Chlamydia-negative Non-gonococcal Urethritis Research Articles

Editorial Commentary:Nongonococcal Urethritis and Antibiotic‐ResistantMycoplasma genitaliumInfection

The finding of Mycoplasma genitalium in the urethra of men with nongonococcal urethritis (NGU) [1, 2] and its later unequivocal and significant association, not only with NGU as a whole, but also with chlamydia-negative NGU [3], has at least partially filled the void in our understanding of the etiology of NGU in men. Although tetracyclines (in particular, doxycycline) were the antibiotics of choice for the treatment of NGU before the finding of M. genitalium, it has become apparent that they are not the antibiotics of choice for M. genitalium-associated urethritis. Indeed, this mycoplasma was often found to persist in the urethra of men treated with tetracyclines [4, 5], and it became clear that tetracycline treatment was responsible for some, if not all, cases of persistent or chronic NGU. Fortunately, it seemed, azithromycin was available for the treatment of Chlamydia trachomatis infection; azithromycin was more active in vitro than the tetracyclines, had superior mucosal cell penetration, and could be given effectively as a single dose. When azithromycin was given to M. genitaliumpositive men with urethritis, the organisms were eliminated from the genital tracts of almost all patients; the patients responded accordingly, without the development of chronic disease [6], In hindsight, this should not have been surprising, because the in vitro activity of tetracylines against M. genitalium is poor, and the macrolides have far greater activity, with azithromycin being the most effective [7]. Interestingly, a similar antibiotic profile is seen with Mycoplasma pneumoniaey which is closely related antigenically to M. genitalium. Thus, the notion that NGU of chlamydial or mycoplasmal etiology can be dealt with by a single antibiotic, namely azithromycin, has had considerable clinical appeal. Admittedly, Ureaplasma species are not very susceptible to azithromycin; however, that aside, our understanding of the etiology of NGU and the development of a rational treatment for the disease had progressed. Now, we learn that strains of M. genitalium have developed (and, doubtless, continue to develop) resistance to azithromycin through mutations in region V of the 23S ribosomal RNA gene [8]. This is a potentially serious matter because of the possibility that extensive use of single-dose azithromycin for treatment of G trachomatis or for presumptive treatment of NGU might lead to the development of widespread resistance in M. genitalium strains and, therefore, to worsening disease in both men and women. What measures might be taken to prevent an increase in the prevalence of resistance to azithromycin? Clinicians should realize that single-dose therapy for NGU may create the problem of resistance and that spreading the dosage over several days may overcome the problem. If this is not effective and there is evidence that chronic disease is developing, thought should be given to administering a course of moxifloxacin [9], which has potent activity against M. genitalium [10]. Hopefully, in the future, most clinicians will be able to rely on the assistance of laboratory analysis, which will enable them to make a sensible choice of antibiotic and dosage. The treatment of NGU in patients who are also HIV positive is also uncharted territory. There is some evidence that such subjects are more susceptible to infection due to M. genitalium than are individuals who are HIV negative [11]. Furthermore, animal experiments have clearly shown that a fully functioning immune system is required for the elimination of mycoplasmas (as opposed to simply suppression of their growth) after antibiotic therapy [12]. It remains to be seen whether this is another hurdle that has to be faced in the Received 8 September 2008; accepted 8 September 2008; electronically published 6 November 2008. Reprints or correspondence: Dr. David Taylor-Robinson, 6 Vache Mews. Vache Ln., Chalfont St. Giles. Bucks HP8 4UT, United Kingdom (dtr@vache99.freeserve.co.uk). Clinical Infectious Diseases 2008; 47:1 554-5 © 2008 by the Infectious Diseases Society of America. All rights reserved. 1 058-4838/2008/471 2-0009$1 5.00 D0I: 10.1086/593189

How men with non-chlamydial, non-gonococcal urethritis are managed in Australasia

The aim of this study was to ascertain how sexual health physicians in Australia and New Zealand manage men with chlamydia-negative non-gonococcal urethritis (NGU), particularly in relation to the notification of their female sexual partners. In July 2006, a cross-section survey was sent out to all the members of the Australasian Chapter of Sexual Health Medicine. Seventy-three percent of sexual health physicians believed that female partners of men who present with chlamydia-negative NGU were at risk of adverse reproductive health outcomes. At least 62% usually initiated some form of partner notification of female partners of men with chlamydia-negative NGU. However, only 19% (21/111) of sexual health physicians routinely tested for, and only 65% sometimes tested for, pathogens other than Neisseria gonorrhoeae and Chlamydia trachomatis in men presenting with NGU. These included Mycoplasma genitalium, herpes simplex virus, ureaplasma species, Trichomonas vaginalis and adenoviruses.

