Objectives: To investigate comprehensively the antimicrobial susceptibility and resistance of Neisseria gonorrhoeae during 2005–2006 in a national survey and to recommend effective antimicrobial drugs for the treatment of gonorrhoea in Russia.
Methods: The susceptibility of N gonorrhoeae isolates, cultured mainly from consecutive gonorrhoea patients (n = 1030) during the period January 2005 to December 2006 in Russia, to penicillin G, ceftriaxone, ciprofloxacin, tetracycline and spectinomycin was analysed using the agar dilution method. Nitrocefin discs were used for β-lactamase detection.
Results: All isolates were susceptible to ceftriaxone. During 2005 and 2006, however, 5%, 50%, 70% and 77% displayed intermediate susceptibility or resistance to spectinomycin, ciprofloxacin, tetracycline and penicillin G, respectively. Furthermore, 4% of the isolates were β-lactamase producing during these years. The different federal districts of Russia displayed substantial heterogeneities with regard to the prevalence of gonorrhoea and antimicrobial resistance among N gonorrhoeae isolates.
Conclusions: In Russia, penicillins, ciprofloxacin, or tetracycline should definitively not be used in the empirical treatment of gonorrhoea. The recommended first-line antimicrobial drug should be ceftriaxone. If ceftriaxone is not available, spectinomycin ought to be used. Increasing levels of intermediate susceptibility and resistance to spectinomycin have, however, been observed during recent years and, accordingly, great care and monitoring should be undertaken when using this agent. Continuous local, national and international surveillance of N gonorrhoeae antimicrobial susceptibility, in order to reveal the emergence of new resistance, to monitor changing patterns of susceptibility and to be able to update treatment recommendations on a regular basis, is crucial.
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Gonorrhoea remains one of the most prevalent sexually transmitted infections in most countries.1–3 In Russia, there were 71.5 and 63.7 notified gonorrhoea cases per 100 000 inhabitants in 2005 and 2006, respectively. The incidence varied substantially, however, in the seven federal districts of Russia (range 39.2–150.9 cases per 100 000 inhabitants during these 2 years). Accordingly, the incidence of gonorrhoea in Russia remains relatively high; nevertheless, during 1993–2006 the incidence has decreased almost annually (fig 1).4–6
Up to now in Russia, the most frequently used antimicrobial drugs for the treatment of gonorrhoea have been penicillins, tetracycline and fluoroquinolones (mainly ciprofloxacin). As in most countries,3 7–14 however, according to limited studies,15–18 high levels of resistance to these antimicrobial drugs have also emerged in Russia. In many countries strains displaying intermediate susceptibility or resistance to antimicrobial drugs such as azithromycin and even expanded-spectrum cephalosporins such as cefixime and ceftriaxone have recently emerged, which is a serious concern globally.7 8 10–14 19 Although resistance to spectinomycin is currently rare in most countries,3 7–14 the rapid selection of resistance was reported as early as in the 1980s in Korea.20 Consequently, it is also essential to monitor the antimicrobial susceptibility of N gonorrhoeae comprehensively in Russia. Up to now, in Russia and its highly divergent federal districts knowledge regarding antimicrobial resistance, which is crucial for empirical treatment, has been very limited. As in many of the east European countries, it is therefore crucial to establish local, regional and national antimicrobial resistance networks and, in addition, to monitor antibiotic consumption. During the 1990s in Russia, controlled, centralised provision of antibiotics and/or antimicrobial resistant surveillance ended and the consumption of antibiotics increased significantly.
In Russia, in recent years the Central Research Institute of Dermato-Venereology (CNIKVI), Ministry of Health, Moscow, has initiated a national surveillance programme of antimicrobial resistance of N gonorrhoeae, ie, a Russian gonococcal antimicrobial surveillance programme. The aims are to investigate the levels of antimicrobial resistance to the main antimicrobial drugs used for the treatment of gonorrhoea in Russia and to examine the transmission dynamics of antimicrobial resistant strains using molecular epidemiological typing and characterisation of the genetic basis of the resistance. To be able to fulfil these aims, CNIKVI has elaborated optimised systems for the collection, storage and transportation of clinical specimens, as well as N gonorrhoeae cultures, from the different federal districts of Russia to CNIKVI. Furthermore, minimum inhibitory concentration (MIC) determination using the agar dilution method, in accordance with the recommendations of the Clinical and Laboratory Standards Institute (CLSI),21 was introduced. The present study is the first international report that comprehensively describes the antimicrobial susceptibility of N gonorrhoeae in large geographical areas of Russia.
