Yasuaki Kubota

Threat to Cefixime Treatment for Gonorrhea

To the Editor: From November 2002 through May 2003, 4 Japanese men, ranging in age from 23 to 45 years, visited the Department of Urology at Toyota Memorial Hospital, Toyota, Japan. Physical examinations showed urethral discharge and dysuria. Each had had sexual contact with sex workers in central Japan. Four strains of Neisseria gonorrhoeae were isolated from urethral specimens. Treatment comprised 200 mg cefixime, twice a day for 3 days. However, all 4 patients returned to the clinic with continuing symptoms, despite having completed the prescribed course of cefixime and abstaining from sexual activity. N. gonorrhoeae was again isolated from urethral swabs. Each patient was then treated with 1 g intravenous ceftriaxone. In the 3 patients who returned to the clinic for followup, the ceftriaxone treatment resulted in clinical and microbiologic cure. Pulsed-field gel electrophoresis (PFGE) analysis of the SpeI-digested DNAs of N. gonorrhoeae was performed to assess the relatedness of pre- and posttreatment isolates (1). For these 8 isolates, MICs of penicillin G, tetracycline, cefixime, cefdinir, cefodizime, ceftriaxone, levofloxacin, azithromycin, and spectinomycin were determined on chocolate agar (GC) medium base supplemented with 1% IsoVital X (Becton Dickinson, Franklin Lakes, NJ, USA) and containing serial 2-fold dilutions of each agent (2). Media were inoculated with 104 CFU and incubated at 35°C in 5% CO2 overnight. The MIC was defined as the lowest concentration inhibiting growth to <1 CFU. β-lactamase activity of the isolates was tested with a nitrocefin disk. The nucleotide sequences of the full-length penA gene encoding the penicillin-binding protein 2 (PBP 2) were identified in the isolates (1). Briefly, genomic DNAs from each isolate were subjected to PCR to amplify 3 fragments of the penA gene of N. gonorrrhoeae. PCR products were sequenced by the dye terminator method and with an automatic sequencer. In each of the 4 cases, the PFGE patterns of the pre- and posttreatment isolates had the same numbers of bands (12–16 fragments), and the corresponding bands were the same apparent size; the pre- and posttreatment isolates were indistinguishable (3). MICs of antimicrobial agents for the 8 isolates are shown in the Table. All isolates were enzymatically negative for β-lactamase and possessed identical mosaic alterations in PBP 2. The mosaic PBP 2 was composed of fragments of PBP 2 from N. cinerea and N. perflava and was identical to that identified in our previous study (1). Table Antimicrobial drug susceptibilities of clinical isolates of Neisseria gonorrhoeae from patients with gonococcal urethritis treated unsuccessfully with a 3-day cefixime regimen* Until recently, Japanese guidelines recommended oral administration of cefixime, 200 mg twice a day for 3 days to prolong the period of time for which the serum drug concentration remains above the MIC (4). However, treatment failure with this cefixime regimen was observed in our 4 cases of gonorrhea. The isolates showed cefixime MICs of 0.5–1 μg/mL and harbored mosaic alterations in PBP 2. Most recently, the emergence and spread of such strains in Japan (1,5,6) have led to the recommendation that ceftriaxone and spectinomycin should be used as the primary therapy for gonorrhea instead of oral cephalosporins (7). In 2001, treatment failure was reported in a Caucasian man residing in Hawaii who had been given a single 400-mg dose of cefixime for gonorrhea (8). Pre- and posttreatment strains of N. gonorrhoeae were recovered from this patient, and 1 strain was isolated from his Japanese female sex partner who had visited Hawaii from Japan. Another pretreatment strain was isolated from a Micronesian man with gonorrhea residing in Hawaii, who had had sex with a woman from Malaysia or the Marshall Islands. This man was successfully treated with a single 400-mg dose of cefixime. For these strains, MICs of penicillin, tetracycline, spectinomycin, cefixime, ceftriaxone, ciprofloxacin, and azithromycin were 8.0, 4.0–8.0, <32, 0.25–0.5, 0.125, 8–16, and 0.125–0.25 μg/mL, respectively. The antibiograms of these strains in Hawaii were similar to those of strains with mosaic PBP 2 found in our 4 patients. The introduction to Hawaii of such multidrug resistant strains might be related to sex partners from Asia. Although the strains were not analyzed for alterations in PBP 2, they could have been derived from strains with cefixime resistance-associated mosaic PBP 2. The strains with mosaic PBP 2 showed such decreased susceptibility to cefixime that they were not effectively eradicated by the 3-day treatment. Although it is not clear whether these strains are also resistant to the single 400-mg dose of cefixime (8, 9), their emergence and spread could threaten treatment for gonorrhea with cefixime (10). Global emergence and spread of such multidrug-resistant strains of N. gonorrhoeae would be a matter of serious concern. The antimicrobial susceptibilities of current gonococcal isolates must be monitored periodically. In particular, posttreatment isolates from patients treated unsuccessfully with cefixime should be surveyed.