50. THE MANAGEMENT OF MEN WITH ACUTE CHLAMYDIA-NEGATIVE NON-GONOCOCCAL URETHRITIS: A LACK OF CONSENSUS AMONG AUSTRALIAN SEXUAL HEALTH PHYSICIANS

Objective: In clinical practice, chlamydia-negative non-gonococcal urethritis (NGU) is a common but poorly understood condition. The purpose of this study was to determine how Australian sexual health physicians manage men with this condition. Methods: In July 2006, a survey was mailed to all members of the Australasian Chapter of Sexual Health Medicine. Results: Of 166 surveys mailed out, 111 (67%) were returned completed. The majority of sexual health physicians (73%, n�=�81) indicated that they believed that female partners of men with acute chlamydia-negative NGU were at risk of adverse reproductive health outcomes. However, only 19% (n�=�21) routinely tested men with acute NGU for pathogens other than Neisseria gonorrhoeae and Chlamydia trachomatis. Most commonly, this was for M. genitalium (n�=�16). While 68% of respondents believed that M. genitalium was a cause of acute NGU, only 27% had access to testing for this organism. Other pathogens that were sometimes tested for included herpes simplex virus, Trichomonas vaginalis and adenovirus. Over half of sexual health physicians indicated that they would usually initiate notification of female sexual partners of men presenting with acute NGU, even before confirmatory test results were available. Conclusion: There are substantial differences in how acute, chlamydia-negative NGU is managed by Australian sexual health physicians. In part, these may relate to differences in beliefs around which pathogens are responsible for this condition and the availability of testing for particular pathogens. Notification of female partners is commonplace, even though the underlying cause of urethritis in affected men appears to be poorly defined.

Adenoviral non-gonococcal urethritis

Adenoviruses infect mucous membranes, including - on rare occasions - the urethra. Adenoviruses should therefore be considered as yet another cause of chlamydia-negative non-gonococcal urethritis. The following case illustrates the dilemma posed in a patient with conjunctivitis and urethritis.

Diagnostic assessment of Mycoplasma genitalium in culture-positive women.

Detection of Mycoplasma genitalium-mediated, chlamydia-negative nongonococcal urethritis and other M. genitalium-linked infectious etiologies has been very challenging. Although M. genitalium is considered a leading cause of genitourinary symptoms in men and women, extreme difficulties in its cultivation due to its highly fastidious nature and the lack of routine and effective diagnostic tests have slowed the generation of clinical data which directly implicate the presence of M. genitalium in disease pathogenesis. In this study, we compared enzyme-linked immunosorbent assays (ELISAs) and immunoblot and PCR assays in M. genitalium culture-positive women over 1 to 3 years of clinical visits to determine the usefulness of independent diagnostic strategies. Furthermore, the value of combinatorial diagnostic assessments is described, which provides insights into the dynamics of M. genitalium-host interactions. Overall, we show that neither ELISA nor PCR, alone or in combination, provides the sensitivity required to confidently predict the existence of viable M. genitalium organisms in cervical and vaginal samples. Additionally, culture-positive women exhibited a range of antibody responsiveness to M. genitalium based upon ELISA and immunoblot assessments, indicating immune diversity among this high-risk population.