The aims of the present study were to investigate comprehensively the antimicrobial susceptibility and resistance of N gonorrhoeae during 2005–2006 in a national survey and, in a national context, to recommend effective antimicrobial drugs for the treatment of gonorrhoea in Russia.
MATERIALS AND METHODS
Surveillance sites and study population
In the 2005 survey, 24 dermatovenereological dispensaries situated in 24 different cities of Russia, ie, Moscow, St Petersburg, Yekaterinburg, Nizhny Novgorod, Arkhangelsk, Irkutsk, Murmansk, Samara, Stavropol, Khabarovsk, Ryazan, Kazan, Pskov, Kaluga, Cheboksary, Syktyvkar, Vladimir, Saratov, Kirov, Izhevsk, Astrakhan, Vladivostok, Krasnodar and Omsk, were included. In 2006, 12 additional sites were surveyed, ie, Chita, Penza, Kaliningrad, Chelyabinsk, Voronezh, Perm, Novosibirsk, Rostov-on-Don, Kostroma, Orenburg, Krasnoyarsk and Ufa. Accordingly, in 2006 a total of 36 different cities were surveyed.
Representative, mainly consecutive, patients attending these dispensaries during the period January 2005 to December 2006 were included. Inclusion criteria were being a male or female patient, 12–60 years of age, with diagnosed (clinically and using culture) symptomatic uncomplicated gonorrhoea. Exclusion criteria were: refusing participation and the presence of other serious somatic pathology or disease of the central nervous system.
Diagnostics, culture conditions and preservation of N gonorrhoeae isolates
A thorough clinical examination was performed and clinical specimens (urethral and cervical from women and urethral from men) were collected from all patients.
All clinical specimens were cultured on selective culture media (GC II agar; Becton Dickinson, Cockeysville, USA) supplemented with IsoVitaleX enrichment (Becton Dickinson) and V-C-A-T Inhibitor (Becton Dickinson) at 37°C in 5–10% carbon dioxide for 24–72 h. Species verification of N gonorrhoeae was based on the identification of characteristic colony morphology, the presence of typical Gram-negative diplococci in microscopy, rapid positive oxidase test and biochemical reactivity using BBL Crystal Identification Systems Neisseria/Haemophilus ID Kit (Becton Dickinson).
All N gonorrhoeae isolates were preserved in a cryomedium (40% trypticase soy broth, 50% horse sera and 10% glycerine) at −80°C and, subsequently, transported to CNIKVI frozen in thermo-bags.
Antimicrobial susceptibility testing
At CNIKVI, the susceptibility to penicillin G, ceftriaxone, ciprofloxacin, tetracycline and spectinomycin was determined using the agar dilution method, in accordance with the recommendations of CLSI.21 Consequently, the MIC breakpoints for susceptibility or resistance were ⩽0.06/⩾2, ⩽0.25/–, ⩽0.06/⩾1, ⩽0.25/⩾2 and ⩽32/⩾128 for penicillin G, ceftriaxone, ciprofloxacin, tetracycline and spectinomycin, respectively.21 For quality control in concordance with the CLSI recommendations,21 the international N gonorrhoeae reference strain ATCC 49226 was examined in each run of all the antimicrobial susceptibility testing. β-Lactamase production was identified using a chromogenic cephalosporin test with nitrocefin discs, in accordance with the instructions of the manufacturer (Cefinase discs; Becton Dickinson).
