Sharon Adler M.D., M.P.H. California Prevention Training Center Assistant Clinical Professor UCSF FCM

Transcription

1 Sharon Adler M.D., M.P.H. California Prevention Training Center Assistant Clinical Professor UCSF FCM

2 Sharon Adler MD, MPH has no relevant financial relationships with an entity producing, marketing, re selling, or distributing health care goods or services consumed by, or used on patients.

3 National STD Snapshot cases of congenital syphilis 153% increase in case rate since 2013

4 National STD Snapshot Screening recommendations Syphilis Staging, Diagnosis & Treatment Congenital syphilis Extragenital GC Antibiotic Resistant GC

5 Pregnancy MSM Corrections At first prenatal visit Again in the third trimester and at delivery (if at high risk, or residing in area with high syphilis morbidity) Including those on PrEP Annually, or more frequently, 3-6 months if at high risk (multiple, anonymous partners, meth use) Universal screening based on local area or institutional incidence HIV+ At least annually STD Clinics Regardless of symptoms Client with other STDs CDC 2015 STD Treatment Guidelines

6 Exposure 30 50% Primary Secondary Latent 30% Tertiary 25% Incubation Period 3-4 weeks ( up to 90 days) 2-6 weeks Possible relapse 2-20 years After 3-8 weeks lesions disappear spontaneously Ocular or Neurosyphilis can occur at any stage

7 DMHC SFCC DMHC SFCC SFCC SFCC

8 STD Atlas, 1997 SFCC SFCC San Francisco City Clinic SFCC SFCC SFCC

9 SFCC Raguse et al. AIM SFCC Clinics in Dermatology, 2016

10 Exposure Primary Secondary Usually occurs 3-6 weeks after primary chancre Rash (75-90%), involving palms/soles (60%) Generalized lymphadenopathy (70-90%) Constitutional symptoms (50-80%) Mucous patches (5-30%) Condyloma lata (5-25%) Patchy alopecia (10-15%) Symptoms of neurosyphilis (1-2%) Less common: meningitis, hepatitis, arthritis, nephritis

11 DMHC SFCC DMHC SFCC SFCC DMHC SFCC

12 Tinea versicolor Pityriasis rosea Drug reaction Erythema multiforme Guttate psoriasis Scabies Viral Exanthem Pityriasis rosea Tinea versicolor E. multiforme

13 46 yo HIV+ man presents with peri anal lesions Treated with liquid nitrogen for presumed genital warts. Images courtesy of Joe Engelman City Clinic

14 Also has macular/papular rash on trunk Images courtesy of Joe Engelman City Clinic

15 RPR 1:256 Don t forget to think about syphilis (condylomata lata) when you see something that looks like anogenital warts!

16 Courtesy: Gregory Melcher, UC Davis Susan Philip, SF DPH & UCSF

17 DMHC STD Atlas, 1997

18 All patients with syphilis should be evaluated for neurologic symptoms and signs Asymptomatic CNS invasion is common in early syphilis Early symptomatic forms (months to a few years): Acute syphilitic meningitis (CN VI, VII, VIII) Hearing loss Ocular syphilis Meningovascular (stuttering stroke) Altered mental status Late symptomatic forms (> 2 years): General paresis and tabes dorsalis cdph.ca.gov/programs/cid/dcdc/cdph%20document%20library/neurosyphilisguide.pdf

19 Manifestations: Conjunctivitis, scleritis, and episcleritis Uveitis: anterior and/or posterior Elevated intraocular pressure Chorioretinitis, retinitis Vasculitis Symptoms: Redness Eye pain Floaters Flashing lights Visual acuity loss Blindness Diagnosis: Ophthalmologic exam Serologies: RPR, VDRL, treponemal tests Lumbar puncture Wender, JD et al. How to Recognize Ocular Syphilis. Review of Ophthalmology

