RETURN OF THE CLAP: Emerging Issues in Gonorrhea Management and Antibiotic Resistance

Transcription

1 RETURN OF THE CLAP: Emerging Issues in Gonorrhea Management and Antibiotic Resistance Ina Park, MD, MS University of California San Francisco California Prevention Training Center DISCLOSURE No Relevant Relationships ROADMAP Epidemiology Screening and extragenital infections Treatment options (or lack thereof) Antibiotic resistance Parting words 1

2 GONORRHEA Incidence: #2 reportable disease 395,216 cases in 2015 ( 13%) Causes a range of clinical syndromes Cervicitis, urethritis, epididymitis, proctitis, PID, disseminated infection Often asymptomatic in cervical, oral, and rectal infections Screening is essential to prevent complications GONORRHEA RATES OF REPORTED CASES BY STATE, US AND OUTLYING AREAS, 2015 GONORRHEA RATES BY RACE/ETHNICITY, UNITED STATES,

3 ESTIMATED PROPORTION* OF MSM, MSW, & WOMEN AMONG GONORRHEA CASES BY JURISDICTION, SSUN, 2015 Who Should be Screened for CT/GC? Females MSM Hetero males HIV + Patients on PrEP Post-Tx < 25 annually, 25+ if at risk Pregnant <25, if at risk At least annually Exposed sites: genital, rectal, throat High prevalence settings 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 HIGH PROPORTION OF EXTRAGENITAL CT/GC ASSOCIATED WITH NEGATIVE URINE TEST, STD SURVEILLANCE NETWORK (N=21994) Between 70-90% of infections would be missed by only screening with urine Patton et al CID

4 PHARYNGEAL GC INFECTIONS Majority asymptomatic Potential opportunity for genetic reassortment with other Neisseria spp Mosaic pena mutations in GC with reduced susceptibility to cefixime include DNA from commensal Neisseria spp in pharynx Difficult to eradicate! RECTAL GC INFECTIONS Majority asymptomatic (>80%) Rectum: Isolates may be less PCN and erythrosusceptible, possibly due to mtr locus mutations that reduce outer membrane permeability to hydrophobic molecules that allow survival in rectum GC associated with increased shedding of HIV Kent, CK et al, Clin Infect Dis July 2005 RECTAL GC/CT PREDICTS FUTURE HIV RISK Rectal GC or CT Primary or Secondary Syphilis No rectal STD or syphilis infection 1 in 15 MSM were diagnosed with HIV within 1 year.* 1 in 18 MSM were diagnosed with HIV within 1 year.** 1 in 53 MSM were diagnosed with HIV within 1 year.* *STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61 4

5 GC TREATMENT GONORRHEA TREATMENT PRE-ANTIBIOTICS 5 weeks of rest Avoid alcohol Avoid sex Urethral Dilation 2 weeks of urethral irrigation Slide Courtesy Ned Hook 5

6 Slide Courtesy Ned Hook GONORRHEA DUAL THERAPY UNCOMPLICATED GENITAL, RECTAL, OR PHARYNGEAL INFECTIONS 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 Gonorrhea Treatment Alternatives Anogenital Infections ALTERNATIVE CEPHALOSPORINS: Cefixime 400 mg orally once PLUS Azithromycin 1 g (preferred) or doxycycline 100 mg BID x 7 days, regardless of CT Doxy removed as cotreatment (unless azithro allergy) IN CASE OF SEVERE ALLERGY: Gentamicin Azithromycin 240 mg 2 IM g + orally azithromycin once 2 g PO OR (Caution: GI intolerance, emerging resistance) Gemifloxacin 320 mg orally + azithromycin 2 g PO CDC 2015 STD Treatment Guidelines 6

