Chlamydia and Gonorrhea breakout session - PowerPoint Presentation

Slide1

Chlamydia and Gonorrhea breakout session

Connie L. Celum, MD, MPHProfessor of Global Health and MedicineUniversity of WashingtonSeattle, Washington

1

Slide2

Gonorrhea: Biology & Pathogenesis

Neisseria gonorrhoeaeGram-negative diplococci Optimal growth at 35-37C and 5% CO2

Pili attach mucosal surfaces

Antigenic & phase variation

Allow immune evasion

Other important surface structures:

Por

,

opa

, LOS

Slide3

Gonorrhea syndromes

Slide4

Pharyngeal Gonorrhea

Population

Overall

Test Positivity

% of Urogenital

Cases

Also GC+

MSM

7.9%

(range: 1.2 – 19.3)

32%

Women2.1%(range: 0 – 29.6%)72%

Heterosexual Men2.2%(range: 0.4 – 15.5%)12%

1- Chan PA,

Inf

Dis Ob/

Gyn 20162- Patton, CID 2014 (SsUN data)3- Trebach, STD, 20154 –Wada, J inf chemo, 20125 – Ong, Clin Micro Inf, 20176 – Chow, STD, 2019

Special Populations: Female Contacts to GC: 46% Hetero Male Contacts to GC: 21%6

It’s Common, Asymptomatic and

Underscreened

Source of transmission to genital sites

Source of AMR given lower levels of antibiotics in pharynx and transfer of resistance from commensal Neisseria

Slide5

Rectal Infection & Proctitis

Proctitis SymptomsAnorectal PainItching/IrritationPainful bowel movementsRectal discharge

Rectal bleeding

Rectal gonorrhea

:

Among MSM, ~10% test positive

85% Asymptomatic

Increases HIV acquisition by 2-5 fold

Slide6

Disseminated Gonococcal Infection

Slide7

Current Gonorrhea Treatment Recommendations

Country/Agency

Ceftriaxone Dose

Azithromycin Dose

WHO

250mg

1g

USA

250mg

1g

UK

1gNONE

Europe (2020 Draft)500mg2gAustralia500mg

1g

or

2g (pharyngeal)

Japan1gNONE

Slide8

U.S. CDC’s Antimicrobial Resistant Bacteria

Top Threats

Slide9

1940s

1980

1990

2000

2010

Penicillin &

Tetracycline

Ceftriaxone

Cipro / Cefixime

PCN DOSE INCREASES

2015

Penicillin

Cipro

Cefixime

Doxy /

Azithro

2g

Azithro

/ Dual

Tx

CTX DOSE INCREASE

HISTORICAL PERSPECTIVE:

Recommended Gonococcal Treatments

Drugs removed from

recommended therapy

>2020s

Slide10

What is the backup treatment plan for AMR Gonorrhea?

Increasing the dose of ceftriaxoneResistance Guided TherapyUse susceptibility results (molecular or phenotypic) to guide treatment Works best with asymptomatic infectionsPoint of care tests in development identify quinolone resistant GCRecycle older drugs

Using “last line” IV drugs

E.g.

Ertapenem

Slide11

Chlamydia trachomatis

Obligate intracellular bacteria

Infects mucous membrane surfaces (genital, rectum, eye, throat)

Intracytoplasmic biphasic developmental cycle over 48-72 hours

Incubation period 7-21 days

Slide12

Summary of Clinical Syndromes Caused by

C. trachomatis (“Chlamydia”)

Conjunctivitis

Urethritis

Proctitis

Conjunctivitis

Urethritis

Cervicitis

Proctitis

Conjunctivitis

Pneumonia

Pharyngitis, Rhinitis

Reactive arthritis

Epididymitis

PID

Chronic lung disease (?)

Infertility

Ectopic

pregnancy

Men

Women

Infants

Chronic Pelvic Pain

Reactive arthritis

Slide13

Uncomplicated Chlamydia

Urogenital Manifestations

Urethritis

Occurs in women or men

Dysuria, discharge

Ct causes 15-40% of NGU in men

Cervicitis

Vag

discharge, painful sex, irregular bleeding

Ct is most frequently identified cause of cervicitis (11-50%)

Up to 10% have cervical discharge / friability

Majority (70-80%) Ct-infected men and women asymptomatic with normal exams

1

CDC

2

Lusk and Konecky. Curr Opin Infect Dis. 2008;21:49-55.

Slide14

Uncomplicated Chlamydia

Other Manifestations

Inclusion conjunctivitis

Occurs in women or men

Discharge or irritation

Follicles, “cobblestone effect”

Usually due to autoinoculation

Oropharyngeal infection

Most asymptomatic

Sore throat (pharyngitis) rare

Can be transmitted to genital sites thru

oralgenital sex

* Bernstein KT, et al. Clin Infect Dis 2009;49 and Marcus JL, et al. Sex

Transm

Dis 2011;38

Slide15

Uncomplicated Chlamydia

Other Manifestations

Rectal infection

Often asymptomatic

Sometimes discharge, tenesmus (proctitis)

Occurs in women who deny anal sex

• Severity

• Extent

• Sigmoidoscopy

• Biopsy

LGV strains

Severe

Proctocolitis

Blood, ulcers, pus

Granulomas

Non-LGV strains

Mild

Proctitis

Normal, pus

PMNs

Slide16

25

yo

male with history of chlamydial urethritis 2 months ago

Reports right foot pain.

