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

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

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

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

New diagnoses of syphilis, gonorrhoea, genital herpes and genital warts at GUM clinics by gender, 2003-2012, England Antibiotic resistance in N. gonorrhoeae

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

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

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

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

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

N. gonorrhoeae treatments & resistance timeline Sulphonamide 1930s 1940s Penicillin 1943 Resistance first document (year) Treatment available (year) Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

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

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. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

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

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. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

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

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. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

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

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. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

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

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. 1230 (2011) E19-E28 Antibiotic resistance in N. gonorrhoeae

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

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

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

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

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)

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)

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)

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)

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)

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

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

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

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

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)

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

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

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

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

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

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

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

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