William R. Bowie

Etiology of nongonococcal urethritis. Evidence for Chlamydia trachomatis and Ureaplasma urealyticum.

Chlamydia trachomatis, Ureaplasma urealyticum (T-mycoplasma), and Hemophilus vaginalis have previously been considered possible etiological agents in nongonococcal urethritis (NGU). In this study, current C. trachomatis infection was confirmed by culture and (or) micro-immunofluorescence serology in 26 of 69 men experiencing afirst episode of NGU, and 1 of 39 with no urethritis. Serum IgM immunofluorescent antibody to chlamydia was demonstrated in 16 of 20 men with chlamydia culture positive NGU, and 3 of 39 with chlamydia culture negative NG, and none of 34 with no urethritis. 9 of 10 culture positive men with less than or equal to 10 days symptoms developed immunofluorescent antibody seroconversion in paired sera. U. realyticum was isolated significantly more often and in significantly higher concentration from first voided urine from chlamydia-negative cases of NGU than from chlamydia-positive NGU. Ureaplasmacidal antibody titers increased fourfold in six men, four of whom had negative cultures for for unreaplasma. H. vaginalis was isolated from c9 of 33 men with no urethritis and 2 of 69 with NGU. C. trachomatis is susceptible, and U. urealyticum is resistant to sulfonamides. A 10-day course of sulfisoxazole therapy produced improvement in 13 of 13 chlamydia-positive, unreaplasma-negative, and only 14 of 29 chlamydia-negative, unreaplasma-positive NGU cases (P less than 0.002). Thus, culture, serology, and response to therapy support the etiologic role of chlamydia in NGU. Quantitative culture and response to therapy suggest U. unrealyticum may cause many cases of chlamydia-netative NGU.

Therapy for Nongonococcal Urethritis: Double-Blind Randomized Comparison of Two Doses and Two Durations of Minocycline

We treated 289 men who had nongonococcal urethritis with minocycline, 100 mg once or twice daily for 7 to 21 days. After 21 +/- 7 days, urethritis persisted or recurred in 31 (27%) of 114 given 7-day therapy and only nine (8%) of 110 given 21-day therapy (p = 0.0005). However, by 49 +/- 14 days, the cumulative percent rate of failure was 31% for 7-day and 30% for 21-day therapy. Thus, 21-day therapy only delayed recurrence. The higher daily dosage did not improve outcome. Urethritis persisted or recurred in 19% of men with initial Chlamydia trachomatis infection. Among men without C. trachomatis, urethritis persisted or recurred in 32% with and 52% without Ureaplasma urealyticum infection (p = 0.03). At follow-up, 79% of cases of persistent or recurrent urethritis were culture negative for C. trachomatis and U. urealyticum. The cause of C. trachomatis-negative, U. urealyticum-negative nongonococcal urethritis, which was least responsive to minocycline therapy, remains uncertain.

Acute Pelvic Inflammatory Disease in Outpatients: Association with Chlamydia trachomatis and Neisseria gonorrhoeae

Among 830 women attending a clinic for sexually transmitted disease, Chlamydia trachomatis was isolated from 180 (22%) and Neisseria gonorrhoeae from 84 (10%). Retrospective analysis showed that 43 of the women were given outpatient treatment for acute pelvic inflammatory disease because they had low abdominal pain, deep dyspareunia, or unusual vaginal bleeding, or all of these, for less than 2 months in association with cervical motion or adnexal tenderness, or both. None had adnexal masses. C. trachomatis was isolated from 22 and N. gonorrhoeae from 15 of this subgroup of 43 women. This presentation of pelvic inflammatory disease occurred in 10 of the 37 women in the whole study with both C. trachomatis and N. gonorrhoeae, 12 of 143 women with C. trachomatis alone, five of 47 women with N. gonorrhoeae alone, and 16 of 603 women with neither organism. Thus, in North America, C. trachomatis is associated with a syndrome usually diagnosed as mild pelvic inflammatory disease and managed on an outpatient basis.

Comparison of Gram stain and first-voided urine sediment in the diagnosis of urethritis.