Xray

shows severe destructive arthritis in second MTP

No other joint pain

Diagnosis?Treatment?

Slide17

Chlamydia & Gonorrhea: Diagnostic Testing

Nucleic acid amplification tests (NAAT) recommended for men & womenOptimal specimen: first-catch urine in men and vaginal swabs in womenNAAT optimal for rectal and pharyngeal testing; now FDA approved as of May 2019Cannot perform drug resistance testing on NAAT (need gonorrhea culture if concern)

Do GC cultures if part of SURGG program

Slide18

CDC 2015 STD Tx Guidelines www.cdc.gov/std/treatment

CDC STD Screening Guidelines for WomenSexually active adolescents <25 years of ageRoutine annual chlamydia and gonorrhea screeningOther STDs and HIV based on risk

Women ≥25 years of age

STD/HIV testing based on risk

New sex partner, more than one sex partner, a sex partner with concurrent partners, sex partner with an STI

Pregnant women

Chlamydia and Gonorrhea (<25 years of age or at-risk)

Retest in 3rd trimester if <25 or high-risk HIVSyphilis serologyHep B sAgHep C (if high risk)

Vaginal, endocervical or urine

Slide19

CDC STD Screening Guidelines:

other populations

Men who have sex with women only

No routine screening

Men who have sex with men

Sexually active: annual HIV, syphilis, CT/GC at relevant sites

Every 3-6 months if ongoing high risk behaviors

Recent bacterial STICondomless anal intercourseAnonymous sex partnersSubstance use- methamphetamineTransgender men and womenNo specific recommendation

But: can be at high risk, consider annual-q3 mo HIV, syphilis, GC/CT

Slide20

“Extragenital” Screening

Among MSM, high rates of extra-genital GC & CTPharyngeal GC: 9.2%Rectal GC: 9.7%Rectal CT: 12%The majority of infections are asymptomatic

92% of pharyngeal GC

84 - 86% of rectal GC

Test for GC and CT from rectal and oropharynx for MSM

Slide21

Controversy: Doxycycline for STI Prevention

Studied as both post-exposure and pre-exposure prophylaxisNo resistance to doxycycline among C. trachomatis or T. pallidumResistance among N. gonorrhoeae varies

Slide22

Rationale for studying doxycycline for

STI prophylaxisSafe, well-tolerated, inexpensiveUsed safely & effectively for prophylaxis

Lyme disease (also a spirochete)

malaria prophylaxis

No tetracycline resistance detected in

C. trachomatis

or

T. pallidumTCN resistance is already high in GC and doxy isn’t recommended for useUsed chronically in persons with acneNot commonly used to treat infectious diseases

Slide23

Doxycycline Pre-Exposure Prophylaxis in HIV+

Bolan et al, STD 2015

MSM with ≥2 episodes of syphilis since HIV diagnosis

(N=30)

Once daily doxycycline

(N=15)

Randomized

Contingency management

($ for staying STD-free)

(N=15)

GC or CT: 4

Syphilis: 2

Any STD: 6

(No difference in sexual behavior)

GC or CT: 8

Syphilis: 7

Any STD: 15

p = 0.02

For any STD

Slide24

Doxycycline Post-Exposure Prophylaxis

Molina, et al. Lancet 2017

RCT in open label extension of IPERGAY

PrEP

study

HIV- MSM on event-driven (2:1:1) HIV

PrEP

Doxy 200mg x1 ~24h after sex (≤72h)

Targeting CT & syphilis

↓ time to first STI

No risk compensation

7% discontinuation

Median 7 pills/month (IQR: 3-15)Kaplan-Meier estimates of time to first STI by study group

Slide25

Questions after IPERGAY Doxy study

Will doxy PEP work …?In MSM & TGW living with HIV? (potentially different adherence, efficacy and effect on antimicrobial resistance) In persons taking daily PrEP when they are on 2 different dosing strategies for HIV

PrEP

and STI PEP?

In younger, more heterogeneous populations?

Have partial efficacy against GC when TCN resistance is lower?

How much doxycycline will be used if told to take post-sex and not more than daily?

Will intermittent doxycycline increase antimicrobial resistance?

