6 December 2023
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Neisseria gonorrhoeae, or gonococcus, is a leading cause of bacterial sexually transmitted infections (STI) and a World Health Organization (WHO) high-priority pathogen due to seriously diminishing treatment options. Antimicrobial resistance (AMR) in the gonococcus can arise by several mechanisms, including chromosomal mutation within the organism’s genome or gene acquisition from commensal Neisseria spp., which act as a source of chromosomally-mediated resistance.1 For example, the mosaic genes encoding the MtrCDE export pump and its promoter arose by transforming the gonococcus with gene fragments from commensals, leading to gonococcal resistance to azithromycin.2 In addition, the organism can acquire antimicrobial resistance in a single step by transferring plasmids from one organism to another.
In plasmid-mediated gonococcal AMR, the conjugative plasmid, pConj, confers resistance against tetracycline and doxycycline simultaneously3,4 and encodes a Type IV secretion system that facilitates its transfer among gonococci.5 This plasmid also promotes the spread of the beta-lactamase plasmid, pbla,6 which was a significant reason for discontinuing penicillin therapy against gonococcal disease. Within gonococcal populations, the presence of pConj is associated with pbla, probably due to their co-transfer between gonococci.3
While the routine implementation of doxy-PEP might reduce the incidence of Chlamydia and syphilis in high-risk groups, its widespread effects on the gonococcal population and other pathogens, as well as the microbiome, should be carefully monitored as doxy-PEP is recommended and becomes widespread as a public health measure.
Doxycycline for post-exposure prophylaxis against bacterial STIs
Post-exposure prophylaxis following risky sexual exposures has been successfully implemented to reduce human immunodeficiency virus (HIV) transmission due to unprotected sexual intercourse. This approach has now been proposed for reducing bacterial STIs. Doxycycline post-exposure prophylaxis (doxy-PEP) has been evaluated in two open-label, randomised studies for its effect on bacterial STIs in high-risk populations.7,8 In both the IPERGAY and DoxyPEP studies, Chlamydia infection and syphilis rates were significantly lower in those assigned to receive PEP compared with controls. However, in the IPERGAY study, PEP had no effect against the gonococcus,8 while in the DoxyPEP study, prophylaxis was least effective against N. gonorrhoeae (Relative risk, 0.45; 95% CI, 0.32-0.64).7 Of note, gonococcal infection was the most common STI in both studies. The authors of the DoxyPEP study point out that the limited effect against the gonococcus might be explained, at least in part, by reduced susceptibility to tetracycline and doxycycline.3 This claim is supported by the higher number of infections with tetracycline-resistant gonococci in the group receiving doxy-PEP7 and the complete absence of any effect of doxy-PEP against N. gonorrhoeae infection in the IPERGAY study which reported higher levels of tetracycline resistance.8 The authors of both studies state that there is a need to monitor gonococci for emerging tetracycline resistance.
The threat of plasmid-mediated resistance following doxy-PEP
What are the implications of doxy-PEP on gonococcal AMR? In low and middle-income countries (LMICs) where diagnostic facilities are limited and doxycycline is used for syndromic treatment of STIs, pConj can be found in over 90% of gonococcal isolates: this is associated with a high prevalence of pbla (present in ~ 50% of isolates).3 Therefore, it is likely that the use of doxy-PEP in high-risk individuals, who can act as the source of STIs for the general population, will select for further proliferation of pConj-carrying isolates, severely compromising the effectiveness of doxy-PEP against gonorrhoea. N. gonorrhoeae probably acquired pConj tetM (conferring tetracycline-resistance) in the 1980s from streptococci,4 and the plasmid could potentially facilitate the accumulation of additional resistance genes, which would exacerbate the problem of gonococcal AMR. Further, and perhaps even more concerning, pbla would become more widespread with increasing pConj and might become an extended spectrum β-lactamases (ESBL) plasmid, undermining the use of cephalosporins, the current first-line treatment for gonococcal disease. This would result in multidrug, plasmid-mediated resistance that could spread easily among gonococci, making it a public health disaster for attempts to control this important STI, which has a major impact on women’s sexual and reproductive health and HIV transmission, especially in LMICs. Health policies in high-income countries (HICs) could jeopardise infection control in lower-income regions through the spread of resistant microbes globally.
As we strive to combat infectious diseases by using antimicrobials in a targeted manner to limit the emergence of AMR, it is essential that we thoroughly explore the implications and monitor the impact of community-level interventions both for the disease in question and for wider public health.
