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Sustainable Antimicrobial Surveillance Programs Essential for Controlling Neisseria gonorrhoeae Superbug

Dillon, Jo-Anne R. PhD

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doi: 10.1097/OLQ.0b013e318232459b
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The progressive development of resistance in isolates of Neisseria gonorrhoeae to antimicrobial agents used to treat gonococcal infections has been a characteristic of the microorganism ever since the introduction of sulphonamides.1 Over time, the aspiration that there would be a never-ending supply of effective antibiotics that could be used in single dose, preferably oral, therapy for the treatment of gonococcal infections has steadily eroded.1,2 This on-going concern has been founded in the relentless development of single and multiple resistances in N. gonorrhoeae isolates to antibiotics recommended for treatment. This apprehension has been particularly reflected in recent reports of N. gonorrhoeae isolates resistant to and treatment failures with the remaining effective antibiotics used for single-dose therapy: the third generation cephalosporins.3–6 Especially noteworthy is the recent report from Japan which documents high-level resistance in a strain of N. gonorrhoeae to both ceftriaxone and cefixime as well as multiple antibiotics,7 leading to predictions of N. gonorrhoeae becoming an untreatable superbug.

The threat of potentially untreatable gonococcal infections is not new.8,9 In the early 1990s, this possibility was recognized by the World Health Organization (WHO) and others and resulted in the nascent development and advocacy for international, coordinated antimicrobial surveillance of N. gonorrhoeae.10 This first Gonococcal Antimicrobial Surveillance Program (GASP) initiative was met with limited success. During the 1990s, GASP was initiated in the World Health Organization Southeast Asia Region (SEAR), the Western Pacific Region (WPR), Latin America and the Caribbean (LAC), and a number of other regions.2,10,11 As well, a number of national programs in Europe, the United States of America, and Australia have also been ongoing for some time and are notable for their annual reports on trends in the antimicrobial resistance (AMR) of N. gonorrhoeae isolates.12,13

The report by Martin et al. in this issue underscores a long history of antimicrobial surveillance of N. gonorrhoeae isolates in Canada.14 Their article also highlights inherent challenges in regional, national, and international surveillance strategies. The Canadian study reports on antimicrobial susceptibilities of N. gonorrhoeae collected from Canadian provinces between 2000 and 2009. Thus, of 40,875 cultures collected over the period in Canada, 10,993 were tested for antimicrobial susceptibility, and of these 10,141 were resistant to at least 1 antibiotic. Over the same period, 93,997 cases of infections caused by N. gonorrhoeae were reported in Canada. The Canadian study shows that, over time, the number of cultures obtained for AMR testing represented fewer of the total number of cases reported. Even so, the lowest percentage of cases tested for AMR in Canada was 28.2% in 2009, as compared to 72% in 2000. Compared to the percentage of N. gonorrhoeae isolates tested in many countries for AMR, this percentage is actually quite high. One of the major difficulties with international surveillance of AMR of N. gonorrhoeae is the small number of isolates tested from many regions. Conclusions derived from these small numbers of isolates tested inevitably lead to concerns regarding whether such data should be extrapolated to develop effective treatment guidelines and other public health initiatives.

There are several important features in these seemingly straightforward Canadian statistics on gonococcal AMR which exemplify much GASP-related surveillance internationally. First, the Canadian data has been aggregated over a 10-year period. This work shows that the Canadian national surveillance system had not “lapsed” over this time period but was on-going.2 In fact, the first national study of gonococcal antimicrobial surveillance in Canada was undertaken in 1973 to 1974, and this surveillance activity has endured at some level nationally and regionally ever since.15,16 Data from various surveillance activities were used to inform decisions for updating Canadian national treatment guidelines for N. gonorrhoeae and have been available on national websites (including the Public Health Agency of Canada: PHAC).