The number of polymorphonuclear leukocytes on gram-stained urethral specimens was compared with the number in the sediment of the first-voided urine to determine what constitutes an abnormal number of polymorphonuclear leukocytes in gram-stained specimens. Seventy-three men attending a clinic for sexually transmitted diseases were studied. An attempt was made to select primarily asymptomatic men and men who had minimal symptoms or signs of urethritis because the diagnosis of urethritis is most difficult in these groups. There was a distinct bimodal distribution of the numbers of polymorphonuclear leukocytes by both techniques. Means of four or fewer polymorphonuclear leukocytes per field in five fields (×1,000) with gram stain and of <15 polymorphonuclear leukocytes in all of five fields (×400) in the first-voided urine sediment were considered normal. The results with the two techniques were highly correlated (P = 1.4 × 10+10). In the absence of cultures for Neisseria gonorrhoeae, Chlamydia trachomatis, and possibly Urea-plasma urealyticum to detect the presence of urethral infection, a mean of more than four polymorphonuclear leukocytes per field (×1,000) in a Gram-stained urethral specimen indicates the presence of urethritis.

Etiologies of postgonococcal urethritis in homosexual and heterosexual men: roles of Chlamydia trachomatis and Ureaplasma urealyticum.

Before treatment for urethral gonorrhea, Chlamydia trachomatis was isolated from 18% and Ureaplasma urealyticum from 37% of 121 men. C. trachomatis was recovered from none of 18 homosexual men who had gonorrhea and from 22 of 95 heterosexual men who had gonorrhea (P < 0.05). After treatment with a penicillin, postgonococcal urethritis occurred significantly more often in heterosexual than in homosexual men (P < 0.002). Postgonococcal urethritis developed in all men from whom C. trachomatis was isolated. Among men without U. urealyticum infection, postgonococcal urethritis was significantly associated with C. trachomatis infection (P < 0.02). Among men without C. trachomatis infection, postgonococcal urethritis was less closely associated with U. urealyticum infection (0.1 > P > 0.05). Postgonococcal urethritis was least frequent among men who had neither C. trachomatis nor U. urealyticum infection.

Minocycline Compared with Doxycycline in the Treatment of Nongonococcal Urethritis and Mucopurulent Cervicitis