Quantitative detection of Ureaplasma parvum (biovar 1) and Ureaplasma urealyticum (biovar 2) in urine specimens from men with and without urethritis by real-time polymerase chain reaction.

Background: We previously reported a significant association between Ureaplasma urealyticum (biovar 2) and nongonococcal urethritis (NGU). We also found that the presence of Ureaplasma parvum (biovar 1) in the male urethra might be the result of colonization. Objective: The objective of this study was to clarify the pathogenic role of human Ureaplasma in NGU by assessing the association of bacterial loads with clinical findings and inflammatory responses in the urethra. Study Design: The 16S rRNA gene of Ureaplasma was quantified by a TaqMan-based real-time polymerase chain reaction assay in first-pass urine from 37 men with Ureaplasma-positive nonmycoplasmal nonchlamydial NGU (NMNCNGU) and 30 Ureaplasma-positive men without urethritis. Results: U. urealyticum (biovar 2) loads in 23 men with NMNCNGU were significantly higher than those in 14 men without urethritis. However, U. parvum (biovar 1) loads did not differ significantly between 14 men with NMNCNGU and 20 men without urethritis. Conclusion: The association of increased U. urealyticum (biovar 2) loads with symptomatic urethritis suggests that U. urealyticum (biovar 2) may be a pathogen of NGU. Our results also suggest that the presence of U. parvum (biovar 1) may not be significant in the development of NGU.

Polymerase chain reaction-based subtyping of ureaplasma parvum and ureaplasma urealyticum in first-pass urine samples from men with or without urethritis.

Background: Our previous study suggested a significant association between Ureaplasma urealyticum and nongonococcal urethritis (NGU). However, association of the serovars of U. urealyticum with NGU remains unclear. A polymerase chain reaction (PCR)-based assay can distinguish 4 serovars of Ureaplasma parvum from each other and categorize 10 serovars of U. urealyticum into 3 subtypes: subtype 1 (serovars 2, 5, 8, and 9), subtype 2 (serovars 4, 10, 12, and 13), and subtype 3 (serovars 7 and 11). Goal: The goal of this study was to determine which subtypes of U. urealyticum are associated with NGU as determined by PCR-based assay. Study: The prevalence of U. urealyticum subtypes in 106 ureaplasma-positive men with urethritis was compared with that in 30 ureaplasma-positive men without urethritis. Results: In men with nonchlamydial NGU and men with Mycoplasma genitalium-negative nonchlamydial NGU, only U. urealyticum subtype 1 (serovars 2, 5, 8, and 9) was detected significantly more often than in men without urethritis. Conclusion: This study suggests that subtype 1 of U. urealyticum (serovars 2, 5, 8, and 9) is associated with NGU independently of Chlamydia trachomatis or M. genitalium.

The potential role of prebiopsy magnetic resonance imaging combined with prostate-specific antigen density in the detection of prostate cancer.

