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Ina Park, MD, MSUniversity of California San FranciscoCalifornia Prevention Training Center
RETURN OF THE CLAP: Emerging Issues in Gonorrhea
Management and Antibiotic Resistance
No Relevant Relationships
DISCLOSURE
Epidemiology
Screening and extragenital infections
Treatment options (or lack thereof)
Antibiotic resistance
Parting words
ROADMAP
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Incidence: #2 reportable disease395,216 cases in 2015 (↑13%)Causes a range of clinical syndromesCervicitis, urethritis, epididymitis, proctitis, PID,
disseminated infectionOften asymptomatic in cervical, oral, and rectal
infections
GONORRHEA
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, 2011–2015
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ESTIMATED PROPORTION* OF MSM†, MSW†, &WOMEN AMONG GONORRHEA CASES BY
JURISDICTION, SSUN, 2015
•< 25 annually, 25+ if at risk•Pregnant <25, if at riskFemales
•At least annually•Exposed sites: genital, rectal, throatMSM
•High prevalence settingsHetero males•At least annually•All exposed sitesHIV +
•Every 3 monthsPatients on PrEP•All patients, 3 months after
treatmentPost-Tx
Who Should be Screened for CT/GC?
CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatmentPlus: Guidelines for HIV care and PrEP
HIGH PROPORTION OF EXTRAGENITAL CT/GC ASSOCIATED WITH NEGATIVE URINE TEST,STD SURVEILLANCE NETWORK (N=21994)
Patton et al CID 2014
Between 70-90% of infections would be missed by only screening with urine
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PHARYNGEAL GC INFECTIONS
• Majority asymptomatic
• Potential opportunity for genetic reassortmentwith other Neisseria spp
• Mosaic penA mutations in GC with reduced susceptibility to cefixime include DNA from commensal Neisseria spp in pharynx
• Difficult to eradicate!
• Majority asymptomatic (>80%)
• Rectum:
• Isolates may be less PCN and erythro-susceptible, 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
RECTAL GC INFECTIONS
Kent, CK et al, Clin Infect Dis July 2005
RECTAL GC/CT PREDICTS FUTURE HIV RISK
1 in 15 MSM were diagnosed with HIV within 1 year.*
1 in 53 MSM were diagnosed with HIV within 1 year.*
Rectal GC or CT
1 in 18 MSM were diagnosed with HIV within 1 year.**
Primary orSecondarySyphilis
No rectal STD or syphilis infection
*STD Clinic Patients, New York City. Pathela, CID 2013:57; **Matched STD/HIV Surveillance Data, New York City. Pathela, CID 2015:61
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GC TREATMENT
GONORRHEA TREATMENTPRE-ANTIBIOTICS
5 weeks of restAvoid alcohol Avoid sex
Urethral Dilation 2 weeks of urethral irrigation
Slide Courtesy Ned Hook
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Slide Courtesy Ned Hook
GONORRHEA DUAL THERAPYUNCOMPLICATED GENITAL, RECTAL,
OR PHARYNGEAL INFECTIONS
Ceftriaxone 250 mg IM in a single dose
Azithromycin 1 g orally
(preferred)or
Doxycycline 100 mg BID x 7 days
CDC 2015 STD Treatment Guidelines www.cdc.gov/std/treatment
PLUS*
• Regardless of CT test result
ALTERNATIVE CEPHALOSPORINS:Cefixime 400 mg orally once
PLUSAzithromycin 1 g (preferred) or doxycycline 100
mg BID x 7 days, regardless of CT
IN CASE OF SEVERE ALLERGY:Azithromycin 2 g orally once
(Caution: GI intolerance, emerging resistance)
Gonorrhea Treatment AlternativesAnogenital Infections
Gentamicin 240 mg IM + azithromycin 2 g PO OR
Gemifloxacin 320 mg orally + azithromycin 2 g PO
Doxy removed as co-treatment (unless azithroallergy)
CDC 2015 STD Treatment Guidelines www.cdc.gov/std/treatment
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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)
ALTERNATIVE UROGENITAL GC REGIMENS: AVOID MONOTHERAPY
Kirkcaldy, CID 2014;59:1083-91.
ANY DOWNSIDE TO THE ALTERNATIVE REGIMENS?
