antibiotic resistance in neisseria gonorrhoeae

Michelle ColeGUNA Summer Clinical Meeting 28th June 2013

Antibiotic resistance in Neisseria gonorrhoeae

Today’s presentation• Overview of gonorrhoea

• Disease• UK surveillance data

• Antibiotic resistance• Mechanisms

• Antibiotic resistance surveillance

• Public health response• Emerging resistance• Treatment failures• Treatment guidelines• Action plans

• Future challenges

2 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



Number of new diagnoses of selected STIs, GUM clinics, England : 2011-12

2011 2012 % Change

Chlamydia 186744 206,912 +11%*

Gonorrhoea 21,024 25,525 +21%

Syphilis 2,939 2,978 +1%

* 2011 – 2012 data not comparable

New diagnoses of syphilis, gonorrhoea, genital herpes and genital warts at GUM clinics by gender, 2003-2012, England


Treatment of gonorrhoea


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)

Resistance is common in N. gonorrhoeaeSulphonamides

Penicillin

Tetracycline

Ciprofloxacin

Cephalosporins

Azithromycin

PBP, efflux pumps, pili, porins

Β-lactamase (PPNG)

DNA topoisomerase & gyrase

Ribosomes, efflux pumps, pili, porins, TET-M (TRNG)

23S rRNA

PBP, efflux pumps, porins

What influences resistance


Misuse of antimicrobial agents

Treatment with sub inhibitory dosage

Inadequatedosage

OTC use Incomplete course of therapy (including sex before cleared infection)

Selection of mutants

Correct / continual use

Long term use as treatment of choice

Selective pressure

Mechanisms of antibiotic resistance


Impermeable to antibiotic

Modification

of target

Efflux of

antibiotic


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 Acquisition Plasmids Penicillin (PPNG): tem-1

(Haemophilus) Tetracycline (TRNG): tetM

(Streptococci)

Chromosomal Penicillin/Cephalosporin(Commensal Neisseriae)

SelectionHigh-level, single step Spectinomycin Azithromycin

Additive, multiple steps (mutations in multiple genes)

Penicillin Ciprofloxacin


N. gonorrhoeae treatments & resistance timelineSulphonamide

Penicillin

1930s 1940s

1943

Trea

tmen

t ava

ilabl

e (y

ear)

Resistance first document (year)

Unemo & Shafer, Ann. N. Y. Acad. Sci. 1230 (2011) E19-E28

Penicillin - mechanisms of resistance



• Porins

• Pili

Modification of target – penicillin binding proteins

Enzymatic modification/ degradation of antibiotic

•TEM-1 type β-lactamase plasmid

Penicillinase producing N. gonorrhoeae, high-level

Efflux of antibiotic – Upregulation of efflux pump


N. gonorrhoeae treatments & resistance timelineTr

eatm

ent a

vaila

ble

(yea

r)



Tetracycline

PBP, efflux pumps , pili, porins

Β-lactamase (PPNG)

1930s 1940s

1943 1950s1976

1962

Sulphonamide

Tetracycline - mechanisms of resistance



• Porins

• Pili

Modification of target – High-level plasmid mediated resistance – streptococcal tetM determinant on a conjugative plasmid; reduced binding to ribosomes




eatm

ent a

vaila

ble

(yea

r)



Tetracycline


Β-lactamase (PPNG)

1930s 1940s

1943 1950s1976

1962

Sulphonamide

Ciprofloxacin 1987

1985 Ribosomes, efflux pumps, pili, porins, TET-M (TRNG)

Ciprofloxacin - mechanisms of resistance


Modification of target

• DNA topoisomerase

• DNA gyrase

Both essential for cell division and growth.



eatm

ent a

vaila

ble

(yea

r)Resistance first docum

ent (year)


Tetracycline


Β-lactamase (PPNG)

1930s 1940s

1943 1950s1976

1962

Sulphonamide

Ciprofloxacin 1987

1985

Azithromycin

DNA topoisomerase / gyrase1991

1983


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



eatm

ent a

vaila

ble

(yea


ent (year)


Tetracycline


Β-lactamase (PPNG)

1930s 1940s

1943 1950s1976

1962

Sulphonamide

Ciprofloxacin 1987

1985

Azithromycin


1983

Ceftriaxone

23S rRNA

1980

Cefixime 1983

1999


Cephalosporins - mechanisms of resistance


Impermeable to antibiotic - Porins

• 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




eatm

ent a

vaila

ble

(yea


ent (year)


Tetracycline


Β-lactamase (PPNG)

1930s 1940s

1943 1950s1976

1962

Sulphonamide

Ciprofloxacin 1987

1985

Azithromycin


1983

Ceftriaxone

23S rRNA

1980

Cefixime 1983

1999

2001

2011

PBP, efflux pumps, porins


Super bug??