20 » Patients with suspected ocular syphilis should receive a lumbar puncture and be treated for neurosyphilis Note: a negative LP does not rule out ocular syphilis Treatment for ocular syphilis is IV PCN (neurosyphilis regimen) even if the CSF lab tests are negative» HIV test if not already known to be HIV infected Photo Courtesy: Dr. Kees Rietmeijer, Denver PHD CDC 2015 STD Treatment Guidelines

21 SIGNS OR SYMPTOMS? Chancre PRIMARY YES Rash, etc. SECONDARY +/ +/ Neuro/ocular NEUROSYPHILIS (Either Early or Late/Unknown) YES EARLY LATENT (< 1 year) NO LATENT ANY IN PAST YEAR? Negative syphilis serology Known contact to an early case Good history of typical signs/symptoms 4 fold increase in titer Only possible exposure was this year NO LATE LATENT or UNKNOWN DURATION

22 Sexual Risk Medical history Symptoms & Signs Syphilis? Serology

23 42y/o HIV+ man with mildly painful sore on penis for 3 d VL undetectable No history of genital herpes No syphilis history, RPR negative 10 months ago 3 Male partners in past 6 months, no travel Stat RPR Negative

24 Audience Poll: Management of MSM with genital ulcer and negative RPR A. Wait for tests result to determine treatment B. Presumptively treat for syphilis now C. Order TP-PA D. B and C E. A and C

25 Peeling et al. / Bulletin of the World Health Organization / 2004 / Vol. 82 / No. 6

26 Rare Caveat: Prozone, False Negative in HIV+, Secondary Sena, CID 2010

27 False Negative RPR Rare High Ab titers prevent antibody/antigen lattice formation Occurs ~0.3-2% (early syphilis/ secondary) May be more common in HIV+ and neurosyphilis Jurado RL et al. Arch Intern Med 1993, 153: Geisler MG. South Med Jour 2004, 97: Liu LL et al. Clin Infect Dis 2014, 59:384-9.

28 False negatives Early primary Serology negative in up to 25% primary case Prozone Reaction( RPR/VDRL) Untreated late latent Biologic False Positives Non trep test positive with confirmatory trep test negative Viral illnesses including HIV Recent immunizations, IDU autoimmune and chronic diseases Treponemal Tests Can remain positive for life Specificity issues- FTA-ABS Jurado RL et al. Arch Intern Med 1993, 153: Geisler MG. South Med Jour 2004, 97: Discordant serology EIA or CIA + and RPR Non-syphilis trep infection

29 Asymptomatic 30 y/o Female Syphilis screening results are: Trep IgM/IgG Antibody Positive RPR Non-Reactive TP-PA Reactive

30 CDC 2015 STD Treatment Guidelines

31 CSF VDRL has limitations Very specific but not very sensitive Only test approved for CSF specimen CSF VDRL negative patients consider neurosyphilis treatment if no other etiology identified and CSF WBCs >5 in HIV negative patients CSF WBCs >20 in HIV infected patients* CSF FTA-abs not specific, a negative test result may help rule out neurosyphilis ( not if clinical suspicion is high ** ) CSF- TP-PA limited data but may support diagnosis *CDC 2010 STD Treatment Guidelines **Harding, Ghanem. STD 2012; 39, (4)

32 Syphilis Treatment Primary, Secondary, & Early Latent Benzathine penicillin G* 2.4 million units IM in a single dose * Bicillin L-A is the trade name. DO NOT USE Bicillin C-R! ** No enhanced efficacy of additional doses of BPG, amoxicillin or other antibiotics even if HIV infected Alternatives (non-pregnant penicillin-allergic adults): Doxycycline 100 mg po bid x 2 weeks Tetracycline 500 mg po qid x 2 weeks Ceftriaxone 1 g IV or IM qd x d CDC 2015 STD Treatment Guidelines

