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Gonococcal antimicrobial resistance in the Western Pacific Region Monica M Lahra,1,2 Ying-Ru Lo,3 David M Whiley4,5 1
Microbiology Department, South Eastern Area Laboratory Services, WHO Collaborating Centre for STD, The Prince of Wales Hospital, Sydney, New South Wales, Australia 2 The School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia 3 WHO Regional Office for the Western Pacific, United Nations Avenue, Manila, The Philippines 4 Queensland Paediatric Infectious Diseases Laboratory, Queensland Children’s Health Services, Queensland, Australia 5 Queensland Children’s Medical Research Institute, The University of Queensland, Queensland, Australia Correspondence to Professor Monica Lahra, Microbiology Department, SEALS, Neisseria Reference Laboratory and WHO Collaborating Centre for STD (WPR and SEAR), Level 4 Campus Building, The Prince of Wales Hospital, School of Medical Sciences, The University of New South Wales, Randwick, NSW 2031, Australia; monica.lahra@ SESIAHS.health.nsw.gov.au Received 28 April 2013 Revised 2 September 2013 Accepted 20 September 2013
ABSTRACT Objective To outline the current situation of gonococcal antimicrobial resistance (AMR) in the Western Pacific region and factors that impact on this. Background The Western Pacific region is densely populated with many living in poverty. There are high rates of infectious diseases, and a disproportionate burden of gonococcal disease. In many countries there is uncontrolled antimicrobial use: these are ideal conditions for the emergence of AMR. Methods Gonococcal AMR in this region has been monitored for more than 20 years. Clinical isolates, predominantly from unselected patients attending sexually transmitted diseases clinics, are tested against a panel of antibiotics. Quality assurance and control strategies are in place. Results There is widespread, high level resistance to penicillin and ciprofloxacin. Decreased susceptibility to ceftriaxone (MIC≥0.06 mg/L) is reported in high levels from some countries in the region. Low numbers of isolates tested in some countries reflect capacity for testing, and are suboptimal for surveillance. Conclusion The raised MIC values to ceftriaxone, and the emergence and spread of ceftriaxone resistant strains regionally is alarming. Sustaining and enhancing surveillance is critical; however obtaining an adequate sample size is a long-standing issue. The implementation of molecular surveillance strategies could provide broader information on the spread and threat of AMR.
BACKGROUND This paper will discuss the current situation of gonococcal antimicrobial resistance (AMR) in the Western Pacific which is predominantly monitored by the WHO Gonococcal Antimicrobial Surveillance Programme (GASP), the current regional ceftriaxone AMR data, the challenges for gonococcal disease prevention and disease control in the current context; the strategies of the GASP; and the scope for development of GASP with new strategies for surveillance.
THE WHO WESTERN PACIFIC REGION
To cite: Lahra MM, Lo Y-R, Whiley DM. Sex Transm Infect 2013;89:iv19–iv23.
The Western Pacific Region (WPR) is one of six WHO regions. Geographically the WPR reaches from French Polynesia in the eastern Pacific Ocean, south to New Zealand and north-west to China. The WPR has 37 member states and areas which encompass a spectrum of economic diversity that includes countries of low, middle and high incomes, and rapidly growing economies such as China and Vietnam. There are more than 1.8 billion people living in the WPR, more than a quarter of the world’s population.1 The geographical, cultural and economic diversity of the WPR is reflected in the range; burden and rates of
Lahra MM, et al. Sex Transm Infect 2013;89:iv19–iv23. doi:10.1136/sextrans-2012-050906
infectious, vaccine preventable and emerging infectious diseases, and the scope of the challenges for disease prevention and disease control. In this context, in the WPR, the WHO estimates are that there are 42.0 million new cases of Neisseria gonorrhoeae infection (gonorrhoea) per year; the majority proportion of the 106 million cases of gonorrhoea that the WHO estimates, occur globally, annually in those aged 15–49 years.2 To the east, the WPR is contiguous with the WHO South East Asian Region (SEAR) and the 11 SEAR countries have a similar spectrum of economic development to the Western Pacific, a similar estimated population of 1.7 billion people 3 and an estimated 25.4 million new cases of gonorrhoea annually.
N GONORRHOEAE, GONORRHOEA AND AMR Globally, gonorrhoea disease burden is highest in low income settings, but rates are increasing in high income countries.2 4 Disease is concentrated in those that are economically and socially disadvantaged; in men who have sex with men; commercial sex workers; those in correctional facilities and racial and ethnic minority groups.2 4 5 Gonococcal disease prevention and control is critical to reduce the escalating global infection rates, and the collateral injuries of the associated morbidities for men, women and babies, and for HIV prevention. Central to this is the effective treatment of gonorrhoea, which is pivotal for disease control. However, the highly mutable capacity of the gonococcus to develop AMR to a range of therapeutic options is well recognised, and the development of resistance to the sulphonamides, penicillins, tetracyclines, fluoroquinolones, azithromycin, spectinomycin and the oral cephalosporin antibiotics has been well documented over time.6 7 There is a clear and resonant warning in this history. The introduction of an antibiotic has inevitably been followed by the emergence of resistance in the gonococcus, and thus the ideal therapeutic option for gonorrhoea: an inexpensive, single dose, oral agent has been vanquished with the burgeoning gonococcal AMR over the last 70 years. This has essentially left the injectable, extended spectrum cephalosporin (ESC), ceftriaxone, as the most viable treatment option, and this antibiotic is in widespread use worldwide. However reports of a right shift in ceftriaxone MIC values,8 9 treatment failures and more recently, cases of ceftriaxone resistance10 11 are cause for significant alarm.6 12 A suitable, alternate treatment is yet to be identified. AMR severely compromises the control of gonococcal disease, with the lack of an effective treatment increasing the rate of disease spread; complications iv19
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Supplement and morbidity. Effective strategies for treatment and control of gonorrhoea rely on reliable; current and readily available data on population specific N gonorrhoeae AMR patterns. Surveillance of AMR even in the absence of the threat of rising AMR is a pivotal component of disease control and management.