Aim:  Two‐thirds of patients with a gray‐zone prostate‐specific antigen (PSA) level undergo unnecessary biopsy. Sensitivity is not yet sufficient to permit the use of modified PSA parameters or magnetic resonance (MR) imaging alone for prostate cancer screening. Thus, we evaluated the combination of MR imaging and PSA density (PSAD) for specificity and sensitivity.

Relationship between prostate-specific antigen and obesity in prostate cancer screening: Analysis of a large cohort in Japan

Previous studies have shown that lower prostate‐specific antigen (PSA) levels in obese men might decrease the sensitivity of prostate cancer screening, leading to delayed diagnosis and unfavorable prognosis. We examined whether the effect of obesity is important in prostate cancer screening of Japanese men, who have a low prevalence of obesity. We analyzed 19 294 male subjects from a large cohort of Toyota Motor Corporation (TMC) employees (aged >50 years, serum PSA level ≤4.0 ng/mL) who underwent physical examinations from August 2006 to December 2009. The relationship between PSA level and obesity‐related factors was analyzed by simple and multiple regression analysis. The relationships between six body mass index (BMI) categories, and PSA level and PSA mass (PSA concentration × plasma volume) were analyzed. PSA level decreased significantly with increasing BMI, but the coefficient of determination was very low. Mean PSA values decreased from 1.02 to 0.85 ng/mL as BMI increased from underweight (BMI <18.5) to morbidly obese (BMI >35). However, PSA mass peaked in the overweight category and was slightly reduced with increasing BMI. On multiple regression analysis, PSA level was influenced by age, diastolic blood pressure and high‐density lipoprotein as well as BMI. We found an inverse but weak relationship between PSA level and BMI. Obesity seems to have very limited influence on prostate cancer screening in this population. Nonetheless, when considering indications for prostatic biopsy in obese men, we should be aware that the hemodilution effect might reduce PSA levels.

Treatment of men with urethritis negative for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum and Ureaplasma urealyticum

Objective:  Some patients with symptomatic non‐gonococcal urethritis (NGU) are negative for Chlamydia trachomatis, mycoplasmas and ureaplasmas. The optimal antimicrobial chemotherapy for such NGU has not fully been elucidated, though many studies of antimicrobial chemotherapies for C. trachomatis‐positive NGU have been performed. We assessed the efficacy of antimicrobial agents that are active against C. trachomatis on non‐mycoplasmal, non‐ureaplasmal and non‐chlamydial NGU (NMNUNCNGU).

Failure to detect urethral Trichomonas vaginalis in Japanese men with or without urethritis

Aim: Trichomonas vaginalis may cause symptomatic or asymptomatic urethritis in men. There are few recent studies on the prevalence of T. vaginalis infection in Japanese men, and quantification of the number of cases of urethritis attributable to this pathogen has not been performed in Japan. The aim of this study was to determine the prevalence and morbidity of T. vaginalis infection in Japanese men.

Prevalence and morbidity of urethral Trichomonas vaginalis in Japanese men with or without urethritis

Objectives Trichomonas vaginalis is one of the pathogens causing sexually transmitted infections. This microorganism is a common pathogen among women, but its significance as a cause of morbidity among men remains uncertain. We sought to determine the prevalence and morbidity of T. vaginalis infection in Japanese men with and without urethritis. Methods We examined urine specimens from 215 men with urethritis and 98 men without urethritis for the presence of urethral T. vaginalis by PCR assay. Results Only four patients—one with gonococcal urethritis, one with non-gonococcal chlamydial urethritis, one with non-gonococcal non-chlamydial urethritis and one without urethritis—were positive for T. vaginalis. The prevalence of T. vaginalis was 1.4% in men with urethritis and 1.0% in men without urethritis. A possible relation between the appearance of T. vaginalis and clinical symptoms was not confirmed. Conclusions In the present study, the incidence of urethral T. vaginalis infection appears to be rare in Japanese men with or without urethritis, and T. vaginalis may be an uncommon pathogen in male urethritis in Japan.