The Relationship Between Insertive Oral and Anal Sex and Select Measures of the Composition of the Urethral Microbiota Among Men Who Have Sex With Men.

BACKGROUND: Sexual behavior may influence the composition of the male urethral microbiota, but this hypothesis has not been tested in longitudinal studies of men who have sex with men (MSM). METHODS: From December 2014 to July 2018, we enrolled MSM with nongonococcal urethritis (NGU) attending a sexual health clinic. Men attended 5 in-clinic visits at 3-week intervals, collected weekly urine specimens at home, and reported daily antibiotics and sexual activity on weekly diaries. We applied broad-range 16S rRNA gene sequencing to urine. We used generalized estimating equations to estimate the association between urethral sexual exposures in the prior 7 days (insertive oral sex [IOS] only, condomless insertive anal intercourse [CIAI] only, IOS with CIAI [IOS + CIAI], or none) and Shannon index, number of species (observed, oral indicator, and rectal indicator), and specific taxa, adjusting for recent antibiotics, age, race/ethnicity, HIV, and preexposure prophylaxis. RESULTS: Ninety-six of 108 MSM with NGU attended ≥1 follow-up visit. They contributed 1140 person-weeks of behavioral data and 1006 urine specimens. Compared with those with no urethral sexual exposures, those with IOS only had higher Shannon index ( P = 0.03 ) but similar number of species and presence of specific taxa considered, adjusting for confounders; the exception was an association with Haemophilus parainfluenzae . CIAI only was not associated with measured aspects of the urethral microbiota. IOS + CIAI was only associated with presence of H. parainfluenzae and Haemophilus . CONCLUSIONS: Among MSM after NGU, IOS and CIAI did not seem to have a substantial influence on measured aspects of the composition of the urethral microbiota.

Bacterial vaginosis-associated bacteria in cisgender men who have sex with women: prevalence, association with non-gonococcal urethritis and natural history.

OBJECTIVES: Bacterial vaginosis-associated bacterium 2 (BVAB2), Mageeibacillus indolicus and Sneathia spp are highly predictive of bacterial vaginosis (BV) in cisgender women. They have been associated with non-gonococcal urethritis (NGU) in cisgender men in some but not all populations. We evaluated this association in a cross-sectional study of cisgender men who have sex with women only (MSW). METHODS: MSW without gonorrhoea attending a sexual health clinic (SHC) from 2014 to 2018 completed a computer-assisted self-interview, clinical interview and examination. NGU was defined as ≥5 polymorphonuclear leucocytes/high-power field in urethral exudates plus either urethral symptoms or visible discharge. Urine was tested for Chlamydia trachomatis and Mycoplasma genitalium using Aptima (Hologic) and for BVAB2, M. indolicus, Sneathia spp, Trichomonas vaginalis, Ureaplasma urealyticum, Haemophilus influenzae, herpes simplex virus and adenovirus using quantitative PCR. RESULTS: Of 317 MSW age 17-71, 67 (21.1%) had Sneathia spp, 36 (11.4%) had BVAB2, and 17 (5.4%) had M. indolicus at enrolment. Having ≥3 partners in the past 2 months was the only characteristic that was more common among MSW with than those without these bacteria (BVAB2: 47% vs 23%, M. indolicus: 53% vs 24%, Sneathia spp: 42% vs 22%; p≤0.03 for all). One-hundred seventeen men (37%) were diagnosed with NGU at enrolment. There was no significant association of BVAB2, M. indolicus or Sneathia spp with NGU (adjusted OR=0.59, 95% CI 0.14 to 2.43; aOR=3.40, 95% CI 0.68 to 17.06; aOR=0.46, 95% CI 0.16 to 1.27). Of 109 MSW with monthly samples, 34 (31.2%) had one of the bacteria at one or more follow-up visits, 22 of which were co-colonised with >1. Median persistence over 6 months did not differ significantly (BVAB2=30.5 days, IQR=28-87; M. indolicus=87 days, IQR=60-126; Sneathia spp=70 days, IQR=30-135; p≥0.20 for each comparison). CONCLUSIONS: Neither BVAB2, M. indolicus nor Sneathia spp were associated with increased risk of prevalent NGU in MSW attending an SHC.

The Incidence Rate of Sexual Behaviors Among Cisgender Men Who Have Sex with Men Attending a Sexual Health Clinic.

