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Background: Doxycycline post-exposure prophylaxis (PEP) has been shown to be efficacious for the prevention of bacterial sexually transmitted infections, but resistance implications for Neisseria gonorrhoeae remain unknown. We aimed to use a mathematical model to investigate the anticipated impact of doxycycline PEP on the burden of gonorrhoea and antimicrobial resistance dynamics in men who have sex with men (MSM) in the USA., Methods: Using a deterministic compartmental model, characterising gonorrhoea transmission in a US MSM population comprising three sexual activity groups defined by annual partner turnover rates, we introduced doxycycline PEP at various uptake levels (10-90%) among those with high sexual activity. Infections were stratified by symptom status and resistance profile (ie, susceptible, ceftriaxone-resistant, tetracycline-resistant, or dual-resistant), with ceftriaxone the treatment for active infection. As resistance to tetracycline, not doxycycline, is monitored and reported nationally, we used this as a proxy for doxycycline PEP resistance. We compared the 20-year prevalence, incidence rates, and cumulative incidence of gonococcal infection, resistance dynamics (time to 5% prevalence of ceftriaxone resistance, 5% prevalence of dual resistance, and 84% prevalence of tetracycline resistance), and antibiotic consumption with baseline (ie, no doxycycline PEP)., Findings: Uptake of doxycycline PEP resulted in substantial reductions in the prevalence and incidence of gonorrhoea, but accelerated the spread of tetracycline resistance. The maximum reduction in prevalence over 20 years compared with no uptake ranged from 40·3% (IQR 15·3-83·4) with 10% doxycycline PEP uptake to 77·4% (68·4-84·9) with 90% uptake. Similarly, the maximum reduction in the incidence rate ranged from 38·6% (14·1-83·6) with 10% uptake to 77·6% (68·1-84·7) with 90% uptake. Cumulative gonococcal infections were reduced by a median of 14·5% (IQR 8·4-21·6) with 10% uptake and up to 46·2% (26·5-59·9) with 90% uptake after 5 years, and by 6·5% (3·4-13·0) with 10% uptake and 8·7% (4·3-36·2) with 90% uptake by 20 years. In almost all scenarios explored, doxycycline PEP lost clinical effectiveness (defined as 84% prevalence of tetracycline resistance) within the 20-year period, but its lifespan ranged from a median of 12·1 years (IQR 9·9-15·7) with 10% uptake to 1·6 years (1·3-1·9) with 90% uptake. Doxycycline PEP implementation had minimal impact on extending the clinical lifespan of ceftriaxone monotherapy (5·0 years [IQR 4·0-6·2]), with the median time to 5% prevalence of resistance ranging from 4·8 years (3·9-6·0) for 90% uptake to 5·0 years (4·1-6·2) for 10% uptake. Similarly, the median time to 5% prevalence of dual resistance to ceftriaxone and tetracycline ranged from 4·8 years (3·9-6·0) for 90% uptake to 5·8 years (4·8-7·4) for 10% uptake. Median decrease in ceftriaxone consumption for high doxycycline PEP uptake levels compared with baseline ranged from 41·7% (27·0-54·3) for 50% uptake to 50·2% (29·3-62·7) for 90% uptake at 5 years, but dropped to 11·8% (6·9-32·0) for 50% uptake and 12·1% (7·0-41·6) for 90% uptake after 20 years., Interpretation: Notwithstanding the clear benefits of doxycycline PEP for other sexually transmitted infections, for N gonorrhoeae, model findings suggest that doxycycline PEP is an effective but impermanent solution for reducing infection burden, given eventual selection for resistant strains. This finding presents a challenge for policy makers considering strategies for doxycycline PEP implementation and oversight: the need to balance the clear, short-term clinical benefits with the risk of harm via antimicrobial resistance., Funding: US Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests YHG has received consulting fees from GSK outside the scope of this work. ER is an employee of Analysis Group, outside the scope of this work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: The project described was supported by grant number T32 AI007433 from the National Institute of Allergy and Infectious Diseases. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. This project was funded (in part) by contract 200–2016–91779 with the US Centers for Disease Control and Prevention. The findings, conclusions, and views expressed in this Comment are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. We would like to thank Samantha Palace for helpful comments on this Comment.

