International Journal of Urology (2009) 16, 215216

doi: 10.1111/j.1442-2042.2008.02196.x

Short Communication

Azithromycin treatment for nongonococcal urethritis negative for Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum
Shin-ichi Maeda,1 Mitsuru Yasuda,2 Shin Ito,3 Kensaku Seike,1 Shin-ichi Ito2 and Takashi Deguchi2
1 Department of Urology, Toyota Memorial Hospital, Toyota, Aichi, 2Department of Urology, Graduate School of Medicine, Gifu University, Gifu and 3Ai Clinic, Sendai, Miyagi, Japan

Abstract: Some patients with nongonococcal urethritis (NGU) are negative for Chlamydia trachomatis, mycoplasmas, and ureaplasmas. The optimal antimicrobial chemotherapy for such NGU has not fully been claried. We assessed the efcacy of azithromycin for treatment of nonmycoplasmal, nonureaplasmal, nonchlamydial NGU (NMNUNCNGU). Thirty-eight men whose rst-pass urine was negative for Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum were treated with a single dose of 1 g azithromycin. Urethritis symptoms and polymorphonuclear leukocytes in urethral smears or in rst-pass urine were assessed before and after treatment with azithromycin. Thirty-two (84.2%) of the 38 men with NMNUNCNGU showed no signs of urethral inammation after treatment. The efcacy of this azithromycin regimen was comparable to that of the 7-day regimen of levooxacin, gatioxacin, minocycline, or clarithromycin reported previously. A single dose of 1 g azithromycin, which is effective not only for NGU due to specic pathogens but also for NMNUNCNGU, is an appropriate treatment for NGU. Key words: azithromycin, Chlamydia trachomatis, mycoplasmas, nongonococcal urethritis, ureaplasmas. (Sendai, Japan) between July 2004 and June 2006 in the NGU study. All patients provided informed consent for participation in the NGU study. We enrolled 50 Japanese men with NMNUNCNGU in the present study from the NGU study. All patients showed symptoms (e.g. miction pain, urethral itching or urethral discomfort) and urethral discharge compatible with acute urethritis. In all patients, ve or more PMNL per high-power eld (hpf) (1000) were observed on Gram-stained urethral smears or 15 or more PMNL per hpf (400) were observed in the sediments of rst-pass urine. Gonorrhea was excluded by microscopy and either culture or a commercially available polymerase chain reaction (PCR)-based assay (AMPLICOR CT PCR, Roche Molecular Systems, Branchburg, NJ, USA). The presence of C. trachomatis was tested with PCR-based assay from rst-pass urine samples. Other portions of the rst-pass urine samples were assessed for the presence of M. genitalium, M. hominis, Ureaplasma (U.) parvum (biovar 1), and U. urealyticum (biovar 2) by PCR-based assays as previously reported.10 No patient had received antibiotic treatment within 3 months of visiting the clinic. We treated patients with a single dose of 1 g azithromycin. We instructed patients to practice sexual abstinence for one week and told them to return for re-examination one week later regardless of the presence or absence of symptoms. At the second visit (day 710), we examined the patients for symptoms and obtained urethral smears or rst-pass urine. NMNUNCNGU was considered cured if there were 4 PMNL per hpf in urethral smears (1000) or in sediments of the rst-pass urine (400). If there were 5 PMNL per hpf, NGU was treated with 200 mg gatioxacin twice daily for 7 days or we recommended re-examination one week later without any additional treatment. At successive visits, we assessed the patients with the procedure described above.

Introduction
Chlamydia (C.) trachomatis is one cause of acute nongonococcal urethritis (NGU). Recently, mycoplasmas and ureaplasmas, particularly Mycoplasma (M.) genitalium and Ureaplasma urealyticum (biovar 2),1,2 have been suggested as pathogens of NGU. In 2030% of NGU cases, however, possible pathogens are not identied.2 Many studies of antimicrobial chemotherapies for C. trachomatis-positive NGU have been performed , and treatment of patients with M. genitalium-positive NGU with a variety of antimicrobial agents was recently reported.1,3,4 However, there have been only a few studies evaluating the efcacies of anitmicrobial agents on NGU in which specic pathogens have not been identied. With respect to treatment for NGU negative for C. trachomatis, genital mycoplasmas and ureaplasmas, we previously reported the efcacies of agents active against C. trachomatis, including levooxacin, gatioxacin, minocycline, and clarithromycin.5 Azithromycin also has good activity against C. trachomatis, and a single dose of 1 g azithromycin is highly effective against chlamydial NGU.68 Recently, this regimen was evaluated for treatment of M. genitalium-positive NGU.3,4,9 However, there have not been any studies reporting its clinical efcacy for treatment of nonmycoplasmal, nonureaplasmal, nonchlamydial NGU (NMNUNCNGU). In the present study, we treated 38 men with NMNUNCNGU with a single dose of 1 g azithromycin. To assess the efcacy of this regimen, we examined the men for symptoms of urethritis and the presence of polymorphonuclear leukocytes (PMNL) in urethral smears or in rstpass urine before and after treatment.

