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Introduction Neisseria gonorrhoeae has developed resistance to all first-line recommended therapies, making gonococcal antimicrobial resistance a major public health concern given limited antibiotic options currently and an even smaller antimicrobial development pipeline. Since the release of the Centers for Disease Control and Prevention (CDC) 2015 STD Treatment Guidelines, azithromycin, part of the 2015 dual-drug treatment regimen, has had a rapid rise in resistance. The 2020 CDC Gonorrhea Treatment Recommendations and the 2021 Sexually Transmitted Infections (STI) Treatment Guidelines were developed weighing the priorities of treating the individual, protecting the population, and preventing antimicrobial resistance. Methods Gonorrhea subject matter experts (SME) generated 8 key questions and conducted a literature review of updated data from 2013 to 2019 on gonorrhea antimicrobial resistance, treatment failures, clinical trials, and other key topics. More than 2200 abstracts were assessed, and 248 clinically relevant articles were thoroughly reviewed. SMEs also evaluated N gonorrhoeae antimicrobial resistance data from the Gonococcal Isolate Surveillance Project (GISP). Evidence Although there have been reports of ceftriaxone treatment failures internationally, GISP data suggest that ceftriaxone minimal inhibitory concentrations (MICs) have remained stable in the United States, with 0.25 mcg/mL). However, GISP documented a rapid rise in the proportion of isolates with an elevated MIC (≥ 2.0 mcg/mL) to azithromycin—nearly 5% in 2018. At the same time, new pharmacokinetic/pharmacodynamic data are available, and there is greater recognition of the need for antimicrobial stewardship. Summary The 2021 CDC STI Treatment Guidelines now recommend 500mg ceftriaxone intramuscularly once for the treatment of uncomplicated gonorrhea at all anatomic sites. If coinfection with chlamydia has not been excluded, cotreatment with doxycycline 100mg twice daily for 7 days should be added. Few alternative therapies exist for persons with cephalosporin allergies; there are no recommended alternative therapies for N gonorrhoeae infection of the throat.

BACKGROUND: In 2016, Centers for Disease Control and Prevention initiated Strengthening the US Response to Resistant Gonorrhea (SURRG) in multiple jurisdictions to enhance antibiotic resistant gonorrhea rapid detection and response infrastructure and evaluate the impact of key strategies. METHODS: Eight jurisdictions were funded to establish or enhance local gonococcal culture specimen collection in sexually transmitted disease and community clinics, conduct rapid antimicrobial susceptibility testing AST) in local laboratories, modify systems for enhanced data collection and rapid communication of results, and initiate enhanced partner services among patients with gonorrhea demonstrating elevated minimum inhibitory concentrations (MICs) to ceftriaxone, cefixime or azithromycin. RESULTS: Grantees incorporated genital, pharyngeal, and rectal gonococcal culture collection from all genders at participating clinics. During 2018 to 2019, grantees collected 58,441 culture specimens from 46,822 patients and performed AST on 10,814 isolates (representing 6.8% [3412] and 8.9% [4883] of local reported cases in 2018 and 2019, respectively). Of isolates that underwent AST, 11% demonstrated elevated azithromycin MICs; fewer than 0.5% demonstrated elevated ceftriaxone or cefixime MICs. Among patients whose infections demonstrated elevated MICs, 81.7% were interviewed for partner elicitation; however, limited new cases were identified among partners and contacts. CONCLUSIONS: As a public health model to build capacity to slow the spread of emerging resistance, SURRG successfully expanded culture collection, implemented rapid AST, and implemented an enhanced partner services investigation approach in participating jurisdictions. Findings from SURRG may enhance preparedness efforts and inform a longer-term, comprehensive, and evidence-based public health response to emerging gonococcal resistance. Continued development of innovative approaches to address emerging resistance is needed.

BACKGROUND: Gradient strip antimicrobial susceptibility testing using Etest is conducted by local public health jurisdictions participating in the Strengthening the US Response to Resistant Gonorrhea (SURRG) program to inform public health responses to resistant gonorrhea. Proficiency testing results across the participating laboratories were analyzed and a comparison of Etest with the agar dilution method was conducted. METHODS: Laboratories participating in SURRG performed Etest for azithromycin (AZM), cefixime (CFX), and ceftriaxone (CRO). Concurrence between minimum inhibitory concentrations (MICs) obtained with Etest versus the agar dilution method using corresponding isolates was defined as ±1 double dilution. Specific levels of reduced susceptibility were termed “alerts” and included isolates with the following MICs: ≥2.0 μg/mL (AZM), ≥0.25 μg/mL (CFX), and ≥0.125 μg/mL (CRO). Categorical (alert/nonalert) agreement was calculated for MICs determined using Etest and agar dilution methods. RESULTS: Strengthening the US Response to Resistant Gonorrhea laboratories had high proficiency testing scores (≥98%) and low levels of interlaboratory variations in MICs. The overall concurrence of MICs (essential agreement) determined using agar dilution, and Etest was 96% (CRO), 96% (CFX), and 95% (AZM). Depending on the antibiotic tested, between 27% and 66% of isolates with alert MICs determined by Etest also had alert MICs using the reference agar dilution methodology; however, most of these alert MICs were detected at threshold levels. CONCLUSIONS: This study demonstrates that MICs produced by SURRG laboratories using Etest have a high level of concurrence with agar dilution. Although confirmation of specific alert MICs varied, Etest facilities rapid detection and response to emerging resistant gonorrhea.

