Effects of dosing frequency on the clinical efficacy of ampicillin/sulbactam in Japanese elderly patients with pneumonia: A single-center retrospective observational study.

This study sought to investigate whether dosing frequency (the number of doses per day) affects the antimicrobial efficacy and safety of ampicillin/sulbactam (ABPC/SBT) in Japanese elderly pneumonia patients treated with ABPC/SBT at 6 g/day. This was a retrospective observational study that included hospitalized elderly patients (aged ≥75 years, 10 ml/min ≤CLcr <50 ml/min) who received 3 g every 12 h (BID; n = 61) or 1.5 g every 6 h (QID; n = 45) for the treatment of pneumonia. The primary endpoint was clinical response, assessed by measuring body temperature, white blood cell count, and C-reactive protein levels. Pharmacokinetic and pharmacodynamic simulations were conducted in silico to rationalize the clinical findings. The clinical response rates (extremely effective and effective) in the BID and QID groups were 36.1% and 55.6%, respectively (p = .0459). QID tended to be more effective in patients with gram-negative rods detected (p = .0563). According to the simulated minimum plasma ABPC concentrations at steady state for BID and QID were 2.5 and 7.3 µg/ml, respectively (p < .0001). Based on the simulated time above minimum inhibitory concentration (MIC), pharmacological (not clinical) efficacy was predicted to be higher with QID. Both groups had similar safety profiles. The main adverse event in both groups was liver damage. The present retrospective survey demonstrated that ABPC/SBT treatment for elderly patients with pneumonia and renal dysfunction was more effective with QID than with BID. Therefore, the QID regimen is worthy of consideration to improve the clinical outcomes of ABPC/SBT therapy in the present patient population.

Effect of surfactants or a water soluble polymer on the crystal transition of clarithromycin during a wet granulation process.

To generate products containing a stable form of clarithromycin (CAM) (form II) regardless of the initial crystal form of CAM or type of granulation solvent, the effects of five surfactants, or a water-soluble polymer (macrogol 400) were determined on the crystal transition of CAM. The metastable form (form I) was kneaded with water, after adding surfactants, or a water-soluble polymer. Form II was also kneaded with ethanol, after adding the same additives. The resulting samples were analyzed by powder X-ray diffraction. Form I was completely converted to form II by a wet granulation using water with additives bearing polyoxyethylene chains such as polysorbate 80 (PS80), polyoxyl 40 stearate or macrogol 400. The granulation of the form II using ethanol with these additives did not result in a crystal transition to form I. Furthermore, CAM tablets were manufactured using granules with PS80, and these crystal forms and dissolution behaviors were investigated. As a result, the wet granulation of CAM with PS80 gave CAM tablets containing only form II and PS80 did not have any adverse effects on tablet characteristics. Therefore, these data suggests that the crystal form of CAM can be controlled to be form II using a wet granulation process with additives bearing polyoxyethylene chains regardless of the initial crystal form of CAM or type of granulation solvent.

Optimal dose finding of garenoxacin based on population pharmacokinetics/pharmacodynamics and Monte Carlo simulation.

PURPOSE: Garenoxacin, a novel des-F(6)-quinolone, possesses potent antibacterial activity against infectious pathogens in the respiratory tract. Population pharmacokinetic/pharmacodynamic (PK/PD) modeling and Monte Carlo simulations were used to optimize garenoxacin dosage regimens. METHODS: At the end of phase II stage, the clinical dose of garenoxacin was predicted to be 400 mg once daily by the interim PK/PD analysis using phase I and phase II clinical data. The criteria used to determine an optimal dose were (1) the target attainment of the area under the unbound concentration-time curve divided by the minimum inhibitory concentration (fAUC0₋24/MIC ratio) and (2) the maintenance of a trough concentration above the mutant prevention concentration. In a confirmatory phase III study, garenoxacin was administered 400 mg once daily to 136 patients infected with mild or moderate chronic respiratory diseases. RESULTS: Logistic regression analysis showed that fAUC0₋24/MIC ratio was a significant variable that predicted clinical response (p = 0.0164). Of all subjects, 92.4% reached the target value of fAUC0₋24/MIC ratio > 30 h, and the clinical efficacy rate of this population was 91.8%. On the other hand, there was no significant relationship between exposure values (AUC0₋24 and maximum concentration) and the incidence of adverse events by the Mann-Whitney test. CONCLUSIONS: The antimicrobial efficacy of the actual phase III study was consistent with the expectation from the Monte Carlo PD simulation. We were able to show that the optimal garenoxacin dosage regimens were successfully determined using prospective population PK/PD analysis and clinical trial simulations.

[Efficacy of tosufloxacin in genital chlamydial infections].

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 150 mg b.i.d. (300 mg/day) for 7 days, we performed a comparative multicenter open label study of 150 mg b.i.d. and 300 mg q.d. (300 mg/day). The results indicated complete efficacy with 100% (150 mg b.i.d.: 49/49, 300 mg 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 150 mg b.i.d. group, while these values were 59.6% (34/57), 40.4% (23/57) and 0% (0/57), respectively, in the 300 mg q.d. group. Quinolone therapy for genital chlamydial infections with tosufloxacin doses of 150 mg b.i.d. was confirmed to be effective as recommended in the guidelines. Moreover, tosufloxacin at 300 mg q.d. was shown to be an effective therapy.