ESTABLISHMENT OF THE GONOCOCCAL ANTIMICROBIAL SURVEILLANCE IN THE WPR The WHO regional GASPs form the global surveillance network to monitor antibiotic resistance in N gonorrhoeae. Within each of the WHO Regions, surveillance networks have been established to collect, collate and make available data on gonococcal AMR at the country, regional and global levels. These data assist in facilitation of effective treatment strategy, identification of emerging resistance and informing disease control strategies.13 The WHO GASP in the WPR was established in 1992. At the outset there were 14 centres contributing as regional focal points, with further centres joining the collaboration over the 20 years the WPR GASP has been in place. The WPR GASP has been coordinated since inception by the WHO Collaborating Centre in Sydney, Australia and has run continuously since. Participating laboratories test clinical gonococcal isolates for AMR, predominantly from unselected patients attending sexually transmitted diseases clinics, using a variety of standardised methods (disc diffusion, strip diffusion or mean inhibitory concentration techniques). The nominated core group of antibiotics for the WPR GASP is penicillin, fluoroquinolones, spectinomycin, tetracycline and the extended spectrum ESCs for resistance.13 For quality assurance and quality control of the GASP, a programme specific methods manual was developed and the WHO WPR external quality assurance programme was established.13 A panel of fully characterised gonococcal reference culture control strains, developed and distributed to participating laboratories for incorporation into testing, has enabled the validation of data across the region where testing methods vary.13 Given the breadth and scope of the problem of gonococcal AMR, when interpreting estimates of its pervasion, it is important to note that culture-based surveillance systems, while optimal to provide AMR data, have inherent problems in providing the requisite data at many levels; including laboratory, clinical and political. The fastidious nature of the gonococcus, and the cost, resources and technical skills required to perform gonococcal culture and AMR testing impose significant constraints on the number of isolates tested. In addition there is the necessity in some settings for dependence on syndromic management rather than laboratory diagnosis; and in many others an increasing reliance on nucleic acid amplification testing (NAAT) for diagnosis. In addition, as noted, there are a number of methods in use for testing for gonococcal AMR used across and within the WHO regions. However, variation in the definitions and terms, and differences in laboratory techniques with differing interpretive criteria, means that results of AMR testing across methods (Clinical and Laboratory Standards Institute, European Committee on Antimicrobial Susceptibility Testing and calibrated dichotomous sensitivity) are not always comparable.14 This has been a long-standing and largely unresolved problem with the testing of ESCs.5 Moreover, across the GASP networks the nominated mean inhibitory concentration value for categorising isolates as decreased susceptibility varies. In the WPR isolates with a ceftriaxone MIC value of ≥0.06 mg/L are considered to have decreased susceptibility. The WHO WPR GASP has been conducted continuously for more than 20 years, iv20
under the same conditions, and the annual gonococcal surveillance reports continue to provide trend data for the region as a whole.
EARLY AMR DATA FROM THE WHO WPR GASP The first WPR WHO GASP was reported for 1992–1994 with data from 17 centres regionally testing 20 365 isolates over the period.13 In this, and in the subsequent annual GASP reports from the WPR, data on the prevailing AMR in a core group of antibiotics including penicillin, ciprofloxacin, spectinomycin and the extended spectrum ESCs were reported. The summary findings in the initial GASP Report (1992– 1994) include stable, widespread resistance to penicillin in the region,13 which was first reported in the WPR in the 1970s,4 however, with the exception of the Pacific Islands of Vanuatu and New Caledonia and remote Australia where penicillin resistance rates were low. Spectinomycin resistance in the initial years of the WPR GASP was found consistently in small numbers of strains from China and Papua New Guinea, and sporadically, again in small numbers of isolates, from New Caledonia, Vietnam and Australia.13 However, the period 1992–1994 was pivotal for observing the emergence of resistance to the fluoroquinolone antibiotics in the WPR. In 1992 there was low level quinolone resistance reported in four of eight countries testing (Australia, Japan, Korea and New Caledonia), and this increased considerably over the following 2 years so that by 1994, 12/13 countries reported some level of resistance, and four countries (Hong Kong, China, Japan, Korea and the Philippines) reported high level resistance.13 Over time the proportion of clinical isolates with decreased susceptibility or resistance to fluoroquinolones rapidly increased in the WPR; in the adjacent SEAR and globally, treatment failures were reported; and this antibiotic was no longer a recommended therapeutic option for gonorrhoea regionally by the year 2000.4 7 The availability, use and misuse of fluoroquinolones in some countries in the Asia Pacific likely provided selection pressure for these fluoroquinolone resistant strains, which emerged and spread around the world, probably by travellers to the region.7 The use of extended spectrum ESCs, the oral and the injectable form ceftriaxone, for the treatment of gonorrhoea, followed the fluoroquinolone era. At the time of the 1992–1994 GASP WPR report there had been no clinical resistance to the ESC antibiotics reported and this, in conjunction with the absence of defined precise break points for this group of antibiotics, meant that it was not possible at this time to further interpret surveillance results of the 9544 isolates tested in the period.13 However the widespread introduction of the oral ESC antibiotics was followed by the emergence and spread of gonococcal isolates with raised MIC values in the Asia Pacific and globally; and treatment failures to the oral ESC agents from strains with raised MIC values were reported from the WPR from the early 2000s6 7 By 2008 a survey of treatment strategies for gonococcal infections conducted in the WPR reported that ceftriaxone was in widespread use (11/15 countries), though dosage and route of administration (125 mg IMI—1 g IVI) varied.15