Neisseria gonorrhoeae: Susceptibility testing


• Susceptibility testing

• E-Test

• Disk Diffusion

• To predict therapeutic failure

• Categorise strains into :

• Sensitive

• Intermediate

• Resistance

• Category relates to chance of therapeutic failure

First-line therapy


Monitor trends in resistance

Monitor drift in susceptibility

Detect emergence of resistance

Inform treatment guidelines

Surveillance programmes

Local

National

RegionalGlobal

Gonococcal resistance to antimicrobials surveillance programme (GRASP)


•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

Newcastle

Leeds

Sheffield

Nottingham

Cambridge

Luton

Brighton

London (9)

Liverpool

Manchester

WolverhamptonBirmingham

Northampton

ReadingBristol

Cardiff

NewportGloucester

GRASP 2011


North East3.0%

Yorkshire & Humberside

9.9%

West Midlands

12.3%

EastMidlands

3.5%

East of England

1.8%

South West2.2%

South East4.6%

Wales4.3%

North West9.3%

London49.3%

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%


Ciprofloxacin resistance (MIC≥1mg/L) by gender and sexual orientation, 2000 - 2011

0

10

20

30

40

50

60

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Perc

enta

ge o

f ca

ses

Heterosexual Men MSM Women

Source: Gonococcal Resistance to Antimicrobial Surveillance Programme (GRASP)


Cefixime MIC (mg/L) by gender and sexual orientation, GRASP 2011


0

5

10

15

20

25

30

35

40

45

Per

cent

age

of C

ases

(wei

ghte

d)

.002 .004 .008 .015 .03 .06 .125 .25

GRASP 2011 (GUM Cases)Percentage of Cases by Cefixime MIC (mg/L) and Risk Group

Hetero Male Homo/Bi MaleFemale


Cefixime(MIC≥0.125mg/l) decreased susceptibility by gender and sexual orientation, 2004 - 2011


0

5

10

15

20

25

30

35

40

2004 2005 2006 2007 2008 2009 2010 2011

% D

ecre

ased

Sus

cepti

bilit

y

Heterosexual Men MSM Female


Ciprofloxacin by cefixime MIC (mg/L)


0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0.002 0.004 0.008 0.015 0.03 0.06 0.125 0.25Cefixime MIC mg/L

Cip Resistant Cip Sensitive


Ceftriaxone MIC (mg/L) by gender and sexual orientation, GRASP 2011


0

10

20

30

40

50

60

Per

cent

age

of C

ases

(wei

ghte

d)

Hetero Male Homo/Bi Male Female

GRASP 2011 (GUM Cases)Percentage of Cases by Ceftriaxone MIC (mg/L) and Risk Group

.002 .004 .008

.015 .03

Decreased susceptibility to cefixime (≥0.25mg/L) – Euro-GASP

2009 2010 2011

Location of published cefixime/ceftriaxone treatment failures

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

• 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.


Response to emerging and increasing resistance AND treatment failures

1. Update treatment guidelinesIn response to rise in resistance levels;

WHO >5% of general population CDC >3% in high risk groups

2. Monitor for treatment failures

3. European / WHO / CDC / GRASP response plans


Treatment guidelines 2004-2011

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



Prescribing practice and resistance trends, GRASP 2001-2011


0

5

10

15

20

25

30

35

40

0

10

20

30

40

50

60

70

80

90

100

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

% re

sist

ant

% p

atien

ts p

resc

ribed

antim

icro

bial

s

Cefixime Ceftriaxone Ciprofloxacin % Ciprofloxacin resistance (>=1mg/L) % Cefixime decreased susceptibility (>=0.125mg/L)

Introduction of cefixime/ceftriaxone

Ciprofloxacin prescribed

Ceftriaxone increased dose

Future treatment optionsSingle 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


Response to AMR GC


Public Health Agencies

Global

Regional

National

WHO Global Action Plan

GRASP and CDC Action Plan

ECDC Response Plan

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.



Case definition for confirmed/probable treatment failure

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


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


What is the Challenge?

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


To maintain gonorrhoea as a treatable infection!

Thanks………• For listening!

• To Cathy Ison and the GRASP team for additional slides

• To the GRASP and Euro-GASP collaborators


antibiotic resistance in neisseria gonorrhoeae

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