33 Serologic Response to Therapy in HIV infected Persons with Early Syphilis

34 Syphilis Treatment Late Latent or Latent of Unknown Duration Benzathine penicillin G* 7.2 million units IM total in 3 doses of 2.4 MU each at one week* intervals Maximum day interval (7-9 day ideal) 7 day interval in pregnancy ( 6-8 day may be ok) Alternatives (non-pregnant penicillin-allergic adults): Doxycycline 100 mg po bid x 4 weeks Tetracycline 500 mg po qid x 4 weeks CDC 2015 STD Treatment Guidelines

35 Neurosyphilis/ Ocular Syphilis Treatment Aqueous crystalline penicillin G million units IV daily administered as 3-4 million units IV q 4 hr for days * Consider: BIC 2.4 million units IM once per week up to 3 weeks after completion of day course for late syphilis CDC 2015 STD Treatment Guidelines

36 Jarisch-Herxheimer Reaction Acute febrile reaction that may occur within 24 hours (usually 2-8 hours) of syphilis treatment Headache,myalgias and exacerbation of cutaneous lesions (rash) Most common in primary, secondary Uncommon in latent Does not indicate drug hypersensitivity CDC 2015 STD Treatment Guidelines

37 NEUROSYPHILIS (Either Early or Late/Unknown) Aqueous Crystalline Penicillin G million units IV daily administered as 3-4 million IV q 4 hr for d * BIC IM may be added for late/unk duration to achieve 3-week course PRIMARY SECONDARY EARLY LATENT (< 1 year) Benzathine penicillin G 2.4 million units IM in a single dose * Only one dose of BIC is recommended for early syphilis in HIV-infected persons, extra doses not needed LATE LATENT or UNKNOWN DURATION Benzathine Penicillin G 7.2 million units total, given as 3 doses of 2.4 million units each at 1- week intervals * Max interval = 14 days; 7 days if pregnant *Always order an RPR on the day of treatment!

38 Higher peak titer at treatment, but not checked RPR 1:256 RPR 1:1024 RPR 1:256 Day of initial lab test Day of treatment Day of follow up titer to assess response Establishes baseline to compare response post treatment Frequently forgotten and without baseline makes assessment of titer response difficult

39 Cases of primary/secondary/early latent syphilis (N=470) RPR titer day 0,7,14 post Rx 20% had titer rise 14 day after Rx (88% 2- fold rise, 12% 4-fold rise) Primary cases had greatest titer rise Early rise in titer not indicative of increased risk of Rx failure Holman et al. STD 2012

40 30 y/o HIV+ Male Treated for secondary syphilis with Benzathine PCN 2.4 mu IM Initial Titer 4 days before treatment 1:256 Follow-up Rash resolving 1 week and RPR 1:512 3 month f/u: 1:256 Photos: Engelman, SFCC

41 Audience Poll: How would you interpret month post treatment RPR? A. Failure of titer to drop is treatment failure B. Patient should have an LP C. 3 months can be too early to assess treatment response D. Patient should have retreatment E. None of the above

42 Inadequate period of observation Peak titer not adequately assessed no day of treatment titer available Different test used; different lab; normal lab variation (+/- one dilution) Serofast at high titer (>1:16) Reinfection Treatment failure HIV infected, co-infection could slow treatment response, particularly w/o use of ART

43 » Primary and Secondary Syphilis Examine at ~1 week to confirm improvement of symptoms (1 o and 2 o ) Repeat titers at 6 and 12 months (3, 6, 9, 12, and 24 for HIV+) Expect fourfold decrease in serology in 6-12 months (12-24 months for HIV+)» Latent Syphilis Re-examine at 6, 12, and 24 months (6, 12, 18 and 24 for HIV+) Expect fourfold decrease in serology in months (if titer initially >1:16) ( 24 months for HIV+) CDC 2015 STD Treatment Guidelines

44 45 male presents as contact to early case of syphilis. Asymptomatic, no syphilis findings on exam. RPR is non reactive. Does this contact need treatment?

