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JAC Advance Access originally published online on June 27, 2006
Journal of Antimicrobial Chemotherapy 2006 58(3):580-586; doi:10.1093/jac/dkl264
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Comparability of laboratory diagnosis and antimicrobial susceptibility testing of Neisseria gonorrhoeae from reference laboratories in Western Europe

C. A. Ison1,*, I. M. C. Martin1, C. M. Lowndes2, K. A. Fenton2,{dagger} on behalf of the European Surveillance of Sexually Transmitted Infections (ESSTI) Network

1 Sexually Transmitted Bacteria Reference Laboratory, Health Protection Agency Centre for Infections 61 Colindale Avenue, London NW9 5HT, UK 2 Department of HIV and Sexually Transmitted Infections, Health Protection Agency Centre for Infections 61 Colindale Avenue, London NW9 5HT, UK

*Corresponding author. Tel: +44-208-327-6462; Fax: +44-208-327-6081; E-mail: catherine.ison{at}hpa.org.uk

Received 27 March 2006; returned 19 April 2006; revised 31 May 2006; accepted 1 June 2006


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
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Objectives: The aim of this study was to obtain information on the comparability of methods for the laboratory diagnosis of bacterial sexually transmitted infections (STIs) that contribute to the surveillance data in the European Union (EU) and Norway. Surveillance of bacterial STIs is important across Europe because of the movement of individuals between countries at a time when STI incidence appears to be increasing in many countries.

Methods: Cross-sectional survey using a questionnaire, to provide information on laboratory methods for the diagnosis of gonorrhoea, and a panel of strains of Neisseria gonorrhoeae, to compare susceptibility testing, was circulated to laboratories in the EU and Norway.

Results: The questionnaire revealed marked diversity in the methodologies used for the laboratory diagnosis of gonorrhoea across Europe. Fourteen laboratories participated in an exchange of gonococcal strains to assess the methodology in current use for susceptibility testing. The methods included disc diffusion and determination of the minimum inhibitory concentration (MIC) using agar dilution and/or Etest. There was no common method used, each centre varied from another by at least one procedure. Overall agreement using all methods was >70%, being highest for ceftriaxone and lowest for tetracycline. Disc diffusion gave the lowest agreement with the consensus compared with determination of MIC by either agar dilution or Etest.

Conclusions: A variety of methods were used across the EU and Norway for the laboratory diagnosis and susceptibility testing and resulted in poor concordance between laboratories on the definition of resistant N. gonorrhoeae. This suggests that there is a need for greater standardization of methodology that provides surveillance data in the EU and Norway.

Keywords: gonorrhoea , surveillance , quality assurance


   Introduction
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 Introduction
Methods
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European-level surveillance of sexually transmitted infections (STIs) is necessary to allow comparison of trends and to aid the implementation of regional and country-level intervention programmes. This is of particular importance as the number of cases of bacterial STIs, gonorrhoea, syphilis and chlamydial infection continues to increase in many countries.1 The trends in STIs in different countries across the European Union (EU) may be influenced by common factors and by the increasing movement between countries, fluidity of borders and close proximity to the epidemics of STIs and HIV in Eastern Europe.1

Increases in the incidence of reported gonococcal infections are of particular concern because of the emergence of high-level resistance to ciprofloxacin, which has been used as the therapy of choice in many countries.2 This has been highlighted by the results from the World Health Organization (WHO) Western Pacific Gonococcal Antimicrobial Surveillance Programme where levels of resistance to ciprofloxacin are above 90% in many countries.3 National programmes for surveillance of antimicrobial resistance in Neisseria gonorrhoeae exist in some countries in the EU,4–13 which inform therapy in individual countries. However, there is little information available regarding the comparability of susceptibility testing methods and hence the rates of antimicrobial resistance.

As part of an EU-funded project (European Surveillance of Sexually Transmitted Infections, ESSTI) a survey was undertaken to identify reference or specialist laboratories across Europe and to perform a quality assessment of antimicrobial susceptibility testing for gonorrhoea.