Although nuanced parameterization of sexual behavior may improve estimates from mathematical models of human immunodeficiency virus and sexually transmitted infection transmission, prospective estimates of the incidence of specific sexual behaviors among men who have sex with men (MSM) are limited. From December 2014 to July 2018, MSM with and without nongonococcal urethritis (NGU) completed weekly diaries over 3-12 weeks. Incidence rates of any sex, receptive anal sex, insertive anal sex, insertive oral sex, receptive rimming, and receptive hand-penile contact were 1.19, 0.28, 0.66, 0.90, 0.24, and 0.85 episodes per person-week, respectively, among 104 MSM with NGU at baseline, and 1.33, 0.54, 0.32, 0.95, 0.44, and 0.88 episodes per person-week, respectively, among 25 MSM without NGU at baseline. Most receptive anal sex (NGU + 83%, NGU - 86%) and insertive anal sex (NGU + 85%, NGU - 76%) episodes were condomless. MSM engaged in sex just over once per week, and condom use was infrequent. Insertive oral sex and receptive hand-penile contact were the most common behaviors.

Incidence of Nongonococcal Urethritis in Men Who Have Sex With Women and Associated Risk Factors.

BACKGROUND: Incidence and risk factors for nongonococcal urethritis (NGU) remain poorly defined. We conducted a cohort study to estimate the incidence of NGU and identify risk factors in men who have sex with women. METHODS: We enrolled cisgender male sexually transmitted disease clinic attendees 16 years or older who reported exclusively female partners. At enrollment and 6 monthly follow-up visits, men underwent a clinical examination, provided urethral swab and urine specimens, completed a sexual behavior survey and biweekly diaries, and were tested for Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) using Aptima assays (Hologic, Inc). Nongonococcal urethritis was defined as ≥5 polymorphonuclear leukocytes per high-power field plus either urethral symptoms or visible discharge. We estimated the incidence of NGU overall, asymptomatic and symptomatic NGU, non-CT/non-MG NGU, and CT/MG-associated NGU using Poisson regression for clustered outcomes. We performed relative risk binomial regression for clustered data to identify characteristics associated with incident NGU. RESULTS: From August 2014 to July 2018, 307 participants at risk for NGU contributed 109.4 person-years. Median age was 32 years, and 52% were White. At enrollment, 107 men had NGU; of these, 88% were symptomatic, 27% had CT, and 22% had MG. Fifty men had 60 cases of incident NGU (incidence rate, 56 per 100 person-years; 95% confidence interval, 43-74). Unlike prevalent NGU at enrollment, CT/MG-associated incident NGU was rare (incidence rate, 7; 95% confidence interval [CI], 4-15), and most (78%) incident NGU was asymptomatic. Risk factors for incident NGU were ≤ high school education (adjusted rate ratio [ARR], 2.45; 95% CI, 1.19-5.00), history of CT (ARR, 2.15; 95% CI, 1.08-4.27), history of NGU (ARR, 2.67; 95% CI, 1.27-5.62), and NGU at enrollment (ARR, 2.03; 95% CI, 1.04-3.98). Neither condom use nor having a new partner was associated with incident NGU; Black race was only associated with incident symptomatic and non-CT/non-MG NGU. CONCLUSIONS: Incidence of NGU was high, predominantly non-CT/non-MG and asymptomatic. Future studies should investigate the etiology and clinical significance of asymptomatic NGU.

Sequence variation and immunogenicity of the Mycoplasma genitalium MgpB and MgpC adherence proteins during persistent infection of men with non-gonococcal urethritis.

Mycoplasma genitalium is a sexually transmitted bacterial pathogen that infects men and women. Antigenic variation of MgpB and MgpC, the immunodominant adherence proteins of M. genitalium, is thought to contribute to immune evasion and chronic infection. We investigated the evolution of mgpB and mgpC sequences in men with non-gonococcal urethritis persistently infected with M. genitalium, including two men with anti-M. genitalium antibodies at enrollment and two that developed antibodies during follow-up. Each of the four patients was persistently infected with a different strain type and each patient produced antibodies targeting MgpB and MgpC. Amino acid sequence evolution in the variable regions of MgpB and MgpC occurred in all four patients with changes observed in single and multiple variable regions over time. Using the available crystal structure of MgpC of the G37 type strain we found that predicted conformational B cell epitopes localize predominantly to the variable region of MgpC, amino acids that changed during patient infection lie in these epitopes, and variant amino acids are in close proximity to the conserved sialic acid binding pocket. These findings support the hypothesis that sequence variation functions to avoid specific antibodies thereby contributing to persistence in the genital tract.

