective (unexpired) media, incubate at 35-37°C, under 5% CO2, or transport the inoculated plate in a CO2-generating system at room temperature. JCM 1988, 26:54-56 Cotton swabs can be toxic to NG. Manual of Clinical Microbiology, ASM, 10th ed.

  43. Proper Inoculation and Streaking “Z” Pattern Primary Inoculation Cross-Streaked

  44. Proper Inoculation Method Step 1

  45. Actual Plate

  46. Proper Inoculation and Streaking Step 2

  47. Ideal Plate

  48. Antimicrobial Susceptibility Testing(AST) • AST is offered at some Private Laboratories • Our Maryland State Public Health Laboratory is among the few state laboratories in the U.S. that offers AST for NG

  49. For disc diffusion: discs containing known amounts of antimicrobial agents are placed on the surface of an agar plate that has been inoculated with NG isolated. • Susceptible isolates usually show inhibition of growth around the disc.

  50. The E-test is a strip containing a known gradient of an antimicrobial and calibrated to give results as MIC of that antibiotic. • The strip is placed on the surface of an agar plate that has been inoculated with NG.

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