Reply to “Management of Pharyngeal Gonorrhea Is Crucial To Prevent the Emergence and Spread of Antibiotic-Resistant Neisseria gonorrhoeae”

REPLY

We are very grateful to Dr. Takashi Deguchi et al. for their positive response on our paper “High-Level Cefixime- and Ceftriaxone-Resistant N. gonorrhoeae in France: Novel penA Mosaic Allele in a Successful International Clone Causes Treatment Failure” (10). Dr. Deguchi, et al. emphasize several important issues and provide many valuable reflections regarding the validated threat of emergence of untreatable gonorrhea in their Letter to the Editor “Management of Pharyngeal Gonorrhea is Crucial to Prevent the Emergence and Spread of Antibiotic-Resistant Neisseria gonorrhoeae.” Accordingly, it is of grave concern that the first two extensively drug resistant (XDR) (8) N. gonorrhoeae strains with high-level ceftriaxone resistance have been confirmed and, furthermore, that they were identified in high-risk, frequently transmitting populations, i.e., the Japanese strain H041 from a female commercial sex worker (7) and the French strain F89 from a man-who-has-sex-with-men (MSM) (10). Both of these strains belong to successful gonococcal clones (multilocus sequence type [MLST] ST7363 [strain H041] and ST1901 [strain F89]) that, together with their evolved closely related genetic subtypes, have been successful in spreading worldwide (7, 10). These successful clones have now shown their capacity to develop high-level resistance to ceftriaxone, the last remaining option for empirical first-line treatment of gonorrhea. Thus, it is a validated fear that gonorrhoea might become untreatable in certain circumstances and, in particular, some settings that cannot afford dual antimicrobial combination therapy. Nevertheless, determination of the biological fitness, enhanced understanding of the mechanisms of ceftriaxone resistance, and monitoring of these ceftriaxone-resistant strains and their international transmission remain imperative. It is also essential to closely monitor the continued evolution and emergence of new penA mosaic alleles. Many novel penA alleles (penA mosaic alleles but also, e.g., altered penA-A501 alleles) will continue to emerge, and their effects on the MICs of extended-spectrum cephalosporins will vary substantially, due to the specific penA allele as well as the presence or absence of additional cephalosporin resistance mechanisms (6, 10). Consequently, it is crucial to elucidate the effects of all amino acid alterations suspected to enhance the MICs of extended-spectrum cephalosporins by performing transformation assays, ideally with site-directed penA mutants into isogenic strain backgrounds (9). It is also imperative to investigate in detail all gonococcal strains suspected to be resistant to the recommended extended-spectrum cephalosporins in order to confirm their phenotypic resistance, predict the possibility of treatment failure and further spread of the strains, and elucidate their genetic characteristics, particularly their resistance determinants.

The gonococcus may be evolving into a superbug, and to meet the large public health challenges from the emergence of multidrug-resistant (MDR) (8) and XDR N. gonorrhoeae and potentially untreatable gonorrhea, many actions are essential worldwide. We completely agree with Dr. Deguchi et al. that pharyngeal gonorrhea, which is a mainly asymptomatic reservoir for gonococcal infection and, compared to urogenital gonorrhea, significantly more difficult to eradicate, increases the risk of selection of antimicrobial-resistant gonococcal clones and that it is likely that the pharynx is the origin of resistance to extended-spectrum cephalosporins, due to horizontal transfer and subsequent recombination with penA alleles from nongonococcal Neisseria species (1, 8). Accordingly, it is of great importance to pay more attention to diagnosis and treatment (higher dose of ceftriaxone or dual antimicrobial combination therapy?) of pharyngeal gonorrhoea, as well as to implement more frequent follow-up examinations and, at least in some settings, mandatory test-of-cure, using highly sensitive diagnostic methods, for pharyngeal gonorrhoea and possibly, in the future, for all gonorrhoea cases. Furthermore, it is important to collect appropriate data regarding epidemiological characteristics, including patients' sexual practices, as well as to take extragenital (pharyngeal and rectal) samples. For some high-risk populations and settings, it may be necessary to screen for pharyngeal gonorrhea, ideally using both culture (for its high specificity and possibilities to perform antimicrobial resistance testing) and highly specific nucleic acid amplification test(s) (due to their higher sensitivity compared to that of culture).

In addition to this enhanced focus on pharyngeal gonorrhoea, a holistic view is essential in order to effectively combat the large public health challenges from the emergence of possibly untreatable gonorrhea. Consequently, enhanced and broad disease control activities to reduce the global burden of gonorrhea, combined with the implementation of wider strategies for general antimicrobial control (use, selection, supplies, quality, etc.), surveillance of antimicrobial resistance and treatment failures worldwide, and public health action plans (global and national perspectives), are crucial (7, 8). However, all these actions will likely only mitigate the spread of MDR and XDR N. gonorrhoeae and, ultimately, there is an urgent need for new treatment strategies, new antimicrobial agents (or other compounds), and ideally, a vaccine for effective treatment and/or prevention of gonorrhea. The use of an increased dose of ceftriaxone has already been implemented in many settings. However, this approach will provide only a short-term solution. Dual-antimicrobial combination treatment for gonorrhea has also recently been introduced in the United States (12) and the United Kingdom (2). However this will, due to cost issues, be challenging in less-well-resourced settings and, from a global public health perspective, an effective antimicrobial for single-drug therapy of gonorrhea appears fundamental. Unfortunately there are few really promising novel treatment alternatives in sight. Nevertheless, gentamicin (3, 4), the new fluoroketolide solithromycin (5), and ertapenem (11) may be effective options for treatment of gonorrhea, particularly for currently identified extended-spectrum cephalosporin-resistant cases and in a dual-antimicrobial combination therapy regimen. All these potential future treatment regimens require comprehensive in vitro and in vivo evaluations, including appropriately designed, randomized, and controlled treatment studies for urogenital and extragenital, especially pharyngeal, gonorrhea.