Background: Since common diagnostic tests for gonorrhea do not provide information about susceptibility to antibiotics, treatment of gonorrhea remains empiric. Antibiotics used for empiric therapy are usually changed once resistance prevalence exceeds a certain threshold (e.g., 5%). A low switch threshold is intended to increase the probability that an infection is successfully treated with the first-line antibiotic, but it could also increase the pace at which recommendations are switched to newer antibiotics. Little is known about the impact of changing the switch threshold on the incidence of gonorrhea, the rate of treatment failure, and the overall cost and quality-adjusted life-years (QALYs) associated with gonorrhea., Methods and Findings: We developed a transmission model of gonococcal infection with multiple resistant strains to project gonorrhea-associated costs and loss in QALYs under different switch thresholds among men who have sex with men (MSM) in the United States. We accounted for the costs and disutilities associated with symptoms, diagnosis, treatment, and sequelae, and combined costs and QALYs in a measure of net health benefit (NHB). Our results suggest that under a scenario where 3 antibiotics are available over the next 50 years (2 suitable for the first-line therapy of gonorrhea and 1 suitable only for the retreatment of resistant infections), changing the switch threshold between 1% and 10% does not meaningfully impact the annual number of gonorrhea cases, total costs, or total QALY losses associated with gonorrhea. However, if a new antibiotic is to become available in the future, choosing a lower switch threshold could improve the population NHB. If in addition, drug-susceptibility testing (DST) is available to inform retreatment regimens after unsuccessful first-line therapy, setting the switch threshold at 1% to 2% is expected to maximize the population NHB. A limitation of our study is that our analysis only focuses on the MSM population and does not consider the influence of interventions such as vaccine and common use of rapid drugs susceptibility tests to inform first-line therapy., Conclusions: Changing the switch threshold for first-line antibiotics may not substantially change the health and financial outcomes associated with gonorrhea. However, the switch threshold could be reduced when newer antibiotics are expected to become available soon or when in addition to future novel antibiotics, DST is also available to inform retreatment regimens., Competing Interests: T.L.G is employed by CDC; other authors declare no competing interests., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Rapid point-of-care tests that diagnose gonococcal infections and identify susceptibility to antibiotics enable individualized treatment. This could improve patient outcomes and slow the emergence and spread of antibiotic resistance. However, little is known about the long-term impact of such diagnostics on the burden of gonorrhea and the effective life span of antibiotics. We used a mathematical model of gonorrhea transmission among men who have sex with men in the United States to project the annual rate of reported gonorrhea cases and the effective life span of ceftriaxone, the recommended antibiotic for first-line treatment of gonorrhea, as well as 2 previously recommended antibiotics, ciprofloxacin and tetracycline, when a rapid drug susceptibility test that estimates susceptibility to ciprofloxacin and tetracycline is available. The use of a rapid drug susceptibility test with ≥50% sensitivity and ≥95% specificity, defined in terms of correct ascertainment of drug susceptibility and nonsusceptibility status, could increase the combined effective life span of ciprofloxacin, tetracycline, and ceftriaxone by at least 2 years over 25 years of simulation. If test specificity is imperfect, however, the increase in the effective life span of antibiotics is accompanied by an increase in the rate of reported gonorrhea cases even under perfect sensitivity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Background: Gonorrhoea is a highly prevalent sexually transmitted infection and an urgent public health concern because of increasing antibiotic resistance in Neisseria gonorrhoeae. Only ceftriaxone remains as the recommended treatment in the USA. With the prospect of new anti-gonococcal antibiotics being approved, we aimed to evaluate how to deploy a new drug to maximise its clinically useful lifespan., Methods: We used a compartmental model of gonorrhoea transmission in a US population of men who have sex with men (MSM) to compare strategies for introducing a new antibiotic for gonorrhoea treatment. The MSM population was stratified into three sexual activity groups (low, intermediate, and high) characterised by annual rates of partner change. The four introduction strategies tested were: (1) random 50-50 allocation, where each treatment-seeking infected individual had a 50% probability of receiving either drug A (current drug; a ceftriaxone-like antibiotic) or drug B (a new antibiotic), effective at time 0; (2) combination therapy of both the current drug and the new antibiotic; (3) reserve strategy, by which the new antibiotic was held in reserve until the current therapy reached a 5% threshold prevalence of resistance; and (4) gradual switch, or the gradual introduction of the new drug until random 50-50 allocation was reached. The primary outcome of interest was the time until 5% prevalence of resistance to each of the drugs (the new drug and the current ceftriaxone-like antibiotic); sensitivity of the primary outcome to the properties of the new antibiotic, specifically the probability of resistance emergence after treatment and the fitness costs of resistance, was explored. Secondary outcomes included the time to a 1% resistance threshold for each drug, as well as population-level prevalence, mean and range annual incidence, and the cumulative number of incident gonococcal infections., Findings: Under baseline model conditions, a 5% prevalence of resistance to each of drugs A and B was reached within 13·9 years with the reserve strategy, 18·2 years with the gradual switch strategy, 19·2 years with the random 50-50 allocation strategy, and 19·9 years with the combination therapy strategy. The reserve strategy was consistently inferior for mitigating antibiotic resistance under the parameter space explored and was increasingly outperformed by the other strategies as the probability of de novo resistance emergence decreased and as the fitness costs associated with resistance increased. Combination therapy tended to prolong the development of antibiotic resistance and minimise the number of annual gonococcal infections (under baseline model conditions, mean number of incident infections per year 178 641 [range 177 998-181 731] with combination therapy, 180 084 [178 011-184 405] with the reserve strategy)., Interpretation: Our study argues for rapid introduction of new anti-gonococcal antibiotics, recognising that the feasibility of each strategy must incorporate cost, safety, and other practical concerns. The analyses should be revisited once robust estimates of key parameters-ie, the likelihood of emergence of resistance and fitness costs of resistance for the new antibiotic-are available., Funding: US Centers for Disease Control and Prevention, National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests YHG reports funding for this work from the US Centers for Disease Control and Prevention (CDC; contract 200-2016-91779) and from the National Institute of Allergy and Infectious Diseases (NIAID; grants R01AI132606 and R01AI153521), as well as consulting fees from GlaxoSmithKline outside the scope of the current work. MMR and JAS report funding support from the CDC and the National Center for HIV, Viral Hepatitis, STD, and TB Prevention Epidemiologic and Economic Modeling Agreement (5NU38PS004651RY) for the current work. MMR also receives funding from WHO, the Harvard University Center for AIDS Research Developmental Grant, and Harvard Data Science Exploratory Award all outside the scope of the current work. RY reports R01AI153351 grant funding from NIAID for the current work. TLG and ER declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Pre-existing tetracycline resistance in Neisseria gonorrhoeae limits the effectiveness of post-exposure prophylaxis (PEP) with doxycycline against gonorrhea, and selection for tetracycline resistance may influence prevalence of multi-drug resistant strains. Using genomic and antimicrobial susceptibility data from N. gonorrhoeae, we assessed the near-term impact of doxycycline PEP on N. gonorrhoeae resistance., Competing Interests: Potential conflicts of interest. Y. H. G. has received consulting fees from GSK and serves on the advisory board for Day Zero Diagnostics. Y. H. G. also reports grants or contracts from Wellcome Trust and Smith Family Foundation. T. D. M. reports no potential conflicts. Both authors have 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The World Health Organization recommends changing the first-line antimicrobial treatment for gonorrhoea when ≥ 5% of Neisseria gonorrhoeae cases fail treatment or are resistant. Susceptibility to ceftriaxone, the last remaining treatment option has been decreasing in many countries. We used antimicrobial resistance surveillance data and developed mathematical models to project the time to reach the 5% threshold for resistance to first-line antimicrobials used for N. gonorrhoeae., Methods: We used data from the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP) in England and Wales from 2000-2018 about minimum inhibitory concentrations (MIC) for ciprofloxacin, azithromycin, cefixime and ceftriaxone and antimicrobial treatment in two groups, heterosexual men and women (HMW) and men who have sex with men (MSM). We developed two susceptible-infected-susceptible models to fit these data and produce projections of the proportion of resistance until 2030. The single-step model represents the situation in which a single mutation results in antimicrobial resistance. In the multi-step model, the sequential accumulation of resistance mutations is reflected by changes in the MIC distribution., Results: The single-step model described resistance to ciprofloxacin well. Both single-step and multi-step models could describe azithromycin and cefixime resistance, with projected resistance levels higher with the multi-step than the single step model. For ceftriaxone, with very few observed cases of full resistance, the multi-step model was needed to describe long-term dynamics of resistance. Extrapolating from the observed upward drift in MIC values, the multi-step model projected ≥ 5% resistance to ceftriaxone could be reached by 2030, based on treatment pressure alone. Ceftriaxone resistance was projected to rise to 13.2% (95% credible interval [CrI]: 0.7-44.8%) among HMW and 19.6% (95%CrI: 2.6-54.4%) among MSM by 2030., Conclusions: New first-line antimicrobials for gonorrhoea treatment are needed. In the meantime, public health authorities should strengthen surveillance for AMR in N. gonorrhoeae and implement strategies for continued antimicrobial stewardship. Our models show the utility of long-term representative surveillance of gonococcal antimicrobial susceptibility data and can be adapted for use in, and for comparison with, other countries., (© 2023. The Author(s).)

