A comparative study of two different regimens of sparfloxacin versus doxycycline in the treatment of non-gonococcal urethritis in men

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1 Journal of Antimicrobial Chemotherapy (996) 37, Suppl. A, 3-34 A comparative study of two different regimens of versus in the treatment of non-gonococcal urethritis in men I. Phillips', C. Dimian*, D. Barlow*, H. Moi% E. Stolz', W. Weidner' and E. Perea' 'Department of Microbiology, and b Department of Genito-Urinary Medicine, St Thomas' Hospital, London SE 7EH, UK;'Department for STD and HIV, GronlandPK, N-33, Oslo, Norway; d Dermatologie an Venerologie, Academisch ziekenhuis 35GD, Rotterdam, The Netherlands;'Zentr. Chirurgie Abt. Urologie, Georg August Universitat, 34 Gottingen, Germany; f Catedratico de Microbiologia de la Facultad de Medicina, Universidad de Sevilla, E-49, Seville, Spain A multicentre, double-blind, randomised study comparing the efficacy and safety of oral ( mg on day followed by mg daily for or 6 additional days) with ( mg once daily for 7 days) in the treatment of non-gonococcal urethritis in men was conducted. The overall success rates for the three treatment groups were statistically equivalent both at the end of treatment and at the follow-up visits. For chlamydial urethritis, the rates of relapse or possible reinfection were similar in the 7-day and groups. For ureaplasmal urethritis and urethritis of unknown aetiology, the rates of relapse or possible reinfection were lower in the 7-day group than in the other two treatment groups. Sparfloxacin was well tolerated. A 7-day regimen appears to be a useful alternative to for the treatment of non-gonococcal urethritis in men. Introduction In recent years the incidence of non-gonococcal urethritis (NGU) has increased in the Western world while that of gonorrhoea has decreased. NGU has now replaced gonorrhoea as the commonest cause of urethritis. NGU is an infection of multiple aetiology, usually characterised by scanty urethral discharge and the patient may complain only of slight dysuria or discomfort in the urethra in the morning. Diagnosis is confirmed by microscopy of a Gram-stained urethral smear showing an excess of polymorphonuclear leucocytes (PMN) of >5 per high power (x ) microscopic field (on average -4 pus cells) and by culture to exclude gonorrhoea. Chlamydia trachomatis is the principal pathogen isolated in NGU and is associated with 3-5% of cases. Ureaplasma urealyticum is isolated less frequently and the remaining one-third of cases have no known cause. Trichomonas vaginalis, Corynebacterium genitalium, Haemophilus parainfluenzae and Candida spp. have been isolated from the male urethra as have the Group B streptococci and mycoplasmas, but their role in NGU remains uncertain. Tetracyclines and macrolides are satisfactory therapeutic agents for NGU, curing over 9% of C. trachomatis infections in patients Downloaded from at Pennsylvania State University on April 3, /96/37A3 + $./ The British Society for Antimicrobial Chemotherapy

2 4 I. Phillips et al. who comply fully with a multi-dose daily treatment regimen. However, compliance with existing treatment regimens is poor and adverse effects are common. Several studies have shown ofloxacin to be effective in the treatment of NGU (Kitchen et al., 99; Mogabgab et al., 99) and, a newly developed fluoroquinolone, has greater in-vitro activity against Chlamydia spp., U. urealyticum and Mycoplasma hominis than ofloxacin (Martin, Cammarata & Grubb, 99). Therefore, a study was conducted to compare the efficacy and safety of relative to the standard treatment of in men with NGU. Trial design and treatment Methods This double-blind, randomised, multicentre study was carried out between January 99 and April 99. Twenty-six European centres were involved: the UK (76 patients, centre); Sweden (36 patients, 8 centres); The Netherlands (65 patients, 3 