Genitourin Med: first published as 10.1136/sti.62.5.329 on 1 October 1986. Downloaded from

Genitourin Med 1986;62:329-332

Persistent due to Ureaplasma urealyticum in conjugal or stable partnerships

0 P ARYA* AND B C PRATTt

From the *Department of Genitourinary Medicine, Royal Liverpool Hospital, and the tDepartment of Medical Microbiology, University ofLiverpool, Liverpool

SUMMARY A study of four conjugal partnerships is described in which the male partners pre- sented with persistent or recurrent non-gonococcal, non-chlamydial, but ureaplasma positive urethritis. Resolution ofsymptoms and signs in the male partners was achieved only after treatmentto eliminate Ureaplasma urealyticum from both partners.

Introduction Patients, materials, and methods Ofthe mycoplasmal flora, hominis and Between July and December 1984, four men presented Ureaplasma urealyticum are the most to the department of genitourinary medicine of the commonly isolated from the human genital tract in the Royal Liverpool Hospital because of persistent or presence or absence of disease. Though the aetiology recurrent urethral discharge or urinary symptoms, of non-gonococcal urethritis in men has not been despite treatment with various courses ofantibiotics by finally settled, M hominis has largely been dismissed their general practitioners or investigations and further as having no role in this disease. Uurealyticum, on the treatment by urologists, or both. They were all seen by other hand, may cause urethritis according to some the same clinician (OPA) after whose persuasion the http://sti.bmj.com/ workers,'2 but only in a small proportion of people female partners of the patients also attended. from whom the organism can be isolated.3 Attempts to History and clinical examination included explain this phenomenon by quantitative studies4 have demographic data, past history, relevant history of provided conflicting results. In a detailed review, exposure, details of treatment already received, and Taylor-Robinson and McCormack considered other symptoms and signs. explanations, including the possibility that only certain serotypes of Uurealyticum may be pathogenic or that SPECIMENS TAKEN on September 23, 2021 by guest. Protected copyright. the organism may be of low invasiveness, and hence Men clinically recognisable may result in only a Urethral specimens were collected with plastic loops small proportion of exposed men.' No single explana- for urethral smear for Gram staining and culture for tion has yet proved satisfactory, however, and until the Neisseria gonorrhoeae. Specimens for aetiological role of U urealyticum in an individual trachomatis, , and virus patient is better defined, the indications for treatment were obtained with swabs made of sterile plain cotton will remain unclear, as will the optimum treatment and wool on a thin metal wire (Medical Wire Equipment the need for contact tracing. Co, Corsham, Wiltshire) inserted 3-5 cm into the Our recent experience prompted us to undertake an urethra and rotated several times. Non-gonococcal investigation of men with persistent or recurrent urethritis was diagnosed if five or more urethritis and their female partners to try to clarify the polymorphonuclear leucocytes were seen in a high situation concerning its cause and treatment power field (magnification x 1000), Gram negative diplococci were not seen, and culture for Neisseria gonorrhoeae gave negative results. Ifchronic prostatitis Address for reprints: Dr 0 P Arya, Departnent of Genitourinary was considered to be a possibility, prostate examina- Medicine, Royal Liverpool Hospital, Prescot Street, Liverpool L7 8XP tion and tests were carried out using the segmented culture technique described by Meares and Stamey5 Accepted for publication 29 January 1986 and Stamey.6 329 Genitourin Med: first published as 10.1136/sti.62.5.329 on 1 October 1986. Downloaded from