Methods
We enrolled the Japanese men with NGU who visited the Department of Urology at Toyota Memorial Hospital (Toyota, Japan) or Ai Clinic
Correspondence: Mitsuru Yasuda MD PhD, Department of Urology, Division of Disease Control, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu City, Gifu 501-1194, Japan. Email: super7@gifu-u.ac.jp Received 28 April 2008; accepted 24 September 2008.

Results
The 50 patients with NMNUNCNGU ranged in age from 19 to 57 years (mean, 33.8 years). Thirty-eight of the 50 patients with NMNUNCNGU returned for re-examination after treatment. Clinical
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Table 1 Symptoms and polymorphonuclear leukocytes (PMNL) in urethral smears or rst-pass urine in men with nonmycoplasmal, nonureaplasmal, nonchlamydial, nongonococcal urethritis after treatment with a single dose of 1 g azithromycin Symptoms No. men with PMNL in urethral smears or in rst-pass urine 04 PMNL Resolved Persistent 29 3 5 PMNL 4 2 No. men with normalization of urethral PMNL/No. men treated with the agent (%)

32/38 (84.2)

outcomes and PMNL responses in urethral smears or rst-pass urine from these 38 men are summarized in Table 1. Thirty-two (84.2%) of the 38 men with NMNUNCNGU showed no signs of urethral inammation after treatment, but three complained of some symptoms of urethritis (Table 1). Six (15.8%) of the 38 men had signicant numbers of PMNL in urethral smears or rst-pass urine, but four of these six men showed no symptoms. The two men with positive urethral smears and symptoms were treated with gatioxacin for 7 days, and the remaining four men were not treated with any antibiotics. The two men returned after the second treatment and had negative urethral smears. Only one of the four men not re-treated returned and had a negative urethral smear.

Discussion
Azithromycin is an acid-stable antibiotic with good bioavailability. This agent is concentrated rapidly within tissues and cells and is subsequently released slowly with a half-life of 5676 h.8 In addition, phagocytic cells accumulate azithromycin, deliver it to sites of infection, and release it slowly, further increasing the local drug concentration.8 Based on these characteristic pharmacokinetics and the good antimicrobial activity against C. trachomatis, administration of a single-dose azithromycin has been used to treat genital chlamydial infections. Therefore we decided the second visit would be day 710 because the effect of azithromycin would have disappeared and the result of the PCR-based assay would have been clear about 7 days after the rst visit. The microbiological cure rates of a single dose of 1 g azithromycin in patients with chlamydial NGU have been reported to range from 83% to 100%.3,68 This regimen is highly effective against chlamydial NGU. With respect to treatment of M. genitalium-positive NGU with a single dose of 1 g azithromycin, the microbiological eradiation rates for M. genitalium are reported to be 8285%.1,4,9 Recently, however, failure of this regimen to eradicate M. genitalium associated with reduced susceptibility to azithromycin has been observed.9 The microbiological eradiation rates for U. urealyticum with this regimen are reported to be 7387%.3,6,7 In our present study, the efcacy of a single dose of 1 g azithromycin for normalization of urethral smears or rst-pass urine at the second visit was 84.2%. In our previous study,8 we reported clinical efcacies of various antimicrobial agents in the treatment of 100 patients with NMNUNCNGU, including 12 patients treated with 100 mg minocycline twice daily, 43 treated with 200 mg clarithromycin twice daily, 29 treated with 100 mg levooxacin three times daily, and 16 treated with 200 mg gatioxacin twice daily for 7 days. The efcacy for normalization of urethral smears after treatment was 75.0% for minocycline, 90.7% for clarithromycin, 89.7% for levooxacin, and 87.5% for gatioxacin. The efcacy of a single dose of 1 g azithromycin is compatible with that of the 7-day regimen of minocycline, clarithromycin, levofloxacin, or gatioxacin.
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In clinical settings, in addition to the difculty of the point-of-care test of C. trachomatis at the time of treatment for NGU, sensitive and rapid tests for detection of genital mycoplasmas and ureaplasmas are not available commercially. Therefore, prescription of a single dose of 1 g azithromycin, which is effective against not only pathogen-specic NGU but also NMNUNCNGU, is appropriate for treatment of patients with NGU. In addition, patient compliance with a single-dose regimen may have signicant advantages in clinical practice because there is a risk of poor compliance with a week-long chemotherapy regimen, resulting in treatment failure. The limitations of our present study are the small number of participants, the lack of detection of other possible pathogens, including Trichomonas vaginalis and viruses, and insufcient follow up in most patients after treatment. Further studies are needed; however, our present results may be helpful for establishing protocols for management of patients with NGU, including NMNUNCNGU.

References
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2009 The Japanese Urological Association