The recent emergence of strains of Neisseria gonorrhoeae associated with treatment failures to ceftriaxone, the foundation of current treatment options, has raised concerns over a future of untreatable gonorrhea. Current global data on gonococcal strains suggest that several lineages, predominately characterized by mosaic penA alleles, are associated with elevated minimum inhibitory concentrations (MICs) to extended spectrum cephalosporins (ESCs). Here we report on whole genome sequences of 813 N. gonorrhoeae isolates collected through the Gonococcal Isolate Surveillance Project in the United States. Phylogenomic analysis revealed that one persisting lineage (Clade A, multi-locus sequence type [MLST] ST1901) with mosaic penA-34 alleles, contained the majority of isolates with elevated MICs to ESCs. We provide evidence that an ancestor to the globally circulating MLST ST1901 clones potentially emerged around the early to mid-20th century (1944, credibility intervals [CI]: 1935–1953), predating the introduction of cephalosporins, but coinciding with the use of penicillin. Such results indicate that drugs with novel mechanisms of action are needed as these strains continue to persist and disseminate globally., Resistance of Neisseria gonorrhoeae to extended spectrum cephalosporins is an increasing concern. Here, the authors conduct whole genome sequencing of isolates from the United States and find that most resistant isolates were associated with a persistent circulating lineage.

BackgroundSince 2014, Neisseria gonorrhoeae azithromycin (AZM) susceptibility has declined in the United States, but high-level AZM resistance (HL-AZMR) has been infrequent and sporadic. We describe a cluster of 14 N. gonorrhoeae isolates with HL-AZMR identified in Indianapolis over 13 months.MethodsN. gonorrhoeae culture specimens (genital and extragenital) were collected from attendees of the Bell Flower Clinic. Isolates underwent antimicrobial susceptibility testing (AST) using Etest. AZM minimum inhibitory concentrations ≥256 µg/mL were classified as HL-AZMR. Local disease intervention specialists interviewed patients whose isolates demonstrated HL-AZMR and conducted partner services. Relatedness of isolates was investigated by genomic analyses.ResultsDuring 2017–2018, AST was performed in 1016 N. gonorrhoeae isolates collected at the Bell Flower Clinic. Fourteen isolates (1.4%) from 12 men collected over 13 months demonstrated HL-AZMR; all were cephalosporin susceptible. Of the 12 men, 9 were white and reported male sex partners. Nine of the men were able to be retested; all were cured with 250-mg ceftriaxone plus 1-g AZM. Two men named each other as partners; no other partners in common were reported. Genomic analysis demonstrated close relatedness of the HL-AZMR isolates and a novel combination of a mosaic-mtrR promoter along with 23S ribosomal RNA mutations that appear to have emerged from circulating strains.ConclusionsThe close genetic relatedness with limited epidemiologic linkages between patients highlights the challenges of gonorrhea partner investigations and suggests undetected local transmission. Local AST, rapid public health action, and epidemiologic investigations combined with genomic analysis provides a multipronged approach to understanding an outbreak of sexually transmitted disease.

BACKGROUND The most recent estimates of the number of prevalent and incident sexually transmitted infections (STIs) in the United States were for 2008. We provide updated estimates for 2018 using new methods. METHODS We estimated the total number of prevalent and incident infections in the United States for 8 STIs: chlamydia, gonorrhea, trichomoniasis, syphilis, genital herpes, human papillomavirus, sexually transmitted hepatitis B, and sexually transmitted HIV. Updated per-capita prevalence and incidence estimates for each STI were multiplied by the 2018 full resident population estimates to calculate the number of prevalent and incident infections. STI-specific estimates were combined to generate estimates of the total number of prevalent and incident STIs overall, and by sex and age group. Primary estimates are represented by medians, and uncertainty intervals are represented by the 25th (Q1) and 75th (Q3) percentiles of the empirical frequency distributions of prevalence and incidence for each STI. RESULTS In 2018, there were an estimated 67.6 (Q1, 66.6; Q3, 68.7) million prevalent and 26.2 (Q1, 24.0; Q3, 28.7) million incident STIs in the United States. Chlamydia, trichomoniasis, genital herpes, and human papillomavirus comprised 97.6% of all prevalent and 93.1% of all incident STIs. Persons aged 15 to 24 years comprised 18.6% (12.6 million) of all prevalent infections; however, they comprised 45.5% (11.9 million) of all incident infections. CONCLUSIONS The burden of STIs in the United States is high. Almost half of incident STIs occurred in persons aged 15 to 24 years in 2018. Focusing on this population should be considered essential for national STI prevention efforts.