   Methods
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 Methods
Results
 Discussion
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Network of laboratories

A single laboratory responsible for reference or specialist work for N. gonorrhoeae was identified in each of 15 countries across the EU and in Norway.

Questionnaire

A questionnaire to establish the methodologies used for the isolation, identification and susceptibility testing of N. gonorrhoeae was constructed and circulated to all centres.

Quality assessment of susceptibility testing

A panel of 30 cultures of N. gonorrhoeae, which consisted of 10 strains in triplicate, was circulated frozen on cryobeads, to 14 laboratories (Norway did not participate) in June 2003. The strains were randomized and the triplicates blinded to the testing laboratory. The panel included strains exhibiting resistance to the antimicrobial agents most commonly used for therapy. Each laboratory agreed to test all strains using the current methodology in routine use in their laboratory and to include a core set of antimicrobial agents, penicillin, ciprofloxacin, tetracycline and a cephalosporin.

Analysis

The responses to the questionnaire were collated manually. The results of the susceptibility testing of the panel of gonococcal cultures exchanged between laboratories were reported both as category of susceptibility, resistant, susceptible or intermediate (where appropriate) and as MIC or zone around the disc using the definitions used routinely by each laboratory. Results were entered into an Excel spreadsheet and transferred electronically to the central laboratory. Before analysis, each centre was given a unique identifier in order to blind the source of the results. Analysis was performed using category of susceptibility only. Consensus was defined as the majority result by category or MIC result. Each centre also submitted details of the methodology used for testing and for definitions of the categories in addition to the initial questionnaire.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Transparency declarations
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Network of laboratories

It was possible to identify laboratories in 15 countries across the EU and Norway that are reference or specialist centres for the laboratory diagnosis of gonorrhoea. Laboratories in eight countries reported that they are designated as national reference laboratories (Belgium, Denmark, Finland, France, Greece, Scotland, Spain, Sweden), two are regional specialist laboratories (The Netherlands, Portugal) and five are specialist laboratories (Austria, England, Germany, Italy, Norway).

Questionnaire

Isolation and identification of N. gonorrhoeae. Of the 15 laboratories who completed the questionnaire, eight received clinical specimens, with numbers ranging from 10 to 14 500 specimens per year. Thirteen laboratories received cultures, ranging from 30 up to 1000 specimens per year. There was great diversity in the number of laboratories referring to these laboratories ranging from 2 to 230. A wide range of media was being used for isolation of N. gonorrhoeae, including GC agar (7 centres), Columbia agar (1) and chocolate agar prepared in house or commercially (6). A range of different supplements was used either alone or in combination, yeast autolysate (2), IsoVitaleX (3), Vitox (3), Polyvitex (2), Kellogg's supplements (1), blood (8), haemoglobin (2) and serum (2). Antibiotics used for selection included vancomycin (8) (or lincomycin, 3), colistin (9), trimethoprim (6) and amphotericin (6) or nystatin (4). Data were missing for one centre. Incubation was undertaken in 5% carbon dioxide in 11 centres, 8% carbon dioxide in one centre and in a candle jar in two centres. Identification was undertaken in all laboratories and was predominantly oxidase and Gram stain together with coagglutination reagents (7), carbohydrate utilization (7) and kits for identification (5).

Susceptibility testing

Susceptibility testing was performed routinely in 13 of the 15 centres. All of these laboratories used the chromogenic cephalosporin nitrocefin for detecting ß-lactamase production, while disc diffusion (7/13) and Etest (9/13) were the most popular methods for susceptibility testing. More than one method was sometimes used. When asked if a reference method was being used, 9 of 13 laboratories reported using the NCCLS method,14 now known as CLSI and 5 of these reported using the ATCC 49226 strain as a control. A wide range of antimicrobial agents were being tested across the laboratories but most were testing penicillin and ciprofloxacin, the agents most frequently used as first-line therapy. Of the 15 laboratories that responded to this questionnaire, eight participated in an external QA, five in a surveillance programme and 10 organized a surveillance programme.

