Identification of Demographic and Behavioral Risk Factors for Antibiotic Resistant Gonorrhea Infections to Combat the Emergence of Potentially Untreatable Infections

The research by Cole et al.1 in this issue of Sexually Transmitted Diseases highlights a number of important findings related to behavioral and demographic risk factors for antimicrobial resistance (AMR—i.e., resistance to ceftriaxone, cefixime, azithromycin, and ciprofloxacin) in people infected with Neisseria gonorrhoeae. They found that heterosexuals, people older than 25 years, and persons not concurrently infected with chlamydia were more likely to carry infections resistant to cefixime and/or ciprofloxacin. More surprisingly, Cole et al. report a significant decrease in the geometric mean of European gonococcal cefixime and ceftriaxone minimum inhibitory concentrations (MICs) between 2009 and 2011, especially among men who have sex with men (MSM). In 2011, heterosexual men exhibited the highest MICs to both these antibiotics as compared with MSM and women. Univariate and multivariate analyses of the risk factors associated with gonococcal resistance to ciprofloxacin, cefixime, and azithromycin indicated that slightly different risk factors were associated with resistance to the different antibiotics. For example, azithromycin resistance (univariate analysis) was associated with male heterosexuals, no concurrent chlamydial infections, or previous gonorrhea, and year of isolation was negatively associated with this resistance. In the multivariate analysis of gonococcal azithromycin resistance, only no concurrent chlamydial infection and year of isolation were significant. Interestingly, isolates from the pharynx were not more likely to be associated with resistance to azithromycin, ciprofloxacin, or cefixime. This finding contrasts with research indicating that resistance to third-generation cephalosporins is associated with horizontal gene transfer from commensal Neisseria species carried in the pharynx to N. gonorrhoeae isolates.2 The findings by Cole et al.1 are important because they provide evidence useful for identifying individuals potentially at higher risk for acquiring AMR gonorrhea infections. This study also adds to the very small number of published studies that link comprehensive epidemiological data with antimicrobial susceptibility data to identify potential behavioral and demographic risk factors for AMR gonorrhea infections. In this era of rising gonococcal resistance to the last class of antibiotic used in monotherapy, the third-generation cephalosporins, and facing the threat of potentially untreatable infections,2 the application of behavioral and demographic factors, which can be elicited in a clinical visit, to identify those at higher risk for AMR infection could play a central role in tailoring effective policies to combat resistant infections. The current literature regarding behavioral and demographic risk factors associated with gonococcal AMR identifies a number of factors associated with increased MICs to various antibiotics. Being in an older age group, for example, has been found in previous studies to be associated with probable resistance or resistance to ceftriaxone,3 quinolones,4 and azithromycin.5 In addition, association of male (heterosexual) sex and increased MICs to tetracycline and ceftriaxone3 and to quinolones4 has been previously reported. A 2014 study3 found an association between alcohol use and tetracycline resistance, which was interpreted as a potential marker for other, more proximate risk behaviors, such as having multiple sex partners, which might be more plausibly associated with resistant infection.3 Several studies from the previous decade have identified an association of resistance to various antibiotics with MSM.6–9 Other factors found to be associated with gonorrhea infections resistant to quinolones include recent antibiotic use and race/ethnicity,6 and, among sex workers, self-prescribed antibiotic use.10 Lastly, one study found sex with a female sex worker to be associated with resistance to azithromycin.5 The type of information produced by Cole et al.1 in analyzing the association of demographic and behavioral risk factors and gonococcal AMR is extraordinarily difficult to obtain, and the authors point out some of the inherent difficulties. They indicate that susceptibility testing information and epidemiological surveillance data on gonorrhea cases are separately reported through the European Surveillance System. It is remarkable that the same informatics system was used to link patient and gonococcal antimicrobial susceptibility data. Many jurisdictions, both regional and national, often have multiple, different systems for reporting microbiological and epidemiological information, thereby posing significant challenges for data linkage. The ability to link data from multiple countries in a common, linkable data base is indeed remarkable. From a global perspective, it may be very difficult to harmonize information systems for collecting this information. The organization best placed to do so would be the World Health Organization (WHO). Furthermore, many countries collect virtually no epidemiological/patient information on gonorrhea cases. The urgency for an epidemiological assessment