45 Report all syphilis cases to Local Health Department/ Social Hygiene Contacts to primary, secondary or early latent Exposed 90 days before diagnosis Might be infected even if seronegative (can take up to 90 days for serology to convert); treat presumptively Exposed >90 days before diagnosis serologic tests are negative, no treatment is needed If follow up uncertain or serology unavailable then treat presumptively CDC 2015 STD Treatment Guidelines

46 Infection of the fetus or newborn at any stage during pregnancy Manifestations can be early or late including: Stillbirth, miscarriage, neurologic abnormalities, bony abnormalities, hearing loss, visual loss Syphilitic Rhinitis Syphilitic Rash Photos courtesy of Public Health Image Library, CDC and Dr. Norman Cole

47 Source CDC

48 Congenital Syphilis: Rates of Reported Cases by Year & Race/Ethnicity of Mother Source :CDC

49 1) Screen for syphilis in the 1 st trimester 2) Repeat screening at 28 weeks and again at delivery (in areas with high prevalence of syphilis among women) Do not D/C mom and baby without documenting a negative serology 3) Timely treatment of syphilis during pregnancy At least 4 weeks prior to delivery Benzathine PCN is the only treatment option, no alternatives CDC 2015 STD Treatment Guidelines

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51 Females MSM Hetero males HIV + Patients on PrEP Post Tx < 25 annually, 25+ if at risk Pregnant (first trimester) At least annually Exposed sites: genital, rectal, throat High prevalence settings (corrections, STD clinics) At least annually All exposed sites Every 3 months All patients, 3 months after treatment CDC 2015 STD Tx Guidelines Plus: Guidelines for HIV care and PrEP

52 Rectal Infections 86% 84% Urethral Infections Chlamydia n=316 Gonorrhea n=264 10% Asymptomatic Symptomatic 42% Chlamydia n=315 Gonorrhea n=364 Kent, CK et al, Clin Infect Dis July 2005

53 Patton et al CID 2014 Between 70-90% of infections would be missed by only screening with urine

54 Medical Monitoring Project, nationally representative sample of adults in HIV care 69% had been screened for syphilis in last year 43% had been screened for CT/GC Mattson, 2016 CID

55 Syphilis serology Pharyngeal GC Urine GC/CT Rectal GC/CT

56 Nucleic Acid Amplification tests have not been cleared by FDA for the rectum and pharynx Several commercial laboratories have undergone validation procedures for off label use Similar validation procedures apply for self-collected specimens MMWR. Mar ;63(No RR-12):1-19.

57 Systematic literature review STD clinics, non-sexual health clinics, CBO Prevalence: 9.2% rectal GC, 1.7% rectal CT Often asymptomatic: occur in women who report anal sex & in women who deny anal sex Possible transmission routes: oral/ anal, GI tract, autoinoculation via vaginal No USPSTF or CDC recommendation to routinely screen Dewart et al. STD 2018

58 Ceftriaxone 250 mg IM in a single dose Regardless of CT test result PLUS* Azithromycin 1 g orally (preferred) or Doxycycline 100 mg BID x 7 days CDC 2015 STD Treatment Guidelines

59 Cefixime 400 mg orally once PLUS Azithromycin 1 g (preferred-doxy removed as cotreatment unless azithromycin allergy) IN CASE OF SEVERE ALLERGY: Gentamicin 240 mg IM + azithromycin 2 g PO OR Gemifloxacin 320 mg orally + azithromycin 2 g PO CDC 2015 STD Treatment Guidelines

60 Gentamicin Regimen Gemifloxacin Regimen Route IM or IV Oral Nausea 27% 37% Vomiting (<1 3% 7% hour) Availability OK FDA reported shortage in May 2015 Volume Need 6 cc (40mg/cc)

61 Cefixime 400mg PO provides lower bactericidal levels compared to ceftriaxone 250mg IM Time above the MIC is not as prolonged Efficacy is reduced Pharynx variable PK, individual variation CDC 2015 STD Treatment Guidelines

62 Patients with pharyngeal GC treated with an alternative regimen Obtain test of cure 14 days after treatment, using either culture or NAAT Cases of suspected treatment failure, culture AND simultaneous NAAT Consider if using other non recommended or monotherapy CDC 2015 STD Treatment Guidelines