STIs (GC, CT, syphilis)

Sources of transferable resistance (

Neisseria spp.) S. aureus (when doxycycline is sometimes used for MRSA)

Impact on gut microbiome

Slide26

MSM & TGW

Living with HIV or

On HIV

PrEP

n = 780 in

SF and Seattle

Doxy PEP Study Schema

No PEP

Month 0 3 6 9 12

2:1 randomization

Intervention

:

Open label

doxycycline 200 mg taken as PEP after

condomless

sexual contact

1

o

endpoint:

Combined incidence of GC, CT & syphilis

Aim 1:

STI reduction & safety/tolerability

Aim 2:

Impact on antimicrobial resistance (GC, commensal Neisseria, S. Aureus)

Exploratory CT, syphilis, gut

resistome

STI testing

Doxy PEP

Status: Started late 2019, paused for COVID with 99 enrolled; ill be enrolling again Aug-Sept

Slide27

What Doxy PEP study will add

Additional evidence about effectiveness of doxy PEP in US MSM, primarily using daily PrEP

First evidence about effectiveness, safety and antimicrobial resistance in MSM living with HIV

Data on doxy PEP adherence: user-friendly app about sexual behavior & hair

Acceptability of doxy PEP

Qualitative insights into doxy PEP use

Doxycycline resistance in GC, CT, and syphilis

Doxy resistance in commensal Neisseria, Staph Aureus and gut microbiome

Slide28

Courtesy of: Cohen S;

Blechinger

D, 2018.

High level of interest in doxycycline for STD prevention among MSM

1301 respondents to Grindr survey

16% PLWH, 37% on

PrEP

, 47% not on

PrEP

80% with

condomless

sex, 39% with bacterial STI in past year

African American & Latino MSM were more likely to report interest that non-Hispanic white MSM

Spinelli et al STD 2018

Slide29

Lis et al, CID 2015 (slide courtesy of Lisa Manhart)

M. genitalium Associations with STI Syndromes

Syndrome

Summary risk estimate

OR (95% CI)

S

tudies

accounting for CT (subset)

NGU

5.5 (4.3 – 7.0)

-

Female Urethritis

2.2 (1.6 – 2.9)

2.1 (1.5 – 2.9)

Cervicitis

1.6 (1.4

– 2.0)1.9 (1.4 – 2.8)

PID / Endometritis1.9 (1.3 – 3.5)

2.0 (0.95 – 4.0)

Preterm

Delivery

1.9 (1.2

–

2.9)

2.3 (1.1 – 5.0)

Spontaneous Abortion

1.8 (1.1 – 3.0)

2.3 (1.0 – 4.9)

Infertility

3.0 (1.3 – 6.7)

3.7 (1.7 – 8.1)

HIV

2.0 (

1.4 – 2.8)

-

Slide30

M. genitalium

Treatment

Manhart 2013, Mena 2009, Schwebke 2011,

Getman

2016, Kikuchi 2014, Manhart - Bradshaw & Jensen personal communication

Antibiotic

Approximate cure rates

Notes

Doxycycline

100mg BID x 7d

30-40%

Despite in vitro susceptibility

Azithromycin

1g

po

x 1

40%Rapidly emerging resistance: ~40-50% in US settings

Moxifloxacin

100% (initially),

69-88%

(more recently)

Rapidly emerging resistance: 20% in 2011 to 47% in 2013 in Japan

Slide31

Efficacy of currently recommended antibiotics for M. genitalium

Doxycycline 100mg bid x 7d

30%

to

45%

effective

1

Lau 2015;

2

Li 2017; Read 2017

Slide courtesy Lisa

Manhart

Slide32

Nongonococcal

Urethritis TreatmentCDC Guidelines, 2015

King County STD Clinic

Azithromycin or doxycycline

Azithromycin if doxy initially

Metronidazole if

trich

prevalent, (MSW only)

Moxifloxacin 400mg x 7 days

Doxycycline

or azithromycin

Moxifloxacin 400mg x 7 days

European & Australian guidelines recommend

M. gen

testing, preferably with macrolide resistance testing. U.S. guidelines do not.

Australian Guidelines

Guidelines assume microscopic assessment to differentiate NGU from gonococcal urethritis

Doxycycline + M gen testing w/ macrolide resistance testing

Persistent or recurrent NGU (M. gen most common cause)

Persistent or recurrent NGU

Followed by:

Moxifloxacin 400mg x 7 days

Or

Azithromycin 1g x1 then 500mg daily x 3 days

Slide33

Mycoplasma

genitalium: Who To TestPersons with STD syndromes (urethritis, cervicitis, PID, NOT vaginal discharge alone)Option #1 – Test all persons with syndromes

Identifies persons at time of symptom presentation

Some persons with urethritis have symptoms transiently resolve with persistent infection – symptoms can recur

Option #2 - Test persons with persistent/recurrent syndromes

Limits testing

May add an additional visit

Sex partnersLimit to current sex partners – Goal is to avoid reinfectionPersons screening for STDs –

NO

– No evidence to support a screening program

Slide34

Multisite Screening in MSM and TGW

All sexually active MSM and transgender or non-binary persons who have sex with menAny rectal or pharyngeal exposure in past yearScreen at least annually, orScreen Q3 months if any of the following:

Bacterial STD in the past year

Methamphetamine or popper use in past year

≥10 sex partners (oral or anal) in the past year

Condomless

anal intercourse with an HIV

serodiscordant partner in the past yearTaking PrEP

Self-testing is acceptable & sensitive

Slide35

Which patients need in-person visits during COVID?

Patients with symptoms of STIs

Known STI contacts

Individuals at risk for complications

Concern for PID

vaginal discharge and abdominal pain

Pregnant with syphilis

Symptoms concerning for neurosyphilisRoutine screening visits should be deferred during emergency responses