Summary: Background: The number of cases of gonorrhoea in the USA and worldwide caused by Neisseria gonorrhoeae is increasing (555 608 reported US cases in 2017, and 87 million cases worldwide in 2016). Many countries report declining in vitro susceptibility of azithromycin, which is a concern because azithromycin and ceftriaxone are the recommended dual treatment in many countries. We aimed to identify strain types associated with decreased susceptibility to azithromycin. Methods: We did a genomic analysis of N gonorrhoeae isolates obtained by the US Gonococcal Isolate Surveillance Project. Isolates were whole-genome sequenced based on decreased susceptibility to azithromycin (minimal inhibitory concentration [MIC] ≥2 μg/mL, using agar dilution antibiotic susceptibility testing) and geographical representation. Bioinformatic analyses established genomic diversity, strain population dynamics, and antimicrobial resistance profiles. Findings: 410 isolates were sorted into more than 20 unique phylogenetic clades. One predominant persistent clade (consisting of 97 isolates) included the most isolates with azithromycin MICs of 2 μg/mL or higher (61 of 97 [63%] vs 59 of 311 [19%]; p

Background Antibiotic-resistant gonorrhoea has been a chronic public health burden since the mid-1930s. Recent emergence of isolates resistant to the current recommended antibiotics for gonorrhoea further magnifies the threat of untreatable gonorrhoea. The lack of new, effective antibiotics highlights the need for better understanding of the population structure of Neisseria gonorrhoeae in order to provide greater insight on how to curtail the spread of antimicrobial-resistant N. gonorrhoeae. Objectives To explore a potential application of MALDI-TOF MS to differentiate N. gonorrhoeae displaying different levels of susceptibility to the antibiotic azithromycin. Methods We conducted MALDI-TOF MS using the Bruker Biotyper on 392 N. gonorrhoeae isolates collected through the Gonococcal Isolate Surveillance Project (GISP) and/or the Strengthening the United States Response to Resistant Gonorrhea (SURRG) project. The MALDI-TOF MS spectra were visually analysed to assess the presence of distinctive peak(s). Statistical analysis was performed to assess the relationship between gonococcal isolates with the distinct protein peak and antibiotic susceptibility. Results In this study, we were able to differentiate N. gonorrhoeae isolates into two distinct subpopulations using MALDI-TOF MS. Isolates were distinguished by the presence or absence of a spectral peak at 11 300 Da. Notably, these two groups exhibited different levels of susceptibility to azithromycin. Conclusions We have shown that in addition to its ability to identify N. gonorrhoeae, MALDI-TOF MS could also be used to differentiate gonococcal isolates with different levels of susceptibility to azithromycin.

Disseminated gonococcal infection (DGI) is a rare complication caused by the systemic dissemination of Neisseria gonorrhoeae to normally sterile anatomical sites. Little is known about the genetic diversity of DGI gonococcal strains and how they relate to other gonococcal strains causing uncomplicated mucosal infections. We used whole genome sequencing to characterize DGI isolates (n = 30) collected from a surveillance system in Georgia, United States, during 2017–2020 to understand phylogenetic clustering among DGI as well as uncomplicated uro- and extragenital gonococcal infection (UGI) isolates (n = 110) collected in Fulton County, Georgia, during 2017–2019. We also investigated the presence or absence of genetic markers related to antimicrobial resistance (AMR) as well as surveyed the genomes for putative virulence genetic factors associated with normal human-serum (NHS) resistance that might facilitate DGI. We found that DGI strains demonstrated significant genetic variability similar to the population structure of isolates causing UGI, with sporadic incidences of geographically clustered DGI strains. DGI isolates contained various AMR markers and genetic mechanisms associated with NHS resistance. DGI isolates had a higher frequency of the porB1A allele compared with UGI (67% vs 9%, P

BACKGROUND: Jurisdictions participating in Strengthening the United States Response to Resistant Gonorrhea (SURRG) implemented specimen collection for culture and antimicrobial susceptibility testing (AST) from a sample of persons of all genders (at multiple anatomic sites) attending STD clinics and community clinics. We describe the percentage and characteristics of patients whose isolates demonstrated reduced susceptibility (RS) to azithromycin, ceftriaxone, or cefixime. METHODS: We included patients from clinics that participated in SURRG whose isolates underwent AST by Etest. We defined RS as azithromycin minimum inhibitory concentrations (MICs) ≥2 μg/ml (AZM-RS), ceftriaxone MICs ≥0.125 μg/ml (CRO-RS), or cefixime MICs ≥0.25 μg/ml (CFX-RS). Patients with repeated infections appeared >1 time in the data. We calculated the frequency and percentage of patients with an isolate demonstrating RS by epidemiological characteristics. RESULTS: During 2018–2019, 10,013 patients from eight jurisdictions provided 10,735 isolates. Among 10,013 patients, 11.0% (n=1,099) had ≥1 isolate with AZM-RS (range by jurisdiction 2.5%–18.0%). Approximately 11.3% of 8,771 of patients visiting STD clinics and approximately 8.8% of 1,242 patients visiting community clinics had an AZM-RS isolate. Nearly 6% of 1,013 females had an AZM-RS isolate; among males, the percent of patients with an AZM-RS isolate was 17.7% among 4,177 men who have sex only with men and 6.1% among 3,581 men who have sex only with women. Few (0.4%) patients had isolates with CFX-RS (n=40) or CRO-RS (n=43). CONCLUSIONS: Although infections with reduced cephalosporin susceptibility were rare, AZM-RS infections were prevalent in this sample of patients in multiple jurisdictions and across gender and gender of sex partner categories. SHORT SUMMARY: Data from SURRG demonstrated that 11% of sampled patients attending STD clinics and community clinics had an isolate with reduced azithromycin susceptibility

