1. Antibiotic resistance in Neisseria gonorrhoeae
Michelle Cole
GUNA Summer Clinical Meeting
28th June 2013

2. Today’s presentation Overview of gonorrhoea Antibiotic resistance
Disease
UK surveillance data
Antibiotic resistance
Mechanisms
Antibiotic resistance surveillance
Public health response
Emerging resistance
Treatment failures
Treatment guidelines
Action plans
Future challenges
Antibiotic resistance in N. gonorrhoeae

3. Gonorrhoea Neisseria gonorrhoeae (gonococcus / GC)
Gram negative diplococci
Obligate human pathogen
Causes primarily a mucosal infection
Colonises the urogenital tract / pharynx / rectum = discharge / pain on urination
Is asymptomatic in many women = infertility / pelvic inflammatory disease
Conjunctivitis
Rarely invades to the blood = disseminated gonococcal infection
Facilitate transmission of HIV
Antibiotic resistance in N. gonorrhoeae

4. Number of new diagnoses of selected STIs, GUM clinics, England : 2011-12
2012
% Change
Chlamydia
186744
206,912
+11%*
Gonorrhoea
21,024
25,525
+21%
Syphilis
2,939
2,978
+1%
* 2011 – 2012 data not comparable
Antibiotic resistance in N. gonorrhoeae

5. New diagnoses of syphilis, gonorrhoea, genital herpes and genital warts at GUM clinics by gender, , England
Antibiotic resistance in N. gonorrhoeae

6. Treatment of gonorrhoea
Resistance is common in N. gonorrhoeae
Individual patient management
Interrupt transmission
Single dose used to aid compliance
Often administered before lab results known
Co-treatment for chlamydial infection advised
National/international guidelines informed by surveillance data
To achieve >95% therapeutic success (WHO)
Sulphonamides
PBP, efflux pumps, pili, porins
Penicillin
Β-lactamase (PPNG)
Ribosomes, efflux pumps, pili,
porins, TET-M (TRNG)
Tetracycline
DNA topoisomerase &
gyrase
Ciprofloxacin
Azithromycin
23S rRNA
Cephalosporins
PBP, efflux pumps,
porins
Antibiotic resistance in N. gonorrhoeae

7. What influences resistance
Misuse of antimicrobial agents
Treatment with sub inhibitory dosage
Inadequate
dosage
OTC use
Incomplete course of therapy (including sex before
cleared infection)
Correct / continual use
Long term use as
treatment of choice
Selective pressure
Selection of mutants
Antibiotic resistance in N. gonorrhoeae

8. Mechanisms of antibiotic resistance
Modification
of target
Impermeable to antibiotic
Efflux of
antibiotic
Antibiotic resistance in N. gonorrhoeae

9. Antibiotic resistance in N. gonorrhoeae
Versatile organism.
Highly competent for genetic exchange
Other Neisseria (e.g. in throat)
Mixed infection is thought to occur frequently.
Adept at developing mechanisms of resistance to therapeutic agents.
Antibiotic resistance in N. gonorrhoeae

10. Antibiotic resistance in N. gonorrhoeae
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 (mutations in multiple genes)
Penicillin
Ciprofloxacin
Antibiotic resistance in N. gonorrhoeae

11. N. gonorrhoeae treatments & resistance timeline
Sulphonamide
1930s
1940s
Penicillin
1943
Resistance first document (year)
Treatment available (year)
Unemo & Shafer, Ann. N. Y. Acad. Sci (2011) E19-E28
Antibiotic resistance in N. gonorrhoeae

12. Penicillin - mechanisms of resistance
Modification of target – penicillin binding proteins
Enzymatic modification/ degradation of antibiotic
TEM-1 type β-lactamase plasmid
Penicillinase producing N. gonorrhoeae, high-level
Impermeable to antibiotic
Porins
Pili
Efflux of antibiotic – Upregulation of efflux pump
Antibiotic resistance in N. gonorrhoeae

13. N. gonorrhoeae treatments & resistance timeline
Sulphonamide
1930s
1940s
PBP, efflux pumps , pili, porins
1950s
1943
1976
Β-lactamase (PPNG)
Tetracycline
1962
Resistance first document (year)
Treatment available (year)
Unemo & Shafer, Ann. N. Y. Acad. Sci (2011) E19-E28
Antibiotic resistance in N. gonorrhoeae

14. Tetracycline - mechanisms of resistance
Modification of target – High-level plasmid mediated resistance – streptococcal tetM determinant on a conjugative plasmid; reduced binding to ribosomes
Impermeable to antibiotic
Porins
Pili
Efflux of antibiotic – Upregulation of efflux pump
Antibiotic resistance in N. gonorrhoeae

15. N. gonorrhoeae treatments & resistance timeline
Sulphonamide
1930s
1940s
PBP, efflux pumps, pili, porins
1950s
1943
1976
Β-lactamase (PPNG)
Tetracycline
Ribosomes, efflux pumps, pili,
porins, TET-M (TRNG)
1962
1985
Resistance first document (year)
Ciprofloxacin
1987
Treatment available (year)
Unemo & Shafer, Ann. N. Y. Acad. Sci (2011) E19-E28
Antibiotic resistance in N. gonorrhoeae