330 O P Arya and B C Pratt Women orally twice daily for 10 days. Details of the times of Specimens were collected with cotton wool swabs taking the tablets and their relation with food were from the urethra and cervix for smears for Gram stain- emphasised. ing and for culture for N gonorrhoeae and mycoplasmas, and from the cervix only for culture for Results C trachomatis. Swabs from the vaginal vault instead of the cervix were obtained from one patient who had Three ofthe men (a businessman, a doctor, and a fire- undergone hysterectomy. High vaginal swabs were man) were married and one (a health inspector) was also obtained for culture for Candida albicans and single but contemplating marriage. Their female . partners included a teacher, a doctor, a sales assistant, Specimens of blood were taken from men and and a full time housewife. women for serology tests. All men at the time of first attendance were experiencing urethral discharge or dysuria, or both; the LABORATORY INVESTIGATIONS women, however, were asymptomatic. None of the Culture methods women had received an during the preceding Specimens were inoculated directly on to modified six weeks. All men and women had negative cultures Thayer-Martin medium forculture forNgonorrhoeae. forNgonorrhoeae, C trachomatis, M hominis, and T Swabs for culture for C trachomatis, mycoplasmas, vaginalis, butpositive cultures for Uurealyticum. The and were placed in their respec- numbers of U urealyticum in the men ranged from 5 x tive transport media and either processed immediately 105 to 5 x 107 ccu/ml and in the women from 5 x 102 to or stored frozen at -70°C pending investigation. 5 x 105 ccu/ml. Cand albicans was isolated from one Material for C trachomatis isolation was inoculated female patient. None of the men showed evidence of on to cover slip cultures of cycloheximide treated chronic prostatitis. McCoy cells. Specimens in A3xB transport medium7 As the clinical features and laboratory findings ofall for culture of mycoplasmas or ureaplasmas were four couples were broadly similar, only one couple is inoculated into and then serially diluted in ten fold described in detail. A 28 year old man had been steps in Hayflick type broths. Broths for growth of U experiencing dysuria intermittently for one year. His urealyticum were adjusted to pH 6X0 and contained general practitioner, after unsuccessfully treating him 1% (w/v) urea, those for growth of M hominis were with several courses ofoxytetracycline, referred him to adjusted to pH 7X4 and contained 1% (w/v) arginine a urologist. The urologist found his prostate and intra- dihydrochloride. Both broths contained 0-002% (w/v) venous urogram to be normal, but urethroscopy phenol red indicator.8 After incubation at 37°C, broths showed a reddened urethra for which two further http://sti.bmj.com/ showing colour change were subcultured to A7 agar7 courses ofoxytetracycline were prescribed. The condi- and mycoplasma agar to confirm the presence of tion recurred yet again and the patient was then ureaplasmas or mycoplasmas, or both. Specimens for referred to one of us (OPA). A detailed interview herpes simplex isolation were inoculated into tubes of showed that this patient's symptoms usually recurred Vero tissue culture. about a week after sexual intercourse with his finacee, with whom he had had a stable relationship for seven

Sensitivities to years. The table shows the sequence ofevents and the on September 23, 2021 by guest. Protected copyright. Minimum inhibitory concentrations (MICs) of each management of the couple after that interview. ureaplasma isolate were measured against oxyte- As the man had already failed to respond to oxyte- tracycline, erythromycin, and doxycycline and were tracycline, he was treated with erythromycin 250 mg carried out in duplicate. The tests were performed in four times daily for one week, and the couple were microtitre well plates and used a standardised advised to abstain from sexual intercourse during the ureaplasma inoculum of 103 - 104 colour changing course of treatment. Whereas the man remained units (ccu)/ml. The antibiotics were diluted in two fold ureaplasma negative after completing the course of steps in urea broth. Plates were incubated at 37°C until erythromycin, the woman was persistently positive, colour changes in the wells were complete, the MIC despite receiving a total of two courses of oxyte- being recorded as the concentration of antibiotic just tracycline and one oferythromycin (see table). At this preventing a colour change. stage they were allowed and indeed encouraged to resume intercourse, which they did. Exactly seven TREATMENT days later the man's dysuria recurred, a Gram stained The following regimens were used: (1) oxytetracycline urethral smear showed excessive leucocytes, and a or erythromycin 250 mg orally four times daily for urethral swab was positive for ureaplasmas. Both seven days, (2) oxytetracycline or erythromycin 500 partners were then treated with doxycycline 200 mg mg orally four times daily for 10 days, or (3) initially followed by 100 mg twice daily for 10 days. doxycycline 200 mg initially, followed by 100 mg The man has remained asymptomatic ever since, and Genitourin Med: first published as 10.1136/sti.62.5.329 on 1 October 1986. Downloaded from

Persistent urethritis due to Ureaplasma urealyticum in conjugal or stable partnerships 331 TABLE Sequence ofevents and management ofone couple