centres); Germany (5 patients, centres); and Spain (7 patients, 3 centres). The randomisation schedule was balanced in each treatment centre. Ethics Committee approval was obtained according to local regulations before initiation of the study at each centre. There were three treatment arms: mg on day followed by mg daily on days and 3 and placebo on days 4-7, mg once daily for 7 days, and mg on day followed by mg daily on days -7. Patients All patients were to have a clinical diagnosis of NGU based on the progressive onset of at least one sign or symptom: urethral discharge (mucoid or mucopurulent), painful micturition, difficult urination and/or pruritus (which was defined as urethral irritation on micturition not amounting to dysuria), with microscopy showing > 5 PMNs per high power field (magnification x ). In addition, the absence of intracellular Gram-negative diplococci and yeasts had to be confirmed by direct examination of urethral samples. Patients were to have voided no later than 3 or 4 h before the initial examination. Patients were excluded if they presented with a severe concomitant disorder likely to interfere with their clinical course, such as uncontrolled cardiovascular disorder, hepatic diseases, renal insufficiency, anaemia, cancer or AIDS, although HIV-positive patients could be included. Patients with a history of photosensitivity or multiple allergies, especially to quinolones or tetracycline, were excluded. No corticosteroid therapy, antacids, iron salts, anticoagulants, gastric emptying modifiers or immunosuppressants could be taken during the study period. The number of PMNs per high power field in the urethral smear and the presence or absence of intracellular Gram-negative diplococci and yeasts by direct microscopic examination were determined before treatment (V,) and at the end-of-treatment visit (V ) and at the follow-up visit (V 3 ). The general state of health was assessed at study entry by means of a full medical history (including the number of episodes of gonococcal urethritis, NGU and genital herpes in the past year) and physical examination. This was repeated at V and V 3. Patients were questioned about previous and current use of condoms at Vi and, if sexual activity had continued, at V and V 3. Downloaded from at Pennsylvania State University on April 3, 4

3 Sparfloxacin for non-gonococcal uretfaritls 5 Urethral samples for bacteriology were obtained at inclusion and at each visit (V and V 3 ) by endourethral swab. These samples were used for culture of Neisseria gonorrhoeae, C. trachomatis, U. urealyticum and M. hominis, and for the detection of C. trachomatis antigen (e.g. immunofluorescence or ELISA tests) where possible. If TV. gonorrhoeae was isolated, susceptibility testing was performed using and discs. Clinical evaluation The primary efficacy analysis was based on the overall efficacy response at V (days 9-) and at V 3 (days -5), combining the clinical and bacteriological responses and the number of PMNs per field in the urethral smear. In order to be eligible for the primary efficacy analysis, the patients had to comply with the following inclusion criteria: negative culture for N. gonorrhoeae at inclusion and at study entry; presence of at least one of the following urethral discharge, painful urination, difficult urination or pruritus associated with > 5 PMNs per high power field. Where there were no clinical signs or symptoms at inclusion, patients were deemed evaluable if the culture was positive for C. trachomatis irrespective of the number of PMNs or for U. urealyticum when associated with > 5 PMNs. In addition, there had to be no other genital infection (such as prostatitis) at entry, at least 3 complete days of treatment with study medication, a satisfactory compliance, and no discontinuation before the end of treatment unless there was treatment failure. In order to be evaluable for the primary efficacy analysis