BACKGROUND: Reduced antibiotic susceptibility (RS) in Neisseria gonorrhoeae (GC) may increase treatment failure. Conducting tests of cure (TOC) for patients with RS-GC may facilitate identification of treatment failures. METHODS: We examined 2018 to 2019 data from 8 jurisdictions participating in the US Centers for Disease Control and Prevention’s Strengthening US Response to Resistant Gonorrhea project. Jurisdictions collected GC isolates and epidemiological data from patients and performed antimicrobial susceptibility testing. Minimum inhibitory concentrations of ceftriaxone, 0.125 μg/mL or greater; cefixime, 0.250 μg/mL or greater; or azithromycin, 2.0 μg/mL or greater were defined as RS. Patients with RS infections were asked to return for a TOC 8 to 10 days posttreatment. We calculated a weighted TOC return rate and described time to TOC and suspected reasons for any positive TOC results. RESULTS: Overall, 1165 patients were diagnosed with RS infections. Over half returned for TOC (weighted TOC, 61%; 95% confidence interval, 50.1%–72.6%; range by jurisdiction, 32%–80%). Test of cure rates were higher among asymptomatic (68%) than symptomatic patients (53%, P = 0.001), and men who have sex with men (62%) compared with men who have sex with women (50%; P < 0.001). Median time between treatment and TOC was 12 days (interquartile range, 9–16). Of the 31 (4.5%) TOC patients with positive results, 13 (42%) were suspected because of reinfection and 11 (36%) because of false-positive results. There were no treatment failures suspected to be due to RS-GC. CONCLUSIONS: Most patients with a RS infection returned for a TOC, though return rates varied by jurisdiction and patient characteristics. Test of cure can identify and facilitate treatment of reinfections, but false-positive TOC results may complicate interpretation and clinical management.

BACKGROUND We investigated differences in gonococcal antimicrobial susceptibility by anatomic site among cisgender men who have sex with men (MSM) using specimens collected through the Centers for Disease Control and Prevention's enhanced Gonococcal Isolate Surveillance Project and Strengthening the US Response to Resistant Gonorrhea. METHODS During the period January 1, 2018-December 31, 2019, 12 enhanced Gonococcal Isolate Surveillance Project and 8 Strengthening the US Response to Resistant Gonorrhea sites collected urogenital, pharyngeal, and rectal isolates from cisgender MSM in sexually transmitted disease clinics. Gonococcal isolates were sent to regional laboratories for antimicrobial susceptibility testing by agar dilution. To account for correlated observations, linear mixed-effects models were used to calculate geometric mean minimum inhibitory concentrations (MICs), and mixed-effects logistic regression models were used to calculate the proportion of isolates with elevated or resistant MICs; comparisons were made across anatomic sites. RESULTS Participating clinics collected 3974 urethral, 1553 rectal, and 1049 pharyngeal isolates from 5456 unique cisgender MSM. There were no significant differences in the geometric mean MICs for azithromycin, ciprofloxacin, penicillin, and tetracycline by anatomic site. For cefixime and ceftriaxone, geometric mean MICs for pharyngeal isolates were higher compared with anogenital isolates (P < 0.05). The proportion of isolates with elevated ceftriaxone MICs (≥0.125 μg/mL) at the pharynx (0.67%) was higher than at rectal (0.13%) and urethral (0.18%) sites (P < 0.05). CONCLUSIONS Based on data collected from multijurisdictional sentinel surveillance projects, antimicrobial susceptibility patterns of Neisseria gonorrhoeae isolates may differ among MSM at extragenital sites, particularly at the pharynx. Continued investigation into gonococcal susceptibility patterns by anatomic site may be an important strategy to monitor and detect the emergence of antimicrobial resistant gonorrhea over time.

Neisseria gonorrhoeae multi-locus sequence type (ST) 9363 genogroup isolates have been associated with reduced azithromycin susceptibility (AZMrs) and show evidence of clonal expansion in the U.S. Here we analyze a global collection of ST-9363 genogroup genomes to shed light on the emergence and dissemination of this strain. The global population structure of ST-9363 genogroup falls into three lineages: Basal, European, and North American; with 32 clades within all lineages. Although, ST-9363 genogroup is inferred to have originated from Asia in the mid-19th century; we estimate the three modern lineages emerged from Europe in the late 1970s to early 1980s. The European lineage appears to have emerged and expanded from around 1986 to 1998, spreading into North America and Oceania in the mid-2000s with multiple introductions, along with multiple secondary reintroductions into Europe. Our results suggest two separate acquisition events of mosaic mtrR and mtrR promoter alleles: first during 2009-2011 and again during the 2012-2013 time, facilitating the clonal expansion of this genogroup with AZMrs in the U.S. By tracking phylodynamic evolutionary trajectories of clades that share distinct demography as well as population-based genomic statistics, we demonstrate how recombination and selective pressures in the mtrCDE efflux operon granted a fitness advantage to establish ST-9363 as a successful gonococcal lineage in the U.S. and elsewhere. Although it is difficult to pinpoint the exact timing and emergence of this young genogroup, it remains critically important to continue monitoring it, as it could acquire additional resistance markers.