Lack of Association Between the S83I ParC Mutation in Mycoplasma genitalium and Treatment Outcomes Among Men Who Have Sex With Men with Nongonococcal Urethritis.

From February 2015 to October 2017, among 20 men who have sex with men with Mycoplasma genitalium-associated nongonococcal urethritis, 15% had macrolide resistance and S83I ParC mutations. Azithromycin followed by moxifloxacin cleared Mycoplasma genitalium in 2 of 2 with and 11 of 13 without S83I mutations. Dual failures were cleared after doxycycline. S83I mutations were not associated with moxifloxacin failure.

Resolution of Symptoms and Resumption of Sex After Diagnosis of Nongonococcal Urethritis Among Men Who Have Sex With Men.

BACKGROUND: Standard counseling at nongonococcal urethritis (NGU) diagnosis includes advice to abstain from sex for at least 7 days and until symptoms resolve. METHODS: From December 2014 to July 2018, we enrolled men who have sex with men and received azithromycin (1 g) for NGU at the Public Health-Seattle and King County STD Clinic. Over 12 weeks of follow-up, participants reported daily urethral symptoms and sexual activity on web-based diaries. Nongonococcal urethritis was defined as urethral symptoms or visible urethral discharge plus 5 or greater polymorphonuclear leukocytes per high-power field. Time of symptom resolution was defined as the first of 5 consecutive asymptomatic days. RESULTS: Of 100 participants with NGU and no Chlamydia trachomatis (CT)/Mycoplasma genitalium (MG) coinfection, 36 (36%), 22 (22%), and 42 (42%) had CT-NGU, MG-NGU, and non-CT/non-MG NGU, respectively. Among men with MG-NGU, 94% had a macrolide resistance mutation. For all etiologies, median time to symptom resolution after azithromycin was 7 days (95% confidence interval [CI], 5-9); 37% had symptoms lasting longer than 7 days. For men with CT-NGU, MG-NGU, and non-CT/non-MG NGU, median time to symptom resolution was 4 days (95% CI, 2-6; 16% >7 days), undefined days (95% CI, 7 to undefined; 60% >7 days), and 7 days (95% CI, 5-11; 46% >7 days), respectively. Median time to first sexual activity (any type) was 12 days (95% CI, 11-17); it was 16 days (95% CI, 12-18) to first urethral sexual exposure. Twenty-seven percent did not avoid urethral exposure for the recommended period. CONCLUSIONS: Counseling at NGU diagnosis should educate patients that symptoms may persist more than 7 days, particularly for non-CT NGU, and emphasize the rationale for the 7-day abstinence period.

Cross-sectional study of urethral exposures at last sexual episode associated with non-gonococcal urethritis among STD clinic patients.

OBJECTIVE: Although Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) are major causes of non-gonococcal urethritis (NGU), up to 50% of cases are of unknown aetiology. We sought to identify urethral exposures at last sexual episode associated with NGU and non-CT/non-MG NGU to identify anatomical sites from which aetiologically relevant micro-organisms may be acquired. METHODS: We enrolled STD clinic patients with and without NGU assigned male sex at birth and age ≥16 into a cross-sectional study. NGU was urethral symptoms or visible discharge plus ≥5 polymorphonuclear leucocytes without Neisseria gonorrhoeae. Urine was tested for CT and MG (Aptima). We used logistic regression to estimate the association between urethral exposures at last sex and NGU separately among cisgender men and transgender women who have sex with men (MSM/TGWSM) and cisgender men who have sex with women (MSW). RESULTS: Between 8 August 2014 and 1 November 2017, we enrolled 432 patients, including 183 MSM/TGWSM (118 NGU+, 65 NGU-) and 249 MSW (126 NGU+, 123 NGU-). The mean age was 34; 59% were white. CT and MG were detected in 72 (30%) and 49 (20%) NGU+ participants, respectively. Compared with MSM/TGWSM reporting only non-urethral exposures at last sex, those reporting insertive anal intercourse (IAI) only (adjusted OR (AOR)=4.46, 95% CI 1.09 to 18.19) and IAI with insertive oral sex (IOS) (AOR=7.88, 95% CI 2.67 to 23.26) had higher odds of NGU. MSM/TGWSM reporting IOS only had no significant increased odds (AOR=1.67, 95% CI 0.58 to 4.85). Compared with MSW whose only urethral exposure at last sex was vaginal sex (VS), MSW reporting IOS and VS had similar odds of NGU (OR=0.84, 95% CI 0.50 to 1.41). The results were similar for non-CT/non-MG NGU. CONCLUSIONS: Among MSM/TGWSM, IAI may lead to transmission of yet-unidentified rectal micro-organisms that cause non-CT/non-MG NGU, in addition to transmission of known pathogens. Sites of urethral exposure appear less important for understanding NGU risk among MSW due to minimal variation in behaviour.