Background: Neisseria gonorrhoeae is a major public health problem due to increasing incidence and antimicrobial resistance. Genetic markers of reduced susceptibility have been identified; the extent to which those are representative of global antimicrobial resistance is unknown. We evaluated the performance of whole-genome sequencing (WGS) used to predict susceptibility to ciprofloxacin and other antimicrobials using a global collection of N. gonorrhoeae isolates., Methods: Susceptibility testing of common antimicrobials and the recently developed zolifodacin was performed using agar dilution to determine minimum inhibitory concentrations (MICs). We identified resistance alleles at loci known to contribute to antimicrobial resistance in N. gonorrhoeae from WGS data. We tested the ability of each locus to predict antimicrobial susceptibility., Results: A total of 481 N. gonorrhoeae isolates, collected between 2004 and 2019 and making up 457 unique genomes, were sourced from 5 countries. All isolates with demonstrated susceptibility to ciprofloxacin (MIC ≤0.06 μg/mL) had a wild-type gyrA codon 91. Multilocus approaches were needed to predict susceptibility to other antimicrobials. All isolates were susceptible to zoliflodacin, defined by an MIC ≤0.25 μg/mL., Conclusions: Single marker prediction can be used to inform ciprofloxacin treatment of N. gonorrhoeae infection. A combination of molecular markers may be needed to determine susceptibility for other antimicrobials., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have 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., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The aetiological bacterial agent of gonorrhoea, Neisseria gonorrhoeae, has become resistant to each of the first-line antibiotics used to treat it, including ciprofloxacin. One diagnostic approach to identify ciprofloxacin-susceptible isolates is to determine codon 91 in the gene encoding the A subunit of DNA gyrase, gyrA, where coding for the wild-type serine (gyrA 91S ) is associated with ciprofloxacin susceptibility and phenylalanine (gyrA 91F ) with resistance. The aim of this study was to investigate the possibility of diagnostic escape from gyrA susceptibility testing., Methods: We used bacterial genetics to introduce pairwise substitutions in GyrA positions 91 (S or F) and 95 (D, G, or N), which is a second site in GyrA associated with ciprofloxacin resistance, into five clinical isolates of N gonorrhoeae. All five isolates encoded GyrA S91F, an additional substitution in GyrA at position 95, substitutions in ParC that are known to cause an increased minimum inhibitory concentration (MIC) to ciprofloxacin, and GyrB 429D, which is associated with susceptibility to zoliflodacin (a spiropyrimidinetrione-class antibiotic in phase 3 trials for treatment of gonorrhoea). We evolved these isolates to assess for the existence of pathways to ciprofloxacin resistance (MIC ≥1 μg/mL) and measured MICs for ciprofloxacin and zoliflodacin. In parallel, we searched metagenomic data for 11 355 N gonorrhoeae clinical isolates with reported ciprofloxacin MICs that were publicly available from the European Nucleotide Archive for strains that would be identified as susceptible by gyrA codon 91-based assays., Findings: Three clinical isolates of N gonorrhoeae with substitutions in GyrA position 95 associated with resistance (G or N) maintained intermediate ciprofloxacin MICs (0·125-0·5 μg/mL), which has been associated with treatment failure, despite reversion of GyrA position 91 from phenylalanine to serine. From an in-silico analysis of the 11 355 genomes from N gonorrhoeae clinical isolates, we identified 30 isolates with gyrA codon 91 encoding a serine and a ciprofloxacin resistance-associated mutation at codon 95. The reported MICs for these isolates varied from 0·023 μg/mL to 0·25 μg/mL, including four with intermediate ciprofloxacin MICs (associated with substantially increased risk of treatment failure). Finally, through experimental evolution, one clinical isolate of N gonorrhoeae bearing GyrA 91S acquired ciprofloxacin resistance through mutations in the gene encoding for the B subunit of DNA gyrase (gyrB) that also conferred reduced susceptibility to zoliflodacin (ie, MIC ≥2 μg/mL)., Interpretation: Diagnostic escape from gyrA codon 91 diagnostics could occur through either reversion of the gyrA allele or expansion of circulating lineages. N gonorrhoeae genomic surveillance efforts might benefit from including gyrB, given its potential for contributing to ciprofloxacin and zoliflodacin resistance, and diagnostic strategies that reduce the likelihood of escape, such as the incorporation of multiple target sites, should be investigated. Diagnostics that guide antibiotic therapy can have unintended consequences, including novel resistance determinants and antibiotic cross-resistance., Funding: US National Institutes of Health National Institute of Allergy and Infectious Diseases, National Institute of General Medical Sciences, and the Smith Family Foundation., Competing Interests: Declaration of interests YHG receives or has received support from Wellcome Trust, Pfizer, and Merck; receives or has received consulting fees from GlaxoSmithKline, Quidel, and the National Basketball Association; receives or has received payment for expert testimony from Merck; and serves on the advisory board for Day Zero Diagnostics. DHFR and TDM declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Neisseria gonorrhoeae is an urgent public health threat due to the emergence of antibiotic resistance. As most isolates in the United States are susceptible to at least one antibiotic, rapid molecular antimicrobial susceptibility tests (ASTs) would offer the opportunity to tailor antibiotic therapy, thereby expanding treatment options. With genome sequence and antibiotic resistance phenotype data for nearly 20,000 clinical N. gonorrhoeae isolates now available, there is an opportunity to use statistical methods to develop sequence-based diagnostics that predict antibiotic susceptibility from genotype. N. gonorrhoeae, therefore, provides a useful example illustrating how to apply machine learning models to aid in the design of sequence-based ASTs. We present an overview of this framework, which begins with establishing the assay technology, the performance criteria, the population in which the diagnostic will be used, and the clinical goals, and extends to the choices that must be made to arrive at a set of features with the desired properties for predicting susceptibility phenotype from genotype. While we focus on the example of N. gonorrhoeae, the framework generalizes to other organisms for which large-scale genotype and antibiotic resistance data can be combined to aid in diagnostics development., (© 2022 New York Academy of Sciences.)