7 ALTERNATIVE UROGENITAL GC REGIMENS: AVOID MONOTHERAPY NIH-sponsored non-comparative randomized trial in adults with urethral or cervical gonorrhea 1. gentamicin 240 mg IM + azithromycin 2 g PO, or 2. gemifloxacin 320 mg PO + azithromycin 2 g PO Per-protocol efficacy: gentamicin + azithromycin = 100% (202/202) gemifloxacin + azithromycin = 99.5% (198/199) Kirkcaldy, CID 2014;59: ANY DOWNSIDE TO THE ALTERNATIVE REGIMENS? 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) PARTNER MANAGEMENT Clinical evaluation first-line option Concurrent patient-partner therapy can be effective for those with one primary partner Offer expedited partner treatment (EPT) CT/GC if partner cannot be promptly treated Use of prepackaged medication is recommended Dual therapy (cefixime 400 mg + azithromycin 1 g) is crucial if EPT is used for GC CDC 2015 STD Treatment Guidelines: 7

8 NEW ANTIBIOTIC REGIMENS Solithromycin, novel oral fluoroketolide Phase 2 trail (1200 mg and 1000 mg) Inclusion crtieria: + NAAT, +Gram stain, female contacts to male GC case Total n=59, n=28 (1200 mg) & n=31 (1000 mg) 46 (78%) GC culture positive, 100% cured (neg culture) with either dose GI side effects common and dose-related Hook, EW et al CID 2016 OTHER STRATEGIES IN PIPELINE Zoliflodacin (ETX0914/AZD0914) Topoisomerase II inhibitor with activity against NG isolates with cipro-r and reduced susceptibility to extended-spectrum cephalosporins Alm RA, Antimicrob Agents Chemother GENOMIC EPI OF NG Extended-spectrum cephalosporin reduced susceptibility predominantly clonal (assoc w mosaic pena XXXIV) 98% sensitive for cefixime, 91% for ceftriaxone Quinolone resistance also clonal (gyra and parc) Azithromycin reduced susceptibility has multiple mechanisms 36% of isolates have no clear basis for resistance Cefixime/quinolone resistant isolates amenable to sequence-based dx testing Grad YH, JID

9 ANTIBIOTIC-RESISTANT GONORRHEA 9

10 HISTORY OF ANTIBIOTICS FOR GC Sulfa 72 mg x 2 doses Penicillin PPNG Tetracycline Spectinomycin 3rd Gen Ceph Cipro Penicillinase-Producing N. Gonorrhoeae (1970s s) Spread of Ciprofloxacin Resistance (1990s s) DISTRIBUTION OF ISOLATES WITH PCN, TETRACYCLINE, AND/OR CIPRO RESISTANCE, GONOCOCCAL ISOLATE SURVEILLANCE PROJECT (GISP), 2015 NOTE: PenR = penicillinase-producing Neisseria gonorrhoeae and chromosomally-mediated penicillin-resistant N. gonorrhoeae; TetR = chromosomally- and plasmid-mediated tetracycline-resistant N. gonorrhoeae; and QRNG = quinolone-resistant N. gonorrhoeae. 10

11 % OF ISOLATES WITH ELEVATED CEFTRIAXONE MINIMUM INHIBITORY CONCENTRATIONS (MICS) ( ΜG/ML) AND ELEVATED CEFIXIME MICS ( 0.25 ΜG/ML), GONOCOCCAL ISOLATE SURVEILLANCE PROJECT (GISP), US: 0.9% EU: 4.5% China: 21% * Isolates not tested for cefixime susceptibility in 2007 and Cole MJ, et al.euro Surveill (45); Zheng H et al. Japan J Infect Dis :288-91; Hamasuna R et al Japan J Infect Dis :571-8; Hamasuna R et al J Infect Chemo :1-6 CEPHALOSPORIN TREATMENT FAILURES Oral cephalosporin treatment failures reported worldwide Japan, Hong Kong, England, Austria, Norway, France, South Africa, and Canada Ceftriaxone treatment failures in pharyngeal gonorrhea and a few isolates with high level ceftriaxone resistance reported The New Yorker 2012 NEISSERIA GONORRHOEAE DISTRIBUTION OF AZITHROMYCIN MINIMUM INHIBITORY CONCENTRATIONS (MICS) BY YEAR, GONOCOCCAL ISOLATE SURVEILLANCE PROJECT (GISP),