BACKGROUND Sexual networks are difficult to construct because of incomplete sexual partner data. The proximity of people within a network may be inferred from genetically similar infections. We explored genomic data combined with partner services investigation (PSI) data to extend our understanding of sexual networks affected by Neisseria gonorrhoeae (NG). METHODS We used 2017-2019 PSI and whole-genome sequencing (WGS) data from 8 jurisdictions participating in Centers for Disease Control and Prevention's Strengthening the US Response to Resistant Gonorrhea (SURRG) project. Clusters were identified from sexual contacts and through genetically similar NG isolates. Sexual mixing patterns were characterized by describing the clusters by the individual's gender and gender of their sex partners. RESULTS Our study included 4627 diagnoses of NG infection (81% sequenced), 2455 people received a PSI, 393 people were negative contacts of cases, and 495 were contacts with an unknown NG status. We identified 823 distinct clusters using PSI data combined with WGS data. Of cases that were not linked to any other case using PSI data, 37% were linked when using WGS data. Overall, 40% of PSI cases were allocated to a larger cluster when PSI and WGS data were combined compared with PSI data alone. Mixed clusters containing women, men who report sex with women, and men who report sex with men were common when using the WGS data either alone or in combination with the PSI data. CONCLUSIONS Combining PSI and WGS data improves our understanding of sexual network connectivity.

BACKGROUND The prevalence of Neisseria gonorrhoeae (GC) isolates with elevated minimum inhibitory concentrations to various antibiotics continues to rise in the United States and globally. Genomic analysis provides a powerful tool for surveillance of circulating strains, antimicrobial resistance determinants, and understanding of transmission through a population. METHODS Neisseria gonorrhoeae isolates collected from the US Gonococcal Isolate Surveillance Project in 2018 (n = 1479) were sequenced and characterized. Whole-genome sequencing was used to identify sequence types, antimicrobial resistance profiles, and phylogenetic relationships across demographic and geographic populations. RESULTS Genetic characterization identified that (1) 80% of the GC isolates were represented in 33 multilocus sequence types, (2) isolates clustered in 23 major phylogenetic clusters with select phenotypic and demographic prevalence, and (3) common antimicrobial resistance determinants associated with low-level or high-level decreased susceptibility or resistance to relevant antibiotics. CONCLUSIONS Characterization of this 2018 Gonococcal Isolate Surveillance Project genomic data set, which is the largest US whole-genome sequence data set to date, sets the basis for future prospective studies, and establishes a genomic baseline of GC populations for local and national monitoring.

Background The most recent prevalence and incidence estimates for chlamydia and gonorrhea, the 2 most reported sexually transmitted infections in the United States, were for 2008. We present updated estimates of the number of prevalent and incident chlamydial and gonococcal infections for 2018. Methods We estimated chlamydial prevalence directly from the 2015 to 2018 cycles of the National Health and Nutrition Examination Survey and chlamydial incidence using a mathematical model primarily informed by National Health and Nutrition Examination Survey and case report data. Total and antimicrobial-resistant gonococcal prevalence and incidence were estimated using mathematical models primarily informed by case report and Gonococcal Isolate Surveillance Program data. Estimates were calculated for the total population, all women, and all men aged 15 to 39 years, stratified by age group. Primary estimates represent medians and uncertainty intervals represent the 25th (Q1) and 75th (Q3) percentiles of the empirical frequency distributions of prevalence and incidence for each infection. Results Among persons aged 15 to 39 years in the United States in 2018, we estimate 2.35 (Q1, 2.20; Q3, 2.51) million prevalent and 3.98 (Q1, 3.77; Q3, 4.22) million incident chlamydial infections, and an estimated 209,000 (Q1, 183,000; Q3, 241,000) prevalent and 1.57 (Q1, 1.44; Q3, 1.72) million incident gonococcal infections. Of all gonococcal infections, there were 107,000 (Q1, 94,000; Q3, 124,000) prevalent and 804,000 (Q1, 738,000; Q3, 883,000) incident infections demonstrating antimicrobial resistance or elevated minimum inhibitory concentrations to selected antibiotics. Conclusions Chlamydia and gonorrhea were very common in the United States in 2018. Estimates show that more than 800,000 newly acquired gonococcal infections in 2018 demonstrated resistance or elevated minimum inhibitory concentrations to currently or previously recommended antibiotics.

A2059G mutation in the 23S rRNA gene is the only reported mechanism conferring high-level azithromycin resistance (HL-AZMR) in Neisseria gonorrhoeae . Through U.S. gonococcal antimicrobial resistance surveillance projects, we identified four HL-AZMR gonococcal isolates lacking this mutational genotype. Genetic analysis revealed an A2058G mutation of 23S rRNA alleles in all four isolates. In vitro selected gonococcal strains with homozygous A2058G recapitulated the HL-AZMR phenotype.

In 2016, the proportion of Neisseria gonorrhoeae isolates with reduced susceptibility to azithromycin rose to 3.6%. A phylogenetic analysis of 334 N. gonorrhoeae isolates collected in 2016 revealed a single, geographically diverse lineage of isolates with MICs of 2 to 16 μg/ml that carried a mosaic-like mtr locus, whereas the majority of isolates with MICs of ≥16 μg/ml appeared sporadically and carried 23S rRNA mutations.