Quality assessment of susceptibility testing

Twelve of the 14 laboratories that participated in the quality assessment programme retrieved and tested the panel of 30 cultures, and the remaining two laboratories retrieved and tested 29 strains each, resulting in a total of 418 strains tested. The panel of strains with different antimicrobial susceptibility profiles was chosen at one centre but when the results were analysed the consensus or majority result was used. The mode of susceptibility testing varied between laboratories and included disc testing (3 centres) and determination of the MIC by Etest (ET) or agar dilution (AD).

Susceptibility testing was performed using disc diffusion in three laboratories. The agar medium used was either chocolatized blood agar (two centres) or GC agar base supplemented with 1% IsoVitaleX (1). Gonococcal suspensions were prepared in saline (3) either using 50–100 colonies (1) or to a density equivalent to a 0.5 MacFarland turbidity standard (2). All centres read the results after 24 h incubation at 36–37°C, using various breakpoints to determine category of susceptibility (Table 1).


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  		Table 1. Breakpoints used for disc diffusion

 
Eleven centres determined the MIC, five using agar dilution and six using Etests. The medium used for agar dilution was predominantly GC agar base (4) supplemented with either 1% Vitox (1), Kellogg's supplement (2) or 10% horse blood, 2.5% yeast dialysate and 1% glucose (1). One centre used Diagnostic Sensitivity Agar (DST) supplemented with 5% lysed horse blood and 1% IsoVitaleX. Gonococcal suspensions were prepared in saline (4) or Mueller–Hinton broth (1) to produce a final inoculum of 103 (1), 104 (3) or 105 colony forming units (cfu) (1). The centres using Etests used chocolatized blood agar alone (1) or supplemented with Polyvitex (1) or GC agar supplemented with Vitox (2) or 1% IsoVitaleX alone (1) or with 1% haemoglobin (1). Gonococcal suspensions were prepared in saline (3), water (1), phosphate-buffered saline (1) or nutrient broth (1) to a density equivalent to 0.5 MacFarland turbidity standard (4), 2.0 MacFarland turbidity standard (1) or to produce a semi-confluent growth (1). Each centre using either agar dilution or Etests read the results after 24 h at 36–37°C. The breakpoints used for categorization of susceptibility used by the majority of these 11 centres for susceptible, intermediate resistance and resistant were for penicillin, ≤0.06 mg/L, 0.12–1 mg/L and ≥2 mg/L; for tetracycline, ≤0.25 mg/L, 0.5–1 mg/L and ≥2 mg/L; and for ciprofloxacin, ≤0.06 mg/L, 0.12–0.5 mg/L and ≥1.0 mg/L. Results for ceftriaxone were determined using a breakpoint of ≤0.25 mg/L for susceptible strains, no resistance was encountered. Exceptions to these breakpoints to define resistance were for penicillin ≥1 mg/L (two centres) and for ciprofloxacin 0.5 mg/L (1). All 14 centres differed in the methodology used by at least one procedure.

The panel of gonococcal strains tested exhibited a range of susceptibility to therapeutic agents for gonorrhoea (Table 2) as determined by the consensus results. The intra-laboratory concordance for the categories assigned for the triplicates for each of the 10 strains was high, penicillin [127 of 138 (93%), tetracycline (111 of 138, 80%), ciprofloxacin (127 of 138, 93%) and ceftriaxone (127 of 138, 92%)]. The overall concordance, which reflects both intra- and inter-centre variation, using all methods and a total of 418 cultures was over 70%, being highest for ceftriaxone (93%) and lowest for tetracycline (72%) (Table 3). Disc diffusion, used by three centres testing a total of 90 cultures, gave the lowest overall concordance for each of the antimicrobial agents, penicillin (86%), tetracycline (66%), ciprofloxacin (62%) and ceftriaxone (74%). This compared with concordance obtained by MIC which was used at 11 centres (AD at 5 centres, 149 cultures and ET at 6 centres, 179 cultures), of penicillin (AD 88%, ET 90%), tetracycline (AD 89%, ET 78%), ciprofloxacin (AD 93%, ET 88%) and ceftriaxone (AD 100%, ET 99%) (Table 3). Comparison of each category of susceptibility, (susceptible, intermediate resistant, and resistant), for the total cultures (418) tested by each method to the category agreed by the consensus showed that determination of the MIC by either method gave the highest agreement for ceftriaxone, ciprofloxacin, and tetracycline but not for penicillin (Table 4). Disc diffusion gave results closest to the consensus by all methods for penicillin. Strains defined as showing intermediate resistance were the most variable by all methods (Table 4).