at V, the patient had to be evaluated between days 7 and 6 inclusive (if only one visit was performed after inclusion, it was considered V if it took place before day 7 and V 3 if it took place on or after day 7). To be evaluable for primary efficacy at V 3, the patient had to be evaluated on or after day 7 and could not have taken any systemic antibiotic treatment between V and V 3, except in the case of failure or relapse/reinfection. All patients who fulfilled the inclusion criteria and received at least one tablet of study medication were included in the intent-to-treat-analysis. All patients who received at least one dose of study medication were included in the safety analysis. Criteria for assessment of outcome Clinical cure was defined as complete disappearance of urethral discharge and painful or difficult urination. Improvement was defined as disappearance of urethral discharge with decrease or persistence of at least one other symptom. The bacteriological response was defined as follows: eradication disappearance of all pathogens (C. trachomatis, U. urealyticum) present at inclusion; persistence persistence of at least one of the initial pathogens; reinfection eradication of the initial pathogen and replacement by a new pathogen; superinfection persistence of the initial pathogen with appearance of a new pathogen; indeterminate no pathogen at inclusion or at each visit; appearance appearance of a pathogen with no pathogen at inclusion; unassessable positive culture at inclusion and culture not repeated at the endpoint visit; relapse/possible reinfection eradication of all initial pathogens at V with presence of at least one pathogen at the follow up visit (V 3 ). M. hominis was not considered to be a causative pathogen. When the patient was judged clinically 'cured', 'indeterminate' or 'improved', U. urealyticum was not considered to be a pathogen if it appeared or persisted at V or V 3. Downloaded from at Pennsylvania State University on April 3, 4

4 6 I. Phillips et al. For the primary efficacy analyses, the assessments for each visit were defined for the purpose of the statistical analysis as success or non-success (the non-successes would represent cases that would generally be interpreted by the investigators as failures irrespective of the classification used in the study) as follows: At the end-of-treatment visit (V ), success clinical cure irrespective of the number of PMNs, or clinical improvement with ^ 5 PMNs, together with the absence of C. trachomatis (whether U. ureaplasma was isolated or not); non-success all other cases. At the follow-up visit (V 3 ), success clinical cure with ^ PMNs and always fewer than at V and absence of C. trachomatis (whether U. urealyticum was isolated or not); non-success all other cases. When either V or V 3 was missed, a patient classified as non-success at one visit was still classified as non-success in the missing visit but a patient classified as 'success' at one visit would not be evaluable at the missing visit. Adverse events A laboratory profile was obtained at inclusion and V and, if clinically significant abnormal values were found, it was repeated at V 3. The profile included: haematology RBC count, haemoglobin, platelet count, total and differential WBC count, prothrombin, activated PTT and ESR; biochemistry sodium, potassium, chloride, bicarbonate, total protein, glucose, uric acid, total bilirubin, ASAT (SGOT), ALAT (SGPT), alkaline phosphatase, creatinine, calcium, phosphate; and urinalysis protein, blood and glucose (by dip stick). Clinical events, whether volunteered by the patient or elicited by the investigator by non-specific questioning, were recorded at V and V 3. All were classified by the investigator with regard to severity and possible relation to study medication. Statistical methods All statistical analyses were carried out with SAS software, release 6.6 (SAS Institute, Gary, North