U.S. gonorrhea rates are rising, and antibiotic-resistant Neisseria gonorrhoeae (AR-Ng) is an urgent public health threat. Since implementation of nucleic acid amplification tests for N. gonorrhoeae identification, the capacity for culturing N. gonorrhoeae in the United States has declined, along with the ability to perform culture-based antimicrobial susceptibility testing (AST). Yet AST is critical for detecting and monitoring AR-Ng. In 2016, the CDC established the Antibiotic Resistance Laboratory Network (AR Lab Network) to shore up the national capacity for detecting several resistance threats including N. gonorrhoeae. AR-Ng testing, a subactivity of the CDC’s AR Lab Network, is performed in a tiered network of approximately 35 local laboratories, four regional laboratories (state public health laboratories in Maryland, Tennessee, Texas, and Washington), and the CDC’s national reference laboratory. Local laboratories receive specimens from approximately 60 clinics associated with the Gonococcal Isolate Surveillance Project (GISP), enhanced GISP (eGISP), and the program Strengthening the U.S. Response to Resistant Gonorrhea (SURRG). They isolate and ship up to 20,000 isolates to regional laboratories for culture-based agar dilution AST with seven antibiotics and for whole-genome sequencing of up to 5,000 isolates. The CDC further examines concerning isolates and monitors genetic AR markers. During 2017 and 2018, the network tested 8,214 and 8,628 N. gonorrhoeae isolates, respectively, and the CDC received 531 and 646 concerning isolates and 605 and 3,159 sequences, respectively. In summary, the AR Lab Network supported the laboratory capacity for N. gonorrhoeae AST and associated genetic marker detection, expanding preexisting notification and analysis systems for resistance detection. Continued, robust AST and genomic capacity can help inform national public health monitoring and intervention.

Background In-vitro susceptibility distributions to antibiotics can evolve over time because of emerging resistance determinants. This can affect clinical drug efficacy and interpretation of laboratory susceptibility tests. In January 2019, the Clinical Laboratory Standards Institute (CLSI) analyzed Neisseria gonorrhoeae (Ng) susceptibility parameters for ceftriaxone (CRO), cefixime (CFX) and azithromycin (AZI) to review interpretive criteria for laboratory tests. Methods GISP (Gonococcal Isolate Surveillance Project) is a United States national surveillance project at approximately 25 sentinel STD clinics, collecting about 5,000 yearly urethral isolates from symptomatic men. From 1987–2017, minimal inhibitory drug concentrations (MIC) of 164,506 isolates were determined by agar dilution using CLSI-recommended protocols. Susceptibility parameters were calculated with R software, and included mean MIC, 98.5% MIC indicating end of wild-type distribution, and percent isolates meeting 2019 CLSI susceptibility (S) criteria (CRO, CFX, AZI Results Since 1987, only 5 isolates did not meet CRO S criteria. CRO alerts peaked at 1.05% in 1991. Mean MICs were highest in 2016 (0.013 μg/mL; 95% CI: 0.013–0.013), but compared to the mean MIC when GISP began (0.011 μg/mL; 95% CI: 0.010–0.011) the difference was less than a full drug dilution. Isolates not meeting CFX S criteria, 76 since 1987, were at a 0.17% peak in 1992, as were mean MICs. Isolates not meeting AZI S criteria were highest at 3.6% and 4.4% in 2016 and 2017, respectively, as were mean MICs. Conclusion Ng CRO and CFX in-vitro susceptibilities have not uniformly decreased since GISP began, while most indicators suggest declining AZI in-vitro susceptibility. CLSI reviewed these data in conjunction with clinical, pharmacokinetic/-dynamic and other international susceptibility data and kept steady (CRO, CFX) or established new (AZI) 2019 laboratory testing susceptibility criteria. Disclosure No significant relationships.

Background Azithromycin resistance in Neisseria gonorrhoeae has been attributed to several resistance-associated mutations including mutations in the 23S rRNA genes conferring varying levels of azithromycin resistance. Here, we report the emergence of a novel A to G mutation at the 2058 nucleotide residue (A2058G) in the 23S rRNA genes, in two gonococcal isolates, that confers high-level resistance to azithromycin (HLAziR; ≥ 256 mg/ml). Methods The collection and antimicrobial susceptibility testing of N. gonorrhoeae isolates were performed as part of the Gonococcal Isolate Surveillance Project (GISP). Isolates with elevated minimum inhibitory concentration to azithromycin (≥ 2 mg/ml) were subjected to molecular analysis using Sanger PCR sequencing and/or whole genome sequencing analysis. Etest® was performed to confirm azithromycin susceptibility level and to determine the hetero-resistance phenotype (a concentration-dependent response to antibiotic) of the reported isolates. Results Molecular analysis of GISP isolates from 2014–2018 revealed two isolates collected from two patients having the A2058G mutation in the 23S rRNA genes. One isolate had the HLAziR phenotype and A2058G mutations in all four 23S rRNA. The second isolate had the A2058G mutation in three of the four alleles and displayed a hetero-resistance phenotype (azithromycin MIC ranging from 4 mg/ml to ≥ 256 mg/ml). The wild-type allele was very conducive to A2058G conversion and resulted in a complete HLAziR phenotype. This mutational nucleotide conversion occurred in less than twenty hours after exposure to azithromycin using Etest®. Conclusion HLAziR in N. gonorrhoeae had largely been confined to isolates harboring a point mutation at nucleotide residue A2059G of the 23S rRNA genes. The newly discovered A2058G mutation further illuminates the genomic plasticity in N. gonorrhoeae when responding to antibiotic exposure and suggests a rapid recombination frequency between the 23S rRNA alleles at this nucleotide residue. Disclosure No significant relationships.