THE CURRENT STATUS OF REGIONAL AMR IN THE WPR From 2009 the difficulties in interpreting surveillance data for the ESCs have been in part addressed by the introduction and use of WHO N gonorrhoeae reference strains to assist in the detection of altered susceptibility to the ESCs.16 In 2010 six countries in the WPR tested 7024 gonococcal isolates and reported the
Lahra MM, et al. Sex Transm Infect 2013;89:iv19–iv23. doi:10.1136/sextrans-2012-050906
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Supplement proportion of isolates with decreased susceptibility to ceftriaxone (MIC≥0.06 mg/L): Singapore (1.3%), Australia (4.8%), Japan (20.3%), Hong Kong, China (23.3%), Korea (29.3%) and China (55.8%).17 The 2011 GASP WPR data are shown in table 1. The proportion of decreased susceptibility to ceftriaxone (MIC ≥0.06 mg/L) in 2011 are similar in Australia and Korea, lower in China, Hong Kong SAR and Japan, and higher in Singapore when compared with 2010. The extent to which the data reflects the status of AMR is difficult to determine, and to what extent is attributable to the inherent problems with testing ESCs is unclear, however the GASP data are quality assured and the use of the WHO control strains has coincided with improved EQA performance. The WPR GASP findings are supported by recent studies from China: in the most recent, of 1250 consecutive clinical gonococci isolated from 2001–2011 from Guangzhou, China the proportion of strains less susceptible to ceftriaxone rose from 17% to 46.5%18 However altered susceptibility to ESC antibiotics had been reported at the country level from the WPR from much earlier. The National Centre for STD Control in Nanjing, China reported surveillance data from 1208 clinical isolates with decreased susceptibility to ceftriaxone (MIC ≥0.06 mg/L) annually for the period 1999–2006 ranging from 17.86% in 1999 to 57.89% in 2003 and 38.38% in 200619 and, from 2001 onwards, low numbers of isolates with slightly raised ceftriaxone MICs have been found in Australia.20 In this period two ceftriaxone-resistant gonococcal strains: H041 and F89, were isolated in Japan and France, respectively.10 11 In 2010, the first ceftriaxone-resistant N gonorrhoeae strain (MIC=2.0 mg/ mL), H041, was observed in Japan, and this was soon followed by the ceftriaxone resistant F89 strain in France (MIC=2.0 mg/mL).10 11 Molecular studies have confirmed that international transmission of N gonorrhoeae strains is a key factor in spreading decreased susceptibility to ceftriaxone.10 So far, there have been no further reports of the H041 strain in Japan or elsewhere, suggesting the strain was not successful in
becoming established in sexual networks. The F89 strain however has since been found in Spain.21 Penicillin and fluoroquinolone resistance remains at a high level, is widespread, and has unchanged or increased over time, despite these antibiotics not being in clinical use in most of the region (table 1). The exception to this continues to be in areas of remote Australia and some Pacific Islands, where penicillin is still in clinical use.17 22 Spectinomycin resistance continues to be reported sporadically, and at low levels, within the WPR.17 Over the period of the GASP the sample size of isolates tested for AMR surveillance from some countries continues to be low, as shown in table 1, and is a recognised concern regarding representativeness, however as outlined above, capacity limits AMR testing and in many settings this is difficult to address.
NEW STRATEGIES FOR AMR SURVEILLANCE: WHAT IS THE ROLE FOR MOLECULAR SURVEILLANCE? While culture remains the most definitive means of ascertaining AMR of an individual gonococcal isolate, its broader utility is undermined by an inability, or decreasing opportunity, to isolate gonococci in sufficient numbers from a wide range of settings to provide representative data for surveillance. In short, continued reliance solely on bacterial culture will be insufficient to meet the needs of this situation. The ideal means of enhancing culture-based surveillance is the development of molecular AMR tools, so that gonococcal AMR can be detected using NAAT-positive samples (in the absence of an isolate for that sample). While still in their infancy, a number of methods have thus far been described for direct use on clinical samples, and validated to predict N gonorrhoeae susceptibility. These include real-time PCR methods for direct detection of N gonorrhoeae resistance to fluoroquinolones,23 penicillin24 and ceftriaxone.25 The main advantage of these molecular surveillance methods is that they can be used to test almost any N gonorrhoeae
Table 1 2011 WHO Gonococcal Antimicrobial Surveillance Programme Western Pacific region (WPR) data showing the number of isolates tested in each participating country, the proportion of isolates resistant to penicillin, ciprofloxacin and azithromycin, and decreased susceptibility to ceftriaxone (MIC >/=0.06 mg/L). Data provided by the WHO Collaborating Centre Sydney Decreased susceptibility Ceftriaxone
Resistance Azithromycin
Penicillin
Country WPR 2011
Number of isolates tested
No.
%
No.
Ciprofloxacin %
No.
%
No.
%
Australia (Urban) Australia (Remote) Brunei Darussalam China Fiji Hong Kong (China)‡ Japan The Republic of Korea New Caledonia‡ New Zealand The Philippines Singapore Vietnam Total
3647 459 295 1349 252† 1225 441 64 166 317 34 160 75 8484
132 2 3 288 0 19 21 16 NT 10 0 11 1 503
3.6 0.4 1.0 21 0 1.6 4.8 25 NT 3.2 0 6.9 1.3 6.2
1116 16 263 1341 0 1213 332 57 10 143 32 134 72 4729
31 3.5 89 99 0 99 75 89 6.0 45 94 84 96 57
48 1 NT NT NT 48 NT NT NT NT NT NT 1 98
1.3 0.2 NT NT NT 3.9 NT NT NT NT NT NT 1.3 1.2
1034 19 194 584* 17 666 198 32 15 91 29 97 37 3013
28 4.1 66 43 6.7 54 45 50 9.0 29 85 61 49 36
*From China 584 of 1349 (43.3%) isolates were penicillin resistant by β-lactamase (PPNG). Gonococci with chromosomally mediated resistance to penicillin (CMRP) were not reported. †In Fiji only strains that are penicillin resistant are tested for ceftriaxone and ciprofloxacin susceptibility (n=17 in 2011). ‡Area of the Western Pacific Region. NT, not tested.