In total, N gonorrhoeae isolates from 509 patients (453 men and 56 women) and 521 patients (458 men and 63 women) in 2005 and 2006, respectively, were included. The mean ages of the women and men were 18.6 years (median age 18.0 years and range 12–60) and 19.5 years (median age 19.0 years and range 15–57), respectively. The majority (85%) of the patients were between 16 and 35 years old.
Antimicrobial susceptibility of N gonorrhoeae (n = 1030) in Russia
The results of the MIC determination of all N gonorrhoeae isolates included (n = 1030) are summarised in table 1.
Briefly, the proportion of isolates displaying intermediate susceptibility or resistance to the antimicrobial drug in 2005 and 2006 (in parentheses) were as follows: penicillin G 78.4% (74.8%), tetracycline 65.2% (74.5%), ciprofloxacin 49.4% (51.5%), spectinomycin 1.4% (7.9%) and ceftriaxone 0% (0%) (table 1).
Of the N gonorrhoeae isolates, 5.4% (varied from 0% to 16.2% in the different federal districts) and 2.5% (varied from 0% to 7.3% in the different federal districts) were β-lactamase producing in 2005 and 2006, respectively.
The levels of intermediate susceptibility or resistance to the antimicrobial drugs in the seven federal districts of Russia in 2005 and 2006 are depicted in table 2.
In short, during 2005 and 2006 the levels of intermediate susceptibility or resistance to penicillin G (range 69.9–100%), tetracycline (range 56.9–100%) and ciprofloxacin (range 40.6–100%) were high in all federal districts of Russia. Most disquieting, intermediate susceptibility or resistance to spectinomycin was displayed in six of the seven federal districts, ranging from 2.6% to 14.6%. Of all Russian isolates from 2005 and 2006 (n = 1030), however, only 0.4% (n = 4) were resistant and the remaining isolates displayed intermediate susceptibility (4.3%; table 2). The major longitudinal trends of the antimicrobial susceptibility of N gonorrhoeae in the different federal districts of Russia were difficult to deduce as a result of the relatively limited and divergent sample sizes from each federal district as well as the short time period for studying dynamics.
The incidence of gonorrhoea in Russia remains relatively high; nevertheless, during 1993–2006 the incidence has decreased almost annually.
In Russia, the levels of resistance to all antimicrobial drugs used in traditional gonorrhoea treatment (penicillins, tetracycline and ciprofloxacin) are exceedingly high and these should not be used for the empirical treatment of gonorrhoea.
All Russian isolates were susceptible to ceftriaxone and this antimicrobial agent should be the recommended first-line treatment.
If ceftriaxone is not available, spectinomycin should be used. Increasing levels of intermediate susceptibility and resistance to spectinomycin have, however, been observed during recent years and, accordingly, great care and monitoring should be undertaken when using spectinomycin.
This study is the first internationally reported multicentre study that comprehensively describes the antimicrobial susceptibility of N gonorrhoeae in Russia, including all the seven highly divergent federal districts. Previously, thorough knowledge regarding these issues has been entirely lacking and very limited studies have been performed.15–18 This has been mainly the result of suboptimal diagnostics, including the rare use of culture and a lack of antimicrobial susceptibility testing for N gonorrhoeae.17 22–24 The present national surveillance programme has, however, recently implemented appropriate, standardised and quality assured culture diagnostics, as well as effective and quality assured antimicrobial susceptibility testing, in accordance with international recommendations21 25–29 in Russia. These implementations have formed the basis for the provision of the present unique and valuable information regarding antimicrobial resistance of N gonorrhoeae and are also fundamental for a more effective and reliable epidemiological surveillance and case reporting of gonorrhoea in Russia.