Background The emergence of Neisseria gonorrhoeae strains with reduced susceptibility to the extended-spectrum cephalosporins (ESCs) cefixime and ceftriaxone has raised concerns over a future of untreatable gonorrhea. In 2015, a treatment regimen consisting of ceftriaxone and azithromycin were recommended to assist in delaying the further selection of resistant strains, including those with elevated cephalosporin minimum inhibitory concentrations (MICs) (ESCem). Recently, we conducted a retrospective study to assess the genetic relatedness of isolates in the United States from 2006–2017, and describe the emergence and dissemination of ESCem lineages over time. Methods We examined the genomes of 637 N. gonorrhoeae isolates collected through the Gonococcal Isolate Surveillance Project (GISP), including 317 isolates with elevated cefixime MICs (CFXem; MIC ≥ 0.25 μg/mL), 96 isolates with elevated ceftriaxone MICs (CROem; MIC ≥ 0.125 μg/mL), and 224 accompanying cephalosporin-susceptible isolates matched by region and collection date. We generated a core-genome SNP phylogeny, and examined the distribution of antimicrobial determinants known to be associated with cephalosporin resistance. Results The majority of gonococcal isolates with elevated MICs to either cephalosporin or both (n = 337) possessed the mosaic penA XXXIV allele (cefixime: 87%, 276/317, P Conclusion The prevalence of mosaic penA XXXIV alleles was highest among gonococcal isolates with reduced susceptibility to ESCs over a 12-year period. Genomic methods can aid in efforts to monitor antimicrobial resistance markers of concern and ultimately slow the emergence and spread of circulating ESCem strains. Disclosure No significant relationships.

Background Azithromycin (AZI) is recommended with ceftriaxone (CRO) for treatment of uncomplicated gonococcal urethritis and cervicitis in the United States, and an AZI-susceptibility breakpoint is needed. Neither the Food and Drug Administration (FDA) nor the Clinical and Laboratory Standards Institute (CLSI) has set interpretive breakpoints for AZI susceptibility. As a result, AZI antimicrobial susceptibility testing (AST) cannot be interpreted using recognized standards. This has contributed to increasingly unavailable clinical laboratory AST, although gonorrhea is on the rise with >550 000 US gonorrhea cases reported to the Centers for Disease Control and Prevention in 2017, the highest number of cases since 1991. Methods This article summarizes the rationale data reviewed by the CLSI in June 2018. Results The CLSI decided to set a susceptible-only interpretive breakpoint at the minimum inhibitory concentration of ≤1 µg/mL. This is also the epidemiological cutoff value (ECV) (ie, the end of the wild-type susceptibility distribution). This breakpoint presumes that AZI (1-g single dose) is used in an approved regimen that includes an additional antimicrobial agent (ie, CRO 250 mg, intramuscular single dose). Conclusions Having a breakpoint can improve patient care and surveillance and allow future development and FDA regulatory approval of modernized AST to guide treatment. The breakpoint coincides with a European Committee on AST decision to remove previously established, differing AZI breakpoints and use the ECV as guidance for testing. The CLSI breakpoint is now the recognized standard that defines AZI susceptibility for gonococcal infections.

The nimbleness of Neisseria gonorrhoeae to evade the effect of antibiotics has perpetuated the fight against antibiotic-resistant gonorrhea for more than 80 years. The ability to develop resistance to antibiotics is attributable to its indiscriminate nature in accepting and integrating exogenous DNA into its genome. Here, we provide data demonstrating a novel combination of the 23S rRNA A2059G mutation with a mosaic-multiple transferable resistance (mosaic-mtr) locus haplotype in 14 N. gonorrhoeae isolates with high-level azithromycin MICs (≥256 μg/ml), a combination that may confer more fitness than in previously identified isolates with high-level azithromycin resistance. To our knowledge, this is the first description of N. gonorrhoeae strains harboring this novel combination of resistance determinants. These strains were isolated at two independent jurisdictions participating in the Gonococcal Isolate Surveillance Project (GISP) and in the Strengthening the U.S. Response to Resistant Gonorrhea (SURRG) project. The data suggest that the genome of N. gonorrhoeae continues to shuffle its genetic material. These findings further illuminate the genomic plasticity of N. gonorrhoeae, which allows this pathogen to develop mutations to escape the inhibitory effects of antibiotics.

Background Concurrent gonococcal infections could impact treatment success in cases of anatomic site-specific strains with different antimicrobial susceptibilities; however, little is known about same-patient differences in susceptibility as most antibiotic resistance surveillance is based on only male urethral isolates. Methods In August 2017, the enhanced Gonococcal Isolate Surveillance Project (eGISP) began collecting male and female genital and extragenital gonococcal isolates from patients in 12 STD clinics. Minimum Inhibitory Concentrations (MICs) for penicillin, tetracycline, ciprofloxacin, gentamicin, cefixime, ceftriaxone and azithromycin were determined by agar dilution. We identified patients with isolates from multiple anatomic sites of infection collected during the same clinic visit. Isolate sets were categorized as pairs or triplets based on the number of culture positive anatomic sites. We identified same-patient isolate sets with differing MICs (≥2 dilution difference) for each antibiotic, and identified if the difference affected susceptibility categorization. All isolates in a set were tested in the same batch run by the same laboratory. Results From August 2017-February 2019, 280 isolates were collected from 135 patients, representing 136 isolate sets (128 pairs and 8 triplets); one patient contributed 2 isolate sets. Of the 136 isolate sets, the majority (72; 53%) were grouped as genital and pharyngeal isolates (Table 1). Overall, 33 isolate sets (24%) had differing MICs for ≥1 antibiotic and 21 sets (15%) for ≥2 antibiotics. Across all anatomical site combinations, differing MICs were most common for ciprofloxacin (10.3%), penicillin (9.6%) and azithromycin (9.6%). Only 18 isolate sets (13%) demonstrated differing MICs where an isolate was considered susceptible and another was considered resistant or reduced-susceptible. Conclusion Among persons with concurrent gonococcal infections, MICs can vary by ≥2 dilutions between sites and may change susceptibility interpretation. Variation by the anatomic site can result from initial infection with multiple strains or differential development of resistance after infection. Continued surveillance of multi-site infections could help understand resistance development and inform patient management. Disclosures All authors: No reported disclosures.