Nongonococcal urethritis and cervicitis are the most prevalent sexually transmitted infections in industrialized countries. In as many as 60% of cases, these conditions are associated with Chlamydia trachomatis, although other organisms such as Ureaplasma urealyticum have also been implicated [1]. The infections are frequently asymptomatic, particularly in women, and the highest age-related prevalence occurs among female adolescents. Untreated chlamydial infections have serious sequelae such as epididymitis, salpingitis, and pelvic inflammatory disease. Given the clinically significant morbidity associated with long-term sequelae, these infections are a major public health problem. Early diagnosis and safe and effective antimicrobial therapy are crucial to both a prevention and a control strategy. Relatively few antibiotics are effective in the treatment of chlamydial genitourinary infections, and many are associated with adverse reactions. Tetracyclines, including minocycline and doxycycline, have excellent in vitro antichlamydial activity [2], and all have been used successfully in men and women with urethritis and cervicitis. The tetracycline analogs, doxycycline hyclate and minocycline hydrochloride, have longer serum half-lives than tetracycline and allow less frequent administration [3]. The advantage of less frequent administration has been shown in a study comparing doxycycline with tetracycline for the treatment of gonococcal infections. Patient compliance improved with doxycycline, accounting for lower failure rates in patients treated with this drug [3]. If drug administration could be further reduced to a single daily dose, one could expect compliance to increase further. No data exist to support the rationale for a course of tetracycline therapy exceeding 7 days, although treatment of at least 5 days is necessary to effectively eradicate these slow-growing organisms [2]. Studies using 14 or 21 days of therapy have reported similar rates of recurrence if follow-up is continued for 6 weeks. Adverse effects are associated with all tetracyclines, but vestibular toxicity is a special concern with minocycline. These side effects appear to be dose-related. Doxycycline, twice a day for 7 days, is currently considered the drug of choice for nongonococcal urethritis and mucopurulent cervicitis. Our randomized, double-blind study was designed to compare the efficacy and tolerability of minocycline, 100 mg nightly compared with doxycycline, 100 mg twice daily, each for 7 days in men with nongonococcal urethritis and women with mucopurulent cervicitis. Methods Study Criteria We conducted our study at the Sexually Transmitted Disease Clinics in Edmonton, Alberta and Vancouver, British Columbia. Men visiting the clinics with complaints of urethral discharge or dysuria for less than 1 month whose urethral smear showed 4 or more polymorphonuclear leukocytes per high-power field (x 1000) in five or more fields were eligible for study entry. The urethral smear also had to be negative for intracellular gram-negative diplococci. In addition, male contacts of women with mucopurulent cervicitis or with cervical C. trachomatis infections were also considered eligible regardless of whether urethritis was documented. Women who were diagnosed as having mucopurulent cervicitis were eligible. The diagnosis of mucopurulent cervicitis required both the presence of endocervical mucopus and 10 or more polymorphonuclear leukocytes per high-power field in a Gram stain of cervical mucus that contained fewer than 100 vaginal squamous epithelial cells when collected from a nonmenstruating woman. The presence of mucopus was determined by an off-white or yellow endocervical mucopurulent discharge when viewed on a white-tipped swab. In addition, female contacts of men with nongonococcal urethritis or with urethral C. trachomatis infections were also considered eligible regardless of whether mucopurulent cervicitis was documented. All study participants were older than 16 years, were willing to attend the clinic regularly for 7 weeks, had not received antimicrobial agents with anti-chlamydial activity in the preceding month, had negative cultures for gonorrhea, and were not allergic to tetracyclines. Women were required to use an effective form of birth control and could not enter if they were pregnant or breast feeding. Women with vaginitis, vaginosis, or pelvic inflammatory disease were excluded, as were men with orchitis or epididymitis. Examination and Laboratory Studies At the pretreatment evaluation, patients had a standardized interview and genital examination. In men, urethral discharge was classified as difficult to milk through to heavy spontaneous. Urethral exudate was examined by Gram stain and cultured on Chocolate and Thayer-Martin medium to exclude Neisseria gonorrhoeae. A calcium alginate urethrogenital swab was inserted into the urethra 1 to 2 cm beyond the fossa navicularis and left in place for 10 to 15 seconds. It