Long Duration of Asymptomatic Mycoplasma genitalium Infection After Syndromic Treatment for Nongonococcal Urethritis.

BACKGROUND: Although Mycoplasma genitalium (MG) is an acknowledged cause of nongonococcal urethritis (NGU), access to diagnostic testing is limited. Syndromic management is common, yet little is known about natural history. METHODS: Between August 2014 and April 2016, 13 heterosexual men aged ≥16 years with MG were identified within a cohort study of men with and without NGU attending an urban sexually transmitted diseases clinic. Men had 6-7 monthly visits. NGU was defined as ≥5 polymorphonuclear leukocytes per high-power field on urethral Gram stain plus either visible urethral discharge or urethral symptoms. Men with NGU received 1 g of azithromycin. Men with persistent NGU received moxifloxacin 400 mg for 14 days. First-void urine was retrospectively tested for MG using transcription-mediated amplification. Resistance-associated mutations were detected by polymerase chain reaction (PCR) and sequencing. Organism load was determined by quantitative PCR. RESULTS: Sixty-two percent of MG-positive men had macrolide resistance-mediating mutations (MRMM) at enrollment; 31% had parC mutations (all outside the quinolone resistance-determining region). MG persisted after azithromycin in 7 men, 6 of whom had MRMM. The median duration of persistence in the absence of curative therapy was 143 days (range, 21-228). Five men experienced symptom resolution after azithromycin, but MG persisted for another 89-186 days before moxifloxacin. Organism load was somewhat lower in MRMM than wild-type infections (P = .16). CONCLUSIONS: The high prevalence of macrolide resistance and long duration of infection after symptom resolution highlights the need for diagnostic MG testing of men with NGU to direct therapy.

Primary Syphilis in the Male Urethra: A Case Report.

We documented urethral Treponema pallidum infection in a man with nongonococcal urethritis and a negative syphilis serology using broad-range bacterial polymerase chain reaction (PCR) and sequencing, targeted PCR, and immunofluorescence microscopy. He subsequently seroconverted for syphilis. Early syphilis may present as urethritis. Urethral T. pallidum shedding can occur before seroconversion.

Efficacy of standard therapies against Ureaplasma species and persistence among men with non-gonococcal urethritis enrolled in a randomised controlled trial.

OBJECTIVE: Ureaplasma urealyticum biovar 2 (UU-2), but not Ureaplasma parvum (UP), has been associated with non-gonococcal urethritis (NGU), but little is known about species-specific responses to standard therapies. We examined species-specific treatment outcomes and followed men with treatment failure for 9 weeks. METHODS: From May 2007 to July 2011, men aged ≥16 attending a sexually transmitted disease (STD) clinic in Seattle, Washington, with NGU (urethral discharge or urethral symptoms plus ≥5 polymorphonuclear leucocytes /high-powered field) enrolled in a double-blind, randomised trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice a day ×7 days) + placebo azithromycin. Ureaplasma were detected in culture followed by species-specific PCR. Outcomes were assessed at 3, 6 and 9 weeks. At 3 weeks, men with persistent Ureaplasma detection received 'reverse therapy' (e.g., active doxycycline if they first received active azithromycin). At 6 weeks, persistently positive men received moxifloxacin (400 mg×7 days). RESULTS: Of 490 men, 107 (22%) and 60 (12%) were infected with UU-2 and UP, respectively, and returned at 3 weeks. Persistent detection was similar for UU-2-infected men initially treated with azithromycin or doxycycline (25% vs. 31%; p=0.53), but differed somewhat for men with UP (45% vs. 24%; p=0.11). At 6 weeks, 57% of UU-2-infected and 63% of UP-infected men who received both drugs had persistent detection. Failure after moxifloxacin occurred in 30% and 36%, respectively. Persistent detection of UU-2 or UP was not associated with signs/symptoms of NGU. CONCLUSIONS: Persistent detection after treatment with doxycycline, azithromycin and moxifloxacin was common for UU and UP, but not associated with persistent urethritis. TRIAL REGISTRATION NUMBER: NCT00358462.