Given the potential threat of untreatable gonococcal infections, there is an urgent need to understand global trends in the development of antimicrobial resistance in N. gonorrhoeae isolates. Such information must be accessed and communicated in a timely fashion, preferably on an annual basis and in nationally and internationally accessible formats. At present, the main means of communicating N. gonorrhoeae antimicrobial susceptibility surveillance information internationally is through the peer-reviewed literature. Several countries maintain reasonably up-to-date web sites on gonococcal AMR trends, but the prospect of accessing numerous websites to consolidate and update information on an international scale is daunting.

Aside from many regions for which there is certainly no information on AMR trends for N. gonorrhoeae isolates, many countries and regions actually retain considerable unpublished information or unanalyzed data on the issue: “data in the drawer.” Various countries or regions may collect some form of AMR testing data but do not have the resources for any of a number of functions related to the timely reporting of this data. These functions include, but are not limited to, participation in national or international quality assurance programs to ensure data integrity, timely data analysis methods, dissemination and follow-up of AMR information from the laboratory to appropriate public health personnel, ability to publish data locally, or publishing in international peer-reviewed journals. As an example, during the 1990s, several countries in the Caribbean were actually monitoring the number of penicillinase-producing N. gonorrhoeae isolates in response to the emergence of this penicillin-resistant phenotype. However, their data remained local, and sometimes unanalyzed, until a specific request and appropriate assistance was provided to aggregate and report these laboratory-based results.17 Aside from various local and individual reports, data from the GASP in Latin America and the Caribbean over its phase 1, 10-year period in the 1990s were aggregated and reported as a single report due to significant structural issues then (and now) inherent in reporting international data on an annual basis.17 A recent retrospective inquiry into GASP-related activity in the LAC region indicated that various levels of AMR surveillance for N. gonorhhoeae has been maintained from 2000 to the present in several countries and some countries are initiating new AMR surveillance activities.18 However, the analysis and dissemination of this information remains difficult to accomplish and the GASP Phase 2 program in the region aims to solve some of these important issues. The difficulty in reporting antimicrobial susceptibility information is widespread. The net result of this lack of information may be reflected in outdated or ineffective national treatment guidelines for N. gonorrhoeae infections in the LAC region and elsewhere with all the attendant public health issues that this may bring. These critical concerns include the uncontrolled spread of infections caused by N. gonorrhoeae; complications arising from untreated gonococcal infection, especially to female reproductive health; the spread of HIV; and, the economic burden associated with the spread of antibiotic resistant isolates.19 The World Health Organization, with various partners, has held a series of meetings to determine how global surveillance of antimicrobial resistance in N. gonorrhoeae might be enhanced and timelier reporting effected.20

What might be done to encourage surveillance and timely reporting of AMR in N. gonorrhoeae isolates? First, Martin et al. address the issue of the shift, especially in resource-advantaged countries, from the use of culture, which is presently essential for antimicrobial susceptibility testing, to the use of nucleic acid amplification tests (NAATs) for the diagnosis of gonorrhea.14,21 This explains the decrease in the number of isolates available for testing in countries such as Canada and the United States of America where the use of NAATs has dramatically increased. The authors suggest that it may be helpful to evaluate the public health practice of using a network of STI clinics and laboratories which can continue to obtain cultures for AMR determination.14 In other, usually more resource-limited settings, the issue is not the type of sample collected but whether a sample can be acquired at all. Many regions use syndromic management approaches to diagnose potential gonococcal infections, and cultures are not available. In these cases, education on how to design and optimize protocols for surveillance and clinical specimen collection, specimen transport and culture, N. gonorrhoeae identification, and AMR testing is required. The international GASP network, advocated by the WHO, is in a good position to collaboratively develop strategies and training programs to address some of these issues, although the issue of economic sustainability of such programs needs to be addressed urgently.17