A high level of intermediate susceptibility and resistance to all antimicrobial drugs used in the traditional treatment of gonorrhoea (penicillins, tetracycline and ciprofloxacin) was also identified in Russia. All Russian isolates were, however, susceptible to ceftriaxone and as yet no gonorrhoea treatment failures using ceftriaxone have been described worldwide. Regarding susceptibility to spectinomycin in Russia, in 2005 intermediate susceptibility or resistance was relatively rare (1.4%). Most disquieting, however, in 2006 it was substantially more prevalent (7.9%), which may reflect a consistent increase as a result of its frequent use, which can rapidly select spectinomycin resistance.20 Most remarkably, overall most of the isolates (4.3%) displayed intermediate susceptibility and not full resistance to spectinomycin (only 0.4%). Furthermore, the MIC distribution for spectinomycin seemed somewhat skewed and, consequently, some wild-type isolates may have been erroneously considered as intermediately susceptible. Currently, further phenotypic and genotypic investigations regarding this and other methodological issues are in progress, in order thoroughly to validate and quality assure the agar dilution method used in the present study.
In this study, N gonorrhoeae isolates were collected from all the seven federal districts of Russia, which significantly differ regarding geographical location, as well as social, demographic and epidemiological characteristics. These districts also displayed substantial heterogeneities with regard to the prevalence of gonorrhoea and antimicrobial resistance among the N gonorrhoeae isolates. The districts displaying the highest incidences of gonorrhoea, such as Far-eastern, Siberian and Urals, also with the exception of spectinomycin, comprised the highest levels of antimicrobial resistance. These districts are characterised by long stretching territories, the presence of mountain chains and, in most cases, long distances between resident area and sexually transmitted infection diagnostic and treatment facilities. In addition, the Far-eastern district is neighbouring Asian countries such as China, Japan and Korea, in which a high level of resistance to most antimicrobial drugs for N gonorrhoeae has been described.12 Accordingly, the importation of resistant N gonorrhoeae strains from these countries is likely. The Central district is different, for example, because this federal district contains a very high density of the population and is also the main centre where migration paths meet. The Central district may also be characterised as epidemiologically unsuccessful, despite its economic and other substantial prerequisites, because of the relatively high prevalence of gonorrhoea and high levels of antimicrobial resistance. In the remaining districts, ie, Southern, Volga and North-western, a lower prevalence of gonorrhoea as well as antimicrobial-resistant strains, with the exception of spectinomycin, were identified. This is possibly caused by ethnic, religious and behavioural features of the inhabitants of those districts.
The present national Russian survey thus clearly emphasises that penicillins, tetracycline and fluoroquinolones should not be used for the empirical treatment of gonorrhoea. In Russia the recommended first-line antimicrobial drug should be ceftriaxone and, if ceftriaxone is not available, spectinomycin should be used. Nevertheless, during recent years in Russia increasing levels of intermediate susceptibility and resistance to spectinomycin have been observed and great care and monitoring should be undertaken when using spectinomycin. In 2006, isolates displaying intermediate susceptibility or resistance to spectinomycin were identified in six of the seven federal districts of Russia. In five of these federal districts, the levels exceeded the critical 5% limit, which has been the recommended level for the exclusion of an antimicrobial drug from the standard treatment regimen.3 30 The data from the present study have also formed the basis for new national guidelines regarding the treatment of gonorrhoea in Russia.
In conclusion, the present national survey unambiguously highlights that the levels of resistance to all antimicrobial drugs used in traditional gonorrhoea treatment (penicillins, tetracycline and ciprofloxacin) are exceedingly high all over Russia. Accordingly, these antimicrobial drugs should not be used for the empirical treatment of gonorrhoea. The recommended first-line antimicrobial drug for gonorrhoea treatment should be ceftriaxone. If ceftriaxone is not available, spectinomycin should be used. The levels of intermediate susceptibility and resistance to spectinomycin seem to be increasing, however, and consequently great care and monitoring should be undertaken when using this antimicrobial agent. The present study also emphasises the importance of continuous local, national and international surveillance of N gonorrhoeae antimicrobial susceptibility.
The authors are grateful for the collaboration of the heads and staff of all the surveillance sites included.
Competing interests: None.
Contributors: AK, NF, AK, SS, MD and MU designed and initiated the present study as well as analysed all the data in collaboration with all co-authors; TP, SP, NA performed the laboratory examinations of the isolates; VS was responsible for the logistics and contact with all surveillance sites; AK, NF and MU wrote the manuscript in collaboration with all co-authors.
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