was then placed in chlamydia transport media and immediately inoculated in McCoy cells or frozen at 70C for subsequent isolation of C. trachomatis in McCoy cells [4]. The same swab was then used to isolate genital mycoplasmas [5]. At the initial visit only, rectal and pharyngeal cultures were also obtained for N. gonorrhoeae. At each subsequent visit, the urethral Gram stain as well as urethral cultures for chlamydia and the genital mycoplasmas were repeated. All men were asked not to void for 4 hours before their clinic visit. Women had a pelvic and bimanual examination at each visit. Endocervical discharge was described by color and quantity. Ectocervical erythema, edema, and friability (induced mucosal bleeding) were recorded as well as the area of ectopy. An endocervical Gram smear was obtained at each visit, as was a vaginal wet mount and pH. Endocervical, urethral, rectal, and pharyngeal cultures for N. gonorrhoeae were obtained at the initial visit only. Urethral and endocervical swabs were obtained at each visit for C. trachomatis isolation. Finally, urethral and vaginal cultures for the genital mycoplasmas were obtained at each visit. Follow-up Patients were asked to return 14 3, 28 5, and 49 7 days after the start of therapy. All study visits for women were scheduled so as to fall at nonmenstrual times of their cycle. At each visit, patients were questioned regarding symptoms, adverse effects of therapy, and interim sexual activity. Study Drugs At each site, patients were randomly assigned in a double-blind fashion to one of two treatment groups. Each patient received a blister package of 14 identically appearing capsules on the first visit. There were seven vertical columns and two horizontal rows. Each horizontal row was clearly labeled am or pm. Patients were instructed to take one capsule in the morning and evening. The blister packages were returned at the first follow-up visit. The two treatment groups were minocycline, 100 mg nightly, and doxycycline, 100 mg twice daily, each administered for 7 days. Evaluation The number of polymorphonuclear leukocytes in urethral or endocervical Gram-stained smears was used as an objective measure of response. The primary end point was a clinical cure defined as clinical symptoms subsiding or resolving by day 14 with subsequent complete resolution of symptoms that did not reappear during the remainder of the follow-up period. A secondary end point was bacteriological cure for C. trachomatis, defined for a patient with chlamydia as a microbiological cure at day 14 3 and at all subsequent follow-up visits. A clinical symptoms and signs score was calculated at each visit. Each symptom and sign was assigned a score from 0 to 3 (absent, mild, moderate, or severe). For men, symptoms included urethral discharge, urethral itch, and dysuria with signs consisting of both quantity and quality of urethral discharge. Symptoms in women included vaginal discharge, external and internal dysuria, deep and introital dyspareunia, abnormal bleeding, and lower abdominal pain, whereas signs comprised ectocervical erythema, edema, and friability. Side effects were elicited by asking the patients if they felt different in any way since beginning the medications. Statistical Analysis The Cochran-Mantel-Haenszel test was used in the combined gender group to compare rates in the two treatment groups; the Fisher exact test was used when men and women were considered separately. Logistic regression analysis was performed on the incidence of adverse drug reactions to determine significant factors within each treatment group. The paired t-test was used for analysis of the change from baselines in clinical symptoms and signs scores within each treatment arm. An analysis of covariance adjusting for the baseline score was used to test for differences between treatment arms at each return visit. Results Initial Microbiological Results A total of 253 patients were enrolled between March 1989 and October 1990 (151 men and 102 women). The mean ages for men and women were 28.2 years (SD, 8.3) and 23.5 years (SD, 5.1), respectively. Eighty-eight percent of the patients were white and 97% were heterosexual. The mean number of sexual partners in the past year was 6 for the men (range, 1 to 50; SD, 8) and 2.7 for women (range, 1 to 11; SD, 1.7). Demographics and baseline microbiologic results did not differ for the two treatment groups or for the two study centers. The results of initial cultures for C. trachomatis and the genital mycoplasmas are shown in Table 1. An equal proportion of men and women (31% and 40%) had C. trachomatis isolated. More women than men had either U. urealyticum or Mycoplasma hominis isolated. No organisms were isolated from 55 (37%) of the men enrolled, whereas only 10 (10%) women had negative cultures. Table 1. Initial Isolation of Chlamydia trachomatis, Ureaplasma urealyticum, and Mycoplasma hominis Genital mycoplasmas were isolated from 30% (14 of 46) of men with and 4