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Supplement NAAT-positive sample from a given region and therefore provide greater representation for AMR surveillance. In our opinion, such methods would be ideal to supplement bacterial culture methods for a given population, where culture is used to ascertain general resistance trends for a broad range of antibiotics, and then PCR is used for high level sampling for particular antibiotics of critical importance. Exactly which antibiotics would be considered of importance would depend on the particular population, but ceftriaxone is clearly a standout in the current global environment. For example, the immediate implementation of H041 or F89 PCR testing into Japan and Europe, respectively, could go a long way towards understanding the local epidemiology, if any, in these regions. Elsewhere, use of PCR to screen for the N gonorrhoeae mosaic penA gene, associated with reduced susceptibility to ceftriaxone and the key ‘building block’ of ceftriaxone resistance in the H041 and F89 strains, would provide useful data on the broader spread of reduced susceptibility to ceftriaxone and threat of resistance development. Disadvantages of molecular AMR methods include that that they cannot currently provide as definitive data as bacterial culture in predicting resistance, given the targeted nature of molecular testing (ie, only targeting selected genetic mechanisms) and that the genetics of N gonorrhoeae AMR can be complex, and yet to be fully elucidated. The costs of PCR-based AMR testing, including reagents and infrastructure, may also be prohibitive in certain settings.
DISCUSSION In 2013, despite the gaps in surveillance regionally and globally, we are left in little doubt as to the gravity of the threat of gonococcal AMR. The prediction for the future is bleak based on the information globally, and from the WPR: high proportions of isolates in some countries in the region with raised MIC values to ceftriaxone; emergence of ceftriaxone resistant MDR strains,10 11 widespread uncontrolled antibiotic use,26 rising rates of disease,2 27 no new treatment options and the increasing fear of uncontrolled disease spread. In context, AMR in bacteria is a global public health challenge that is not confined to the gonococcus, and emergence of AMR in the healthcare setting and the community is facilitated by many factors including the relative ease of international travel and widespread unregulated use of antimicrobials around the world.26 28 In a recent perspective article focused on AMR in the WPR, four key areas were outlined to strategise a response: improved surveillance that is standardised, structured and quality assured; focused, basic research on resistant bacteria to understand mechanisms of AMR and transmission; appropriate control and use of antimicrobials; and infection prevention and control strategies.28 Specific strategies outlined in the WHO Global Action Plan to control gonococcal AMR include improving early detection, and strengthening laboratory capacity for diagnosis and surveillance.29 In addition, effective screening and treatment programmes in key populations are important.27 These factors need to be heeded and supported at the national, regional and global levels to control AMR. Disease prevention and disease control strategies rely on effective treatment protocols informed by timely and representative surveillance data. Further, surveillance of AMR is essential for providing information on the magnitude and trends in resistance, and also for monitoring the effects of interventions. Calls continue for enhanced surveillance at the national, international and global levels,7 16 30 and the use of available molecular strategies and development and use of new and aligned technology, will optimise the information available for monitoring AMR. iv22
That said, the key factors that facilitate the development of AMR and directly impact on disease control are uncontrolled antibiotic use and unchecked disease spread. At the most pragmatic level control of gonorrhoea and gonococcal AMR will be best achieved by disease prevention. Public health campaigns for safe sex in conjunction with routine screening in high-risk populations, advocating for improved use of antibiotics inside and outside the health system are essential counterparts to AMR surveillance in developing a functional solution to contain gonococcal disease and gonococcal AMR.
Key messages ▸ With disproportionately high, and rising, gonococcal disease rates, increasing antimicrobial resistance and no ideal alternate treatment, the Western Pacific region is facing a serious public health threat ▸ At local, national and regional levels, disease prevention and disease control strategies; appropriate control and use of antimicrobials; and improved antimicrobial resistance surveillance are paramount ▸ Effective surveillance is key to understanding the magnitude and trends of gonococcal resistance, and for monitoring effects of interventions ▸ In conjunction with culture based surveillance, use of available molecular strategies will optimise the information available for monitoring antimicrobial resistance
Acknowledgements The authors acknowledge Professor John Tapsall AM who was at the forefront of the establishment of the WPR GASP, the staff at the WHO Collaborating Centre in Sydney; Mrs Athena Limnios; Dr Tiffany Hogan; Mr Rodney Enriquez and Mr Ratan Kundu; and the work of Dr Namraj Goire. This review was written on behalf of our regional collaborators in the WHO WPR: The National Neiseria Network, Australia; Ms HJH Mahani, Brunei; Dr Sopheak Hem, Cambodia; Dr Yueping Yin, China; Mr Parmod Kumar, Fiji; Dr Tony Ng, Hong Kong (China); Professor Masatoshi Tanaka, Fukuoka, Japan; Professor Takashi Deguchi, Gifu City, Japan; Dr Y Watanabe, Kanagawa, Japan; Dr Kyungwon Lee, Seoul, Korea; Dr Phengta Vongprachanh, The Lao People's Democratic Republic Dr Sabet Negar Shafei, Malaysia; Dr Odgerel Tundev, Mongolia; Ms Marian Smith, Auckland, New Zealand; Ms Helen Heffernan, Christchurch, New Zealand; Dr Regis Goursad, Nouvelle-Caledonie; Mr Leo Latorre, Boroko, Papua New Guinea; Ms Pamela Toliman, Boroko, Papua New Guinea; Dr Celia Carlos, Manila, Philippines; Dr Elizabeth O Telan, Sta Cruz, Philippines; Dr Ai Ling Tan, Singapore; Mr Sitanilei Hoko, Tonga; Mr Le Van Hung, Vietnam; whose long-standing commitment has driven the WPR GASP for more than 20 years. Contributors MML is the Director of the WHO Collaborating Centre for STD, Sydney, which is the Coordinating Centre of the WHO GASP for the WPR and SEAR. The gonococcal AMR surveillance data was collated from this Centre. All authors contributed to the writing of this paper. Funding The WHO CC,Sydney is funded by the Australian Government Department of Health and Ageing for the Australian Gonococcal Surveillance Programme and the WHO WPRO for the WPR GASP. This review was supported in part of the Gonorrhoea Resistance Assessment by Nucleic Acid Detection (GRAND) study supported by a National Health and Medical Research Council (NHMRC) Australia, Project Grant (APP1025517). Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