Considering the broad implications of public health measures
While the routine implementation of doxy-PEP might reduce the incidence of Chlamydia and syphilis in high-risk groups, its widespread effects on the gonococcal population and other pathogens, as well as the microbiome, should be carefully monitored as doxy-PEP is recommended and becomes widespread as a public health measure. It is possible, and perhaps likely, that doxy-PEP will complicate the treatment and control of N. gonorrhoeae, which rely on available effective antimicrobials. As we strive to combat infectious diseases by using antimicrobials in a targeted manner to limit the emergence of AMR, it is essential that we thoroughly explore the implications and monitor the impact of community-level interventions both for the disease in question and for wider public health. The routine implementation of doxy-PEP may have widespread effects on the gonococcal population, which should be carefully considered before doxy-PEP is recommended as a public health measure. If implemented, further long-term prospective studies are needed to evaluate the broader ecological impacts of doxy-PEP on STIs, resistance and the microbiome. Additionally, developing rapid, low-cost diagnostic tests would allow targeted rather than blanket use of antimicrobials.
References
- Goytia M, Wadsworth CB (2022) Canary in the coal mine: How resistance surveillance in commensals could help curb the spread of AMR in pathogenic Neisseria. mBio 13.
- Wadsworth CB, Arnold BJ, Sater MRA, Grad YH (2018) Azithromycin resistance through interspecific acquisition of an epistasis-dependent efflux pump component and transcriptional regulator in Neisseria gonorrhoeae. mBio 9.
- Cehovin A, Jolley KA, Maiden MCJ, Harrison OB, Tang CM (2020) Association of Neisseria gonorrhoeae plasmids with distinct lineages and the economic status of their country of origin. J Infect Dis 222:1826–1836.
- Morse SA, Johnson SR, Biddle JW, Roberts MC (1986) High-level tetracycline resistance in Neisseria gonorrhoeae is result of acquisition of streptococcal tetM determinant. Antimicrob Agents Chemother 30:664–670.
- Pachulec E, van der Does C (2010) Conjugative plasmids of Neisseria gonorrhoeae. PLoS One 5:e9962.
- Roberts MC, Knapp JS (1988b) Transfer of β-lactamase plasmids from Neisseria gonorrhoeae to Neisseria meningitidis and commensal Neisseria species by the 25.2-megadalton conjugative plasmid. Antimicrob Agents Chemother 32:1430–1432.
- Luetkemeyer AF, Donnell D, Dombrowski JC, Cohen S, Grabow C et al. (2023) Postexposure doxycycline to prevent bacterial sexually transmitted infections. N Engl J Med 388:1296–1306.
- Molina JM, Charreau I, Chidiac C, Pialoux G, Cua E, et al. (2018) Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: an open-label randomised substudy of the ANRS IPERGAY trial. Lancet Infect Dis 18:308-317.
Christoph Tang is Professor of Cellular Pathology at the Sir William Dunn School of Pathology, University of Oxford. He has a distinguished track record of research in infectious diseases through his pioneering work on the characterisation of microbial virulence determinants, and the development of novel vaccine strategies. He developed new genetic methods for genome-wide mutagenesis of the human Neisseria meningitidis, which led to the discovery of nearly 80 genes necessary for virulence.
Ann E. Jerse is Professor and Vice Chair of the Department of Microbiology and Immunology at the Uniformed Services University of the Health Sciences (USUHS) in Bethesda, Maryland, USA. One of Ann’s laboratory’s main areas of research is animal modelling, including murine models of ascending Neisseria gonorrhoea (Ng) genital tract infection and Ng-Chlamydial coinfection. Ann also works in the area of antibiotic resistance by maintaining a biorepository and reference laboratory for resistant Ng in the US and at overseas sites for the U.S. Department of Defense surveillance program.
Martin Maiden is Professor of Molecular Epidemiology at Oxford and a Fellow of Hertford College. His research group develops population genomics approaches, studying the relationships of genetic traits with defined bacterial phenotypes. Martin’s graduate studies at the University of Cambridge pioneered the investigation of sugar transport proteins in Escherichia coli with sequence-based approaches, work which established the close relationship of bacterial and eukaryotic transport proteins.
William Shafer is a Professor of Microbiology and Immunology at Emory University School of Medicine in Atlanta, USA and the Co-Director of the Emory Antibiotic Resistance Center. His laboratory is interested in proteins produced by Neisseria gonorrhoeae that form drug efflux pumps that export antimicrobial compounds to the extracellular fluid. He is also working with collaborators to develop inhibitors of bacterial efflux pumps so that previously used antibiotics that were removed from clinical practice due to over-expression of efflux pumps can be returned to treat gonorrheal infections.
The authors declare that they do not have any relationships or affiliations that could be construed as a potential conflict of interest.