Suboptimal adherence to doxycycline and treatment outcomes among men with non-gonococcal urethritis: a prospective cohort study.

OBJECTIVE: Doxycycline, one of two recommended therapies for non-gonococcal urethritis (NGU), consists of a 7-day course of therapy (100 mg BID). Since suboptimal adherence may contribute to poor treatment outcomes, we examined the association between self-reported imperfect adherence to doxycycline and clinical and microbiologic failure among men with NGU. METHODS: Men aged ≥16 years with NGU attending a Seattle, WA, sexually transmitted diseases clinic were enrolled in a double-blind, parallel-group superiority trial from January 2007 to July 2011. Men were randomised to active doxycycline/placebo azithromycin or placebo doxycycline/active azithromycin. Imperfect adherence was defined as missing ≥1 dose in 7 days. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), and Ureaplasma urealyticum-biovar 2 (UU-2) using nucleic acid amplification tests. Clinical failure (symptoms and ≥5 PMNs/HPF or discharge) and microbiologic failure (positive tests for CT, MG, and/or UU-2) were determined after 3 weeks. RESULTS: 184 men with NGU were randomised to active doxycycline and provided data on adherence. Baseline prevalence of CT, MG and UU-2 was 26%, 13% and 27%, respectively. 28% of men reported imperfect adherence, and this was associated with microbiologic failure among men with CT (aRR=9.33; 95% CI 1.00 to 89.2) and UU-2 (aRR=3.08; 95% CI 1.31 to 7.26) but not MG. Imperfect adherence was not significantly associated with clinical failure overall or for any specific pathogens, but it was more common among imperfectly adherent men with CT (aRR=2.63; 0.93-7.41, p=0.07). CONCLUSIONS: Adherence may be important for microbiologic cure of select pathogens. Factors other than adherence should be considered for CT-negative men with persistent NGU.

Asymptomatic urethritis is common and is associated with characteristics that suggest sexually transmitted etiology.

We evaluated 236 asymptomatic men for urethritis, assessed sexual behaviors, and tested urine for pathogens. Asymptomatic urethritis was present in 38 (16.1%). Of these, nearly half (42.1%) had a previously unrecognized discharge on examination; only 18.4% had a known pathogen. Correlates included black race, anal intercourse, and number of sex partners.

Standard treatment regimens for nongonococcal urethritis have similar but declining cure rates: a randomized controlled trial.

BACKGROUND: Azithromycin or doxycycline is recommended for nongonococcal urethritis (NGU); recent evidence suggests their efficacy has declined. We compared azithromycin and doxycycline in men with NGU, hypothesizing that azithromycin was more effective than doxycycline. METHODS: From January 2007 to July 2011, English-speaking males ≥16 years, attending a sexually transmitted diseases clinic in Seattle, Washington, with NGU (visible urethral discharge or ≥5 polymorphonuclear leukocytes per high-power field [PMNs/HPF]) were eligible for this double-blind, parallel-group superiority trial. Participants received active azithromycin (1 g) + placebo doxycycline or active doxycycline (100 mg twice daily for 7 days) + placebo azithromycin. Urine was tested for Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Ureaplasma urealyticum biovar 2 (UU-2), and Trichomonas vaginalis (TV) using nucleic acid amplification tests. Clinical cure (<5 PMNs/HPF with or without urethral symptoms and absence of discharge) and microbiologic cure (negative tests for CT, MG, and/or UU-2) were determined after 3 weeks. RESULTS: Of 606 men, 304 were randomized to azithromycin and 302 to doxycycline; CT, MG, TV, and UU-2 were detected in 24%, 13%, 2%, and 23%, respectively. In modified intent-to-treat analyses, 172 of 216 (80%; 95% confidence interval [CI], 74%-85%) receiving azithromycin and 157 of 206 (76%; 95% CI, 70%-82%) receiving doxycycline experienced clinical cure (P = .40). In pathogen-specific analyses, clinical cure did not differ by arm, nor did microbiologic cure differ for CT (86% vs 90%, P = .56), MG (40% vs 30%, P = .41), or UU-2 (75% vs 70%, P = .50). No unexpected adverse events occurred. CONCLUSIONS: Clinical and microbiologic cure rates for NGU were somewhat low and there was no significant difference between azithromycin and doxycycline. Mycoplasma genitalium treatment failure was extremely common. Clinical Trials Registration.NCT00358462.