The evolution of the obligate human pathogen Neisseria gonorrhoeae has been shaped by selective pressures from diverse host niche environments and antibiotics. The varying prevalence of antibiotic resistance across N. gonorrhoeae lineages suggests that underlying metabolic differences may influence the likelihood of acquisition of specific resistance mutations. We hypothesized that the requirement for supplemental CO 2 , present in approximately half of isolates, reflects one such example of metabolic variation. Here, using a genome-wide association study and experimental investigations, we show that CO 2 dependence is attributable to a single substitution in a β-carbonic anhydrase, CanB. CanB 19E is necessary and sufficient for growth in the absence of CO 2 , and the hypomorphic CanB 19G variant confers CO 2 dependence. Furthermore, ciprofloxacin resistance is correlated with CanB 19G in clinical isolates, and the presence of CanB 19G increases the likelihood of acquisition of ciprofloxacin resistance. Together, our results suggest that metabolic variation has affected the acquisition of fluoroquinolone resistance., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Neisseria gonorrhoeae poses an urgent public health threat because of increasing antimicrobial resistance; however, much of the circulating population remains susceptible to historical treatment regimens. Point-of-care diagnostics that report susceptibility could allow for reintroduction of these regimens, but development of such diagnostics has been restricted to ciprofloxacin, for which susceptibility can be predicted from a single locus. We aimed to define genetic variants associated with susceptibility to penicillin and tetracycline., Methods: We collected publicly available global whole-genome sequencing data (n=12 045) from clinical N gonorrhoeae isolates, with phenotypic resistance data for penicillin (n=6935), and tetracycline (n=5727). Using conditional genome-wide association studies, we defined genetic variants associated with susceptibility to penicillin and tetracycline. We excluded isolates that could not be classified as either susceptible or resistant. To validate our results, we assembled 1479 genomes from the US Centers for Disease Control and Prevention (CDC)'s Gonococcal Isolate Surveillance Project, for which urethral specimens are collected at sentinel surveillance sites across the USA. We evaluated the sensitivity and specificity of susceptibility-associated alleles using Clinical & Laboratory Standards Institute breakpoints for susceptibility and non-resistance in both the global and validation datasets., Findings: In our conditional penicillin genome-wide association study, the presence of a genetic variant defined by a non-mosaic penA allele without an insertion at codon 345 was associated with penicillin susceptibility and had the highest negative effect size (β) of significant variants (p=5·0x10 -14 , β -2·5). In combination with the absence of bla TEM , this variant predicted penicillin susceptibility with high specificity (99·8%) and modest sensitivity (36·7%). For tetracycline, the wildtype allele at rpsJ codon 57, encoding valine, was associated with tetracycline susceptibility (p=5·6x10 -16 , β -1·6) after conditioning on the presence of tetM. The combination of rpsJ codon 57 allele and tetM absence predicted tetracycline susceptibility with high specificity (97·2%) and sensitivity (88·7%)., Interpretation: As few as two genetic loci can predict susceptibility to penicillin and tetracycline in N gonorrhoeae with high specificity. Molecular point-of-care diagnostics targeting these loci have the potential to increase available treatments for gonorrhoea., Funding: National Institute of Allergy and Infectious Diseases, the National Science Foundation, and the Smith Family Foundation., Competing Interests: Declaration of interests YHG is on the scientific advisory board of Day Zero Diagnostics; has consulted for Quidel and GSK; has received grant funding from Merck, Pfizer, and GSK; and has received payments for participating in National Institutes of Health (NIH) study sections and speaking at the Association for Molecular Pathology conference. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In the absence of point-of-care gonorrhea diagnostics that report antibiotic susceptibility, gonorrhea treatment is empiric and determined by standardized guidelines. These guidelines are informed by estimates of resistance prevalence from national surveillance systems. We examined whether guidelines informed by local, rather than national, surveillance data could reduce the incidence of gonorrhea and increase the effective lifespan of antibiotics used in treatment guidelines. We used a transmission dynamic model of gonorrhea among men who have sex with men (MSM) in 16 U.S. metropolitan areas to determine whether spatially adaptive treatment guidelines based on local estimates of resistance prevalence can extend the effective lifespan of hypothetical antibiotics. The rate of gonorrhea cases in these metropolitan areas was 5,548 cases per 100,000 MSM in 2017. Under the current strategy of updating the treatment guideline when the prevalence of resistance exceeds 5%, we showed that spatially adaptive guidelines could reduce the annual rate of gonorrhea cases by 200 cases (95% uncertainty interval: 169, 232) per 100,000 MSM population while extending the use of a first-line antibiotic by 0.75 (0.55, 0.95) years. One potential strategy to reduce the incidence of gonorrhea while extending the effective lifespan of antibiotics is to inform treatment guidelines based on local, rather than national, resistance prevalence., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RY, TC, JAS, and YHG received funding from the National Institute of Health and the U.S. Centers for Disease Control and Prevention. TLG and SBS are employed by the U.S. Centers for Disease Control and Prevention. YHG has received research funding from Pfizer and Merck for unrelated work and has received consulting fees from GSK.

Background: Genomic epidemiology studies of gonorrhea in the United States have primarily focused on national surveillance for antibiotic resistance, and patterns of local transmission between demographic groups of resistant and susceptible strains are unknown., Methods: We analyzed a convenience sample of genome sequences, antibiotic susceptibility, and patient data from 897 gonococcal isolates cultured at the New York City (NYC) Public Health Laboratory from NYC Department of Health and Mental Hygiene (DOHMH) Sexual Health Clinic (SHC) patients, primarily in 2012-2013. We reconstructed the gonococcal phylogeny, defined transmission clusters using a 10 nonrecombinant single nucleotide polymorphism threshold, tested for clustering of demographic groups, and placed NYC isolates in a global phylogenetic context., Results: The NYC gonococcal phylogeny reflected global diversity with isolates from 22/23 of the prevalent global lineages (96%). Isolates clustered on the phylogeny by patient sexual behavior (P < .001) and race/ethnicity (P < .001). Minimum inhibitory concentrations were higher across antibiotics in isolates from men who have sex with men compared to heterosexuals (P < .001) and white heterosexuals compared to black heterosexuals (P < .01). In our dataset, all large transmission clusters (≥10 samples) of N. gonorrhoeae were susceptible to ciprofloxacin, ceftriaxone, and azithromycin, and comprised isolates from patients across demographic groups., Conclusions: All large transmission clusters were susceptible to gonorrhea therapies, suggesting that resistance to empiric therapy was not a main driver of spread, even as risk for resistance varied across demographic groups. Further study of local transmission networks is needed to identify drivers of transmission., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