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  		Table 2. Characteristics of panel of gonococcal strains [consensus MIC (and range) in mg/L]

 

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  		Table 3. Consensus by category for each strain for penicillin, tetracycline, ciprofloxacin and ceftriaxone (% concordance)

 

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  		Table 4. Concordance by method compared to overall consensus by all methods (%)

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Transparency declarations
 References
 
In establishing a microbiology network across the EU our first task was to identify reference or specialist centres for N. gonorrhoeae in each of the countries. The network now includes 15 centres of which 9 are recognized national reference laboratories. The remaining six laboratories are recognized as specialist or regional laboratories with expertise in the laboratory diagnosis of N. gonorrhoeae. However, there may be other laboratories within these countries with similar expertise that are not currently part of the network.

A questionnaire was circulated to each of the centres in the network to establish the type of reference or specialist service offered. It was evident that the number of laboratories referring to each of the network laboratories varied greatly, as did the number of specimens or gonococcal strains received for testing. This highlights the diversity in the laboratory services offered across Europe, possibly reflecting differences in the prevalence of gonorrhoea and hence the need for national reference laboratories. The methodology used for the isolation and identification of N. gonorrhoeae did show variation but all the techniques used were appropriate for the laboratory diagnosis of N. gonorrhoeae. However, the questionnaire revealed differences between laboratories in the methodology used for susceptibility testing of N. gonorrhoeae. There was no European-wide quality assessment programme to monitor this diversity, although some laboratories participated in the NEQAS scheme, which tests a few strains each year. There was also a lack of control strains being regularly used for quality control except for ATCC 49226, which is a fully susceptible strain of N. gonorrhoeae.

Resistance to therapeutic agents for gonorrhoea, such as penicillin and ciprofloxacin, has been increasing in many parts of the world3 and presents a major threat to the control of gonorrhoea because there are limited alternative agents available and a vaccine is not a realistic possibility. One of the aims of the ESSTI programme is to compare surveillance data for STIs across the EU and Norway including the prevalence of antimicrobial-resistant gonorrhoea during a time of changing epidemiology.4 The first step in this comparison is to gain an understanding of the effect of the differences in methodology on the definition of a resistant strain. In order to achieve this an assessment of susceptibility testing for N. gonorrhoeae was performed using the methodology in current use in each laboratory.

The quality assessment programme was designed to monitor differences both between and within laboratories by circulating a panel of 10 strains, to give inter-laboratory variation, provided in triplicate, to give intra-laboratory variation. Each laboratory was also asked to provide details of the methodology used (in addition to that provided for the questionnaire). The results were analysed by use of categories, susceptible or resistant, and intermediate resistance or reduced susceptibility where appropriate. This allowed a comparison of different methods, zone sizes for disc testing, and MICs for agar dilution and Etest, with varying breakpoints even within each method. The aim of this study was to compare the results from all centres to give information on the variation between centres and methodology, rather than to a single reference centre and hence the results were expressed as the consensus or majority result. A total of 14 laboratories took part in this assessment and there was no common method used. The overall concordance between all methods was ≥79% for the agents used for therapy, penicillin, ciprofloxacin and ceftriaxone, which suggests that there is a need for greater standardization to produce more comparable results. The greatest variation comparing all methods was found for tetracycline and the greatest agreement was seen between determination of the MIC by agar dilution and Etest, being ≥88% for all antimicrobial agents. However, in order to undertake this analysis it was necessary to assimilate the results to a single dilution series as this differed between laboratories using agar dilution and the Etest. In order to achieve agreed cut-offs to define categories using MIC it will be necessary for laboratories to use the same dilution series. Etests are used widely in Europe and offer a simple method particularly for laboratories testing low numbers of strains and a quick result when testing single strains. However, agar dilution is likely to remain the method of choice for many reference centres because it is more time and cost-effective for testing large numbers of strains necessary for surveillance programmes.

