Continued Evolution of Gonococcal Antimicrobial Resistance

(See the Major Article by Katz et al on pages 918–23.)

In this issue of Clinical Infectious Diseases, Katz and colleagues report the latest step in what seems to be the inexorable development of antimicrobial resistance impacting gonorrhea therapy in North America [1]. While decreased susceptibility to cephalosporin antibiotics and high-level resistance to azithromycin have each been documented previously, the 2 forms of resistance had not coexisted among US gonococcal isolates in the past. Furthermore, the isolates causing this outbreak also produced β-lactamase and were resistant to tetracycline and fluoroquinolone antibiotics, all of which were previously recommended for gonorrhea treatment [2]. The report also describes successful rapid detection and expeditious public health investigation of an important sentinel outbreak. What can be learned from this report, and how can this experience can help to address this developing problem? The importance, in part, is that it documents progressive, relatively rapidly developing gonococcal antimicrobial resistance. The report also recapitulates numerous prior observations describing development of antimicrobial resistance by the bacterial pathogen that is currently the second most commonly reported bacterial infection in the United States and documents the utility of surveillance for Neisseria gonorrhoeae antimicrobial resistance on the local level for the purpose of outbreak surveillance [3].

THE OUTBREAK

This report serves to demonstrate several potentially important points regarding the detection, origins, and management of resistant gonorrhea and raises questions to consider going forward. The outbreak occurred in at least 7 persons, all of whom were symptomatic and 5 of whom received care from the Hawaii Department of Health (HDOH) sexually transmitted disease (STD) clinics. Despite reduced antimicrobial sensitivity, all infections were successfully treated using recommended combination ceftriaxone/azithromycin therapy [4] and thus, were the HDOH not engaged in active, culture-based surveillance for resistant gonococci, this outbreak would have been missed until the infection had spread and treatment failures began to occur and were noticed. This success appears to validate the Centers for Disease Control and Prevention’s (CDC) recent decision to support preliminary Etest evaluation of gonococcal isolates at selected health departments for detecting resistant gonococcal strains, which permitted the HDOH to rapidly investigate the outbreak. The HDOH investigation showed that while the infected persons appeared to be epidemiologically unrelated, there were several suggestive links among the cases: Pulsed-field gel electrophoresis indicated that the isolates were genetically related; 2 infected persons reported contact with the same commercial sex worker; and several infections followed contact with partners who had links to Japan where the problem of gonococcal antimicrobial resistance has been seen previously. The speed with which the outbreak was detected using the Etest seems to demonstrate the potential benefit of local laboratory testing for timely detection of resistant strains within communities.

CONTINUING TRUTHS

This report also highlights several recognized characteristics of how antibiotic-resistant N. gonorrhoeae has and continues to emerge within communities, both globally and in North America. We can be confident that the gonococcus will continue to develop antimicrobial resistance to the medications used for treatment. Following introduction as one of the first modern antimicrobials in the 1930s, sulfonamide antimicrobials were recommended for gonorrhea therapy but were effective for less than a decade when progressive antimicrobial resistance had evolved to result in treatment failure for >30% of gonorrhea patients treated with maximal doses of sulfonamides [5]. Subsequently, penicillin became the drug of choice for gonorrhea treatment and remained so for decades, during which time recommended doses escalated to address progressive resistance due to the cumulative effect of chromosomal mutations. The end of the penicillin era came as gonococci acquired a plasmid for β-lactamase production and as high-level chromosomally resistant N. gonorrhoeae cases were detected and associated with treatment failures despite maximal penicillin doses. Fortunately, at that time pharmaceutical companies were producing new, highly active cephalosporin antibiotics such as ceftriaxone and, subsequently, fluoroquinolone antibiotics that reliably cured gonorrhea—until relatively recently. The saga of repeated development of antimicrobial resistance by the gonococcus is testimony to the remarkable genetic plasticity of this organism that allows it to develop resistance to the drugs recommended for treatment.