We estimated the fraction of antibiotic prescribing in the United States attributable to gonorrhea. Gonorrhea contributes to an outsized proportion of antibiotic prescriptions in young adults, males, and in the southern and western United States. A gonococcal vaccine could substantially reduce antibiotic prescribing in these populations., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Novel therapeutic strategies are urgently needed for Neisseria gonorrhoeae, given its increasing antimicrobial resistance. Treatment of oropharyngeal N. gonorrhoeae infections has proven particularly challenging, with most reported treatment failures of the first-line drug ceftriaxone occurring at this site and lower cure rates in recent trials of new antibiotics reported for oropharyngeal infections compared with other sites of infection. However, the accessibility of the oropharynx to topical therapeutics provides an opportunity for intervention. Local delivery of a therapeutic at a high concentration would enable the use of non-traditional antimicrobial candidates, including biological molecules that exploit underlying chemical sensitivities of N. gonorrhoeae but lack the potency or pharmacokinetic profiles required for effective systemic administration., Methods: Two classes of molecules that are thought to limit gonococcal viability in vivo, bile acids and short- and medium-chain fatty acids, were examined for rapid bactericidal activity., Results: The bile acids deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA), but not other bile acid species, exerted extremely rapid bactericidal properties against N. gonorrhoeae, reducing viability more than 100 000-fold after 1 min. The short-chain fatty acids formic acid and hexanoic acid shared this rapid bactericidal activity. All four molecules are effective against a phylogenetically diverse panel of N. gonorrhoeae strains, including clinical isolates with upregulated efflux pumps and resistance alleles to the most widely used classes of existing antimicrobials. DCA and CDCA are both approved therapeutics for non-infectious indications and are well-tolerated by cultured epithelial cells., Conclusions: DCA and CDCA are attractive candidates for further development as anti-gonococcal agents., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Antimicrobial-resistant (AMR) Neisseria gonorrhoeae is an urgent threat to public health, as strains resistant to at least one of the two last-line antibiotics used in empiric therapy of gonorrhoea, ceftriaxone and azithromycin, have spread internationally. Whole genome sequencing (WGS) data can be used to identify new AMR clones and transmission networks and inform the development of point-of-care tests for antimicrobial susceptibility, novel antimicrobials and vaccines. Community-driven tools that provide an easy access to and analysis of genomic and epidemiological data is the way forward for public health surveillance., Methods: Here we present a public health-focussed scheme for genomic epidemiology of N. gonorrhoeae at Pathogenwatch ( https://pathogen.watch/ngonorrhoeae ). An international advisory group of experts in epidemiology, public health, genetics and genomics of N. gonorrhoeae was convened to inform on the utility of current and future analytics in the platform. We implement backwards compatibility with MLST, NG-MAST and NG-STAR typing schemes as well as an exhaustive library of genetic AMR determinants linked to a genotypic prediction of resistance to eight antibiotics. A collection of over 12,000 N. gonorrhoeae genome sequences from public archives has been quality-checked, assembled and made public together with available metadata for contextualization., Results: AMR prediction from genome data revealed specificity values over 99% for azithromycin, ciprofloxacin and ceftriaxone and sensitivity values around 99% for benzylpenicillin and tetracycline. A case study using the Pathogenwatch collection of N. gonorrhoeae public genomes showed the global expansion of an azithromycin-resistant lineage carrying a mosaic mtr over at least the last 10 years, emphasising the power of Pathogenwatch to explore and evaluate genomic epidemiology questions of public health concern., Conclusions: The N. gonorrhoeae scheme in Pathogenwatch provides customised bioinformatic pipelines guided by expert opinion that can be adapted to public health agencies and departments with little expertise in bioinformatics and lower-resourced settings with internet connection but limited computational infrastructure. The advisory group will assess and identify ongoing public health needs in the field of gonorrhoea, particularly regarding gonococcal AMR, in order to further enhance utility with modified or new analytic methods.

BackgroundThe first cases of extensively drug resistant gonorrhoea were recorded in the United Kingdom in 2018. There is a public health need for strategies on how to deploy existing and novel antibiotics to minimise the risk of resistance development. As rapid point-of-care tests (POCTs) to predict susceptibility are coming to clinical use, coupling the introduction of an antibiotic with diagnostics that can slow resistance emergence may offer a novel paradigm for maximising antibiotic benefits. Gepotidacin is a novel antibiotic with known resistance and resistance-predisposing mutations. In particular, a mutation that confers resistance to ciprofloxacin acts as the 'stepping-stone' mutation to gepotidacin resistance.AimTo investigate how POCTs detecting Neisseria gonorrhoeae resistance mutations for ciprofloxacin and gepotidacin can be used to minimise the risk of resistance development to gepotidacin.MethodsWe use individual-based stochastic simulations to formally investigate the aim.ResultsThe level of testing needed to reduce the risk of resistance development depends on the mutation rate under treatment and the prevalence of stepping-stone mutations. A POCT is most effective if the mutation rate under antibiotic treatment is no more than two orders of magnitude above the mutation rate without treatment and the prevalence of stepping-stone mutations is 1-13%.ConclusionMutation frequencies and rates should be considered when estimating the POCT usage required to reduce the risk of resistance development in a given population. Molecular POCTs for resistance mutations and stepping-stone mutations to resistance are likely to become important tools in antibiotic stewardship.

Genotype-based diagnostics for antibiotic resistance represent a promising alternative to empiric therapy, reducing inappropriate antibiotic use. However, because such assays infer resistance based on known genetic markers, their utility will wane with the emergence of novel resistance. Maintenance of these diagnostics will therefore require surveillance to ensure early detection of novel resistance variants, but efficient strategies to do so remain undefined. We evaluate the efficiency of targeted sampling approaches informed by patient and pathogen characteristics in detecting antibiotic resistance and diagnostic escape variants in Neisseria gonorrhoeae , a pathogen associated with a high burden of disease and antibiotic resistance and the development of genotype-based diagnostics. We show that patient characteristic-informed sampling is not a reliable strategy for efficient variant detection. In contrast, sampling informed by pathogen characteristics, such as genomic diversity and genomic background, is significantly more efficient than random sampling in identifying genetic variants associated with resistance and diagnostic escape., Competing Interests: AH, SK, TM, KM, GT, MA, DW, YG No competing interests declared, ML Reviewing editor, eLife, (© 2020, Hicks et al.)

Background: The rise of gonococcal antimicrobial resistance highlights the need for strategies that extend the clinically useful life span of antibiotics. Because there is limited evidence to support the current practice of switching empiric first-line antibiotic when resistance exceeds 5% in the population, our objective was to compare the impact of alternative strategies on the effective life spans of antibiotics and the overall burden of gonorrhea., Methods and Findings: We developed and calibrated a mathematical model of gonorrhea transmission among men who have sex with men (MSM) in the United States. We calibrated the model to the estimated prevalence of gonorrhea, the rate of gonorrhea cases, and the proportion of cases presenting symptoms among MSM in the US. We used this model to project the effective life span of antibiotics and the number of gonorrhea cases expected under current and alternative surveillance strategies over a 50-year simulation period. We demonstrate that compared to the current practice, a strategy that uses quarterly (as opposed to yearly) surveillance estimates and incorporates both the estimated prevalence of resistance and the trend in the prevalence of resistance to determine treatment guidelines could extend the effective life span of antibiotics by 0.83 years. This is equivalent to successfully treating an additional 80.1 (95% uncertainty interval: [47.7, 111.9]) gonorrhea cases per 100,000 MSM population each year with the first-line antibiotics without worsening the burden of gonorrhea. If the annual number of isolates tested for drug susceptibility is doubled, this strategy could increase the effective life span of antibiotics by 0.94 years, which is equivalent to successfully treating an additional 91.1 (54.3, 127.3) gonorrhea cases per 100,000 MSM population each year without increasing the incidence of gonorrhea. Study limitations include that our conclusions might not be generalizable to other settings because our model describes the transmission of gonorrhea among the US MSM population, and, to better capture uncertainty in the characteristics of current and future antibiotics, we chose to model hypothetical drugs with characteristics similar to the antibiotics commonly used in gonorrhea treatment., Conclusions: Our results suggest that use of data from surveillance programs could be expanded to prolong the clinical effectiveness of antibiotics without increasing the burden of the disease. This highlights the importance of maintaining effective surveillance systems and the engagement of policy makers to turn surveillance findings into timely and effective decisions., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: RY, TC, JAS, and YHG received funding from the National Institute of Health and the US Centers for Disease Control and Prevention. KH is employed by Massachusetts Department of Public Health. TLG and HC are employed by the US Centers for Disease Control and Prevention.

