21 April 2023

Is Gonorrhoea untreatable?

Catherine Ison

Health Protection Agency, London, UK

Treatment of gonorrhoea

Empirical:

Single dose used to aid compliance

Often syndromic, administered before lab results known

Co-treatment for chlamydial infection can be given

Choice:

National/international guidelines informed by surveillance data

Outcome:

To achieve >95% therapeutic success (WHO)

Sulphonamides

Penicillin

Tetracycline

Quinolones

Cephalosporins

Azithromycin

penA, penB, mtr, penC, ponA penicillinas

e

tet, mtr

23S rRNA

TETM

gyrA, parC

penA mosaic

?

Antimicrobial resistance in GC

Acquisition

Plasmids

Penicillin (PPNG): tem-1 (Haemophilus)

Tetracycline (TRNG): tetM (Streptococci)

Chromosomal

Penicillin/Cephalosporin

(Commensal Neisseriae)

Selection

High-level, single step

Spectinomycin

Azithromycin

Additive, multiple steps

Penicillin

Ciprofloxacin

How does it happen?

Misuse or overuse of antimicrobial agents

Inadequate dosage or incomplete

course

OTC use Long term use of a

single agent

Selection of mutants

First-line therapy

Surveillance programmes

Local

National

RegionalGlobal

Monitor trends in resistance

Monitor drift in susceptibility

Detect emergence of resistance

Inform treatment guidelines

Ciprofloxacin (MIC≥1mg/l) resistance by

gender and sexual orientation, 2000-2009

Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

EuroGASP – informing guidelines

EuroGASP – European Gonococcal Surveillance ProgrammePart of European STI surveillance network coordinated by ECDCInitiated by ESSTI, now funded by ECDCSentinel study, 110 consecutive isolates over 3 months

5%

Gonorrhoea management guidelines

BASHH guideline 2005

Cefixime, 400mg (Cefotaxime).

Ceftriaxone, 125 or 250mg.

Spectinomycin 2g.

Where susceptibility known:

Ciprofloxacin, 500mg (Ofloxacin, Levofloxacin)

Azithromycin, 1g or 2g.

Ampicillin 2g (+ 3g probenecid).

IUSTI guideline 2009

Cefixime, 400mg oral

Ceftriaxone, 250mg IM

Spectinomycin 2g IM

Alternative therapies

Other single dose cephalosporin regimens;

Cefotaxime (500mg or 1gIM)

Cefodizime (500mg IM

Antimicrobial prescribing practice 2000-2010 in GRASP clinics

Prevalence of cases with gonococcal isolates exhibiting decreased cefixime susceptibility (MIC >0.125mg/L) by gender and sexual orientation. GRASP 2010 (GUM Cases)

Countries with strains that exhibit decrease-susceptibility to cefixime (<5%)

Countries with strains that exhibit decrease-susceptibility to cefixime (≥5%)

Cefixime DS GC(MIC = >0.125mg/L)

2009 2010

Ceftriaxone susceptibility

Challenges for treatment

When to change?

What treatment?

Test of cure?

What is treatment failure?

Use diagnostic tests appropriately

Retain expertise for culture

Appropriate diagnostic tests

Highly sensitive and specific

More sensitive than culture at extragenital sites

Uses non-invasively taken specimens, urines, SVS

Easier for screening or testing in primary care

CT/GC result from same test

Poor PPV in low prevalence populations

May require confirmation especially pharyngeal samples

No Molecular test for AMR in routine use

Does not provide a viable organism

Molecular detection

Retain expertise for culture

Provides viable culture for GC sensitivity testing

Essential for emerging resistance

Disadvantages

Requires significant resources

Requires invasively taken specimen

Availability of chaperone

Intolerant to delays in transportation to lab

When to change therapy?

Recommendations

In response to rise in resistance levels;

WHO >5% of general population

CDC >3% in high risk groups

Current situation

Treatment failure emerging –high-level resistance to ceftriaxone in Japan and France documented

True level of treatment failure probably unknown

New alternative therapies lacking

Resistance exists to all previously used agents.

Treatment failure

Why important?

To establish link between dosage given, susceptibility data and failure to respond

What is definition?

Verified clinical failure; Detailed clinical history, exclusion of re-exposure and re-infection and isolates from pre- and post treatment indistinguishable

Challenge?

Definition in the absence of an isolateTapsall JW et al. Expert Rev Anti Ther. 2009;7:821-34

Clinical failures in England

Cefixime (3 cases)

Swindon in 2008, MSM, MIC 0.25mg/l

Newcastle in 2010 – bisexual, MIC 0.25mg/l

Newcastle – verified case – hetero, MIC 0.12mg/l

Isolates resistant to ciprofloxacin and penicillin

NG-MAST ST 1407 or related types (tbpB 110)

Ceftriaxone

None documented

Ison et al, Euro Surveill 2011;16(14):pii:19833Forsyth et al, Int J STD AIDS 2011,22,296-7

Treatment failures in Europe

Cefixime

Small number of cases identified

MICs 0.125mg/L-0.25mg/L

NG-MAST ST1407 or related type

Likely many more cases unidentified

Ceftriaxone

Verified failure, pharyngeal gonorrhoea in Sweden (MIC 0.125-0.25mg/L)

High-level resistant strain from France (MIC 1-2mg/L)

ST1407, also cefixime MIC 4mg/L

No others documentedUnemo et al, Euro Surveill 2010;15(47):pii=19721 Unemo et al. Euro Surveill 2011;16(6):pii=19792UUnemo et al. Antimicrob Agents Chemother, 2011

Options for treatment

Single dose therapy

Ceftriaxone – same or higher dosage (?500mg or 1g)

Gentamicin 240mg

Combination therapy

Ceftriaxone + azithromycin 1g

Gentamicin + azithromycin 1g

Multiple doses

Ceftriaxone followed by cefixime

Alternative agents? – no clinical trials

Test of cure

Why? To confirm compliance and ensure resolution of symptoms

Prevent spread of antimicrobial resistant gonorrhoea

When? Persisting symptoms or signs

Pharyngeal infection

Treatment with anything other than first-line recommendations

How? Culture performed at least 72 hours after completion of therapy

Test with NAATs 2weeks after completion of therapy followed by culture if positive

What is the Challenge?

Use new diagnostic tests appropriately

Retain expertise for culture

Collect a representative sample of viable isolates

Maintain timely surveillance data

Be vigilant for emerging resistance.

Be prepared, responsive and innovative

To maintain gonorrhoea as a treatable infection!