The fact that all of these isolates were detected and successfully treated with currently recommended therapy is reassuring and testimony to the effectiveness of the CDC’s Gonococcal Isolate Surveillance Project (GISP) [6], a system for sentinel monitoring of gonococcal antimicrobial susceptibility initiated in the late 1980s and which has accurately reflected US trends in gonococcal infections for nearly 30 years. GISP has permitted ongoing monitoring of gonococcal antimicrobial susceptibility to permit anticipatory adjustment to treatment recommendations before treatment failures have become a problem at least 3 times in the past decade. The success of GISP is a sterling demonstration of an effective surveillance system for antimicrobial resistance in outpatient settings.

This report also once again demonstrated the tendency of antimicrobial resistance to be detected first in Asia and then disseminate in our ever-shrinking world. While development of resistance can also occur elsewhere and can certainly be selected for through local patterns of antimicrobial use, the pattern in which strains of N. gonorrhoeae with diminished susceptibility are first detected in Asia and then seen first in the western United States has occurred repeatedly. The reasons for this remain unclear.

Finally, perhaps this report will serve to demonstrate the important safety net role for public STD clinics such as the ones operated by the HDOH that detected these isolates, performed the outbreak evaluation, and continue to serve as a source of expertise for persons with limited access to care or who cannot be seen by their healthcare providers in a timely fashion. This story supports a continued role for public health STD clinics.

IMPLICATIONS FOR THE FUTURE

This report likewise may help to clarify some of the continuing questions that will impact ongoing efforts for gonorrhea control in this era of evolving drug resistance and limited treatment options. For instance, whereas the currently recommended ceftriaxone-azithromycin combination did cure the patients described in this report, it is reasonable to anticipate that resistance to these agents will continue to accrue, ultimately making them ineffective. At the same time, the “antibiotic pipeline” has slowed, particularly for affordable, single-dose regimens for public health priorities such as treatment of sexually transmitted infections (STIs) other than human immunodeficiency virus. While several new drugs have recently been evaluated in phase 2 trials, it will still likely be years until they receive full US Food and Drug Administration approval, if larger trials prove them efficacious. Furthermore, whether other, new compounds will be forthcoming is unclear. The National Institutes of Health, CDC, World Health Organization, and industry partners are working to address this problem, but how these initiatives will work and whether or not they succeed remains to be seen. In the interim, vigilance is needed to monitor whether the current strategy of using 2 unrelated medications with different mechanisms of action (eg, ceftriaxone-azithromycin) for gonorrhea therapy in an effort to slow further development of resistance will succeed as hypothesized. While GISP has a record of success in monitoring gonococcal antibiotic resistance trends, recently CDC has chosen to modify GISP and now relies on a reconfigured laboratory network with increased emphasis on use of local Etests for preliminary detection of decreased antimicrobial susceptibility and molecular diagnosis for description of antibiotic resistance. This report appears to validate the efficacy of this newly configured approach and should be monitored as well. It is hoped that this new surveillance system will be as (or more) effective as GISP has been.

While dedicated health department STD clinics have quietly played multiple roles in US STD control efforts, more recently their role is being challenged. The HDOH STD clinic served as the starting point for identification and epidemiologic investigation of the outbreak, demonstrating the importance of public health STD clinics for surveillance and identification of sentinel epidemiologic events while also providing direct healthcare. Such clinics serve as sites where care can be rapidly obtained at little or no cost, by patients who are seeking confidential care, who have limited access to healthcare and/or whose healthcare providers cannot see them in a timely fashion. These functions have been particularly important for caring for at-risk men who, as a group, sometimes have less access to care than women. Further, health department STD control programs have played important roles in monitoring local STI morbidity and as a source of reliable expertise for healthcare providers seeking expert advice. Yet, in some locales, dedicated STD clinics have closed or reduced their hours. One cannot help but wonder if this is the right approach at a time when each of the STIs reportable to the CDC (gonorrhea, chlamydia, and syphilis) have increased over the past year.

In summary, Katz et al have provided us with an important observation, not only documenting continuing development of gonococcal antimicrobial resistance but also reinforcing continuing trends in this process, demonstrating the contributions that public health STD control efforts can make to our understanding of sentinel epidemiologic events, and perhaps raising questions for consideration as the gonococcus continues to evolve and untreatable STIs once again increase in the United States.

Note

Potential conflicts of interest. The author has received grants from the CDC, Hologic, Roche Molecular, and Becton Dickinson, and personal fees from AstraZeneca. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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