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Antimicrobial resistance in Neisseria gonorrhoeae
– epidemiology and diagnostics
Magnus Unemo, Ph.D., Assoc. Professor, Director
WHO Collaborating Centre for Gonorrhoea and other STIs
Swedish Reference Laboratory for Pathogenic Neisseria
Department of Laboratory Medicine, Microbiology
WHO Collaborating
Centre for Gonorrhoea
and other STIs
Örebro University Hospital, Sweden
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WHO`s global incidence estimates of non-viral,
treatable STIs (million adults, 2008)
Gonorrhoea – Major Public Health concern!
600
500
400
300
200
1. High incidence (21% increase since 2005!)
498.9
2. Severe complications, incl. PID, infertility, ectopic
pregnancy, increased HIV transmission
3. High cost – especially calculated as 276.4
“disabilityadjusted life years” (DALY; Ebrahim. STI. 2005)
4. Suboptimal diagnostics, case reporting, surveillance in
many105.7
countries 
incidences?
106.1
100
0
5. High antimicrobial resistance (AMR) and NO AMR
10.6
testing before treatment mainly worldwide!
Chlamydia
Gonorrhoea
Syphilis
WHO EURO: 3.4 million
Trichomoniasis
Total
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1943-mid 1980s
?
(Resistance selection! Not available!)
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Proportion of resistant N. gonorrhoeae
Euro-GASP (London, Örebro, Copenhagen) 2004-2011 (21 participating countries!)
70
2004 (965 isolates)
60
2006 (836 isolates)
2007 (1374 isolates)
Percentage
50
2008 (1284 isolates)
2009 (1366 isolates)
40
2010 (1766 Isolates)
2011 (1902 Isolates)
30
20
10
5%
0
Ciprofloxacin
PPNG
Azithromycin
2011 – 2 isolates with high-level AzR (>256 mg/L)
Spectinomycin - no resistance
Cefixime
PPNG – Penicillinase producing N. gonorrhoeae
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Decreased susceptibility to cefixime (MIC>0.125 mg/L)
- 2009
Euro-GASP (London, Örebro, Copenhagen)
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Decreased susceptibility to cefixime (MIC>0.125 mg/L)
- 2010
Euro-GASP (London, Örebro, Copenhagen)
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Decreased susceptibility to cefixime (MIC>0.125 mg/L)
- 2011
17 isolates with MIC≥0.5 mg/L!
Cefixime treatment failures
- Previously, verified treatment failures only
published from Japan (since about 10 years)!
Euro-GASP (London, Örebro, Copenhagen)
Source: ECDC unpublished
data
(21 participating
countries!)
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Decreased susceptibility to cefixime (MIC>0.125 mg/L)
- 2011
Cefixime treatment failures
- Previously, verified treatment failures only
published from Japan (since 2003)!
- 2010: First treatment failures, strictly verified
using WHO criteria, beyond Japan (in Norway)!
(Unemo, Golparian, Syversen, Vestrheim, Moi.
Euro Surveill. 2010)!
Euro-GASP (London, Örebro, Copenhagen)
Source: ECDC unpublished
data
(21 participating
countries!)
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Decreased susceptibility to cefixime (MIC>0.125
mg/L) 2010 and verified cefixime treatment failures
Unemo et al. Euro Surveill. 2010, Ison et al. Euro Surveill. 2011,
Unemo et al. Euro Surveill. 2011. Unemo et al. AAC. 2011
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Verified failures using cefixime (beyond Japan)
Country
Country of
exposure
MIC
(mg/L)
MLST/NGMAST
Reference
Norway
Philippines/
Spain/Norway
0.250.5*
ST1901/
ST1407
Unemo, et al. Euro
Surveill. 2010
United Kingdom
0.25
?/
ST3779/
ST3431
Ison, et al. Euro
Surveill. 2011
Austria
Germany
1.0*
ST1901/
ST1407
Unemo, et al. Euro
Surveill. 2011
France
France
4.0*
(XDR)
ST1901/
ST1407
Unemo, et al.
