According to the 2006 and 2008 “Guidelines for diagnosis and treatment of sexually transmitted diseases” by the Japanese Society for Sexually Transmitted Diseases, quinolones, macrolides and tetracyclines are recommended to treat chlamydial infections. The administration method based on pharmacokinetic/pharmacodynamic theory, as well as the selection of antimicrobial drugs, is important in antimicrobial therapy. It is currently assumed that the efficacy of administering high-dose quinolones once a day is greater than dividing the dose over multiple administrations. To verify the treatment effects of the recommended tosufloxacin dose of 150mg b.i.d. (300mg/day) for 7 days, we performed a comparative multicenter open label study of 150mg b.i.d. and 300mg q.d. (300mg/day). The results indicated complete efficacy with 100% (150mg b.i.d.: 49/49, 300mg q.d.: 57/57) eradication of Chlamydia trachomatis at both dosages. The clinical efficacy was “markedly effective” in 57.1% (28/49) of cases, “effective” in 42.9% (21/49), and “not effective” in 0% (0/49) in the 150mg b.i.d. group, while these values were 59.6% (34/57), 40.4% (23/57) and 0% (0/57), respectively, in the 300mg q.d. group. Quinolone therapy for genital chlamydial infections with tosufloxacin doses of 150mg b.i.d. was confirmed to be effective as recommended in the guidelines. Moreover, tosufloxacin at 300mg q.d. was shown to be an effective therapy.

We investigated antifungal susceptibility of 96 Candida species strains (37 strains of Candida albicans, 30 of Candida glabrata, 16 of Candida tropicalis and 13 of Candida parapsilosis) isolated from patients with invasive fungal peritonitis. Antifungal activity showed micafungin (MCFG), voriconazole (VRCZ)>itraconazole (ITCZ)>fluconazole (FLCZ). Judged by clinical breakpoints of Clinical and Laboratory Standards Institute (CLSI), FLCZ-resistant C. albicans, ITCZ-resistant C. albicans and VRCZ resistant C. albicans were detected in the frequency of 5.4% (2/37), 21.6% (8/37) and 5.4% (2/37), respectively. We also retrospectively investigated the association of both antifungal susceptibility judged by CLSI breakpoints and clinical efficacy in 16 patients with invasive fungal peritonitis treated by injectable ITCZ. Clinical success and failure were obtained in cases of ITCZ MIC ≦1m g/mL and ≧4m g/mL, respectively. We conclude that we should re-consider CLSI breakpoints on ITCZ.

The aims of this study were to develop a population pharmacokinetic model for cefozopran in pediatric patients, and to use this model to evaluate the pharmacodynamics of cefozopran regimens against common bacterial populations. Plasma drug concentration data (110 samples from 31 pediatric patients) were modeled using the NONMEM program. The mean estimate and interindividual variance of the model were used in a Monte Carlo simulation to estimate the probabilities of attaining the bactericidal target for cefozopran (the time which the drug concentration remains above the minimum inhibitory concentration for the bacterium is 70% of the dosing interval). A two-compartment model fitted the data and body weight (BW, kg) was the most significant covariate. The final model was: Cl (l/h)=0.674×BW^0.538, V_c (l)=0.00233×BW^2.25+1.85, Q (l/h)=1.46, and V_p (l)=0.0964×BW, where Cl is the clearance, V_c, and V_p are the volumes of distribution of the central and peripheral compartments, and Q is the intercompartmental clearance. The approved regimens of 20- or 40-mg/kg four times a day (0.5-h infusions), which were more effective than the corresponding three times a day-regimens, provided sufficient bactericidal effects on common bacterial populations (Escherichia coli, Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas aeruginosa) in most typical patients. These results better define the pharmacokinetics of cefozopran and help in the choice of appropriate regimens for pediatric patients.

We present here a new model of Legionella pneumophila lung infection in DBA/2 mice. By intranasal inoculation with 10⁶ colony-forming units of L. pneumophila strain suzuki serogoup 1, persistent non-lethal lung infection was established as reflected by the detection of more than 10⁴ CFU/lung of the organism 14 days after infection. Treatment of mice with cyclophosphamide before infection enhanced bacterial replication in the lungs and all cyclophosphamide-treated mice experienced lethal infection. Histopathologically, the course of non-lethal lung infection was characterized by early response of neutrophiles, then monocyte/macrophages response in the alveoli with disease progression, and diffuse alveolar wall thickening with lymphocyte migration at later phase of infection. Transmission electron microscopic evaluation of the lungs confirmed that L. pneumophila located intracellularly within neutrophiles and infrequently intracellular bacteria were observed undergoing binary fission. Therefore, the mouse model of replicative L. pneumophila lung infection provides method for evaluating pathogenesis of L. pneumophila lung infection and antibacterial therapy.

The in vitro and in vivo antibacterial activities of levofloxacin (LVFX), a quinolone antibacterial, against clinically isolated Legionella pneumophila were investigated in comparison with those of existing antimicrobial agents approved for legionnaires disease.

The minimum inhibitory concentrations (MICs) of the agents against 42 strains of L. pneumophila isolated in Japan were determined using agar dilution methods with buffered starch yeast extract agar. MIC₉₀ of LVFX was 0.03𝜇g/ml and this activity was similar to ciprofloxacin and pazufloxacin, and higher than telithromycin and minocycline.

Therapeutic efficacy of LVFX was studied against a pneumonia model induced by intranasal of L. pneumophila strain suzuki serogoup 1 in DBA/2 mice. Therapeutic doses in mice were selected that would closely match human exposure profile, area under the concentration-time curve (AUC) for a human oral dose of LVFX at 500mg once a day. LVFX decreased significantly the bacterial burden in the lungs from the next day of commencing treatment.

These results, including in vitro antibacterial activity against clinical isolates and therapeutic efficacy of a humanized dosing regimen, provide good evidence to support the use of LVFX at 500mg once a day for treating patient with legionnaires disease.