Khalil Ghanem, MD, PhD Associate Professor of Medicine Johns Hopkins University School of Medicine Director, STD/HIV/TB Clinical Services Baltimore City Health Department October 4, 2012 Jafar H. Razeq, PhD, HCLD(ABB) Chief, Public Health Microbiology Laboratories Administration Maryland Department of Health and Mental Hygiene

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Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene Gonorrhea Incidence Rates in Maryland,

Source: Center for STI Prevention, Maryland Department of Health and Mental Hygiene Gonorrhea Incidence Rates by Gender Maryland,

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

 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

 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

ORAL SEX ANAL SEX Oral SexMalesFemales Active Oral Passive Oral Active Oral Passive Oral Lifetime77%79%68%73% Last sex27%28%19%28%  Young MSM: 50%  Young heterosexual men and women: % Ekstrand M, et al. AIDS 1999; 13 (12): Halperin D, et al. AIDS Patient Care STDs 1999; 13(12); Michael RT, et al. Sex in America: A Definitive Survey. Little, Brown and Co. UK. 1994

 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

 All persons should be tested for rectal and pharyngeal gonorrhea if they report pharyngeal or rectal exposures  Sensitivity of culture 90% sensitivity for Nucleic Acid Amplification Tests (NAATs) Sex Transm Infect Jun;85(3):182-6  The CDC recommends that NAATs be used to detect these extragenital infections MMWR Recomm Rep ;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

 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

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

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 History of Antibiotic Resistance

 126 GISP isolates with reduced susceptibility to azithromycin (at MIC ≥2 μ g 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 μ g per milliliter) identified in the United States was detected in Hawaii in 2011 and several strains have now been detected in Hawaii and California Clin Infect Dis 2012; 54:841 MMWR ;60(18):579-81

MMWR 2011 Jul 8;60(26):873-7 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 μ g per milliliter or below, and μ g per milliliter or below, respectively N Engl J Med. 2012;366(6):485-7

 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

 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 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 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.

 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 + Azithromycin 1g PO X1 or 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

If an alternate regimen is used to treat GC, patient should return 1 week after treatment for 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

 Culture relevant clinical sites and perform antimicrobial susceptibility testing using disk diffusion, Etest, or agar dilution  Treat with Ceftriaxone 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

 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 ( or CDC ( )for treatment advice, and report the case to CDC through the local or state health department within 24 h of diagnosishttp://  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

 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

 All Maryland providers are obligated by law to report all gonococcal infections and treatment information to local or State health officials   eportable-diseases.aspx eportable-diseases.aspx

CLINICAL CRITERIALABORATORY 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 μ g/ml, or  Ceftriaxone MIC ≥0.125 μ g/ml 33

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 Microbiol 2002;40(10):

 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

 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

CPT CodeLabCorp Test Code Quest Test Code GC Culture (urethral, cervical, rectal, pharyngeal) 87081* X Genital: 6916R Anal: R Eye: 86421A GC NAA Genital ** (several)11362X* (several) GC NAA Rectal X GC NAA Pharyngeal X GC + CT Rectal NAA & X GC+CT Pharyngeal NAA & X *If culture is positive, identification will be performed using separate CPT code(s): or or or or Antibiotic susceptibilities are only performed when appropriate (CPT code(s): or or or 87186) ** Several Lab Test Codes exist depending on the specimen source (urethral, urine, cervical) NAA=nucleic acid amplification test; GC= gonorrhea; CT= chlamydia

 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

Jafar H. Razeq, PhD Part 2

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David B. Fankhauser University of Cincinnati Claremont College

 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% CO 2, or transport the inoculated plate in a CO 2- generating system at room temperature. JCM 1988, 26:54-56 Cotton swabs can be toxic to NG. Manual of Clinical Microbiology, ASM, 10 th ed.

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

Proper Inoculation Method Step 1

Actual Plate

Proper Inoculation and Streaking Step 2

Ideal Plate

 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

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.

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.

 From 2000 to 2009, more than 11,400 isolates from countries in Latin America were tested and found:  Ciprofloxacin resistance increased from 2% to 31%  Azithromycin resistance increased from 6% to 23% Sex Transm Dis Oct,39(19):  Results from 17 EU Member States in 2009 showed that 5% of isolates had decreased susceptibility to cefixime, an upward trend in the minimum inhibitory concentrations of ceftriaxone and a high prevalence of resistance to ciprofloxacin (63%) and azithromycin (13%). The European gonococcal antimicrobial survelliance programme, 2009.

 Emergence of high-level azithromycin resistance in N. gonorrhoeae in England and Wales.  The 2009 study showed a major shift in six isolates recovered from patients attending STI clinics with azithromycin MICs of > 256 mg/L. J. Antimicrob Chemother 2009; 64,  The proportion of N. gonorrhoeae isolates with decreased susceptibility and resistance to cefixime and ceftriaxone have increased over the years in Sweden.  All available Swedish isolates (331) from were tested and results showed that 9.1% of the isolates displayed resistance to cefixime, and 0.3% resistance to ceftriaxone. Sex Transm Infect 2010; 86:

USA % Resistant Penicillin Tetracycline Ciprofloxacin For Cefixime and Ceftriaxone : An average of 5,865 isolates tested annually during The percentage of isolates with an MIC of > 0.25 µg/ml for cefixime increased from 0.2% in 2000 to 1.4% in 2010 The percentage of isolates with an MIC of > µg/ml for ceftriaxone increased from 0.1% in 2000 to 0.3% in 2010

MD % Resistant Penicillin36 Tetracycline2027 Ciprofloxacin5.44 Azithromycin : 5 isolates have been detected with an MIC of > 1.0 µg/ml

CDC recommends that State and local health departments should promote maintenance of laboratory capacity to culture NG to allow antimicrobial susceptibility testing of isolates for cephalosporin resistance `CDC/MMWR July 8, 2011/(60), 26:

 The capacity of laboratories in the United States to isolate NG by culture is declining rapidly because of the widespread use of NAATs for gonorrhea diagnosis.  It is essential that culture capacity for NG be maintained to monitor antimicrobial resistance trends and determine susceptibility to guide treatment following treatment failure.  Laboratories must maintain culture capacity or develop partnerships with laboratories that can perform culture. Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections. MMWR August 10, 2012 / 61(31);

 To help control gonorrhea in the United States, health- care providers must maintain the ability to collect specimens for culture and be knowledgeable of laboratories to which they can send specimens for culture. Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections. MMWR August 10, 2012 / 61(31);

 Health-care systems and health departments must support access to culture. Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections. MMWR August 10, 2012 / 61(31);

IF NOT, then we will go from Resistant NG and Multi-Drug Resistant NG TO Extensively-Drug-resistant NG Pan/Totally Drug-Resistant NG Untreatable NG!

“It is probably only a matter of time before extensively drug-resistant N. gonorrhoeae strains become widespread and treatment failures, particularly for pharyngeal gonorrhoea, become commonplace.” “Action is therefore urgently needed at local and international levels to combat the problem. We advise that government agencies take this threat seriously and provide urgently needed funds for increased research, surveillance activities and vaccine development.” Whiley DM, Goire N, Lahra MM, et al. The ticking time bomb: escalating antibiotic resistance in Neisseria gonorrhoeae is a public health disaster in waiting. J Antimicrob Chemother 2012; 67:

Maryland Department of Health and Mental Hygiene Prevention and Health Promotion Administration Center for Sexually Transmitted Infection Prevention healthcare-providers.aspx Division of Infectious Disease Surveillance Center for Surveillance, Infection Prevention and Outbreak Response Laboratories Administration Division of Public Health Microbiology

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