63 STD Atlas, 1997 DGI: Two forms Tenosynovitis, dermatitis, polyarthralgia Purulent arthritis

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65 Publication date: February

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67 Slide courtesy of Dr. Heidi Bauer

68 Source: CDC 2017 STD Surveillance Report

69 Neisseria gonorrhoeae Percentage of Isolates with Elevated Azithromycin Minimum Inhibitory Concentrations (MICs) ( 2.0 µg/ml), Elevated Ceftriaxone MICs ( µg/ml), and Elevated Cefixime MICs ( 0.25 µg/ml), Gonococcal Isolate Surveillance Project (GISP), Azithromycin Elevated MIC: Elsewhere in the World Canada: 0.4% % 2014 UK: 0.9% % 2015 Yikes! China: 5% % 2013 NOTE: Isolates not tested for cefixime susceptibility in 2008.

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71 Heterosexual male with sexual exposure in SE Asia Isolate with: Ceftriaxone MIC=0.5 Azithromycin MIC>256 Susceptible to Spectinomycin Ertapenem MIC =0.032 Treated with ceftriaxone 1g and Spectinomycin Urine NAAT neg, Throat still positive Retreatment with ertapenem x 3 days, successful data/file/701185/hpr1418_mdrgc.pdf

72 2 cases of MDR GC (strains resistant to ceftriaxone, azithro, tetracycline, PCN, cipro) 1 case had sexual exposure in SE Asia 1 case had no recent overseas travel Treatment/Follow up not available

73 Emerging Infectious Diseases, Vol 24 (2), February 2018

74 TEST WITH CULTURE AND NAAT: If GC culture not available, call your local health department.. REPEAT TREATMENT: Gemifloxacin 320 mg + AZ 2g OR Gentamicin 240 mg IM + AZ 2g If reinfection suspected, repeat treatment with CTX AZ 1g REPORT: To your local health department within 24 hours TEST AND TREAT PARTNERS: Treat all partners in last 60 days with same regimen TEST OF CURE (TOC): TOC 7 14 days with culture (preferred) and NAAT

75 Solithromycin: novel oral fluoroketolide Phase 2 trial (1200 mg and 1000 mg) GC treatment 100% cured (neg culture) with either dose GI side effects common and dose related Phase 3 trial underway Drugs in Development Zoliflodacin (ETX0914/AZD0914) Topoisomerase II inhibitor (spiropyrimidinetrione) Activity against NG isolates with ciprofloxacin resistance and reduced susceptibility to extended spectrum cephalosporins Phase 1 tolerability trial underway Hook, EW et al, CID Fernandez, P et al, Bioorg Med Chem Alm RA, Antimicrob Agents Chem. 2015

76 STDs on the rise Syphilis mimics other disease, keep in differential Dx Syphilis Stage of disease guides treatment Get day-of-treatment titer Follow titers to assess treatment Report syphilis to LHD/Social Hygeine Extragenital gonorrhea- test/treat Gonorrhea azithromycin resistance increasing, a few drugs in pipeline ( years!)

77 STD Clinical Consultation Network stdccn.org CDC STD Treatment Guidelines App Available now, free Search for STD TX

78 Questions?

79 » Extra Slides

80 » Titers at weeks of gestation, delivery, and following recommendations for stage of disease» Serologic titers can be checked monthly in highrisk women» Clinical and serologic response should be appropriate for stage Most women will deliver before serologic response to treatment can be assessed CDC 2015 STD Treatment Guidelines

81 Syphilis Treatment Failures Clinical Failure: Slow resolution or relapse of mucocutaneous signs Serologic Treatment Failure: Sustained ( > 2 weeks) fourfold increase in nontreponemal titers Reinfection may be difficult to rule out Serologic Non-response (possible treatment failure): Failure of initially high nontrep titers to decrease four-fold Estimate ~12-20%* don t have 4- fold drop Earlier stage/higher titer more likely to drop 4- fold, conflicting data, some studies- lower titer *Sena et al. STD 2017., Seña AC, et al. CID 2011 *Rolfs RT, et al. NEJM 1997 CDC 2015 STD Treatment Guidelines