Another important feature of the Canadian report by Martin et al. pertains to the actual aggregated AMR trends observed.14 They report on an increasing trend to chromosomal resistance to penicillin, tetracycline and erythromycin, and a declining trend in N. gonorrhoeae isolates with plasmid-mediated resistance to tetracycline and penicillin. They also report a significant increase over the period in resistance to ciprofloxacin (from 1.3% in 2000 to 25.5% in 2009). Neither penicillin nor tetracycline has been recommended for the treatment of gonococcal infections in Canada for several decades, and the rise in ciprofloxacin resistance resulted in a recommendation in 2008 that the use of this antibiotic be discontinued as first line therapy in Canada.22 The authors point out that there are regional differences in ciprofloxacin resistance in N. gonorrhoeae isolates in Canada, an observation borne out in our own studies in the province of Saskatchewan; during the period 2003 to 2008, a total of 5 ciprofloxacin-resistant isolates, of 320 isolates tested (15% of reported provincial cases tested for N. gonorrhoeae AMR), were identified.23 Perhaps data on N. gonorrhoeae AMR should be stratified to uncover possible regional pockets of either susceptibility or extreme resistance to antibiotics recommended for treatment. The emphasis for many years has been on having international and national treatment guidelines which reflect aggregate data. Nevertheless, there are examples where regions have continued to use older, no longer broadly recommended antimicrobial agents in cases where susceptibility data support such a policy.19 At a time when N. gonorrhoeae is being categorized as potentially untreatable, and where there is concern about what antimicrobials could be used in the future to treat gonococcal infections, strategies that would prolong the life of presently effective antimicrobials should be considered. Furthermore, some regions use antibiotics for treatment that are not recommended in other countries: e.g., gentamicin, kanamycin, and thiamphenicol. In order to be proactive, national surveillance could include the prospective periodic review of susceptibility to some of these older antimicrobial agents, as has been recently reported in Europe.24 Some of these older antimicrobial agents have been suggested as possible agents to be used in future combination therapies for gonococcal infections. Proactive, periodic surveillance of the susceptibility of N. gonorrhoeae isolates to these agents is required in anticipation of such future treatment strategies.

The Canadian report indicates a low percentage (1.7%) of isolates resistant to azithromycin, although the modal minimum inhibitory concentration(s) (MICs) had shifted from 0.25 μg/ml in 2000, to 0.5 μg/ml in 2009. This contrasts with reports in other areas, such as Latin America, where resistance to this antibiotic exceeds the 5% resistance level cut-off recommended by the WHO for the discontinuation of an antibiotic used for treatment.18 Although not recommended for the primary treatment of N. gonorrhoeae in most jurisdictions, the cotreatment of chlamydial infections with azithromycin will ensure on-going selective pressure for resistant isolates. Azithromycin has been suggested as an antibiotic that might be used with other antibiotics should combination therapy be recommended at some point for the treatment of gonococcal infections.25 Thus, worldwide monitoring of emerging resistance to this agent is important.

Finally, although all isolates reported in the Canadian study were susceptible to ceftriaxone, the modal MICs between 2000 and 2009 increased from 0.016 μg/ml to 0.063 μg/ml. MIC creep and outright resistance to third generation cephalosporins has been characterized in many reports, providing a sense of déjà vu with the development of high-level chromosomal resistance to penicillin in gonococci several decades earlier.1,6 The Japanese report of a new strain, called H041, with resistance to all antibiotics currently recommended for treatment, including ceftriaxone and other third generation cephalosporins,7 foreshadows the worldwide spread of gonococcal superbugs. The World Health Organization is focusing on the revitalized international GASP programs as a kind of early warning system to monitor the prevalence of multidrug resistant N. gonorrhoeae and especially those isolates resistant to third generation cephalosporins. This key surveillance activity should trigger a series of actions that will make a difference in effectively treating gonococcal infections, including ensuring that appropriate treatment guidelines are in place, preferably reflecting local trends. The challenges are considerable, not the least of which is the sustainability and viability of local programs to culture and determine trends of AMR in N. gonorrhoeae. Meeting this challenge will take intensive international collaboration to train health and laboratory personnel in appropriate methods, to marshal adequate resources, to encourage rapid dissemination of AMR trend information, to investigate new antimicrobials and antibiotic combinations, and to develop new and rapid methods for detecting gonococcal AMR in the era of NAATs.


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