Antimicrob Agents
Chemother. 2011
Sweden
Japan/
Philippines/
Sweden
0.251.0*
ST1901/
ST1407,
other
Unemo, et al. To be
published
United
Kingdom
*Genetic resistance determinants elucidated!
Unemo and Nicholas. Future Microbiol. 2012
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Distribution of MIC for ceftriaxone
(Euro-GASP) - 2004-2011
60
2004 (965 isolates)
2006 (836 isolates)
50
2007 (1374 isolates)
First isolates identified
with decreased
susceptibility to
ceftriaxone (≥0.25 mg/L)
10 isolates from Austria
and Germany
2008 (1284 isolates)
2009 (1366 isolates)
40
2010 (1699 isolates)
%
2011 (1902 isolates)
30
20
10
0
<=0.002
0.004
0.008
0.016
0.032
MIC (mg/L)
0.064
0.125
0.25
0.5
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Distribution of MIC for ceftriaxone
(Euro-GASP) - 2004-2011
60
2004 (965 isolates)
Ceftriaxone
2006 (836 isolates)
50
2007 (1374 isolates) globally!
- Susceptibility decreasing
First Euro-GASP isolates
identified with decreased
2009 failures
(1366 isolates) of pharyngeal gonorrhoea
- Confirmed
treatment
40
susceptibility to
2010 (1699 isolates)
(Unemo, et al. Euro Surveill. 2011)
with ceftriaxone in Sweden
ceftriaxone (≥ 0.25 mg/L)
2011 (1902 isolates)
and Slovenia (Unemo, et al. Euro Surveill. 2012)
!
10 isolates
from Austria
30
and Germany
%
2008 (1284 isolates)
20
10
0
<=0.002
0.004
0.008
0.016
0.032
MIC (mg/L)
0.064
0.125
0.25
0.5
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Distribution of MIC for ceftriaxone EuroGASP,2004-2011
Ceftriaxone
60
2004 (965 isolates)
- Susceptibility decreasing
globally!
2006 (836 isolates)
50
2007 (1374 isolates)
- Confirmed treatment2008
failures
of pharyngealFirst
gonorrhoea
with
Euro-GASP
isolates
(1284 isolates)
identified with decreased
ceftriaxone (Unemo, et
Euro
2009al.
(1366
isolates) Surveill. 2011 and 2012)
%
40
susceptibility to
- H041: First highly 2011
resistant
strain (MIC=2-4
mg/L),
ceftriaxone
(≥ 0.25 mg/L)
(1902 isolates)
10 isolates
from
Austria
associated
with treatment failure, verified
in Japan
- XDR!
30
and Germany
2010 (1699 isolates)
(Ohnishi, et al. AAC. 2011)!
- F89
(MLST ST1901, NG-MAST ST1407): Highly resistant
20
strain (MIC=1-2 mg/L) confirmed in France - XDR! (Unemo,
et10al. AAC. 2011)! (Indistinguishable strain recently found in
Spain (Camara et al. JAC. 2012))
0
Gonorrhoea may become untreatable?
<=0.002
0.004
0.008
0.016
0.032
MIC (mg/L)
0.064
0.125
0.25
0.5
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Introduced treatment and emergence of resistance –
only 1-2 decades needed for international spread of AMR?
2021?
Unemo and Shafer. New York Acad Sci. 2011
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(WHO 2012;
Ndowa, Lustinarasimhan,
Unemo. STI.