12 GONOCOCCAL ISOLATE SURVEILLANCE PROJECT (GISP), PERCENT OF ISOLATES WITH CDC "ALERT" VALUES FOR AZITHROMYCIN IN CA GISP SITES, 1992 APRIL Percent of Isolates '92 '93 '94 '95 '96 '97 '98 ' '01 '02 '03 '04 '05 '06 '07 '08 ' '11 '12 '13 ' '16 Year Note: Alert values are set by CDC as markers to look at possible decreased susceptibility. Azithromycin alerts have MICs 2.0 μg/ml. No data before data are provisional as of 6/20/2016. STD Clinic Sites: Long Beach (ended participation in 2007), Los Angeles (added in 2003), Orange, San Diego, San Francisco Rev. 06/2016 CASE: JAMES, URETHRITIS 23 yr old MSW presents with 2 day history of dysuria He had 1 female partner in the last month On exam he has a small amount of clear urethral discharge Gose, STD 2015 WHAT NEXT? Urine NAAT was sent for GC/CT Azithromycin 1g was given as directly observed therapy His NAAT is positive for gonorrhea He is allergic to PCN (rash as a child) 12

13 UH OH He is treated with azithromycin 2 g orally in a single dose 8 days later, he is still having discharge FYI, recommended therapy: Gentamicin 240 mg IM + azithromycin 2 g PO OR Gemifloxacin 320 mg orally + azithromycin 2 g PO 2015 CDC STD Treatment Guidelines HERE S WHERE IT GETS INTERESTING Day 8: his clinician gets a culture and antibiotic susceptibility testing Culture result: N. gonorrhoeae Azithro: highly resistant (MIC >2048 μg/ml) Ceftriaxone: sensitive (MIC μg/ml) Ciprofloxacin: sensitive (MIC μg/ml) Gose, STD 2015 IT ENDS WELL Day 12: He is treated with ceftriaxone 250 mg IM, he has no allergic reaction Day 14: his discharge is resolved Take home points: new dual tx for patients with PCN allergy dual therapy for GC for all cases Take an allergy history (rash as a child not likely true allergy) 13

14 AZITHROMYCIN TREATMENT FAILURE IN CALIFORNIA Gose et al. STD 2015;42:

15 June 17, 2016 SUSPECTED GC TREATMENT FAILURE 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 TAKE HOME POINTS Remember extragenital screening for MSM Dual therapy for all GC infections Alternative regimens for ceph allergy (gemi or gent + AZ) AZ treatment failure and high level resistance observed in CA and HI Be vigilant for GC treatment failure, the local health dept is your friend 15

16 WANT TO KNOW MORE ABOUT STDS? THERE S AN APP FOR THAT. CDC Treatment Guidelines App for Apple and Android Available from us/app/std-txguide/id ?mt= 8 (Search for STD Tx ) STD CLINICAL CONSULTATION NETWORK (STDCCN) Provides STD clinical consultation services within 1-5 business days, depending on urgency, to healthcare providers nationally Your consultation request is linked to your regional PTC s expert faculty We are just a click away! GONORRHEA: PARTING WORDS watch? feature=player_em bedded&v=8utqt2 svbxg 16

17 THANK YOU Any burning questions? REFERENCES Alm RA, Antimicrob Agents Chemother CDC 2015 STD Tx Guidelines Plus: Guidelines for HIV care and PrEP Gose, STD 2015 Gose et al. STD 2015;42: Grad YH, JID 2016 Hook, EW et al CID ea-will-spread-across-uk-doctors-fear Kent, CK et al, Clin Infect Dis July 2005 Kirkcaldy, CID 2014;59: Patton et al CID