82 Treatment Failure Management: HIV test and CSF evaluation Treat based on CSF findings If LP normal retreat with Benzathine Penicillin G 7.2 million units (2.4 MU weekly x 3) Optimal management unclear for primary/secondary syphilis w/o 4- fold drop in titer Additional serologic/clinical follow-up necessary and HIV test If follow-up uncertain retreat with Benzathine Penicillin G 7.2 million units (2.4 MU weekly x 3) Consider LP Follow titers annually- need for further treatment/lp unclear CDC 2015 STD Treatment Guidelines

83 Available at:

84 Neurologic or ophthalmic symptoms/signs Auditory disease, cranial nerve dysfunction, meningitis, stroke, altered mental status, loss of vibration sense, iritis, uveitis Evidence of tertiary disease aortitis, gumma Serologic Treatment failure In HIV infection, unless neurologic symptoms, there is no evidence that CSF exam is associated with improved outcomes, so not recommended *CDC 2015 STD Treatment Guidelines Guidelines for Prevention and Treatment of OI in HIV+ 2013

85 New Point-of-Care Syphilis Tests Rapid Immunochromatographic Assays: lateral flow immunoassays (e.g. rapid HIV antibody tests, urine HCG) Syphilis Health Check Treponemal only Results in 10 min FDA approved, CLIA waived US $8 per test DPP Syphilis Screen and Confirm Combined treponemal and nontreponemal results Results in 15 min Seeking FDA, eligible for CLIA waiver US 1.50 $2 per test

86 Long term sex partners of patients who have late syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of findings CDC 2015 STD Treatment Guidelines

87 Major conclusions NAATs recommended for detection of genital tract infections in men and women with and without symptoms Optimal specimen types are: First catch urine for men Self collected vaginal swabs from women NAATs recommended for: detection of rectal and oropharyngeal infections - not FDA-approved for rectal or pharyngeal specimens but remain the preferred testing method over culture

88 Rectal Company-Specific Ordering Codes for Combined GC/CT Nucleic Acid Amplified Tests (NAATs) LabCorp* Quest* Company-Specific Ordering Codes for CT test only LabCorp Pharyngeal NAATs are offered at (or from) any location in the country with these two codes. For information on specimen collection and transportation, clinicians should contact the local reference laboratory representative. CT detection by NAAT GC detection by NAAT CPT Billing Codes *CDC does not endorse these laboratories, however, they represent the largest laboratories nationally. There may be other private laboratories that have verified rectal and pharyngeal testing with NAATs. Many PHLs have also verified rectal and pharyngeal testing. Bolan, CDC webinar March 2011

89 » Highly acceptable, similar performance compared to clinician-collected specimens» Self-collection can be performed at laboratory along with blood draw/urine collection or in the exam room before/after the provider visit» May save patient an office visit» May save the provider time Van der helm, 2009, STD; Sexton, 2013 J Fam Pract; Dodge, 2012 Sex Health Freeman 2011, STD; Alexander 2008, STI; Moncada 2009, STD

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91 Limited evidence for timing of test of cure using modern NAATs Of 77 patients: 5 self-cleared GC before treatment 10 lost to follow up 62 remaining patients all cleared. Median time to clearance: 2 days Range 1-7 days for RNA-based NAAT Range 1-15 days for DNA-based NAAT» Wind et al. Clin Infect Dis 2016;62:

92 How soon can I retest for CT/GC? Need to wait at least 3 weeks for CT to clear for NAAT testing GC clearance is generally thought to be 1 week, but possibly up to 2 weeks for pharyngeal infection 3 months is the target, but retest opportunistically whenever patient returns in the next 1 12 months CDC 2015 STD Tx Guidelines,