2012. Editorial)
A
Available at: www.who.int/reproductivehealth/publications/rtis/9789241503501
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ECDC
Response Plan, 2012
ECDC: van de Laar M, Spiteri G,
Sfetcu O
Experts: Ison C, Unemo M, Cole M,
Hoffman S, Bignell C, Poder A
(IUSTI), Ndowa F (WHO)
STI network
STI coordination group
Available at: www.ecdc.europa.eu/en/publications/Publications/1206-ECDC-MDR-gonorrhoea-response-plan.pdf
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CDC, USA
Response Plan, 2012
Available at: www.cdc.gov/std/gonorrhea/default.htm
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Components of response plans
 Holistic views – prevention, diagnostics, treatment, etc.
 Improving diagnostics and surveillance of gonorrhoea
 Strengthening quality assured (2008 WHO strains (Unemo et al.
JAC. 2009) distributed worldwide) surveillance of antimicrobial
susceptibility
 Maintaining and developing capacity for culture and
susceptibility testing
 Establishing a strategy to timely detect treatment failures
(test of cure, case definitions and reporting)
 Recommended public health actions
 Increasing awareness
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WHO Global Gonococcal Antimicrobial
Surveillance Programme (GASP)
(Focal Centre: WHO Headquarter, Geneva)
Europe (53 countries)
(Magnus Unemo, Cathy Ison, ECDC)
GISP
(CDC [Gail Bolan],
USA)
SE Asia
(Manju Bala)
Africa
(David Lewis)
Latin America
(Jo-Anne Dillon)
Western Pacific
(Monica Lahra)
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WHO European region – 53 countries
(EU/EEA: 30 countries)
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Valid gonococcal AMR surveillance in ”East WHO Euro”?
(Unemo, Shipitsyna, Domeika. STI. 2010; and APMIS. 2011)
RU-GASP (WHO protocols)
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Russian Gonococcal Antimicrobial Susceptibility Program
(RU-GASP) – initiated in 2004 at CNIKVI, Moscow
Sex Transm Infect. 2008; 84:285-9
Euro Surveill. 2010
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IUSTI European Guidelines 2009
Uncomplicated anogenital gonorrhoea
in adults and adolescents
Recommended regimens
 Ceftriaxone, 250 mg intramuscular (IM) x1 OR
 Cefixime, 400 mg oral x1 OR
 Spectinomycin 2 g IM x1
Bignell. Int J STD AIDS. 2009
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2012 European Gonorrhoea Guidelines
Bignell and Unemo. Int J STD AIDS. Accepted
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Crucial research and
surveillance issues:
- Future treatment: New antimicrobials OR other
compounds, in vitro and in vivo clinical trials!
- Vaccine?
- Strict verification of treatment failures – magnitude of the
problem?, evidence-basis for recommended doses, resistance
breakpoints, genetic resistance determinants, etc.
- Genetic resistance determinants, genetic AMR testing
and molecular epidemiology (national and international
transmission of successful clones)
- Harmonize the phenotypic AMR methods (MIC
determination where possible!) and the breakpoints used!
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Agar dilution method=gold standard
1 mg/L
0.5 mg/L
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Etest
 Highly comparable to
agar dilution, and more
practical, i.e., if limited
number of strains!
 Medium: Difco GC Agar +
1% IsoVitalex/Vitox
(manufacturer’s instruction)
 QC: 2008 WHO N.
gonorrhoeae strains
(Unemo, et al. JAC. 2009)
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Disc diffusion (suboptimal for gonococci;
zone size does commonly not reflect MIC!)
CDS: Annular radius
Medium
Columbia agar base (Oxoid) with 8%
horse blood "chocolated" at 70C for
30 minutes.
Other media need evaluation!
 QC: 2008 WHO N. gonorrhoeae
strains (Unemo, et al. JAC. 2009)
CLSI: Zone diameter
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Evaluation of Neisseria gonorrhoeae AMR testing
methods – ideal method and is any disc diffusion
method sufficient?
Larsson M, Golparian D, Matuschek E,
Kahlmeter G, Unemo M
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Acknowledgement and In Memoriam
Excellent
mentor, scientist
and friend!
Professor John Tapsall, 1945 – December 2010
WHO CC for STDs, Sydney, Australia