16. Ciprofloxacin - mechanisms of resistance
Modification of target
DNA topoisomerase
DNA gyrase
Both essential for cell division and growth.
Antibiotic resistance in N. gonorrhoeae

17. N. gonorrhoeae treatments & resistance timeline
Sulphonamide
1930s
1940s
PBP, efflux pumps, pili, porins
1950s
1943
1976
Β-lactamase (PPNG)
Ribosomes, efflux pumps, pili,
porins, TET-M (TRNG)
Tetracycline
1962
1985
Resistance first document (year)
Ciprofloxacin
1987
1991
DNA topoisomerase / gyrase
Treatment available (year)
Azithromycin
1983
Unemo & Shafer, Ann. N. Y. Acad. Sci (2011) E19-E28
Antibiotic resistance in N. gonorrhoeae

18. Azithromycin - mechanisms of resistance
Azithromycin not recommended first line therapy but 2g is effective. Use for co-treatment (1g) for chlamydia (40% co-infected)
Modification of ribosomal target
23S RNA methylases
Mutations in 23S rRNA alleles
High-level >256 mg/L from mutations in at least 3 / 4 alleles. Sporadic worldwide detection
Crystal violet tolerant
Efflux of antibiotic – Upregulation of efflux pump
Antibiotic resistance in N. gonorrhoeae

19. N. gonorrhoeae treatments & resistance timeline
Sulphonamide
1930s
1940s
PBP, efflux pumps, pili, porins
1950s
1943
1976
Β-lactamase (PPNG)
Ribosomes, efflux pumps, pili,
porins, TET-M (TRNG)
Tetracycline
1962
1985
Resistance first document (year)
DNA topoisomerase / gyrase
Ciprofloxacin
1987
1991
Treatment available (year)
Azithromycin
1983
1999
23S rRNA
Cefixime
1983
Ceftriaxone
1980
Unemo & Shafer, Ann. N. Y. Acad. Sci (2011) E19-E28
Antibiotic resistance in N. gonorrhoeae

20. Cephalosporins - mechanisms of resistance
Modification of target – penicillin binding protein encoded by penA.
Mosaic penA gene fragments from other commensal Neisseria spp
Usually found in the throat
Naturally less susceptible to cephalosporins
Impermeable to antibiotic - Porins
Efflux of antibiotic – Upregulation of efflux pump
Antibiotic resistance in N. gonorrhoeae

21. N. gonorrhoeae treatments & resistance timeline
Sulphonamide
1930s
1940s
PBP, efflux pumps, pili, porins
1950s
1943
1976
Β-lactamase (PPNG)
Ribosomes, efflux pumps, pili,
porins, TET-M (TRNG)
Tetracycline
1962
1985
Resistance first document (year)
DNA topoisomerase / gyrase
Ciprofloxacin
1987
1991
Treatment available (year)
Azithromycin
1983
1999
23S rRNA
Cefixime
1983
2001
PBP, efflux pumps, porins
2011
Ceftriaxone
1980
Super bug??
Unemo & Shafer, Ann. N. Y. Acad. Sci (2011) E19-E28
Antibiotic resistance in N. gonorrhoeae

22. Neisseria gonorrhoeae: Susceptibility testing
E-Test
Disk Diffusion
To predict therapeutic failure
Categorise strains into :
Sensitive
Intermediate
Resistance
Category relates to chance of therapeutic failure
Antibiotic resistance in N. gonorrhoeae

23. First-line therapy Surveillance programmes
Monitor trends in resistance
Monitor drift in susceptibility
Detect emergence of resistance
Inform treatment guidelines
Local
National
Regional
Global
Antibiotic resistance in N. gonorrhoeae

24. Gonococcal resistance to antimicrobials surveillance programme (GRASP)
Newcastle
Leeds
Sheffield
Nottingham
Cambridge
Luton
Brighton
London (9)
Liverpool
Manchester
Wolverhampton
Birmingham
Northampton
Reading
Bristol
Cardiff
Newport
Gloucester
Began in 2000
26 participating GUM clinics and laboratories
Regional representation
3 month collection each year
One isolate from consecutive patients
Monitors resistance to:
Penicillin
Tetracycline
Ciprofloxacin
Azithromycin
Spectinomycin
Ceftriaxone and cefixime
Antibiotic resistance in N. gonorrhoeae

25. GRASP 2011
1480 samples were collected from patients attending GRASP GUM clinics in 2011
Almost half of which were from the London region (49.3%)
48.8% (665) of patients were men who have sex with men (MSM), 28.4 (387) were heterosexual men and 22.9% (312) were women.
Retrieval rate was 88.5%
Data completeness varied slightly >85%
Antibiotic resistance in N. gonorrhoeae

26. Ciprofloxacin resistance (MIC≥1mg/L) by gender and sexual orientation, 2000 - 2011
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
Antibiotic resistance in N. gonorrhoeae
Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