Carolina, USA). The primary statistical methodology was the calculation of 9% confidence intervals for difference in success rates between the three treatment groups at V and V 3. Equivalence was accepted when the upper limit of the interval was < %. The probabilities excluding % from these intervals when treatment regimens were truly equivalent were also calculated. All other analyses were descriptive. Results A total of 75 patients were included in the study: 43 were randomised to the 3 days group, 39 to the 7 days group and 43 to the 7 days group. Of the 75 patients randomised to the study, 4 were lost to follow-up just after inclusion and no information was available on drug intake. A further two were excluded from the intent-to-treat analysis because they had no clinical signs or symptoms and negative cultures. The number of patients included in the intent-to-treat analysis and in the primary efficacy analyses at V and V 3 are presented in Table I. Downloaded from at Pennsylvania State University on April 3, 4

5 Sparfloxacin for nod-gonococcal nrethritis 7 Table I. Summary of exclusions from primary efficacy analysis Randomised Evaluable for intent-to-treat analysis Not evaluable for primary efficacy analysis no symptoms N. gonorrhoeae at inclusion > 4 days between V, and drug intake previous antibiotic treatment treatment <3 days treatment stopped poor compliance prostatitis total Evaluable for primary efficacy analysis Evaluable for primary efficacy analysis at V : Evaluable for primary efficacy analysis at V 3 Demographic data 3-Day 43 (9.5%) 7 4 4(5.8%) 6 (84.8%) 95 (8.%) 86(76.5%) 39 3 (96.%) 4 3 (4.6%) 9(9.6%) (88.7%) 96 (8.%) 43 3 (95.%) 6(6.6%) 5(88.5%) (8.7%) 83(75.3%) Patient characteristics and sexual practices were similar in the three treatment groups (Table II). In approximately 6% of cases, symptoms of NGU had been present for more than one week before inclusion. Urethral discharge (most often mild and mucoid) was observed in approximately 8% of cases. Among the symptoms, painful urination was observed more often (6% of patients) than difficult urination (%) or pruritus (3%). The distribution of clinical signs and symptoms was also similar in the three treatment groups. All except 4 patients had >5 PMNs per high power field in the urethral smear. Two-thirds of the patients had > PMNs per high power field. Table II. Patient characteristics at inclusion (treated population) Mean age in years (range) Mean weight in kg (range) > sexual partner in the previous weeks Current use of condoms Urethral discharge Painful urination Pruritus Number of PMNs < > 3-Day (n = ) 7.6(8-5) 77.5(56-7) (9.%) (7.3%) 67(75.%) 5(56.3%) 73 (3.9%) 7 (3.%) 65 (9.3%) 88 (39.6%) 6 (8.%) (/! = 3) 8.(8-6) 77.6(57-7) 7(7.4%) 7(.%) 8(79.%) 4 (6.9%) 6 (7.%) 6 (.6%) 5(.7%) (48.7%) 6 (6.9%) (n = 3) 8.4(8-66) 76.9(5-7) 7(7.4%) 6(.%) 85(8.%) 45(6.8%) 7 (3.7%) (4.8%) 53 (.9%) 4(45.%) 63 7.%) Downloaded from at Pennsylvania State University on April 3, 4

6 8 I. Phillips et al. Table ID. Bacteriological findings at inclusion (population evaluable for primary efficacy) Organism 3-Day Total No pathogen 9(44.%) 4(47.5%) (47.%) 96(46.3%) C. trachomatis 6(3.%) 65(9.7%) 7(33.%) 98(3.9%) C. trachomatis+u. urealvticum 3(6.3%) (9.%) 9(4.%) 4(6.6%) U. urealyticum ' 4(9.4%) 3(3.7%) 34(5.8%) 4(6.3%) Bacteriology The bacteriological findings at inclusion are provided in Table III. In less than half of patients entered, no pathogens were identified in the urethral sample. Spain had the highest rate of success in identifying a pathogen (76.9%) whereas The Netherlands had the lowest rate (35.6%). The rate of isolation of C. trachomatis alone was approximately 37%, whether or not with U. urealyticum and was lowest in Spain (9.