Is Gonorrhoea untreatable?

Catherine Ison

Health Protection Agency, London, UK 29 April 2020

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

penA, penB, mtr, penC, ponA penicillinase

Tetracycline Quinolones

tet, mtr TETM gyrA, parC

Azithromycin Cephalosporins 23S rRNA

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 Global Local Regional National

 Monitor trends resistance in  Monitor drift susceptibility in  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 70 Ciprofloxacin 60 50 40 30 20 10 0 2004 (965) 2006 (836) 2007 (1374) 2008 (1284) 2009 (1366) 2010 (1712)

5%  EuroGASP – European Gonococcal Surveillance Programme  Part of European STI surveillance network coordinated by ECDC  Initiated by ESSTI, now funded by ECDC  Sentinel study, 110 consecutive isolates over 3 months

Gonorrhoea management guidelines

BASHH guideline 2005



Cefixime, 400mg (Cefotaxime).



Ceftriaxone, 125 or 250mg.



Spectinomycin 2g.

IUSTI guideline 2009

  

Cefixime, 400mg oral Ceftriaxone, 250mg IM Spectinomycin 2g IM Where susceptibility known:



Ciprofloxacin, 500mg (Ofloxacin, Levofloxacin)



Azithromycin, 1g or 2g.



Ampicillin 2g (+ 3g probenecid).

Alternative therapies



Other single dose cephalosporin regimens;

 Cefotaxime (500mg or 1gIM)  Cefodizime (500mg IM

Antimicrobial prescribing practice 2000-2010 in GRASP clinics

100 90 80 30 20 10 0 70 60 50 40 2000 Fluoroquinolones 2001 2002 Cephalosporins 2003 2004 2005 2006 % Ciprofloxacin resistance (>=1mg/l) 2007 2008 2009 2010 40 35 30 25 20 15 10 5 0 % Cefixime decreased susceptibility (>=0.125mg/l)

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

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

Countries with strains that exhibit decrease susceptibility to cefixime (<5%) Countries with strains that exhibit decrease susceptibility to cefixime (≥5%) 2009 2010

Ceftriaxone susceptibility

Challenges for treatment

Use diagnostic tests appropriately Retain expertise for culture When to change?

What is treatment failure?

What treatment?

Test of cure?

Appropriate diagnostic tests

Molecular detection



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

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 isolate

Tapsall 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:19833 Forsyth 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 documented

Unemo et al, Euro Surveill 2010;15(47):pii=19721 Unemo et al. Euro Surveill 2011;16(6):pii=19792U Unemo 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?

To maintain gonorrhoea as a treatable infection!

      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