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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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ANTIBIOTIC-RESISTANT GONORRHEA

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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

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'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