Three centres used disc diffusion and this method gave the greatest variability for all four antimicrobial agents tested. There was also considerable variation in the zone sizes used to define the categories, the disc content and methodology used. Disc diffusion is a method that is inexpensive and rapid to perform and is often used in diagnostic laboratories for testing clinical isolates for individual patient management. However, this study demonstrated that a number of strains were categorized as resistant by disc diffusion that the consensus result found susceptible and therefore it would seem appropriate to modify the interpretative criteria to avoid errors or to confirm any resistant results using Etest. Reference laboratories involved in surveillance studies should determine the MIC using either agar dilution or Etest.

Susceptibility testing requires internal controls to monitor the performance of the testing methodology. The use of standardized controls allows comparison of results within a centre over time and comparability of results between centres. N. gonorrhoeae (ATCC 49226) is a fully susceptible isolate and is recommended by NCCLS, and was the control strain most often used by centres in this study. However, it is not suitable for use as a control strain for high-level resistance to antimicrobial agents. The WHO issue a range of control strains (WHO A–H) and these strains are appropriate for penicillin, tetracycline, spectinomycin and intermediate resistance to ciprofloxacin. However, this panel of strains was compiled before additional antimicrobial agents, such as ciprofloxacin and azithromycin, were available for the treatment of gonorrhoea and do not exhibit the appropriate resistance patterns to act as control strains for these antimicrobial agents. The panel of strains used in this study will form the basis for a new set of quality control strains to be used by individual laboratories in Europe as internal quality controls to monitor the performance of susceptibility testing in their laboratories. However, a number of the strains exhibited intermediate resistance or levels near a breakpoint, which may have contributed to the lack of concordance between the results obtained at different centres. The choice of strains for any quality control panel is crucial and should be carefully considered.

The ESSTI programme has established a network of laboratories that are reference or specialist centres for the laboratory diagnosis of gonorrhoea. This network did not exist prior to this programme and the work described is the first step in establishing a European Gonococcal Antimicrobial Susceptibility Programme (EuroGASP). The high levels of ciprofloxacin resistance among N. gonorrhoeae isolated in many countries in Europe, as well as in many other parts of the world, highlight the need for continued surveillance to detect the possible emergence of resistance to the third-generation cephalosporins. EuroGASP aims to provide training programmes, quality assessment programmes and sentinel surveillance studies in the future.


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None to declare.


   Footnotes
 
{dagger}Members are listed in the Acknowledgements section. Back


   Acknowledgements
 
Financial support for this study was provided by the European Commission (DG SANCO), Agreement No. S12.325878 (2001CVG4-018): ESSTI European Surveillance of Sexually Transmitted Infections.

