The Treatment ofnon-gonococcal Urethritis with Single Dose Oral Azithromycin

The Journal of International Medical Research 1995; 23: 386-393 The Treatment ofnon-gonococcal Urethritis with Single Dose Oral Azithromycin T ERDOGRU\ A AGA9FIDAff, M ONELz,S BADUR z, 0 ANG 2 AND S TELALLOGLU 1 "Department of Urology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; 2Department of Microbiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey In an uncontrolled study, the efficacy ofazithromycin in the treatment of was assessed in 41 male patients aged between 20 and 40 years with a mean age of 27 ± 5 years. Clinical and microbiological diagnosis confirmed that 28 men were found positive for Chlamydia trachomatis, 10 for Ureaplasma urealyticum and three for both C. trachomatis and U. urealyticum. All patients received 1 g azithromcyin orally (four 250 mg capsules). The length of time between the treatment and following visits were 7-10 days and 14-21 days for second and third visits, respectively. Complete eradication was achieved in 27 out of 41 patients. Of the remaining 14, six were found positive for C. trachomatis and were excluded as they did not return for the follow-up visit, one patient did not achieve complete eradication, one patient infected with both C. trachomatis and U. urealyticum failed to achieve complete eradication, and six patients infected with U. urealyticum failed to be completely cured. No adverse effects were reported in any patient. Single dose administration of 1 g azithromycin appears to be an 386

T Erdogru et al. effective and well-tolerated treatment for chlamydial urethritis and an advantage in terms ofpatient compliance. KEY WORDS: NON-GONOCOCCAL URETHRITIS; AZITHROMYCIN- TREATMENT INTRODUCTION Chlamydia trach amatis and Ureaplasma urealyticum are the most common causes of.':' C. trachomatis causes both urethritis and cervicitis in sexually active adults as well as epididymitis, endometritis, acute salpingitis, ectopic pregnancy and obstructive infertility in women.i-' C. trachomatis is a slow growing, obligate intracellular organism which is difficult to treat as the cells release new elementary bodies into the extracellular environment. Medication needs to be present over several days in order to penetrate the intracellular inclusions.':' Currently recommended treatment regimens for have major drawbacks, as antibiotics have to be administered in multiple doses and over several days, incurring the potential problem of non-compliance," Azithromycin is the prototype of a new group of antibiotics known as azalides. It differs structurally from the macrolide erythromycin by the insertion of a methyl-substituted nitrogen at position 9a in the lactone ring, creating a 15-membered ring structure. In vitro, azithromycin has good activity against C. trachomatis with a minimal inhibitory concentration of 0.03-0.25 mg per litre." - 9 Azithromycin also has good in vitro activity against other sexually transmitted pathogens, including U. urealyticum. More importantly it has good bioavailability with sustained high levels in tissue after a single oral dose. 1 o,11 In recent studies, tissue levels of 1.44 mg and 2.54 mg of azithromycin per gram were measured in the female genital tract and prostate, respectively, after a single 500 mg dose of the drug. The halflife in the female genital tract was 67 hand 60 h in the prostate.f:" This pharmacokinetic profile suggests that azithromycin may be effective after even a single dose. The aim ofthis study is to evaluate the efficacy, safety and tolerability of azithromycin 1 g single dose in the treatment of males with non-gonococcal urethritis. PATIENTS AND METHODS The Faculty Ethics Committee approved the open non-comparative study. A total of 69 male patients suffering from urethritis were screened confirming 41 patients (59.42%) both clinically and microbiologically with. A medical history was taken and physical examination performed on each patient; individuals were asked about the frequency of intercourse, number of partners and condom use. Patients were evaluated clinically and microbiologically on the first day. Urethral discharge, dysurea, itching, meatal erythema and frequency were assessed and rated on a 4 point scale: 0 absent; 1-mild; 2-moderate, 3-severe. 5 Concomitant conditions and medications were investigated in every patient with full examination of urine and blood before treatment and follow-up visits were arranged. Four samples were collected from the 387

T Erdogru et al. urethra: two for enzyme immuno-assay (EIA) and Direct Fluorescent Assay (DFA) for C. trachomatis, one for Gram stain and microscopy, and one for Neisseria gonotrboeoe and U. ureolyticum culture. Both assays were performed according to the manufacturer's instructions (kits were supplied by Syva, Micro Trak, USA). Cultivation of U. urealyticum and N. gonortboeae was performed in ureaplasma broth and placental-blood agar, respectively. The inclusion criteria were male outpatients between 18-60 years of age suffering from confirmed both clinically and microbiologically. The exclusion criteria were: patients with gonococcal urethritis; patients receiving another antimicrobial agent within 2 weeks prior to enrollment into the study, unless there was a documented failure of the other agent; patients with any other specific urethritis, e.g. trichomonas; patients known to be allergic to macrolides or azithromycin; treatment with any investigational drug within 1 month prior to enrollment into the study; concurrent treatment with ergotamine or carbamazipine: and evidence of an intestinal condition that may affect the absorption of the study drug. Patients gave an oral informed consent before entering the study. The use of a condom in order to avoid unprotected intercourse with an untreated partner was recommended during the treatment and follow-up periods so as to minimize the risk of reinfection. Patients received azithromycin 1 g (CP-62, 993-Pfizer) orally as a single dose (four capsules x 250 mg) 1 h before or 2 h after meals. On completion of therapy, patients were seen for follow-up on day 7-10 (second blind visit) and on day 14-21 (third visit) for clinical and microbiological assessments. After treatment, EIA and DFA were performed for C. tracnomatis. In addition, isolation of C. ttuchomatis, which included a second blind passage, was also performed as described by Ripa & Mardh" for confirmation of the antigen detection tests. The FIGURE 1 Urethral discharge Absent Mild o Moderate Severe The effect of singledose oral 1 g azlthromycln on urethral discharge of 35 males with. 388