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Gonococcal antimicrobial resistance in the Western Pacific Region Monica M Lahra,1,2 Ying-Ru Lo,3 David M Whiley4,5 1
Microbiology Department, South Eastern Area Laboratory Services, WHO Collaborating Centre for STD, The Prince of Wales Hospital, Sydney, New South Wales, Australia 2 The School of Medical Sciences, The University of New South Wales, Sydney, New South Wales, Australia 3 WHO Regional Office for the Western Pacific, United Nations Avenue, Manila, The Philippines 4 Queensland Paediatric Infectious Diseases Laboratory, Queensland Children’s Health Services, Queensland, Australia 5 Queensland Children’s Medical Research Institute, The University of Queensland, Queensland, Australia Correspondence to Professor Monica Lahra, Microbiology Department, SEALS, Neisseria Reference Laboratory and WHO Collaborating Centre for STD (WPR and SEAR), Level 4 Campus Building, The Prince of Wales Hospital, School of Medical Sciences, The University of New South Wales, Randwick, NSW 2031, Australia; monica.lahra@ SESIAHS.health.nsw.gov.au Received 28 April 2013 Revised 2 September 2013 Accepted 20 September 2013
ABSTRACT Objective To outline the current situation of gonococcal antimicrobial resistance (AMR) in the Western Pacific region and factors that impact on this. Background The Western Pacific region is densely populated with many living in poverty. There are high rates of infectious diseases, and a disproportionate burden of gonococcal disease. In many countries there is uncontrolled antimicrobial use: these are ideal conditions for the emergence of AMR. Methods Gonococcal AMR in this region has been monitored for more than 20 years. Clinical isolates, predominantly from unselected patients attending sexually transmitted diseases clinics, are tested against a panel of antibiotics. Quality assurance and control strategies are in place. Results There is widespread, high level resistance to penicillin and ciprofloxacin. Decreased susceptibility to ceftriaxone (MIC≥0.06 mg/L) is reported in high levels from some countries in the region. Low numbers of isolates tested in some countries reflect capacity for testing, and are suboptimal for surveillance. Conclusion The raised MIC values to ceftriaxone, and the emergence and spread of ceftriaxone resistant strains regionally is alarming. Sustaining and enhancing surveillance is critical; however obtaining an adequate sample size is a long-standing issue. The implementation of molecular surveillance strategies could provide broader information on the spread and threat of AMR.
BACKGROUND This paper will discuss the current situation of gonococcal antimicrobial resistance (AMR) in the Western Pacific which is predominantly monitored by the WHO Gonococcal Antimicrobial Surveillance Programme (GASP), the current regional ceftriaxone AMR data, the challenges for gonococcal disease prevention and disease control in the current context; the strategies of the GASP; and the scope for development of GASP with new strategies for surveillance.
THE WHO WESTERN PACIFIC REGION
To cite: Lahra MM, Lo Y-R, Whiley DM. Sex Transm Infect 2013;89:iv19–iv23.
The Western Pacific Region (WPR) is one of six WHO regions. Geographically the WPR reaches from French Polynesia in the eastern Pacific Ocean, south to New Zealand and north-west to China. The WPR has 37 member states and areas which encompass a spectrum of economic diversity that includes countries of low, middle and high incomes, and rapidly growing economies such as China and Vietnam. There are more than 1.8 billion people living in the WPR, more than a quarter of the world’s population.1 The geographical, cultural and economic diversity of the WPR is reflected in the range; burden and rates of
Lahra MM, et al. Sex Transm Infect 2013;89:iv19–iv23. doi:10.1136/sextrans-2012-050906
infectious, vaccine preventable and emerging infectious diseases, and the scope of the challenges for disease prevention and disease control. In this context, in the WPR, the WHO estimates are that there are 42.0 million new cases of Neisseria gonorrhoeae infection (gonorrhoea) per year; the majority proportion of the 106 million cases of gonorrhoea that the WHO estimates, occur globally, annually in those aged 15–49 years.2 To the east, the WPR is contiguous with the WHO South East Asian Region (SEAR) and the 11 SEAR countries have a similar spectrum of economic development to the Western Pacific, a similar estimated population of 1.7 billion people 3 and an estimated 25.4 million new cases of gonorrhoea annually.
N GONORRHOEAE, GONORRHOEA AND AMR Globally, gonorrhoea disease burden is highest in low income settings, but rates are increasing in high income countries.2 4 Disease is concentrated in those that are economically and socially disadvantaged; in men who have sex with men; commercial sex workers; those in correctional facilities and racial and ethnic minority groups.2 4 5 Gonococcal disease prevention and control is critical to reduce the escalating global infection rates, and the collateral injuries of the associated morbidities for men, women and babies, and for HIV prevention. Central to this is the effective treatment of gonorrhoea, which is pivotal for disease control. However, the highly mutable capacity of the gonococcus to develop AMR to a range of therapeutic options is well recognised, and the development of resistance to the sulphonamides, penicillins, tetracyclines, fluoroquinolones, azithromycin, spectinomycin and the oral cephalosporin antibiotics has been well documented over time.6 7 There is a clear and resonant warning in this history. The introduction of an antibiotic has inevitably been followed by the emergence of resistance in the gonococcus, and thus the ideal therapeutic option for gonorrhoea: an inexpensive, single dose, oral agent has been vanquished with the burgeoning gonococcal AMR over the last 70 years. This has essentially left the injectable, extended spectrum cephalosporin (ESC), ceftriaxone, as the most viable treatment option, and this antibiotic is in widespread use worldwide. However reports of a right shift in ceftriaxone MIC values,8 9 treatment failures and more recently, cases of ceftriaxone resistance10 11 are cause for significant alarm.6 12 A suitable, alternate treatment is yet to be identified. AMR severely compromises the control of gonococcal disease, with the lack of an effective treatment increasing the rate of disease spread; complications iv19
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Supplement and morbidity. Effective strategies for treatment and control of gonorrhoea rely on reliable; current and readily available data on population specific N gonorrhoeae AMR patterns. Surveillance of AMR even in the absence of the threat of rising AMR is a pivotal component of disease control and management.