Gentamicin Regimen
GemifloxacinRegimen
Route IM or IV Oral
Nausea 27% 37%
Vomiting (<1hour)
3% 7%
Availability OK FDA reported shortage in May
2015
Volume Need 6 cc (40mg/cc)
• 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
PARTNER MANAGEMENT
CDC 2015 STD Treatment Guidelines: www.cdc.gov/std/treatment
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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 (negculture) with either dose
GI side effects common and dose-related
NEW ANTIBIOTIC REGIMENS
Hook, EW et al CID 2016
Zoliflodacin
(ETX0914/AZD0914)Topoisomerase II inhibitor
with activity against NG isolates with cipro-R and reduced susceptibility to extended-spectrum cephalosporins
OTHER STRATEGIES IN PIPELINE
Alm RA, Antimicrob Agents Chemother. 2015
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
mechanisms36% of isolates have no clear basis for resistance
Cefixime/quinolone resistant isolates amenable to sequence-based dx testing
GENOMIC EPI OF NG
Grad YH, JID 2016
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HISTORY OF ANTIBIOTICS FOR GC
1937 1943 1976 1985 1993 2007
Sulfa
3rd Gen Ceph
Cipro
Penicillin
Tetracycline
PPNG
Spectinomycin
72 mg x 2 doses
Penicillinase-Producing N. Gonorrhoeae (1970s - 1980s)
Spread of Ciprofloxacin Resistance(1990s - 2000s)
DISTRIBUTION OF ISOLATES WITH PCN, TETRACYCLINE, AND/OR CIPRO RESISTANCE, GONOCOCCAL ISOLATE
SURVEILLANCE PROJECT (GISP), 2015
N O T E : P e n R = p e n i c i l l i n a s e - p r o d u c i n g N e i s s e r i a g o n o r r h o e a e a n d c h r o m o s o m a l l y - m e d i a t e d p e n i c i l l i n - r e s i s t a n t N . g o n o r r h o e a e ; T e t R = c h r o m o s o m a l l y - a n d p l a s m i d - m e d i a t e d t e t r a c y c l i n e - r e s i s t a n t N . g o n o r r h o e a e ; a n d Q R N G = q u i n o l o n e - r e s i s t a n t N . g o n o r r h o e a e .
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% OF ISOLATES WITH ELEVATED CEFTRIAXONE MIN IMUM INHIBITORY CONCENTRATIONS (MICS) (≥0.1 25 ΜG/ML) AND ELEVATED CEF IXIME
MICS (≥0.25 ΜG/ML) , GONOCOCCAL ISOLATE SURVEILLANCE PROJECT (G ISP) , 2006–2015
* I s o l a t e s n o t t e s t e d f o r c e f i x i m e s u s c e p t i b i l i t y i n 2 0 0 7 a n d 2 0 0 8 .
US: 0.9%EU: 4.5%China: 21%
Cole MJ, et al.Euro Surveill 2014 19(45); Zheng H et al. Japan J Infect Dis 2014 67:288-91; Hamasuna R et al Japan J Infect Dis 203 19:571-8; Hamasuna R et al J Infect Chemo 2015 21:1-6
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
CEPHALOSPORIN TREATMENT FAILURES
The New Yorker 2012
NEISSERIA GONORRHOEAE — DISTRIBUTION OF AZITHROMYCIN MINIMUM INHIBITORY CONCENTRATIONS (MICS)
BY YEAR, GONOCOCCAL ISOLATE SURVEILLANCE PROJECT (GISP) , 2011–2015
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0
2
4
6
'92 '93 '94 '95 '96 '97 '98 '99 2000 '01 '02 '03 '04 '05 '06 '07 '08 '09 2010 '11 '12 '13 '14 2015 '16
Percent of Isolates
Year
GONOCOCCAL ISOLATE SURVEILLANCE PROJECT (GISP), PERCENT OF ISOLATES WITH CDC "ALERT"
VALUES FOR AZITHROMYCIN IN CA GISP SITES, 1992–APRIL 2016
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 1992. 2015-2016 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)
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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 0.008 μg/mL)
Ciprofloxacin: sensitive (MIC 0.015 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 allergydual therapy for GC for all casesTake an allergy history (rash as a child—not likely
true allergy)
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AZITHROMYCIN TREATMENT FAILURE IN CALIFORNIA
Gose et al. STD 2015;42:279‐80.
http://www.theguardian.com/society/2016/apr/17/gonorrhoea-will-spread-across-uk-doctors-fear
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June 17, 2016
SUSPECTED GC TREATMENT FAILURE
•If GC culture not available, call your local health department
TEST WITH CULTURE AND NAAT:
•Gemifloxacin 320 mg + AZ 2g OR Gentamicin 240 mg IM + AZ 2g•If reinfection suspected, repeat treatment with CTX 250 + AZ 1g
REPEAT TREATMENT:
•To your local health department within 24 hours
REPORT:
•Treat all partners in last 60 days with same regimen
TEST AND TREAT PARTNERS:
•TOC 7-14 days with culture (preferred) and NAAT
TEST OF CURE (TOC):
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
TAKE HOME POINTS
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WANT TO KNOW MORE ABOUT STDS? THERE’S AN APP FOR THAT.
CDC Treatment Guidelines App for Apple and Android
Available from https://itunes.apple.com/us/app/std-tx-guide/id655206856?mt=8
(Search for “STD Tx”)
STD CLINICAL CONSULTATION NETWORK (STDCCN)
Provides STD clinical consultation services within 1-5business days, depending on urgency, to healthcareproviders nationally
Your consultation request is l inked to your regional PTC’sexpert faculty
We are just a click away! www.STDCCN.org
GONORRHEA: PARTING WORDS
https://www.youtube.com/watch?feature=player_embedded&v=8UtqT2sVBxg
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THANK YOU Any burning questions?
Alm RA, Antimicrob Agents Chemother. 2015
CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment. Plus: Guidelines for HIV care and PrEP
Gose, STD 2015
Gose et al. STD 2015;42:279-80
Grad YH, JID 2016
Hook, EW et al CID 2016
http://www.theguardian.com/society/2016/apr/17/gonorrhoea-will-spread-across-uk-doctors-fear
Kent, CK et al, Clin Infect Dis July 2005
Kirkcaldy, CID 2014;59:1083-91.
Patton et al CID 2014
REFERENCES
Recommended