Date Man Date Woman 1984 1984 23 July Dysuria 25 July No symptoms Urethritis absent (last urinated one Clinically normal hour before) Neisseria gonorrhoeae \ Neisseria gonorrhoeae f Chlamydia trachomatis> negative cultures Trichomonas vaginalis , negative cultures Herpes simplex virus J Candida albicans | Mycoplasma hominis J Ureaplasma urealyticum positive 30 July Dysuria Urethritis present (last urinated four hours before) Mycoplasma hominis negative Ureaplasma urealyticum positive (5 x 1 ccu/ml) Erythromycin 250 mg four times 1 Aug Oxytetracycline 250 mg four daily for 7 days times daily for 7 days 10 Aug No symptoms 28 Aug Urethritis absent 22 Aug U urealyticum positive (5 x 101 ccu/ml) U urealyticum negative 29 Aug Erythromycin 250 mg four times daily for 7 days 10Oct No symptoms Urethritis absent 3 Oct U urealyticum positive (5 x 103 ccu/ml) U urealyticum negative 15 Oct U urealyticum positive (5 x 105 ccu/mI) Oxytetracyline 500 mg four times daily for 10 days 6 Nov No symptoms Urethritis absent U urealyticum negative 7 Nov U urealyticum positive (5 x 103 ccu/ml) 8 Dec Sexual intercourse resumed http://sti.bmj.com/ 18 Dec Dysuria for three days Urethritis present U urealyticum positive (5 x IC4 ccu/nl) Doxycycline 200 mg initially then 19 Dec Doxycycline 200 mg initially then 100 mg twice daily for 10 days 100 mg twice daily for 10 days 1985

8Jan No symptoms on September 23, 2021 by guest. Protected copyright. Urethritis absent U urealyticum negative 16 Jan U urealyticum negative 18 Feb No symptoms Urethritis absent U urealyticum negative 27 Feb U urealyticum negative follow up swabs from both ofthem 1, 2, and 9 months cate U urealyticum in any of the patients so treated. after treatment have remained negative for Erythromycin gave similar results in women: two were ureaplasmas. treated with erythromycin base 250 mg four times Similarly, the symptoms and signs in the other three daily for seven days, but both were still harbouring U men and the infective agent (U urealyticum) in these urealyticum after completing these courses. This con- men and their sexual partners did not clear until both trasted with the man in whom the organism was cleared partners had been adequately treated, which suggests after treatment with erythromycin 250 mg four times that U urealyticum was the cause of the recurrent daily for seven days. He remained free ofthe organism urethritis in these men. for over four months, at which time he was considered Oxytetracycline 250 mg four times daily for seven to be reinfected. days (in one man and three women) or 500 mg four The MICs for these strains, whether isolated before times daily for 10 days (in one woman) failed to eradi- or after treatment, were typically 2-4 mg/l for oxyte- Genitourin Med: first published as 10.1136/sti.62.5.329 on 1 October 1986. Downloaded from