Anaerobic bacteria in men with urethritis

Aim Investigation of the urethral flora in men with urethritis, with particular reference to anaerobic bacteria.Methods Multiple cultures were performed on three urethral samples from 110 men attending the STD Clinic of the School of Medicine in Seville: 35 with no evidence of urethritis (control group), and 75 with urethritis (17 gonococcal urethritis (GU) and 58 non-gonococcal urethritis (NGU)). In the 58 men with NGU, Chlamydia trachomatis was isolated in 16 (27.5%), Ureaplasma urealyticum in 18 (31%), Trichomonas vaginalis in two (3.4%) and no pathogens were isolated in the remaining 22 (38%) patients.Results Aerobic flora, mainly Staphylococcusspp., were isolated less frequently (41%) in patients with GU than in the control group (80%), and those with NGU (72%). Anaerobic flora were isolated in 62% of patients, with similar isolation rates in each group. Gram-negative anaerobes were more frequently isolated in men with urethritis, especially NGU, compared to controls (P<0.05). Prevotellaspp. and Bacteroidesspp. were significantly more frequently isolated in patients with NGU, including Chlamydia-negative NGU. Fusobacteriumspp. were more frequent in the Chlamydia-positive NGU than in the controls (P<0.05). P. magnus was the most frequent anaerobic species found in the control group, while P. prevotii was most frequently seen in the urethritis group. B. ureolyticus, P. prevotii and P. tetradius were more frequent on the NGU group (P<0.05). B. ureolyticus was commoner in patients with Chlamydia-negative NGU, while P. tetradius and P. asaccharolytica was commoner in those where C. trachomatis was isolated than in the control group.Conclusion Urethral microflora isolated showed ten bacterial genus and 25 different species of anaerobes. The spectrum of these microflora changed with the presence of urethritis and varied with its aetiology.

Sexually transmitted diseases in men who have sex with men. Acquisition of gonorrhea and nongonococcal urethritis by fellatio and implications for STD/HIV prevention.

Despite trends toward safer sex practices in homosexually active men, some such people remain at high risk for acquiring sexually transmitted diseases (STD). This study was designed to assess behavioral and demographic determinants of STD acquisition in men who have sex with men (MSM), to guide prevention interventions. A cross-sectional medical record review was undertaken of MSM who attended an urban STD clinic from January, 1993 through December, 1994. Gonorrhea, chlamydial infection, Chlamydia-negative nongonococcal urethritis (NGU), and newly documented human immunodeficiency virus (HIV) infection were analyzed in relation to demographic and behavioral variables. Among 1,253 MSM, 196 (15.6%) had nonchlamydial NGU, 105 (8.4%) had gonorrhea, 31 (2.5%) had chlamydial infection, and 162 (12.9%) had known or newly documented HIV infection. Known HIV infection was an independent predictor of urethral gonorrhea (odds ratio [OR] 2.3, 95% confidence interval [CI95] 1.2-4.8). Oral insertive intercourse was independently associated with urethral gonorrhea (OR 4.4, CI95 1.4-13.4) and nonchlamydial NGU (OR 2.2, CI95 1.3-3.7), and receptive anal intercourse was associated with newly documented HIV infection (OR 2.6, CI95 1.3-4.9). Neither number of sex partners nor condom use was associated with any incident STD outcome, including new HIV infection. MSM who attend STD clinics represent a subgroup of homosexually active men who remain at high risk for STDs, including HIV infection. Fellatio, commonly thought to be a "safe" sexual practice, is an independent risk factor for urethral gonorrhea and nonchlamydial NGU. A history of consistent condom use or of few sex partners should not dissuade clinicians from performing screening tests for HIV and other STDs. Repeated STD screening and counseling about safer sex are indicated for many HIV-infected MSM.

Urethral lymphocyte isolation in non-gonococcal urethritis.

A pilot feasibility study to investigate the local immune response in patients with non-gonococcal urethritis (NGU). Urethral lymphocytes were extracted from first void urine (FVU) of patients with non-gonococcal urethritis and gonorrhoea using magnetic beads coated with antibody against either the pan-T cell marker CD2 or to CD4. The CD2+ and CD4+ lymphocyte content of FVU were compared between chlamydia-positive and chlamydia-negative and between first and subsequent attacks of NGU. Median CD2+ lymphocyte content of FVU was significantly higher in cases of gonorrhoea and chlamydia-positive urethritis than in chlamydia-negative NGU. Median CD2+ lymphocyte content of FVU in chlamydia-negative NGU was 15.6 x 10(4), (n = 14 range 3.2-111) which was significantly lower than in chlamydia positive NGU (35.2 x 10(4), n = 18, range 7.4-390 p = 0.037) and gonorrhoea (67.7 x 10(4), n = 8 range 13-501, p = 0.019). Comparing the first with subsequent attacks of NGU, CD2+ cell numbers were greater in those presenting with their first episode of chlamydia-negative NGU (21.8 x 10(4), range 5.6-111) compared with those who had experienced NGU before (12.3 x 10(4), range 3.2-20.4, p = 0.033), but not in those presenting with chlamydia-positive NGU. There was no difference in CD4+ cells between any of the groups. The lower total lymphocyte content of subsequent attacks of chlamydia-negative NGU compared with the first attack chlamydia-positive and negative NGU suggests that a different aetiology may be operating in some of these patients. Sufficient lymphocytes can be isolated from the urethra in patients with NGU for studies of lymphocyte subsets to be carried out.