Eradication of chlamydia trachomatis from the urethras of men with nongonococcal urethritis by treatment with amoxicillin

Twenty men with nongonococcal urethritis were treated orally with amoxicillin (750 mg three times daily for 10 days). One man had herpes simplex virus infection of the urethra. Chlamydia trachomatis was isolated from the urethras of six (32) of the remaining men. Urethral specimens cultured for C. trachomatis became negative during amoxicillin therapy for all six men and remained negative for all five men who were followed for 24-48 days. Amoxicillin did not eradicate Ureaplasma urealyticum from any of 13 colonized men. Nongonococcal urethritis persisted or recurred at greater than or equal to 14 days after initiation of treatment in one of five men with, and ten of twelve men without initial C. trachomatis infection (P = 0.06). Since multiple-dose penicillin regimens are used for the treatment of acute pelvic inflammatory disease and epididymitis, which are frequently caused by C trachomatis, the apparent efficacy of high-dose amoxicillin therapy for chlamydial urethritis in this study is of interest. However, until the results of further study of the efficacy of multiple-dose penicillin regimens for infections due to C. trachomatis are known, tetracyclines remain the treatment of choice for the majority of such complications.

Etiology and treatment of nongonococcal urethritis.

The significant progress of the last decade in determining the etiology of nongonococcal urethritis is reviewed, and current treatments are assessed. Convincing evidence that Chlamydia trachomatis is the cause of 30-50% of cases of nongonococcal urethritis has been developed by many groups from isolation data, serologic studies, urethral inoculation of monkeys, and studies of postgonococcal urethritis. Other evidence that C. trachomatis is a urethral pathogen is that its selective eradication results in alleviation of urethritis in C. trachomatis-infected men. The cause of nongonococcal urethritis when C. trachomatis infection cannot be proven by isolation or serologic testing is unclear. The most likely cause of a significant proportion of the C. trachomatis-negative cases is Ureaplasma urealyticum. Although studies of the role of U. urealyticum as a urethral pathogen have been complicated by the fact that in health the rate of urethral colonization is strongly correlated with an individuals total number of sex partners, and serologic studies have not supported a role for U. urealyticum, other evidence is consistent with such a role, including treatment studies and experimental inoculation. Assuming both C. trachomatis and U. urealyticum are etiologic agents, in another 20% of men with the disease neither organism is initially isolated. False-negatives probably account for some of the cases, but poor response to treatment for the 2 pathogens suggests they constitute another group. Although the incidence of gonorrhea has tended to stabilize recently, that of nongonococcal urethritis continues to rise sharply. Management requires diagnosis of urethritis, exclusion of urethral infection with Neisseria gonorrheae, choosing an appropriate antimicrobial for the patient, treatment of sexual contacts, and follow-up of the patient. When the patient is symptomatic, has a readily expressible discharge, and the exudate contains many polymorphonuclear leukocytes but not gram-negative diplococci, diagnosis is easy. However, when symptoms or signs are minimal, arbitrary criteria must be utilized in diagnosis. In individual cases it is impossible to distinguish between gonorrheal and nongonococcal urethritis on clinical grounds, and the final diagnosis requires laboratory examination for N. gonorrheae. Tetracyclines, erythromycins, and a combination of sulfonamides and an aminocyclitol, which almost always eradicate C. trachomatis, were recognized as the most effective therapies by the 1950s. Although many studies have been done, the optimal drug dose and duration of therapy have not been determined.

Isoenzyme patterns of isolates of Trichomonas vaginalis from Vancouver.

Isoenzyme patterns of 63 isolates of Trichomonas vaginalis obtained in Vancouver were evaluated by use of thin-layer starch-gel electrophoresis. We attempted to use eight enzymes, but only four gave reproducible and interpretable results. There were four patterns with malic enzyme, two with malate dehydrogenase, one with hexokinase, and four with lactate dehydrogenase. The isoenzyme patterns of the 63 isolates were classified into 15 groups, but 49 (78%) fell into five groups and 14 (22%) fell into ten groups. There was no obvious correlation between groups and magnitude of symptoms and signs, past history of trichomoniasis, or likelihood of treatment failure. Results were consistent for isolates obtained from the same patient on different days. This system will allow differentiation of isolates into groups, a procedure that could be useful. However, groups do not appear to correlate with clinical or historical features or with outcome of treatment.

Partial efficacy of clindamycin against Chlamydia trachomatis in men with nongonococcal urethritis

Tetracyclines are the drugs of choice for treatment of Chlamydia trachomatis infection, but alternative antimicrobial agents are needed. Clindamycin has moderate in-vitro activity against C. trachomatis. In this study clindamycin (600 mg orally three times daily for seven days) was given to 76 men with nongonococcal urethritis. Initial microbiologic and clinical responses were significantly better in men from whom C. trachomatis was initially isolated, compared with men from whom Ureaplasma urealyticum was initially isolated, but by 42 +/- 7 days after initiation of treatment, persistence or recurrence of urethritis had occurred in 39% of men with either organism initially isolated. C. trachomatis was ultimately reisolated at follow-up evaluation from seven of 23 men who initially had had positive cultures for C. trachomatis. There was no apparent relationship between the in-vitro susceptibility of C. trachomatis and the ultimate response. These results indicate that clindamycin cannot be relied upon to eradicate C. trachomatis from men with urethritis.