332 O P Arya and BC Pratt tracycline and 4 mg/l for erythromycin. The same The partnerships presented here were not inves- strains, when tested against doxycycline, gave MICs tigated for anaerobic organisms or for Mycoplasma in the range 0-125-0-5 mg/l. Doxycycline in the genitalium'4 as possible causes ofmale urethritis, and dosage regimen used(200 mg initially followed by 100 these organisms should be borne in mind in interpret- mg twice daily for 10 days) eradicated the organism in ing the outcome oftreatment, as should the possibility all cases. ofan as yet unknown infective cause. Nevertheless, we believe our results serve to emphasise the importance Discussion of considering U urealyticum as a cause of persistent non-gonococcal, non-chlamydial urethritis in men, Our findings, which suggest a causative role for U and in addition point to the necessity for adequate urealyticum in the recurrent urethritis experienced by treatment ofboth partners ofthe conjugal relationship a selected group ofmen in stable conjugal partnerships, to eliminate the signs and symptoms of the disease in are similar to those in the one case described by Ford the man. and Henderson,'0 except that in our investigation we were not able to serotype the isolates. Because of the ubiquitous nature of Uurealyticum, we agree with the We thank Mrs Karen Scott for her invaluable technical view that routine swabbing of patients for these help throughout this investigation. organisms is not reallyjustifiable. I Nevertheless, part ofthat same view suggested that Uurealyticum should References be considered as a possible aetiological agent of non- gonococcal urethritis in cases that fail to clear with 1. Taylor-Robinson D, McCormack WM. The genital tetracycline because tetracycline resistant strains are mycoplasmas.N EnglJ Med 1980;302:1003-10. that the 2. Taylor-Robinson D, Csonka GW, Prentice MJ. Human known to be circulating.'2 Our findings suggest intraurethral inoculation of ureaplasmas. Q J Med 1977; management of such patients should be extended to 46:309-26. include their female partners. The optimum treatment 3. Coufalik ED, Taylor-Robinson D, Csonka GW. Treatment of regimen for U urealyticum infection is not known, but nongonococcal urethritis with rifampicin as a means ofdefining in this the role of Ureaplasma urealyticum. British Journal of our limited experience presented study does Venereal Diseases 1979;55:36-43. suggest that oxytetracycline or erythromycin 250 mg 4. Hunter JM, Smith IW, Peutherer JF, MacCauley A, Tauch S, four times daily for one week are unsatisfactory, at Young H. Chlamydia trachomatis and Ureaplasma least in women. This was perhaps surprising in view of urealyticum in men attending a sexually transmitted diseases the observed MICs of and clinic. British Journal of Venereal Diseases 1981;57:130-3. oxytetracycline 5. Meares EM Jr, Stamey TA, Bacteriological localisation pat- erythromycin for the U urealyticum isolates as on the terns in bacterial prostatitis and urethritis. Investigative Urol- http://sti.bmj.com/ basis of these results no strain could be considered to ogy 1968;5:492-518. be resistant. Relative resistance of U urealyticum to 6. Stamey TA. Prostatitis. JRoy Soc Med 1981;74:22-40. tetracyclines has, however, been correlated with an 7. Shepard MC, LuncefordCD. Differential agarmedium(A7) for identification of Ureaplasma urealyticum (human MIC of 4-8 mg/l,8 and this could possibly explain the T mycoplasmas) in primary cultures ofclinical material. J Clin failure of oxytetracycline to eradicate the organism Microbiol 1976;3:613-25. from either the cervix or from the male urethra in 8. Mardh P-A. , , and mycoplasmas. In: Holmes KK, Mirdh P-A, Sparling PF, Wiesner PJ, eds. our patients. on September 23, 2021 by guest. Protected copyright. Sexually transmitted diseases. London: McGraw-Hill, In the case oferythromycin, the lower activity ofthis 1984:829-56. antibiotic at an acid pH has been suggested as a reason 9. Taylor-Robinson D, Furr PM. The static effect of rosaramicin for its failure to eradicate U urealyticum from the on Ureaplasma urealyticum and the development of antibiotic , despite its effectiveness in removing the resistance. JAntimicrob Chemother 1982;10.185-91. 10. Ford DK, Henderson E. Non-gonococcal urethritis due to organism from the male urethra.'3 This suggestion T-mycoplasma (Ureaplasma urealyticum) serotype 2 in a would seem to be borne out by our results, as in the conjugal sexual partnership. British Journal of Venereal case of the one couple detailed in the table the man's Diseases 1976;52:341-2. urethritis was successfully treated with erythromycin 11. Taylor-Robinson D, McCormack WM. The genital mycoplasmas. N Engl J Med 1980;302:1063-7. and he remained free of symptoms until reinfected by 12. McCormack WM, Taylor-Robinson D. The genital his sexual partner. This occurred despite the observed mycoplasmas. In: Holmes KK, M&rdh P-A, Sparling PF, low MICs of erythromycin for the original isolates Wiesner PJ, eds. Sexually transmitted diseases. London: from both the man and woman. Treatment with McGraw-Hill, 1984:408-21. 13. Russo ME, Thompson MIB. Pharmacology of drugs used in doxycycline was completely effective in all patients, venereology. In: Holmes KK, Mirdh P-A, Sparling PF, however, both men and women, and in none of the Wiesner PJ, eds. Sexually transmitted diseases. London: couples so treated has the man showed signs ofrelapse, McGraw-Hill, 1984:891-922. nor has any of the couples shown evidence of 14. Taylor-Robinson D, Furr PM, Hanna NF. Microbiological and serological study of non-gonococcal urethritis with special recolonisation with Uurealyticum during nine months reference to . Genitourin Med of follow up. 1985;61:319-24. I