ESTABLISHMENT OF THE GONOCOCCAL ANTIMICROBIAL SURVEILLANCE IN THE WPR The WHO regional GASPs form the global surveillance network to monitor antibiotic resistance in N gonorrhoeae. Within each of the WHO Regions, surveillance networks have been established to collect, collate and make available data on gonococcal AMR at the country, regional and global levels. These data assist in facilitation of effective treatment strategy, identification of emerging resistance and informing disease control strategies.13 The WHO GASP in the WPR was established in 1992. At the outset there were 14 centres contributing as regional focal points, with further centres joining the collaboration over the 20 years the WPR GASP has been in place. The WPR GASP has been coordinated since inception by the WHO Collaborating Centre in Sydney, Australia and has run continuously since. Participating laboratories test clinical gonococcal isolates for AMR, predominantly from unselected patients attending sexually transmitted diseases clinics, using a variety of standardised methods (disc diffusion, strip diffusion or mean inhibitory concentration techniques). The nominated core group of antibiotics for the WPR GASP is penicillin, fluoroquinolones, spectinomycin, tetracycline and the extended spectrum ESCs for resistance.13 For quality assurance and quality control of the GASP, a programme specific methods manual was developed and the WHO WPR external quality assurance programme was established.13 A panel of fully characterised gonococcal reference culture control strains, developed and distributed to participating laboratories for incorporation into testing, has enabled the validation of data across the region where testing methods vary.13 Given the breadth and scope of the problem of gonococcal AMR, when interpreting estimates of its pervasion, it is important to note that culture-based surveillance systems, while optimal to provide AMR data, have inherent problems in providing the requisite data at many levels; including laboratory, clinical and political. The fastidious nature of the gonococcus, and the cost, resources and technical skills required to perform gonococcal culture and AMR testing impose significant constraints on the number of isolates tested. In addition there is the necessity in some settings for dependence on syndromic management rather than laboratory diagnosis; and in many others an increasing reliance on nucleic acid amplification testing (NAAT) for diagnosis. In addition, as noted, there are a number of methods in use for testing for gonococcal AMR used across and within the WHO regions. However, variation in the definitions and terms, and differences in laboratory techniques with differing interpretive criteria, means that results of AMR testing across methods (Clinical and Laboratory Standards Institute, European Committee on Antimicrobial Susceptibility Testing and calibrated dichotomous sensitivity) are not always comparable.14 This has been a long-standing and largely unresolved problem with the testing of ESCs.5 Moreover, across the GASP networks the nominated mean inhibitory concentration value for categorising isolates as decreased susceptibility varies. In the WPR isolates with a ceftriaxone MIC value of ≥0.06 mg/L are considered to have decreased susceptibility. The WHO WPR GASP has been conducted continuously for more than 20 years, iv20
under the same conditions, and the annual gonococcal surveillance reports continue to provide trend data for the region as a whole.
EARLY AMR DATA FROM THE WHO WPR GASP The first WPR WHO GASP was reported for 1992–1994 with data from 17 centres regionally testing 20 365 isolates over the period.13 In this, and in the subsequent annual GASP reports from the WPR, data on the prevailing AMR in a core group of antibiotics including penicillin, ciprofloxacin, spectinomycin and the extended spectrum ESCs were reported. The summary findings in the initial GASP Report (1992– 1994) include stable, widespread resistance to penicillin in the region,13 which was first reported in the WPR in the 1970s,4 however, with the exception of the Pacific Islands of Vanuatu and New Caledonia and remote Australia where penicillin resistance rates were low. Spectinomycin resistance in the initial years of the WPR GASP was found consistently in small numbers of strains from China and Papua New Guinea, and sporadically, again in small numbers of isolates, from New Caledonia, Vietnam and Australia.13 However, the period 1992–1994 was pivotal for observing the emergence of resistance to the fluoroquinolone antibiotics in the WPR. In 1992 there was low level quinolone resistance reported in four of eight countries testing (Australia, Japan, Korea and New Caledonia), and this increased considerably over the following 2 years so that by 1994, 12/13 countries reported some level of resistance, and four countries (Hong Kong, China, Japan, Korea and the Philippines) reported high level resistance.13 Over time the proportion of clinical isolates with decreased susceptibility or resistance to fluoroquinolones rapidly increased in the WPR; in the adjacent SEAR and globally, treatment failures were reported; and this antibiotic was no longer a recommended therapeutic option for gonorrhoea regionally by the year 2000.4 7 The availability, use and misuse of fluoroquinolones in some countries in the Asia Pacific likely provided selection pressure for these fluoroquinolone resistant strains, which emerged and spread around the world, probably by travellers to the region.7 The use of extended spectrum ESCs, the oral and the injectable form ceftriaxone, for the treatment of gonorrhoea, followed the fluoroquinolone era. At the time of the 1992–1994 GASP WPR report there had been no clinical resistance to the ESC antibiotics reported and this, in conjunction with the absence of defined precise break points for this group of antibiotics, meant that it was not possible at this time to further interpret surveillance results of the 9544 isolates tested in the period.13 However the widespread introduction of the oral ESC antibiotics was followed by the emergence and spread of gonococcal isolates with raised MIC values in the Asia Pacific and globally; and treatment failures to the oral ESC agents from strains with raised MIC values were reported from the WPR from the early 2000s6 7 By 2008 a survey of treatment strategies for gonococcal infections conducted in the WPR reported that ceftriaxone was in widespread use (11/15 countries), though dosage and route of administration (125 mg IMI—1 g IVI) varied.15