T Erdogru et a1. monolayers were stained with iodine and examined under the microscope for intracellular chlamydial inclusion bodies. Treatment was judged successful when the culture and at least one of the non-culture tests was negative and there was no clinical sign of urethritis. The clinical efficacy of the treatment was assessed as follows: cure (disappearance of all base-line signs); improvement (reduction without complete disappearance of base-line signs); failure (no improvement and reinfection unlikely i.e. no new sexual contact); relapse (partial or complete disappearance of symptoms), but reappearance on control, second, or third visit, and unevaluable (patients with new sexual contacts and no condom use). The patients with base-line cultures positive for C. trachomatis or U. urealyticutn were assessed for their microbiological response as follows; eradication, eradication with recurrence and resistance. Patients were questioned on treatment compliance and adverse events. RESULTS Screening took place of 69 patients in this study. Confirmed gonococcal infections and other bacteria excluded 28; 41 patients (59.42%) were positive for C. trachomotis, U. urealyticum. Their ages range between 20 40 years with a mean age of 27 ± 5 years. The duration of illness varied between 1 and 16 weeks with a mean duration of 5.1 ± 3.5 weeks. The disease was acute in 39 cases (95%) and acute exacerbation or chronic in two cases (5%). Twenty-eight cases were found positive for C. trachotuatis (68%), 10 for U. urealyticum (24'Yc,J and three for both C. trachoniatis and U. urealyticutn (7%). After a single dose of 1 g azithromycin treatment, six patients who were infected with C. trachomatis were excluded from the study because they did not return for any followup visits, leaving 22 patients with chlarnydial urethritis available for evaluation after treatment. FIGURE 2 Itching Absent Mild o Moderate Severe 3rd visit The effect of single dose oral 1 g azlthromycln on Itching of 35 males with nongonococcal urethritis. 389

T Erdogru et al. The effect of azithromycin treatment on different signs and symptoms (urethral discharge, itching, dysuria and meatal erythema) were evaluated on the second and third visits after therapy (Figures 1-4). Clinical improvement or resolution of symptoms occurred in 20 out of the 22 patients (91 %) with chlamydial urethritis on the second visit. Clinical relief was also achieved in those patients. On the second visit (7-10 days) after treatment six patients out of 10 (60'}\,) were still positive for U. urealyticum, two were still positive for mixed C. trachomatis and U. urealyticum and two out of 22 (9%) for C. trachomatis. On the third visit (14-21 days after treatment) only one patient remained positive out of 22 (5%) for C. trachomatis and only one patient out of three for mixed C. trachomatis and U. urealyticum. The cumulative eradication rate with azithrornycin was 95% (21 out of 22) in the chlamydia! urethritis group. Overall eradication rate was 92% (23 out of 25), 22 C. trachomatis, and three C. trachomatis and U. urealyticum. No concomitant conditions and medications were reported in any patient. Two patients presented with mild gastrointestinal symptoms and abdominal pain but otherwise no adverse effects due to treatment were reported. Among the laboratory tests no clinically significant changes were detected. DISCUSSION Sexually active adolescents have the highest reported rates of genital chlamydiai infec- FIGURE 3 35 Meatal erythema Absent Mild E:I Moderate Severe 3rd visit The effect of single dose oral 1 g azlthromycln on meatal erythema of 35 males with. 390

T Erdogru et at. tion; the prevalence ranges from 6-35%.15.1fi The relatively long growth cycle of C. trachomatis of 48-72 h has important implications for therapy because of the need to ensure adequate drug levels throughout the cycle. Azithromycin has a unique pharmacokinetic profile characterized by excellent oral bioavailability and tissue levels that are sustained at high levels after a single dose; its half-life in genital tissue and prostate is 60 h or longer.":" Doxycycline, tetracycline and erythromycin do not produce sustained high-tissue concentration to the same degree and multiple doses must be administered to maintain adequate intracellular levels of drug. Current treatment requires multiple dose regimens with these drugs but compliance is frequently poor. Adequate treatment depends on patients compliance in non -gonococcal urethritis. Azithromycin achieves high concentrations in phagocytic cells and in fibroblasts. It appears that fibroblasts serve as a reservoir of azithromycin in tissues, allowing activity against organisms and possibly transferring it to phagocytic cells for activity against intracellular pathogens and delivery to infection sites." In this study, after 1 week of treatment, complete cure with eradication of infecting pathogens was observed in 20 out of 22 patients only infected with C. trachomatis (91 %). The eradication rate increased to 95% (21/22) at the third visit. However, only four of ten patients with U. ureajyticum were completely cured (40%) while the other six did not respond (60%). Two cases with mixed C. trachomatis and U. ureajyticum were cured. The cumulative eradication rate of the U. ureajyticum-positive group after 3 weeks of treatment (40%) is clearly lower than that reported by Lauharanta et aj. 5 and Steingrimsson et al." We conclude that the number of males with urethritis caused by U. FIGURE 4 Dysuria Absent Mild III Moderate D Severe 5 The effect of single dose 1 g oral azlthromycln on dysuria of 35 males with nongonococcal urethritis. 391

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