%), which had the highest rate of isolation of U. urealyticum alone (57.7%), and highest in Sweden (4.8%). The overall success rates were statistically equivalent at V and V 3 in the three treatment groups both in the intention-to-treat population and the patients evaluable for primary efficacy. The confidence interval of the difference of the success rate was always under % in all analyses, confirming equivalence. The individual success rates at both endpoints intention-to-treat and evaluable patients are presented in Table IV. Overall efficacy at V and V 3 according to the pathogen isolated is presented in Tables V-VII. The regimen was slightly more effective than the two regimens in the 3 evaluable patients with chlamydial urethritis, but the relapse rates at V 3 appeared equivalent in the three treatment groups (%, 3%, 5% in the 3-day,, and 7-day regimens, respectively Table V). In contrast, the two regimens were more effective than the regimen in the evaluable patients with ureaplasmal urethritis (Table VI). Moreover, the relapse rate at V 3 (defined as a success at visit and unsuccessful at visit 3) was lower in the 7-day group than in the other two treatment groups (% vs 8% in the 3-day and 7% in the group). However, the numbers involved were small. In the 76 evaluable patients with no pathogens isolated at inclusion, the 7-day regimen was as effective as the regimen but the relapse rate at V 3 was lower in the 7-day Table IV. Overall efficacy at the end-of-treatment (V ) and follow-up (V 3 ) visits Downloaded from at Pennsylvania State University on April 3, 4 Intent-to-treat population Evaluable population 3-day 7-day 7-day 3-day 7-day 7-day Success at \ Success at V 3 77/ (8.5%) 4/ (56.4%) 83/3 (79.6%) 34/3 (58.3%) 78/3 (77.%) 3/3 (56.3%) 59/95 (8.5%) 3/86 (6.8%) 74/ (8.%) /96 (6.7%) 6/ (8.%) /83 (6.%)

7 Sparfloxadn for non-gonococcal urethritis 9 Table V. Overall efficacy at V and V 3 in patients in whom C. trachomatis, with or without U. urealyticum, was isolated 3-Day sparfloxadn Outcome {n = 73f (n = 8)* (n =!Sf Success V and V 3 Success V ; non-evaluable V 3 Success V ; non-success V 3 Non-success V and V 3 43 (58.9%) 5 (6.8%) 9 (.3%) 6(.9%) 5 (6.%) 6 (7.3%) (3.4%) 4(7.%) 38 (5.7%) 8 (.7%) (4.7%) 8 (4.%) The number of patients evaluable at each visit is less than the number of patients evaluable for the primary efficacy analysis (Table III), because some patients were excluded from the analysis due to a visit date out of the admissible range, or due to the use of systemic antibiotics in spite of failure. Table VI. Overall efficacy at V and V 3 in patients in whom U. urealyticum was isolated 3-Day Outcome (n = 39) (n = 9) (n = 34) Success V and V 3 Success V ; non-evaluable V 3 Success V ; non-success V 3 Non-success V and V 3 8(7.8%) (.6%) 7(7.9%) 3 (7.7%) 7(58.6%) (6.9%) 5(7.%) 5(7.%) 4 (7.6%) (5.9%) 4(.8%) 4(.8%) Table VII. Overall efficacy at V and V 3 in patients in whom no pathogen was isolated 3-Day Outcome (n = 83) (n = ) (n = 9) Success V and V 3 35 (4.%) 49 (48.5%) 43 (46.7%) Success V ; non-evaluable V 3 (3.3%) 3(.9%) 8(9.6%) Success V ; non-success V 3 (4.%) (9.8%) 3(4.%) Non-success V and V 3 7(.5%) 9(8.8%) 8(9.6%) group. The relapse rate for the 3-day group was markedly higher (Table VII). The results in the cases evaluable for bacteriological efficacy at V are presented in Table VIII; the eradication rates for C. trachomatis were close to % in the three groups: 3-day, 7-day and 7-day groups. The eradication rates of U. urealyticum were also close to % in all three groups. When U. urealyticum persisted or appeared at the end of the treatment, this was rarely associated with a clinical failure (/6, /5, /6 in the above groups, respectively). The results in the bacteriologically evaluable cases at V 3 are presented in Table VIII; the eradication rates for C. trachomatis were 88.% (59/67), 96.% (73/76) and 97.% (64/66) in the 3-day, 7-day and 7-day groups, Downloaded from at Pennsylvania State University on April 3, 4