The sexually transmitted pathogen Neisseria gonorrhoeae is regarded as being on the way to becoming an untreatable superbug. Despite its clinical importance, little is known about its emergence and evolution, and how this corresponds with the introduction of antimicrobials. We present a genome-based phylogeographical analysis of 419 gonococcal isolates from across the globe. Results indicate that modern gonococci originated in Europe or Africa, possibly as late as the sixteenth century and subsequently disseminated globally. We provide evidence that the modern gonococcal population has been shaped by antimicrobial treatment of sexually transmitted infections as well as other infections, leading to the emergence of two major lineages with different evolutionary strategies. The well-described multidrug-resistant lineage is associated with high rates of homologous recombination and infection in high-risk sexual networks. A second, multisusceptible lineage is more associated with heterosexual networks, with potential implications for infection control.

Whole genome sequencing (WGS) has been used to investigate transmission of Neisseria gonorrhoeae, but to date, most studies have not combined genomic data with detailed information on sexual behaviour to define the extent of transmission across population risk groups (bridging). Here, through combined epidemiological and genomic analysis of 2,186N. gonorrhoeae isolates from Australia, we show widespread transmission of N. gonorrhoeae within and between population groups. We describe distinct transmission clusters associated with men who have sex with men (MSM) and heterosexuals, and men who have sex with men and women (MSMW) are identified as a possible bridging population between these groups. Further, the study identifies transmission of N. gonorrhoeae between HIV-positive and HIV-negative individuals receiving pre-exposure prophylaxis (PrEP). Our data highlight several groups that can be targeted for interventions aimed at improving gonorrhoea control, including returning travellers, sex workers, and PrEP users.

Antimicrobial resistance in Neisseria gonorrhoeae is a major issue of public health, and there is a critical need for the development of new antigonococcal strategies. In this study, we investigated the effectiveness of antimicrobial blue light (aBL; wavelength, 405 nm), an innovative nonpharmacological approach, for the inactivation of N. gonorrhoeae. Our findings indicated that aBL preferentially inactivated N. gonorrhoeae, including antibiotic-resistant strains, over human vaginal epithelial cells in vitro. Furthermore, no aBL-induced genotoxicity to the vaginal epithelial cells was observed at the radiant exposure used to inactivate N. gonorrhoeae. aBL also effectively inactivated N. gonorrhoeae that had attached to and invaded into the vaginal epithelial cells in their cocultures. No gonococcal resistance to aBL developed after 15 successive cycles of inactivation induced by subtherapeutic exposure to aBL. Endogenous aBL-activatable photosensitizing porphyrins in N. gonorrhoeae were identified and quantified using ultraperformance liquid chromatography, with coproporphyrin being the most abundant species in all N. gonorrhoeae strains studied. Singlet oxygen was involved in aBL inactivation of N. gonorrhoeae. Together, these findings show that aBL represents a potential potent treatment for antibiotic-resistant gonococcal infection., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

The goal of the Sexually Transmitted Infection Clinical Trial Group's Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, nonprofit and industry to discuss the current state of research, gaps and challenges in research and technology and priorities and new directions to address the continued emergence of multidrug-resistant NG infections. Topics discussed at the meeting, which will be the focus of this article, include AMR NG global surveillance initiatives, the use of whole genome sequencing and bioinformatics to understand mutations associated with AMR, mechanisms of AMR, and novel antibiotics, vaccines and other methods to treat AMR NG. Key points highlighted during the meeting include: (i) US and International surveillance programs to understand AMR in NG; (ii) the US National Strategy for combating antimicrobial-resistant bacteria; (iii) surveillance needs, challenges, and novel technologies; (iv) plasmid-mediated and chromosomally mediated mechanisms of AMR in NG; (v) novel therapeutic (eg, sialic acid analogs, factor H [FH]/Fc fusion molecule, monoclonal antibodies, topoisomerase inhibitors, fluoroketolides, LpxC inhibitors) and preventative (eg, peptide mimic) strategies to combat infection. The way forward will require renewed political will, new funding initiatives, and collaborations across academic and commercial research and public health programs.

Rising azithromycin nonsusceptibility among Neisseria gonorrhoeae isolates threatens current treatment recommendations, but the cause of this rise is not well understood. We performed an ecological study of seasonal patterns in macrolide use and azithromycin resistance in N. gonorrhoeae, finding that population-wide macrolide use is associated with increased azithromycin nonsusceptibility. These results, indicative of bystander selection, have implications for antibiotic prescribing guidelines.

Infections with Neisseria gonorrhoeae, a sexually transmitted pathogen that causes urethritis, cervicitis, and more severe complications, are increasing. Gonorrhea is typically treated with antibiotics; however, N. gonorrhoeae has rapidly acquired resistance to many antibiotic classes, and lineages with reduced susceptibility to the currently recommended therapies are emerging worldwide. In this review, we discuss the contributions of whole genome sequencing (WGS) to our understanding of resistant N. gonorrhoeae. Genomics has illuminated the evolutionary origins and population structure of N. gonorrhoeae and the magnitude of horizontal gene transfer within and between Neisseria species. WGS can be used to predict the susceptibility of N. gonorrhoeae based on known resistance determinants, track the spread of these determinants throughout the N. gonorrhoeae population, and identify novel loci contributing to resistance. WGS has also allowed more detailed epidemiological analysis of transmission of N. gonorrhoeae between individuals and populations than previously used typing methods. Ongoing N. gonorrhoeae genomics will complement other laboratory techniques to understand the biology and evolution of the pathogen, improve diagnostics and treatment in the clinic, and inform public health policies to limit the impact of antibiotic resistance., (© 2018 New York Academy of Sciences.)