27. Cefixime MIC (mg/L) by gender and sexual orientation, GRASP 2011
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
Antibiotic resistance in N. gonorrhoeae
Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

28. Cefixime(MIC≥0.125mg/l) decreased susceptibility by gender and sexual orientation, 2004 - 2011
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
Antibiotic resistance in N. gonorrhoeae
Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

29. Ciprofloxacin by cefixime MIC (mg/L)
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
Antibiotic resistance in N. gonorrhoeae
Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

30. Ceftriaxone MIC (mg/L) by gender and sexual orientation, GRASP 2011
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
Antibiotic resistance in N. gonorrhoeae
Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

31. Decreased susceptibility to cefixime (≥0.25mg/L) – Euro-GASP
Countries with strains that exhibit decreased-susceptibility to cefixime (<5%)
Countries with strains that exhibit decreased-susceptibility to cefixime (≥5%)
Countries with no strains that exhibit decreased-susceptibility to cefixime
2010
2011
2009
Location of published cefixime/ceftriaxone treatment failures
All ST1407 or closely related
Pre / post treatment isolate not always available

32. Global surveillance WHO Western Pacific Region GASP.
WHO South-East Asia Region
Gonococcal Isolate Surveillance Program (GISP) – USA.
Americas and the Caribbean.
Euro-GASP / WHO Europe (53 countries).
National programmes, i.e GRASP (E&W), Sweden, Denmark, Belgium, the Netherlands, Australia, Russia.
Antibiotic resistance in N. gonorrhoeae

33. Response to emerging and increasing resistance AND treatment failures
Update treatment guidelines
In response to rise in resistance levels;
WHO >5% of general population
CDC >3% in high risk groups
Monitor for treatment failures
European / WHO / CDC / GRASP response plans
Antibiotic resistance in N. gonorrhoeae

34. Treatment guidelines 2004-2011 Since 2011 First-line
Cefixime, 400mg (Cefotaxime).
Ceftriaxone, 125 or 250mg.
Spectinomycin 2g.
Since 2011
First-line:
Ceftriaxone – 500mgs IM + Azithromycin 1g
Second-line:
Cefixime 400mgs + Azithromycin, 1g
Antibiotic resistance in N. gonorrhoeae

35. Prescribing practice and resistance trends, GRASP 2001-2011
Ceftriaxone increased dose
Ciprofloxacin prescribed
Introduction of cefixime/ceftriaxone
Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)
Antibiotic resistance in N. gonorrhoeae
Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)

36. Future treatment options
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
Antibiotic resistance in N. gonorrhoeae

37. Response to AMR GC Public Health Agencies Global Regional National
WHO Global Action Plan
ECDC Response Plan
Global
Regional
GRASP and CDC Action Plan
National
Antibiotic resistance in N. gonorrhoeae

38. GRASP Action Plan
Provision of robust and timely surveillance data on antimicrobial resistant gonorrhoea in England & Wales.
Advising on appropriate changes to the national guidelines for the management of gonorrhoea.
Giving technical advice to clinical microbiologists on appropriate methods for detection of decreased susceptibility or resistant gonococcal isolates in the laboratory.
Providing support to allow rapid detection of treatment failures to cefixime, ceftriaxone and azithromycin.
Communication to all healthcare professionals and at risk groups to raise awareness of the threat of untreatable gonorrhoea.
Promote prevention messages to enhance public health control of gonorrhoea.
Antibiotic resistance in N. gonorrhoeae

39. Case definition for confirmed/probable treatment failure
Antibiotic resistance in N. gonorrhoeae

40. Monitoring treatment failure
Launched in May 2011
On line submission, through GUMCAD portal
In first year:12 cases reported, 10 from MSM, 4/12 cases seen before guideline change
Reporting of failures retrospective, needs to be real-time
Plan to modify form and send monthly alert to GUM clinics
Lack of isolates data to obtain laboratory confirmation – archiving of isolates
Need to link more effectively to microbiologists
?Reporting mechanism for microbiologists
Antibiotic resistance in N. gonorrhoeae

41. Technical advice to laboratories
Retain skills in GC isolation
Provides viable culture for GC sensitivity testing
Essential for emerging resistance/treatment failure
Issues
Requires significant resources
Requires invasively taken specimen
Availability of chaperone
Intolerant to delays in transportation to lab
Antibiotic resistance in N. gonorrhoeae

42. What is the Challenge?
To maintain gonorrhoea as a treatable infection!
Use new diagnostic tests appropriately
Retain expertise for culture
Timely, representative and global surveillance data
Be vigilant for emerging resistance / treatment failures
Use appropriate treatment and consider alternatives:
Higher and multiple doses
New / old / combination therapies
Anti-infectives / vaccines
Antibiotic resistance in N. gonorrhoeae

43. Thanks……… For listening!
To Cathy Ison and the GRASP team for additional slides
To the GRASP and Euro-GASP collaborators
Antibiotic resistance in N. gonorrhoeae