8 Table VIII. Bacteriological efficacy at visit (V ) and visit 3 (V 3 ) on C. trachomatis and U. urealyticum-documenled infections Bacteriological outcome at V Bacteriological outcome at V., 3-Day 3-Day C. trachomatis doxycyline Eradication 67(95.7%) 79(.%) 7(97.5%) 59(88.%) 73(96.%) 64(97.%) Persistance 3 Relapse 6 Unassessable Total 7(.%) 79(.%) 74(.%) 67(.%) 76(.%) 66(.%) Appearance U. urealyticum Bacteriological outcome at visit Bacteriological outcome at visit 3 Eradication 48(94.%) 45(95.7%) 4(93.%) 43(86.%) 38(8.9%) 3(77.5%) Persistance Relapse Total 5(.%) 47(.%) 43(.%) 5(.%) 47(.%) 4(.%) Appearance rom at Pennsylvania State University on April 3, 4

9 Sparfloxacin for non-gonococcal nrethritis 3 respectively. A relapse or possible reinfection with C. trachomatis was observed in 6, and patient in the 3-day, 7-day and 7-day groups, respectively. The eradication rates of U. urealyticum were 86.% (43/5), 8.9% (38/47) and 77.5% (3/4) in the 3-day, 7-day and 7-day groups, respectively. The eradication rates of U. urealyticum were 86.% (43/5), 8.9% (38/47) and 77.5% (3/4) in the 3-day, 7-day and 7-day groups, respectively. This organism appeared in five cases in the 3-day group, five cases in the group and nine cases in the 7-day group. However, when U. urealyticum persisted, appeared or reappeared, this was rarely associated with a clinical failure (/, 4/4, 3/8 in the three treatment groups, respectively). Analysis of non-successes at V Of the 68 patients evaluable for overall efficacy at V, 4 were classified as non-success: 36/95 (8.5%) patients who received for 3 days, 38/ (7.9%) who received and 4/ (9.9%) who received for 7 days. Because these patients were classified as non-success at V, they were subsequently classified as non-success at V 3. Pathogens, either C. trachomatis or U. urealyticum, were isolated from % of the cases of non-success (Table IX). Analysis of relapse/reinfection Of the 68 patients evaluable for overall efficacy at V, patients were classified as success at V and non-success at V 3 : 36/95 (8.5%) patients in the 3-day group, 36/ (7.%) in the group and 8/ (3.9%) in the 7-day group. Pathogens were isolated in 6 of the cases of relapse/reinfection (Table X). Adverse events Forty-two of the 75 patients were not evaluable with regard to adverse events because they were lost to follow-up just after inclusion or did not take the study medication. Thus the adverse events analysis included 683 patients ( in the 3-day group, 3 in the group and 3 in the 7-day group). Adverse Table IX. Cases of bacteriologically documented failure Downloaded from at Pennsylvania State University on April 3, 4 3-Day Total Persistence of C. trachomatis Appearance of C. trachomatis Persistence of V. urealyticum'' Appearance of U. urealyticum h Total 4 * 'Missing V : but persistent C. irachomalis at V,. *Case associated with a clinical failure only (asymptomatic carriage is not taken into account)

10 3 I. Phillips et aj. Table X. Cases of bacteriologically documented relapse/reinfection Relapse/reinfection with C. trachomatis Relapse/reinfection with C. urealyticuw Appearance of U. urealyticunf 3-Day Total Total Cases associated with a clinical failure only (asymptomatic carriage is not taken into account) events were reported by 8.4%, 37.%, and 6.4% of the patients for the 3-day, and 7-day groups, respectively. Severe adverse events were reported in few patients: none in the 3-day group, 6% in the group and.5% in the 7-day group. Gastrointestinal disorders such as nausea, abdominal pain and diarrhoea were the most frequently reported (Table XI), particularly in the group. A photosensitivity reaction occurred in one patient in the 3-day group, one patient in the group, and two patients in the 7-day group. These reactions were mild in intensity, always occurred after exposure to sunlight and resolved spontaneously. No life-threatening adverse events were reported during the study. However, five patients discontinued their treatment due to adverse events: one in the 