Background: Increasing antibiotic resistance limits treatment options for gonorrhea. We examined the impact of a hypothetical point-of-care (POC) test reporting antibiotic susceptibility profiles on slowing resistance spread., Methods: A mathematical model describing gonorrhea transmission incorporated resistance emergence probabilities and fitness costs associated with resistance based on characteristics of ciprofloxacin (A), azithromycin (B), and ceftriaxone (C). We evaluated time to 1% and 5% prevalence of resistant strains among all isolates with the following: (1) empiric treatment (B and C), and treatment guided by POC tests determining susceptibility to (2) A only and (3) all 3 antibiotics., Results: Continued empiric treatment without POC testing was projected to result in >5% of isolates being resistant to both B and C within 15 years. Use of either POC test in 10% of identified cases delayed this by 5 years. The 3 antibiotic POC test delayed the time to reach 1% prevalence of triply-resistant strains by 6 years, whereas the A-only test resulted in no delay. Results were less sensitive to assumptions about fitness costs and test characteristics with increasing test uptake., Conclusions: Rapid diagnostics reporting antibiotic susceptibility may extend the usefulness of existing antibiotics for gonorrhea treatment, but ongoing monitoring of resistance patterns will be critical., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Treatment of Neisseria gonorrhoeae infection is empirical and based on population-wide susceptibilities. Increasing antimicrobial resistance underscores the potential importance of rapid diagnostic tests, including sequence-based tests, to guide therapy. However, the usefulness of sequence-based diagnostic tests depends on the prevalence and dynamics of the resistance mechanisms., Methods: We define the prevalence and dynamics of resistance markers to extended-spectrum cephalosporins, macrolides, and fluoroquinolones in 1102 resistant and susceptible clinical N. gonorrhoeae isolates collected from 2000 to 2013 via the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project., Results: Reduced extended-spectrum cephalosporin susceptibility is predominantly clonal and associated with the mosaic penA XXXIV allele and derivatives (sensitivity 98% for cefixime and 91% for ceftriaxone), but alternative resistance mechanisms have sporadically emerged. Reduced azithromycin susceptibility has arisen through multiple mechanisms and shows limited clonal spread; the basis for resistance in 36% of isolates with reduced azithromycin susceptibility is unclear. Quinolone-resistant N. gonorrhoeae has arisen multiple times, with extensive clonal spread., Conclusions: Quinolone-resistant N. gonorrhoeae and reduced cefixime susceptibility appear amenable to development of sequence-based diagnostic tests, whereas the undefined mechanisms of resistance to ceftriaxone and azithromycin underscore the importance of phenotypic surveillance. The identification of multidrug-resistant isolates highlights the need for additional measures to respond to the threat of untreatable gonorrhea., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: New approaches are urgently required to address increasing rates of gonorrhoea and the emergence and global spread of antibiotic-resistant Neisseria gonorrhoeae. We used whole-genome sequencing to study transmission and track resistance in N gonorrhoeae isolates., Methods: We did whole-genome sequencing of isolates obtained from samples collected from patients attending sexual health services in Brighton, UK, between Jan 1, 2011, and March 9, 2015. We also included isolates from other UK locations, historical isolates from Brighton, and previous data from a US study. Samples from symptomatic patients and asymptomatic sexual health screening underwent nucleic acid amplification testing; positive samples and all samples from symptomatic patients were cultured for N gonorrhoeae, and resulting isolates were whole-genome sequenced. Cefixime susceptibility testing was done in selected isolates by agar incorporation, and we used sequence data to determine multi-antigen sequence types and penA genotypes. We derived a transmission nomogram to determine the plausibility of direct or indirect transmission between any two cases depending on the time between samples: estimated mutation rates, plus diversity noted within patients across anatomical sites and probable transmission pairs, were used to fit a coalescent model to determine the number of single nucleotide polymorphisms expected., Findings: 1407 (98%) of 1437 Brighton isolates between Jan 1, 2011, and March 9, 2015 were successfully sequenced. We identified 1061 infections from 907 patients. 281 (26%) of these infections were indistinguishable (ie, differed by zero single nucleotide polymorphisms) from one or more previous cases, and 786 (74%) had evidence of a sampled direct or indirect Brighton source. We observed multiple related samples across geographical locations. Of 1273 infections in Brighton (including historical data), 225 (18%) were linked to another case elsewhere in the UK, and 115 (9%) to a case in the USA. Four lineages initially identified in Brighton could be linked to 70 USA sequences, including 61 from a lineage carrying the mosaic penA XXXIV allele, which is associated with reduced cefixime susceptibility., Interpretation: We present a whole-genome-sequencing-based tool for genomic contact tracing of N gonorrhoeae and demonstrate local, national, and international transmission. Whole-genome sequencing can be applied across geographical boundaries to investigate gonorrhoea transmission and to track antimicrobial resistance., Funding: Oxford National Institute for Health Research Health Protection Research Unit and Biomedical Research Centre., Competing Interests: Declaration of interests The authors have no conflict of interest., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The rise in gonococcal antibiotic resistance and the threat of untreatable infection are focusing attention on strategies to limit the spread of drug-resistant gonorrhea. Mathematical models provide a framework to link the natural history of infection and patient behavior to epidemiological outcomes and can be used to guide research and enhance the public health impact of interventions. While limited knowledge of key disease parameters and networks of spread has impeded development of operational models of gonococcal transmission, new tools in gonococcal surveillance may provide useful data to aid tracking and modeling. Here, we highlight critical questions in the management of gonorrhea that can be addressed by mathematical models and identify key data needs. Our overarching aim is to articulate a shared agenda across gonococcus-related fields from microbiology to epidemiology that will catalyze a comprehensive evidence-based clinical and public health strategy for management of gonococcal infections and antimicrobial resistance., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: The emergence of Neisseria gonorrhoeae with decreased susceptibility to extended spectrum cephalosporins raises the prospect of untreatable gonorrhoea. In the absence of new treatments, efforts to slow the increasing incidence of resistant gonococcus require insight into the factors that contribute to its emergence and spread. We assessed the relatedness between isolates in the USA and reconstructed likely spread of lineages through different sexual networks., Methods: We sequenced the genomes of 236 isolates of N gonorrhoeae collected by the Centers for Disease Control and Prevention's Gonococcal Isolate Surveillance Project (GISP) from sentinel public sexually transmitted disease clinics in the USA, including 118 (97%) of the isolates from 2009-10 in GISP with reduced susceptibility to cefixime (cef(RS)) and 118 cefixime-susceptible isolates from GISP matched as closely as possible by location, collection date, and sexual orientation. We assessed the association between antimicrobial resistance genotype and phenotype and correlated phylogenetic clustering with location and sexual orientation., Findings: Mosaic penA XXXIV had a high positive predictive value for cef(RS). We found that two of the 118 cef(RS) isolates lacked a mosaic penA allele, and rechecking showed that these two were susceptible to cefixime. Of the 116 remaining cef(RS) isolates, 114 (98%) fell into two distinct lineages that have independently acquired mosaic penA allele XXXIV. A major lineage of cef(RS) strains spread eastward, predominantly through a sexual network of men who have sex with men. Eight of nine inferred transitions between sexual networks were introductions from men who have sex with men into the heterosexual population., Interpretation: Genomic methods might aid efforts to slow the spread of antibiotic-resistant N gonorrhoeae through augmentation of gonococcal outbreak surveillance and identification of populations that could benefit from increased screening for asymptomatic infections., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