Detection of Mycoplasma genitalium from male patients with non-gonococcal urethritis by polymerase chain reaction

Mycoplasma genitalium causes urethritis in non-human primates, but studies on its pathogenicity in man have been hampered by the difficulty in isolating this oragnism in culture. We have used a specific polymerase chain reaction to examine the role of M. genitalium in non-gonococcal urethritis (NGU). Oligonucleotide primers were used to amplify a 281 bp of 140-KDa adhesin gene of M. genitalium. A characteristic PCR product was amplified, when M. genitalium DNA was template for the PCR. No amplified product was detected in Mycoplasma pneumoniae DNA, Mycoplasma hominis DNA or other bacterial DNAs. M. genitalium DNA was detected in urethral swabs from 17 (14.9%) of 114 men with NGU. Three (9.1%) of the 33 men with Chlamydia-positive NGU and 14 (17.3%) of the 81 with Chlamydia-negative NGU were positive for M. genitalium DNA, but 29 men without urethritis were negative. The prevalence of M. genitalium in NGU and in Chlamydia-negative NGU was significantly higher than that in the normal control. These findings suggest that M. genitalium would be a cause of NGU.

Chemotactic Activity of Urethral Secretions in Men with Urethritis and the Effect of Treatment

The chemotactic activity of urethral exudate and the effect of treatment were assessed in 67 patients with nongonococcal urethritis (NGU) or gonorrhea. All samples demonstrated chemotactic activity related to the number of neutrophils seen on Gram's staining of the urethral smear. Chemotactic activity decreased after treatment in patients with Chlamydia-positive NGU (mean +/- SE, 21.1 +/- 2.7 cells/high-power field [hpf] before treatment; 8.7 +/- 2.2 after treatment; P < .004) and gonorrhea (25.6 +/- 5.2 cells/hpf before treatment; 1.6 +/- 0.7 after treatment; P < .015). Chemotactic activity increased again in Chlamydia-positive NGU patients to 21.0 +/- 3.3 cells/hpf (P < .05) 2-3 weeks after cessation of therapy in the absence of demonstrable infection or further intercourse. There was no significant decrease in chemotactic activity after therapy in the Chlamydia-negative NGU or persistent urethritis groups. These data suggest a previously unrecognized persistent chemotactic stimulus in urethral exudate from patients with urethritis.

Anaerobic Vaginosis: Study of Male Sexual Partners

One hundred male sexual partners of women with anaerobic vaginosis (AV) were screened for the presence of sexually transmitted diseases (STD). Thirty male partners had evidence of non-gonococcal urethritis (NGU), compared to 5 in the control group (P less than 0.05). Chlamydia trachomatis was isolated from 14 male partners, compared to 3 in the control group. Forty-five male partners required treatment for STDs, compared to 11 in the control group (P less than 0.02). Nine (40%) male partners with chlamydia-negative NGU were successfully treated with metronidazole alone while 10 required Deteclo in addition. There was no significant association between Bacteroides ureolyticus and chlamydia-negative NGU. Screening of male partners resulted in the treatment of STDs in 62 additional patients who would have otherwise not received treatment. The results suggest that examination of male partners of women with AV results in an increased yield of STD diagnoses.

Roxithromycin and erythromycin in chlamydia-negative non-gonococcal urethritis.

The clinical efficacy and safety of roxithromycin 300 mg once a day was compared with that of erythromycin 500 mg twice a day in 87 men with chlamydia-negative non-gonococcal urethritis. In the roxithromycin group the clinical efficacy rate was 88% on day 8 and between 78% and 84% on day 21. In the erythromycin group the clinical efficacy rate was 98% on day 8 and 86% on day 21, a non-significant difference. Side effects were mainly gastrointestinal, occurring in about 15% of patients receiving each treatment.