Background The Gonococcal Isolate Surveillance Project (GISP), which monitors trends in N. gonorrhoeae susceptibility among men with gonococcal urethritis in sexually transmitted disease (STD) clinics, has informed treatment recommendations for 3 decades. However, it has been speculated that susceptibility patterns may differ in women, as well as in the pharynx and rectum. We describe preliminary findings from the enhanced GISP (eGISP), which expands surveillance to pharyngeal, rectal, and endocervical isolates. Methods In August 2017, select jurisdictions were funded to collect urogenital and extragenital specimens from men and women seen in participating STD clinics. Positive gonorrhea cultures were sent to regional laboratories for antimicrobial susceptibility testing (AST) by agar dilution. Isolates with elevated minimum inhibitory concentration (MIC) to azithromycin (AZI) (MIC ≥2.0 μg/mL), cefixime (CFX) (MIC ≥0.25 μg/mL), and/or ceftriaxone (CRO) (MIC ≥0.125 μg/mL) were designated as Alert isolates. Clinical and epidemiological data were linked to AST results. Results From August 2017 to February 2018, 4 clinics in 4 jurisdictions submitted 468 positive gonococcal specimens for AST; 36.1% were from men who have sex with men (MSM), 51.9% from men who have sex with women (MSW), and 12.0% from women. Overall, 71.8% were urethral, 7.9% endocervical, 7.1% rectal, and 13.2% pharyngeal. Seventy-two isolates (15.4%) were Alerts: 97.2% (N = 70) had elevated MICs to AZI, 2.8% (N = 2) had elevated MICs to CFX, and none had elevated MICs to CRO. No isolate had elevated MICs to both AZI and CFX. Among MSM, 15.9% of urogenital isolates and 16.1% of extragenital isolates had an elevated AZI MIC. Among MSW, 11.8% of urogenital isolates and 14.3% of pharyngeal isolates had an elevated AZI MIC. Among women, 24.3% of endocervical isolates and 26.3% of extragenital isolates had an elevated AZI MIC. Conclusion Preliminary eGISP data suggest that enhanced surveillance of pharyngeal, rectal, and endocervical isolates is feasible and that elevated MICs to azithromycin are common among males and females. Including isolates from extragenital anatomic sites and women may help strengthen N. gonorrhoeae surveillance capacity. Disclosures All authors: No reported disclosures.

Background Neisseria gonorrhoeae’s ability to develop resistance to antibiotics used for treatment and a limited development of new therapies have made this organism one of three urgent threat pathogens in the United States. We provide the first report of US trends in multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) gonorrhea. Methods The Gonococcal Isolate Surveillance Project (GISP) monitors trends in antimicrobial susceptibility in N. gonorrhoeae in the United States. Antimicrobial susceptibility testing by agar dilution is performed on urethral isolates from male patients at participating STD clinics. Minimum inhibitory concentration (MIC) are used to identify isolates with resistance or reduced susceptibility using the following criteria: fluoroquinolones (ciprofloxacin [MIC ≥1.0 μg/mL]) and elevated MICs to cephalosporins (cefixime [MIC ≥0.25 μg/mL], ceftriaxone [MIC ≥0.25 μg/mL]) and macrolides (azithromycin [MIC ≥1.0 μg/mL before 2005 and ≥2.0 μg/mL 2005–2016]). In this analysis, MDR is defined as resistance or elevated MICs to ≥2 classes of antimicrobials; XDR as resistance or elevated MICs to ≥3 classes. This classification excludes penicillin and tetracycline due to their long history and high prevalence of gonococcal resistance. Results During 1987–2016, 159,445 isolates were collected through GISP. In 1998, the first MDR strains were identified. Although only 0.04% of isolates that year, these isolates showed elevated MICs to both cephalosporins and macrolides. By 2010, 1.0% of GISP isolates were MDR with elevated MICs or resistance to two of the cephalosporins, macrolides, or fluoroquinolones. In 2011, the proportion of isolates that were MDR peaked at 1.3%. In 2016, after minor fluctuations, 1.1% of GISP isolates were considered MDR. Only one occurrence of XDR, in 2011, has been seen in GISP. The strain was resistant to fluoroquinolones with elevated MICs to both cephalosporins and macrolides. Conclusion MDR and XDR gonorrhea have remained low over the past three decades; however, dual treatment with cephalosporins and macrolides is the last remaining recommended therapy for N. gonorrhoeae. Until new treatment options become available, a combination of surveillance and ensuring appropriate treatment are needed to delay further resistance. Disclosures All authors: No reported disclosures.