Ureaplasma urealyticum is associated with nongonococcal urethritis among men with fewer lifetime sexual partners: a case-control study.

BACKGROUND: Ureaplasmas have been inconsistently associated with nongonococcal urethritis (NGU). We evaluated the association of the newly differentiated species Ureaplasma urealyticum (UU) and Ureaplasma parvum (UP) with NGU using 2 separate control groups. METHODS: Case patients were men who attended a sexually transmitted disease (STD) clinic in Seattle, Washington, during the period 2007-2009 with NGU (defined as visible urethral discharge and/or ≥5 polymorphonuclear neutrophils per high-powered field; n = 329). Control subjects were STD clinic attendees (n = 191) and emergency department (ED) attendees (n = 193) without NGU. Polymerase chain reaction assays detected UU and UP in ureaplasma culture-positive urine. Multivariable logistic regression was used to assess the associations of UU and UP with NGU. RESULTS: UU was only marginally associated with NGU in aggregate multivariable analyses, irrespective of control group (adjusted odds ratio [aOR](STD-control), 1.6 [95% confidence interval {CI}, 0.9-2.8]; aOR(ED-control), 1.7 [95% CI, 0.97-3.0]). This association was significantly stronger when analyses were restricted to men with fewer lifetime sex partners (<10 vaginal partners: aOR(STD-control), 2.9 [95% CI, 1.2-6.7]; aOR(ED-control), 3.2 [95% CI, 1.3-7.6]; <5 vaginal partners: aOR(STD-control), 6.2 [95% CI, 1.8-21.0]; aOR(ED-control), 5.2 [95% CI, 1.3-20.2]). UP was not positively associated with NGU overall or among subgroups. CONCLUSIONS: The absence of an association of UU with NGU among men with more lifetime sex partners suggests that adaptive immunity may attenuate the clinical manifestation of UU infection. Similar relationships were not observed with UP, which suggests that it is not a urethral pathogen.

Demographic, behavioral, and clinical characteristics of men with nongonococcal urethritis differ by etiology: a case-comparison study.

BACKGROUND: Nongonococcal urethritis (NGU) is common, yet up to 50% of cases have no defined etiology. The extent to which risk profiles and clinical presentations of pathogen-associated and idiopathic cases differ is largely unknown. METHODS: Urethral swabs and urine specimens were collected from 370 NGU treatment trial participants who sought care at a sexually transmitted disease clinic in Seattle, WA from 2007 to 2009 and had a visible urethral discharge and/or microscopic evidence of urethral inflammation assessed by Gram-stain (≥5 polymorphonuclear leukocytes per high-powered field [PMNs/HPF]). Neisseria gonorrhoeae, Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Trichomonas vaginalis (TV), and Ureaplasma urealyticum (UU) were detected in urine, using nucleic acid amplification tests. Cases negative for all assessed pathogens were considered idiopathic. Bivariate and multivariate analyses identified clinical, sociodemographic, and behavioral factors associated with detection of specific pathogens. RESULTS: After excluding 3 participants with gonococcal infection, pathogens were detected in only 50.7% of the 367 eligible cases: CT in 22.3%, MG in 12.5%, TV in 2.5%, and UU in 24.0%, with multiple pathogens detected in 9.5%. In all, 3.5% of cases were negative for CT, MG, and TV but lacked speciated ureaplasma results. The remaining cases (45.8%) were considered idiopathic. Pathogen detection was associated with young age, black race, risky sexual behaviors, cloudy or purulent discharge, and visible discharge plus≥5 PMNs/HPF. In contrast, idiopathic cases were more likely to report prior NGU, were older and less likely to be black, or have an abnormal urethral discharge on examination, compared to all other cases. These cases were not associated with any high risk behaviors. CONCLUSIONS: NGU is a heterogeneous condition. Pathogen detection was associated with a variety of traditional risk factors and clinical features; whereas, idiopathic cases tended to be diagnosed among lower-risk men.