New, first-in-class oral antibiotics like zoliflodacin, developed in a public–private partnership, require an optimal introduction strategy while ensuring antibiotic stewardship. Zoliflodacin, given as a single dose for uncomplicated urogenital gonorrhoea, recently demonstrated non-inferiority to ceftriaxone plus azithromycin and safety in a phase 3 randomised controlled trial. Following regulatory approval, zoliflodacin could improve sexually transmitted infection (STI) management and help address the threat of untreatable gonorrhoea, as levels of resistance to current first-line treatments increase. The Global Antibiotic Research & Development Partnership (GARDP) convened an expert meeting during the 2023 STI and HIV World Congress to discuss key questions about the introduction of zoliflodacin in low- and middle-income countries (LMICs). The questions included: which patients to treat in which situations, the timing of introduction, and what additional evidence is needed to change policy for the use of new antibiotics for gonorrhoea. Recommendations from the expert group included: the generation of evidence for the role of a drug like zoliflodacin in clinical treatment failures; the need for additional antimicrobial resistance surveillance; investigation of the role of novel diagnostic approaches, such as point-of-care tests, to improve stewardship; study of preferences and values among the population in need; and modelling of the emergence of N. gonorrhoeae resistance and transmission in different scenarios. Forthcoming World Health Organization (WHO) global guidelines could outline recommendations for a new oral antibiotic like zoliflodacin based on existing evidence, and rational approaches for certain populations or use cases, while the evidence base is further strengthened. [ABSTRACT FROM AUTHOR]

Background Genomic epidemiology studies of gonorrhea in the United States have primarily focused on national surveillance for antibiotic resistance, and patterns of local transmission between demographic groups of resistant and susceptible strains are unknown. Methods We analyzed a convenience sample of genome sequences, antibiotic susceptibility, and patient data from 897 gonococcal isolates cultured at the New York City (NYC) Public Health Laboratory from NYC Department of Health and Mental Hygiene (DOHMH) Sexual Health Clinic (SHC) patients, primarily in 2012–2013. We reconstructed the gonococcal phylogeny, defined transmission clusters using a 10 nonrecombinant single nucleotide polymorphism threshold, tested for clustering of demographic groups, and placed NYC isolates in a global phylogenetic context. Results The NYC gonococcal phylogeny reflected global diversity with isolates from 22/23 of the prevalent global lineages (96%). Isolates clustered on the phylogeny by patient sexual behavior (P <.001) and race/ethnicity (P <.001). Minimum inhibitory concentrations were higher across antibiotics in isolates from men who have sex with men compared to heterosexuals (P <.001) and white heterosexuals compared to black heterosexuals (P <.01). In our dataset, all large transmission clusters (≥10 samples) of N. gonorrhoeae were susceptible to ciprofloxacin, ceftriaxone, and azithromycin, and comprised isolates from patients across demographic groups. Conclusions All large transmission clusters were susceptible to gonorrhea therapies, suggesting that resistance to empiric therapy was not a main driver of spread, even as risk for resistance varied across demographic groups. Further study of local transmission networks is needed to identify drivers of transmission. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial resistance in Neisseria gonorrhoeae is a global health concern. Strains from two internationally circulating sequence types, ST-7363 and ST-1901, have acquired resistance to third-generation cephalosporins, mainly due to mosaic penA alleles. These two STs were first detected in Japan; however, the timeline, mechanism, and process of emergence and spread of these mosaic penA alleles to other countries remain unknown. Methods: We studied the evolution of penA alleles by obtaining the complete genomes from three Japanese ST-1901 clinical isolates harboring mosaic penA allele 34 (penA-34) dating from 2005 and generating a phylogenetic representation of 1075 strains sampled from 35 countries. We also sequenced the genomes of 103 Japanese ST-7363 N. gonorrhoeae isolates from 1996 to 2005 and reconstructed a phylogeny including 88 previously sequenced genomes. Results: Based on an estimate of the time-of-emergence of ST-1901 (harboring mosaic penA-34) and ST-7363 (harboring mosaic penA-10), and > 300 additional genome sequences of Japanese strains representing multiple STs isolated in 1996–2015, we suggest that penA-34 in ST-1901 was generated from penA-10 via recombination with another Neisseria species, followed by recombination with a gonococcal strain harboring wildtype penA-1. Following the acquisition of penA-10 in ST-7363, a dominant sub-lineage rapidly acquired fluoroquinolone resistance mutations at GyrA 95 and ParC 87-88, by independent mutations rather than horizontal gene transfer. Data in the literature suggest that the emergence of these resistance determinants may reflect selection from the standard treatment regimens in Japan at that time. Conclusions: Our findings highlight how antibiotic use and recombination across and within Neisseria species intersect in driving the emergence and spread of drug-resistant gonorrhea. [ABSTRACT FROM AUTHOR]

Neisseria gonorrhoeae infections have been increasing globally, with prevalence rising across age groups. In this study, we report a case of disseminated gonococcal infection (DGI) involving a prosthetic joint, and we use whole-genome sequencing to characterize resistance genes, putative virulence factors, and the phylogenetic lineage of the infecting isolate. We review the literature on sequence-based prediction of antibiotic resistance and factors that contribute to risk for DGI. We argue for routine sequencing and reporting of invasive gonococcal infections to aid in determining whether an invasive gonococcal infection is sporadic or part of an outbreak and to accelerate understanding of the genetic features of N gonorrhoeae that contribute to pathogenesis. [ABSTRACT FROM AUTHOR]

The emergence of resistance to azithromycin complicates treatment of Neisseria gonorrhoeae, the etiologic agent of gonorrhea. Substantial azithromycin resistance remains unexplained after accounting for known resistance mutations. Bacterial genome-wide association studies (GWAS) can identify novel resistance genes but must control for genetic confounders while maintaining power. Here, we show that compared to single-locus GWAS, conducting GWAS conditioned on known resistance mutations reduces the number of false positives and identifies a G70D mutation in the RplD 50S ribosomal protein L4 as significantly associated with increased azithromycin resistance (p-value = 1.08 × 10−11). We experimentally confirm our GWAS results and demonstrate that RplD G70D and other macrolide binding site mutations are prevalent (present in 5.42% of 4850 isolates) and widespread (identified in 21/65 countries across two decades). Overall, our findings demonstrate the utility of conditional associations for improving the performance of microbial GWAS and advance our understanding of the genetic basis of macrolide resistance. The mechanisms underlying resistance of Neisseria gonorrhoeae to the antibiotic azithromycin are incompletely understood. Here, Ma et al. conduct a conditional genome-wide association study to identify new resistance mutations and experimentally confirm that a mutation in ribosomal protein L4 confers increased resistance. [ABSTRACT FROM AUTHOR]