3-day group (mild, generalised rash which disappeared spontaneously the day after treatment discontinuation), two in the group (severe gastrointestinal disorder and/or moderate urticaria) and two in the 7-day group (moderate urticaria 4 days after initiation of treatment and drowsiness/impaired concentration several hours after initiation of treatment). A slight increase in mean total bilirubin, hepatic transaminases, glucose, creatinine Table XI. Most frequently reported adverse events (>% of patients) in the 3-day (no. of patients = ), 7-day (n = 3) and 7-day (n = 3) groups Adverse event Headache Accidental injury Abdominal pain Photosensitivity Diarrhoea Nausea Leucopenia Herpes simplex Pruritus Rash Balanitis Haemaluria Total number of patients 3-Day 8 (3.6%) (.5%) 4(.8%) (.5%) 6(7.%) (5.%) (.5%) 3(.4%) 3(.4%) 3(.4%) 3(.4%) 57 (5.6%) 8 (3.5%) 7 (3.%) (.4%) (4.3%) 3(3.%) 3(.3%) (.4%) 5 (.%) (.4%) 69 (3.%) (.9%) 3(.3%) 6 (.6%) 3(.3%) (4.8%) 8 (3.5%) 3(.3%) (.4%) 4(.7%) (.4%) 3(.3%) 48 (.7%) Downloaded from at Pennsylvania State University on April 3, 4

11 Sparfloxadn for non-gonococcal nretfaritis 33 and eosinophils and a slight decrease in mean alkaline phosphatase was noted in the two groups compared to the group. Few cases were considered to be clinically significant. Discussion The in-vitro anti-chlamydial activity of is equivalent to that of but superior to that of ofloxacin (Martin et al., 99), a fluoroquinolone shown to be effective in the treatment of NGU (Kitchen et al., 99; Mogabgab et al., 99). In addition, has better in-vitro activity than ofloxacin against U. urealyticum and M. hominis and is equally active against -susceptible and -resistant strains (Renaudin & Bebear, 99). In large surveys, % and 88% of,58 strains of U. urealyticum and 4% and % of 99 strains of M. hominis were resistant to and erythromycin, respectively (Spaepen & Kundsin, 966; Poulin & Kundsin, 99). Susceptibility of both organisms to appears to be independent of resistance to, tetracycline and erythromycin (Poulin & Kundsin, 99). Recently reported MIC9 values are: C. trachomatis. mg/l (Martin et al., 99), U. urealyticum.5 mg/l and M. hominis.3 mg/l (Waites et al., 99). In the present study, C. trachomatis was isolated alone in 3% of the cases, which is consistent with the C. trachomatis isolation rates of 3 to 6% reported in the literature (Alani et al., 977; Oriel & Ridgway, 98; Mardh, Paavonen & Puolakkainen, 989) and both C. trachomatis and U. urealyticum were isolated in 7% of cases. Evidence implicating U. urealyticum in NGU remains controversial (Taylor-Robinson, Czonka & Prentice, 977; Matsuda, Takeuchi & Yoshida, 99). Clearly, U. urealyticum can be implicated as a cause of urethritis in a minority of patients in whom the organism is isolated (Taylor-Robinson & McCormack, 98; Taylor-Robinson, 983; Woolley, 99). Pathogen-negative NGU is less likely to respond to conventional therapy with tetracycline or erythromycin and relapse is more likely (Handsfield et al., 976). This suggests either an as yet unidentified micro-organism, less responsive to standard NGU therapy, or a non-infective inflammatory process. Because it is uncertain whether M. hominis is a pathogen in NGU, it was not considered an infecting organism in this study. The overall success rates at the end-of-treatment and the final visit were statistically equivalent in each of the treatment groups. However, when subpopulations with ureaplasmal urethritis and urethritis of unknown aetiology were examined, it was found that the rates of relapse/possible reinfection at the follow-up visits were markedly lower in the 7-day group compared with the other two treatment groups. However, the rates of relapse/possible reinfection for chlamydial urethritis were similar in all three treatment groups. The eradication rates for C. trachomatis were in excess of 95% in all groups at end of treatment and at follow-up except in the 3-day group at follow-up. The eradication rate of U. urealyticum was less than 95% in all groups at end of treatment; they were 86%, 8.9% and 77.5% in the 3-day group, group and 7-day group respectively; however, when this pathogen persisted, appeared or re-appeared at follow-up this was rarely associated with a clinical failure. The three treatment regimens were well tolerated. Adverse events were rarely severe Downloaded from at Pennsylvania State University on April 3, 4