to identify demographic and behavioral factors in isolates of N. gonorrhoeae which are resistant to third generation cephalosporins was acknowledged in a recent WHO global action plan to control the spread and impact of AMR in N. gonorrhoeae.11 Interestingly, the report from Cole et al.1 also indicates that the geometric mean of the MICs to cefixime and ceftriaxone of N. gonorrhoeae isolates significantly decreased over the period tested and that the percentage of cefixime resistant isolates also declined. This decline started before revised treatment guidelines in Europe, which recommended a combination of ceftriaxone (500 mg intramuscularly) and azithromycin (2 g orally), were put into place in response to the WHO call for a global action plan.11 Many countries do not have gonococcal antimicrobial surveillance programs in place so that the global extent of such findings can be evaluated. The global Gonococcal Antimicrobial Susceptibility Program, encouraged by the WHO, will be a key strategy in identifying the burden of gonococcal AMR internationally, coupled with the development of effective prevention strategies, including the identification of relevant demographic and behavioral risk factors. The report by Cole et al.1 of decreasing MICs to third-generation cephalosporins, however temporary, may offer some respite pending the introduction and evaluation of alternative therapeutic strategies. Although the study by Cole et al.1 adds detailed information to the existing literature, including variables that were not significantly associated with gonococcal resistance to specific antibiotics, the number of potential risk factors that might be explored could be expanded. For example, other factors such as alcohol and drug use, or reporting multiple sex partners, might be important makers for membership in high-risk sexual networks, which could plausibly result in higher risk of transmitting AMR infections if individuals in such networks are more frequently infected and therefore more frequently treated. In addition, Cole et al. analyzed only 2 age groups: younger than 25 years and 25 years and older. Further stratification of age could provide information regarding the risk of AMR infection acquisition at a higher level of detail, which would enable more targeted prevention strategies among specific age groups. Because the data analyzed by Cole et al. comes from 21 different countries, it may be difficult to take this generalized information about risk factors and apply it to specific regions. It would be interesting to know whether controlling for the country of origin of the gonococcal isolates would have had any effect on the associations identified. In addition, considering the disaggregation of data could potentially identify specific regions within Europe that are of particular concern. The current state of our understanding of behavioral and demographic risk factors for AMR gonorrhea infections remains limited; establishing behavioral and demographic risk factors for AMR infections could greatly increase efficiency in recommending effective treatments. In the absence of a rapid point-of-care test for gonococcal diagnosis and AMR testing, which would tailor antibiotic treatment to the individual patient, and aside from awareness of local trends (or anecdotal evidence), there is currently no way to target effective therapy to those with N. gonorrhoeae infections which are resistant to antibiotics used for treatment. Ever increasing reports of resistance of N. gonorrhoeae to the third-generation cephalosporins necessitates that the establishment of new methods of delivering timely, effective treatment is an urgent priority. To date, the few studies on behavioral and demographic risk factors for gonococcal AMR come from many different regions, consider a variety of different antibiotics, and include a mixture of different risk factors. A more systematic approach to the identification and analysis of these risk factors is needed; for example, not all studies report the results of multivariate analysis, which provides stronger evidence regarding potential risk factors for AMR gonorrhea infection than univariate analysis. Careful consideration of reasonable boundaries for such studies, because gonorrhea is a network disease, is also needed. For example, how large an area should be reasonably included in a study to accurately determine risk factors for AMR in a given population? Is it plausible to look for globally applicable risk factors? Until such a body of literature is developed, it is difficult to draw any broad conclusions. What can be said with confidence, however, is that the identification of behavioral and demographic risk factors for AMR is a feasible, promising practice. Success will rely on the collection of robust epidemiological data, in addition to laboratory data, to be analyzed using appropriate and rigorous statistical techniques. Specific information on the most plausible risk factors—such as those identified in previous studies, along with factors such as over the counter antibiotic use, and high-risk behaviors that may be markers for participation in high risk networks—is critical to establishing reliable risk profiles for AMR infection.

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.