PREVALENCE OF MYCOPLASMA GENITALIUM DETERMINED BY DNA PROBE IN MEN WITH URETHRITIS

The prevalence of urethral infection with Mycoplasma genitalium was determined by use of a DNA probe in 203 men attending a sexually transmitted disease clinic. M genitalium was detected in 3 (14%) of 21 with acute gonococcal urethritis; 3 (10%) of 30 with acute chlamydia-positive non-gonococcal urethritis (NGU); 4 (13%) of 31 with acute chlamydia-negative NGU; 10 (27%) of 37 with persistent or recurrent NGU; and 10 (12%) of 84 with no urethritis. The organism was more prevalent in homosexual (11 [30%] of 37) than in heterosexual men (19 [11%] of 166; p=0·009). These data do not support an important aetiological role for M genitalium in acute urethritis, but suggest that it may account for some cases of NGU that become persistent or recurrent. The higher prevalence of urethral infection in homosexual men suggests that M genitalium may reside in the gastrointestinal tract.

Chlamydia trachomatis genital infections.

The prevalence and clinical features of Chlamydia trachomatis infection were studied in men with nongonococcal urethritis (NGU), in their female sexual partners, and in other women. Of 92 patients with NGU, 36 (39%) were chlamydia-positive; although all had symptoms of urethritis, fewer than half had evident discharge. Clinical features of chlamydia-positive and chlamydia-negative NGU were indistinguishable. Most female contacts of chlamydia-positive patients with NGU were infected with C. trachomatis; contacts of chlamydia-negative patients with NGU seldom harboured chlamydia. Inflammatory and erosive changes were equally common in the uterine cervix of chlamydia-positive and chlamydia-negative women, although almost half of infected cases had no clinical signs of infection and no specific symptoms. In such women the present unavailability of sensitive screening techniques is a major obstacle to the effective control of chlamydial infection.

Ureaplasma urealyticum and Mycoplasma hominis in chlamydial and non-chlamydial nongonococcal urethritis.

Urethral specimens from 726 patients with nongonococcal urethritis (NGU) were examined for Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis. Chlamydiae were isolated from 35.9% of ureaplasma-positive patients and from 36.5% of ureaplasma-negative patients. Ureaplasmas were isolated from 52.5% of chlamydia-positive patients and from 53.1% of chlamydia-negative patients, an observation which contrasts with that of some workers who have suggested that ureaplasmas are significantly associated with chlamydia-negative NGU. Furthermore, the numbers of ureaplasmas isolated from patients who did or did not harbour chlamydiae were not significantly different nor was there a particular association of ureaplasmas with chlamydia-negative NGU in patients experiencing their first episode of disease. In addition, M. hominis was not isolated more frequently from those from whom chlamydiae were or were not isolated. The only significant associations were the isolation of M. hominis from patients who were ureaplasma-positive and of ureaplasmas from those who were M. hominis-positive. These findings do not necessarily mitigate against ureaplasmas being responsible for some cases of chlamydia-negative NGU.

Examination of men with nongonococcal urethritis and their sexual partners for Chlamydia trachomatis and Ureaplasma urealyticum.

Chlamydia trachomatis was recovered from 39 (52%) of 75 men who had nongonococcal urethritis and from 28 (37%) of their sexual partners. Of the partners of men with Chlamydia-positive nongonococcal urethritis, 64% excreted Chlamydia, compared with 8% of the partners of men with Chlamydia-negative nongonococcal urethritis. In contrast, an apparently sexual mode of transmission was not observed with Ureaplasma urealyticum. Rates of recovery of U. urealyticum from men with nongonococcal urethritis whose cultures were Chlamydia-positive and those whose cultures were Chlamydia-negative were the same. Significant seroconversion was detected bythe single-antigen immunofluorescence test in about 50% of patients who had Chlamydia-postive cultures.

Etiology of Nongonococcal Urethritis

Chlamydia trachomatis was isolated from the urethra from 48 (42 per cent) of 113 men with non-gonococcal urethritis (NGU), four (7 per cent) of 58 without overt urethritis, and 13 (19 per cent) of 69 with gonorrhea. Postgonococcal urethritis (PGU) developed in 11 of 11 men who had C. trum antibody to C. trachomatisis developed. The immunotype specificity of chlamydial antibody corresponded to the immunotype isolated. Among culture-negative patients. chlamydial antibody prevalence correlated with the number of past sex partners and with previous NGU. Herpesvirus hominis, cytomegalovirus, T-mycoplasma, Mycoplasma hominis, other bacteria, and Trichomonas vaginalis were not implicated in NGU or PGU. Thus, the cause of chlamydia-negative NGU and PGU remains obscure. Endocervical chlamydia were found in sex partners of 15 of 22 NGU patients with and two of 24 without urethral chlamydial infection (p smaller than 0.001). Tetracycline treatment of both sex partners appears advisable.