12 34 I. Phillips et al. enough to necessitate discontinuation of treatment. Gastrointestinal adverse events were the most frequently reported, particularly in patients treated with. In summary, a 7-day course of was equally as effective as a 7-day course of and was associated with a lower rate of relapse/possible reinfection in patients with ureaplasmal urethritis and urethritis of unknown aetiology. Sparfloxacin also has good in-vitro activity against C. trachomatis and is well tolerated and therefore should prove to be a useful alternative treatment for NGU in men. References Alani, M. D., Darougar, S., Burns, D. C, Thin, R. N. & Dunn, H. (977). Isolation o( Chlamydia trachomatis from the male urethra. British Journal of Venereal Diseases 53, Handsfield, H. H., Alexander, E. R., Pin Wang, S., Pedersen, A. H. & Holmes, K. K. (976). Differences in the therapeutic response of chlamydia-positive and chlamydia-negative forms of non-gonococcal urethritis. Journal of American Venereal Disease Association, 5-9. Kitchen, V. S., Donegan, C, Ward, H., Thomas, B., Harris, J. R. W. & Taylor-Robinson, D. (99). Comparison of ofloxacin with in the treatment of non-gonococcal urethritis and cervial chlamydia infection. Journal of Antimicrobial Chemotherapy 6, Suppl. D, Mardh, P. A., Paavonen, J. & Puolakkainen, M. (989). Genital and associated infection in the male. In Chlamydia (Mardh, P. A., Paavonen, J. & Puolakkainen, M., Eds), pp Plenum, New York. Martin, D. H., Cammarata, C. L. & Grubb, D. (99). In-vitro activity of (Cl-978, AT-44), ofloxacin,, and tetracycline versus genital tract mycoplasmas and Chlamydia trachomatis. European Journal of Microbiology and Infectious Diseases Special Issue, Matsuda, T., Takeuchi, H. & Yoshida, O. (99). Ureaplasma urealyticum and Mycoplasma hominis in male urethritis. Hinoyokina-Kiyo 37, Mogabgab, W. J., Holmes, B., Murray, H., Beville, R., Brobson Lutz, F. B. & Tack, K. J. (99). Radomised comparison of ofloxacin and for chlamydia and ureaplasma urethritis and cervicitis. Chemotherapy 36, 7-6. Oriel, J. D. & Ridgway, G. L. (98). Genital Infections by Chlamydia Trachomatis. Arnold, London. Poulin, S. & Kundsin, R. B. (99). Susceptibility of Ureaplasma urealyticum and Mycoplasma hominis to (Cl-978, AT-44). European Journal of Microbiology and Infectious Diseases Special Issue, Renaudin, H. & Bebear, C. (99). Activite in vitro de la sur les mycoplasmas. Pathologie et Biologie 4, Spaepen, M. S. & Kundsin, R. B. (966). Simple, direct broth-disk method for antibiotic susceptibility testing of Ureaplasma urealyticum. Antimicrobial Agents and Chemotherapy, Taylor-Robinson, D. (983). The role of mycoplasmas in non-gonococcal urethritis: a review. Yale Journal of Biological Medicine 56, Taylor-Robinson, D., Czonka, G. W. & Prentice, M. J. (977). Human intraurethral inoculation of ureaplasma. Queensland Journal of Medicine 83, Taylor-Robinson, D. & McCormack, W. M. (98). The genital mycoplasmas. New England Journal of Medicine 3, Wakes, K. B., Duffy, L. B., Schmid, T., Crabb, D., Pate, M. S. & Cassel, G. H. (99). In vitro susceptibilities of Mycoplasma pneumoniae, Mycoplasma hominis and Ureaplasma urealyticum to and PD 739. Antimicrobial Agents and Chemotherapy 35, 8-5. Woolley, P. D. (99). Recent advances in non-gonococcal urethritis: pathogenesis, investigation and treatment. International Journal of STD and AIDS, Downloaded from at Pennsylvania State University on April 3, 4