THE CURRENT STATUS OF REGIONAL AMR IN THE WPR From 2009 the difficulties in interpreting surveillance data for the ESCs have been in part addressed by the introduction and use of WHO N gonorrhoeae reference strains to assist in the detection of altered susceptibility to the ESCs.16 In 2010 six countries in the WPR tested 7024 gonococcal isolates and reported the
Lahra MM, et al. Sex Transm Infect 2013;89:iv19–iv23. doi:10.1136/sextrans-2012-050906
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Supplement proportion of isolates with decreased susceptibility to ceftriaxone (MIC≥0.06 mg/L): Singapore (1.3%), Australia (4.8%), Japan (20.3%), Hong Kong, China (23.3%), Korea (29.3%) and China (55.8%).17 The 2011 GASP WPR data are shown in table 1. The proportion of decreased susceptibility to ceftriaxone (MIC ≥0.06 mg/L) in 2011 are similar in Australia and Korea, lower in China, Hong Kong SAR and Japan, and higher in Singapore when compared with 2010. The extent to which the data reflects the status of AMR is difficult to determine, and to what extent is attributable to the inherent problems with testing ESCs is unclear, however the GASP data are quality assured and the use of the WHO control strains has coincided with improved EQA performance. The WPR GASP findings are supported by recent studies from China: in the most recent, of 1250 consecutive clinical gonococci isolated from 2001–2011 from Guangzhou, China the proportion of strains less susceptible to ceftriaxone rose from 17% to 46.5%18 However altered susceptibility to ESC antibiotics had been reported at the country level from the WPR from much earlier. The National Centre for STD Control in Nanjing, China reported surveillance data from 1208 clinical isolates with decreased susceptibility to ceftriaxone (MIC ≥0.06 mg/L) annually for the period 1999–2006 ranging from 17.86% in 1999 to 57.89% in 2003 and 38.38% in 200619 and, from 2001 onwards, low numbers of isolates with slightly raised ceftriaxone MICs have been found in Australia.20 In this period two ceftriaxone-resistant gonococcal strains: H041 and F89, were isolated in Japan and France, respectively.10 11 In 2010, the first ceftriaxone-resistant N gonorrhoeae strain (MIC=2.0 mg/ mL), H041, was observed in Japan, and this was soon followed by the ceftriaxone resistant F89 strain in France (MIC=2.0 mg/mL).10 11 Molecular studies have confirmed that international transmission of N gonorrhoeae strains is a key factor in spreading decreased susceptibility to ceftriaxone.10 So far, there have been no further reports of the H041 strain in Japan or elsewhere, suggesting the strain was not successful in
becoming established in sexual networks. The F89 strain however has since been found in Spain.21 Penicillin and fluoroquinolone resistance remains at a high level, is widespread, and has unchanged or increased over time, despite these antibiotics not being in clinical use in most of the region (table 1). The exception to this continues to be in areas of remote Australia and some Pacific Islands, where penicillin is still in clinical use.17 22 Spectinomycin resistance continues to be reported sporadically, and at low levels, within the WPR.17 Over the period of the GASP the sample size of isolates tested for AMR surveillance from some countries continues to be low, as shown in table 1, and is a recognised concern regarding representativeness, however as outlined above, capacity limits AMR testing and in many settings this is difficult to address.
NEW STRATEGIES FOR AMR SURVEILLANCE: WHAT IS THE ROLE FOR MOLECULAR SURVEILLANCE? While culture remains the most definitive means of ascertaining AMR of an individual gonococcal isolate, its broader utility is undermined by an inability, or decreasing opportunity, to isolate gonococci in sufficient numbers from a wide range of settings to provide representative data for surveillance. In short, continued reliance solely on bacterial culture will be insufficient to meet the needs of this situation. The ideal means of enhancing culture-based surveillance is the development of molecular AMR tools, so that gonococcal AMR can be detected using NAAT-positive samples (in the absence of an isolate for that sample). While still in their infancy, a number of methods have thus far been described for direct use on clinical samples, and validated to predict N gonorrhoeae susceptibility. These include real-time PCR methods for direct detection of N gonorrhoeae resistance to fluoroquinolones,23 penicillin24 and ceftriaxone.25 The main advantage of these molecular surveillance methods is that they can be used to test almost any N gonorrhoeae
Table 1 2011 WHO Gonococcal Antimicrobial Surveillance Programme Western Pacific region (WPR) data showing the number of isolates tested in each participating country, the proportion of isolates resistant to penicillin, ciprofloxacin and azithromycin, and decreased susceptibility to ceftriaxone (MIC >/=0.06 mg/L). Data provided by the WHO Collaborating Centre Sydney Decreased susceptibility Ceftriaxone
Resistance Azithromycin
Penicillin
Country WPR 2011
Number of isolates tested
No.
%
No.
Ciprofloxacin %
No.
%
No.
%
Australia (Urban) Australia (Remote) Brunei Darussalam China Fiji Hong Kong (China)‡ Japan The Republic of Korea New Caledonia‡ New Zealand The Philippines Singapore Vietnam Total
3647 459 295 1349 252† 1225 441 64 166 317 34 160 75 8484
132 2 3 288 0 19 21 16 NT 10 0 11 1 503
3.6 0.4 1.0 21 0 1.6 4.8 25 NT 3.2 0 6.9 1.3 6.2
1116 16 263 1341 0 1213 332 57 10 143 32 134 72 4729
31 3.5 89 99 0 99 75 89 6.0 45 94 84 96 57
48 1 NT NT NT 48 NT NT NT NT NT NT 1 98
1.3 0.2 NT NT NT 3.9 NT NT NT NT NT NT 1.3 1.2
1034 19 194 584* 17 666 198 32 15 91 29 97 37 3013
28 4.1 66 43 6.7 54 45 50 9.0 29 85 61 49 36
*From China 584 of 1349 (43.3%) isolates were penicillin resistant by β-lactamase (PPNG). Gonococci with chromosomally mediated resistance to penicillin (CMRP) were not reported. †In Fiji only strains that are penicillin resistant are tested for ceftriaxone and ciprofloxacin susceptibility (n=17 in 2011). ‡Area of the Western Pacific Region. NT, not tested.