We thank all the microbiology members of ESSTI for participating in the surveillance project: Austria: Angelika Stary, Outpatients centre for infectious venereo dermatological diseases, Vienna. Belgium: Marjan van Esbroeck, Centraal Laboratorium voor Klinische Biologie, Institute of Tropical Medicine, Antwerpen. Denmark: Steen Hoffmann, Neisseria and Streptococcus Reference Laboratory, Statens Serum Institut, Copenhagen. England and Wales: I. M. C. M. and C. A. I., Sexually Transmitted Bacteria Reference Laboratory, Health Protection Agency Centre for Infections, London. Finland: Pentii Huovinen, National Public Health Institute, Turku. France: Patrice Sednaoui, Institut Alfred Fournier, Paris. Germany: Peter Kohl, Klinik fur Dermatologies und Venerologie, Berlin. Greece: Eva Tzelepi, National Reference Center for Neisseria gonorrhoeae, Hellenic Pasteur Institute, Athens. Italy: Paola Stefanelli, Laboratory of Bacteriology and Medical Mycology, Instituto Superiore di Sanita, Rome. The Netherlands: Joke Spaargaren, Public Health Laboratory, Municipal Health Service, Amsterdam. Norway: Jorgen Lassen, National Institute of Public Health, Oslo. Portugal: Maria José Borrego, Centro de Bacteriologia, Instituto Nacional de Saúde Dr. Ricardo Jorge, Avenida Padre Cruz, Lisbon. Scotland: Hugh Young and Helen Palmer, Scottish Neisseria gonorrhoeae Reference Laboratory (SNGRL), Royal Infirmary of Edinburgh, Edinburgh. Spain: Julio A. Vázquez, Reference Laboratory for Neisserias, National Centre for Microbiology, Instituto de Salud, Madrid. Sweden: Magnus Unemo and Hans Fredlund, Department of Clinical Microbiology, University Hospital, Örebro.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Transparency declarations
 References
 
1 Fenton KA and Lowndes CM. (2004) Recent trends in the epidemiology of sexually transmitted infections in the European Union. Sex Transm Infect 80:255–63.[Abstract/Free Full Text]

2 Bignell C. (2001) European guideline for the management of gonorrhoea. Int J STD AIDS 12:Suppl 3:, 27–9.

3 Surveillance of antibiotic resistance in Neisseria gonorrhoeae in World Health Organization Western Pacific Region, 2002. (2003) Commun Dis Intell 27:488–91.[Medline]

4 Lowndes CM and Fenton KA. (2004) The ESSTI (European Surveillance of STIs) Network. Surveillance systems for STIs in the European Union: facing a changing epidemiology. Sex Transm Dis 80:264–71.

5 Paine TC, Fenton KA, Herring A, et al. (2001) GRASP: a new sentinel surveillance initiative for monitoring gonococcal antimicrobial resistance in England and Wales. Sex Transm Infect 77:398–401.[Free Full Text]

6 Bremer V, Marcus U, Hofmann A, et al. (2005) Building a sentinel surveillance system for sexually transmitted infections in Germany, 2003. Sex Transm Infect 81:173–9.[Abstract/Free Full Text]

7 Herida M, Sednaoui P, Goulet V. (2004) Gonorrhoea surveillance system in France:1986-2000. Sex Transm Dis 31:209–14.[Web of Science][Medline]

8 Mavroidi A, Tzouvelekis LS, Kyriakis KP, et al. (2001) Multidrug-resistant strains of Neisseria gonorrhoeae in Greece. Antimicrob Agents Chemother 45:2651–4.[Abstract/Free Full Text]

9 Arreaza L, Salcedo C, Alcala B, et al. (2003) Antibiotic resistance of Neisseria gonorrhoeae in Spain: trend over the last two decades. J Antimicrob Chemother 51:153–6.[Abstract/Free Full Text]

10 Dal Conte I, Lucchini A, Contuzzi E, et al. (2001) Sexually transmitted infections in Italy: an overview. Int J STD AIDS 12:813–8.[Abstract/Free Full Text]

11 Young H and Palmer HM. (2005) Gonococcal antibiotic surveillance in Scotland (GASS): prevalence, patterns and trend 2004. Health Protection Scotland 39:146–7.

12 Hoffmann S. (2001) The laboratory surveillance system for Chlamydia trachomatis and Neisseria gonorrhoeae infections in Denmark. Euro Surveill 6:86–90.[Medline]

13 Nissinen A, Jarvinen H, Liimatainen H, et al. (1997) Antimicrobial resistance in Neisseria gonorrhoeae in Finland, 1976 to 1995. Sex Transm Dis 24:576–81.[Web of Science][Medline]

14 National Committee for Clinical Laboratory Standards. (2003) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Sixth Edition: Approved Standard M7-A6 (NCCLS, Wayne, PA, USA).


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