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Supplement NAAT-positive sample from a given region and therefore provide greater representation for AMR surveillance. In our opinion, such methods would be ideal to supplement bacterial culture methods for a given population, where culture is used to ascertain general resistance trends for a broad range of antibiotics, and then PCR is used for high level sampling for particular antibiotics of critical importance. Exactly which antibiotics would be considered of importance would depend on the particular population, but ceftriaxone is clearly a standout in the current global environment. For example, the immediate implementation of H041 or F89 PCR testing into Japan and Europe, respectively, could go a long way towards understanding the local epidemiology, if any, in these regions. Elsewhere, use of PCR to screen for the N gonorrhoeae mosaic penA gene, associated with reduced susceptibility to ceftriaxone and the key ‘building block’ of ceftriaxone resistance in the H041 and F89 strains, would provide useful data on the broader spread of reduced susceptibility to ceftriaxone and threat of resistance development. Disadvantages of molecular AMR methods include that that they cannot currently provide as definitive data as bacterial culture in predicting resistance, given the targeted nature of molecular testing (ie, only targeting selected genetic mechanisms) and that the genetics of N gonorrhoeae AMR can be complex, and yet to be fully elucidated. The costs of PCR-based AMR testing, including reagents and infrastructure, may also be prohibitive in certain settings.
DISCUSSION In 2013, despite the gaps in surveillance regionally and globally, we are left in little doubt as to the gravity of the threat of gonococcal AMR. The prediction for the future is bleak based on the information globally, and from the WPR: high proportions of isolates in some countries in the region with raised MIC values to ceftriaxone; emergence of ceftriaxone resistant MDR strains,10 11 widespread uncontrolled antibiotic use,26 rising rates of disease,2 27 no new treatment options and the increasing fear of uncontrolled disease spread. In context, AMR in bacteria is a global public health challenge that is not confined to the gonococcus, and emergence of AMR in the healthcare setting and the community is facilitated by many factors including the relative ease of international travel and widespread unregulated use of antimicrobials around the world.26 28 In a recent perspective article focused on AMR in the WPR, four key areas were outlined to strategise a response: improved surveillance that is standardised, structured and quality assured; focused, basic research on resistant bacteria to understand mechanisms of AMR and transmission; appropriate control and use of antimicrobials; and infection prevention and control strategies.28 Specific strategies outlined in the WHO Global Action Plan to control gonococcal AMR include improving early detection, and strengthening laboratory capacity for diagnosis and surveillance.29 In addition, effective screening and treatment programmes in key populations are important.27 These factors need to be heeded and supported at the national, regional and global levels to control AMR. Disease prevention and disease control strategies rely on effective treatment protocols informed by timely and representative surveillance data. Further, surveillance of AMR is essential for providing information on the magnitude and trends in resistance, and also for monitoring the effects of interventions. Calls continue for enhanced surveillance at the national, international and global levels,7 16 30 and the use of available molecular strategies and development and use of new and aligned technology, will optimise the information available for monitoring AMR. iv22
That said, the key factors that facilitate the development of AMR and directly impact on disease control are uncontrolled antibiotic use and unchecked disease spread. At the most pragmatic level control of gonorrhoea and gonococcal AMR will be best achieved by disease prevention. Public health campaigns for safe sex in conjunction with routine screening in high-risk populations, advocating for improved use of antibiotics inside and outside the health system are essential counterparts to AMR surveillance in developing a functional solution to contain gonococcal disease and gonococcal AMR.
Key messages ▸ With disproportionately high, and rising, gonococcal disease rates, increasing antimicrobial resistance and no ideal alternate treatment, the Western Pacific region is facing a serious public health threat ▸ At local, national and regional levels, disease prevention and disease control strategies; appropriate control and use of antimicrobials; and improved antimicrobial resistance surveillance are paramount ▸ Effective surveillance is key to understanding the magnitude and trends of gonococcal resistance, and for monitoring effects of interventions ▸ In conjunction with culture based surveillance, use of available molecular strategies will optimise the information available for monitoring antimicrobial resistance
Acknowledgements The authors acknowledge Professor John Tapsall AM who was at the forefront of the establishment of the WPR GASP, the staff at the WHO Collaborating Centre in Sydney; Mrs Athena Limnios; Dr Tiffany Hogan; Mr Rodney Enriquez and Mr Ratan Kundu; and the work of Dr Namraj Goire. This review was written on behalf of our regional collaborators in the WHO WPR: The National Neiseria Network, Australia; Ms HJH Mahani, Brunei; Dr Sopheak Hem, Cambodia; Dr Yueping Yin, China; Mr Parmod Kumar, Fiji; Dr Tony Ng, Hong Kong (China); Professor Masatoshi Tanaka, Fukuoka, Japan; Professor Takashi Deguchi, Gifu City, Japan; Dr Y Watanabe, Kanagawa, Japan; Dr Kyungwon Lee, Seoul, Korea; Dr Phengta Vongprachanh, The Lao People's Democratic Republic Dr Sabet Negar Shafei, Malaysia; Dr Odgerel Tundev, Mongolia; Ms Marian Smith, Auckland, New Zealand; Ms Helen Heffernan, Christchurch, New Zealand; Dr Regis Goursad, Nouvelle-Caledonie; Mr Leo Latorre, Boroko, Papua New Guinea; Ms Pamela Toliman, Boroko, Papua New Guinea; Dr Celia Carlos, Manila, Philippines; Dr Elizabeth O Telan, Sta Cruz, Philippines; Dr Ai Ling Tan, Singapore; Mr Sitanilei Hoko, Tonga; Mr Le Van Hung, Vietnam; whose long-standing commitment has driven the WPR GASP for more than 20 years. Contributors MML is the Director of the WHO Collaborating Centre for STD, Sydney, which is the Coordinating Centre of the WHO GASP for the WPR and SEAR. The gonococcal AMR surveillance data was collated from this Centre. All authors contributed to the writing of this paper. Funding The WHO CC,Sydney is funded by the Australian Government Department of Health and Ageing for the Australian Gonococcal Surveillance Programme and the WHO WPRO for the WPR GASP. This review was supported in part of the Gonorrhoea Resistance Assessment by Nucleic Acid Detection (GRAND) study supported by a National Health and Medical Research Council (NHMRC) Australia, Project Grant (APP1025517). Competing interests None. Provenance and peer review Commissioned; externally peer reviewed.
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Gonococcal antimicrobial resistance in the Western Pacific Region Monica M Lahra, Ying-Ru Lo and David M Whiley Sex Transm Infect 2013 89: iv19-iv23
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