A Clinical Practice Guideline for the Diagnosis and Management of Acute Otitis Media in Children, in view of the causative organisms of the disease and their drug susceptibility, was issued in March 2006. In the guideline, cefditoren pivoxil (CDTR-PI, Meiact MS^® fine granules 10% for pediatric use) is recommended as an oral cephem antibiotic for the treatment of the disease. To collect information on the appropriate use of the drug in the clinical setting after issuance of the guideline, we conducted a specific postmarketing study of CDTR-PI in pediatric patients with acute otitis media. With this study, 2144 patients were enrolled in 305 medical institutions. Of them, 2006 and 1958 patients were chosen for safety and efficacy analysis, respectively.

The incidence of adverse drug reactions was 1.79% (36/2006 patients). No unexpected or serious adverse drug reactions were reported by this study. The most common adverse drug reaction was diarrhea, which was reported in 26 cases (1.30%). The symptom resolved or subsided during CDTR-PI therapy or after discontinuation or completion of the therapy in all cases. The incidence of diarrhea in patients treated with CDTR-PI at 1.5- to 2-fold the usual dose was 2.70%, which was slightly higher than the usual dose, but that in patients more than 2-fold the usual dose was 1.92% which was not higher than 1.5- to 2-fold the usual dose. The incidence of diarrhea itself was not substantially high.

Concerning the clinical efficacy of CDTR-PI, the response rate was 93.5% (1831/1958 patients). Among 1217 strains from whom 832 patients were detected as causative organisms at baseline bacteriological examination, the response rate by causative organism was 89.7% for Streptococcus pneumoniae, 90.3% for Haemophilus influenzae, and 92.2% for Moraxella catarrhalis. Among documented eradication of 577 strains with 427 patients, the bacterial eradication rate by causative organism was 83.3% for S. pneumoniae, 87.1% for H. influenzae, and 88.9% for M. catarrhalis. For each major resistant strain, the response rate was 88.0% for penicillin-intermediate S. pneumoniae (PISP), 90.1% for penicillin-resistant S. pneumoniae (PRSP), and 92.5% for 𝛽-lactamase negative ampicillin-resistant H. influenzae (BLNAR), while the bacterial eradication rate was 85.7% for PISP, 77.5% for PRSP, and 81.8% for BLNAR.

In addition, 457 patients “without myringotomy” and “tympanic swelling or otorrhea rated as a severity score of 8” (symptoms emphasized in the guideline) were selected as a subpopulation allowing us to define the dose-efficacy relationship more clearly. In this subpopulation, the relationship between the dose and the efficacy of CDTR-PI was assessed. The assessment revealed that the response rate was significantly higher in patients with a mean daily dose of at least 13.5 mg/kg than in those with a mean daily dose below13.5 mg/kg.

In summary, CDTR-PI raised no noteworthy concerns about its safety or efficacy in pediatric patients with acute otitis media. These findings reconfirm the usefulness of the drug.

Since antimicrobial resistance in Streptococcus pneumoniae become serious problem, we have conducted the epidemiological analysis of Streptococcus pneumoniae in Gifu prefecture. We have investigated the mutations of penicillin-binding protein (PBP) cording genes, the mutations of macrolide-resistant cording genes, and antimicrobial susceptibility using broth microdilution method, for 345 strains isolated from clinical specimens between May 2006 and July 2006 at 12 clinical facilities of 5 medical area. The ratio of penicillin-susceptible S. pneumoniae (gPSSP), penicillin-intermediate S. pneumoniae (gPISP), and penicillin-resistant S. pneumoniae (gPRSP), which were judged by molecular techniques, were 7.2%, 53.5%, and 39.4%, respectively. Only 1 gPSSP strain was isolated from children under three years old. There have been regional differences of the isolation rate of gPRSP between Gifu/Chuno area (55～60%) and Tono/Hida area (23～32%) in second- or third-medical facilities. The isolation rate of PBP mutation genes, pbp2x, pbp1a and pbp2b, were 92.8%, 52.5% and 53.3%, respectively. The isolation rate of macrolide-resistant cording genes, mefA only, ermB only, and both mefA and ermB, were 30%, 50% and 8%, respectively. The strains of S. pneumoniae with both mefA and ermB mutations, increased from 4% in 2002 to 8% in 2006. The antimicrobial susceptibility of S. pneumoniae to penicillin G (PCG) showed two peaks around 0.03 and 1𝜇g/mL, and 89% of S. pneumoniae with minimum inhibitory concentration (MIC) value 1𝜇g/mL was gPRSP. The MIC values of PCG against 69% strains of gPRSP distributed between 0.25 and 1𝜇g/mL. There have been the decreased tendency for the differences among medical facilities in penicillin resistant strains. Although cefditoren showed the most effective antimicrobial activity in oral cephems tested, there have been the strains with MIC value of over 1𝜇g/mL. The MIC₉₀ of panipenem was 0.125𝜇g/mL, which was the best antimicrobial activity in carbapenems. The resistant rates of clarithromycin and azithromycin were 85% and 84%, respectively. The strains with the gene mutation of ermB have showed resistant to clindamycin. The MIC₉₀ of tosufloxacin was 0.25𝜇g/mL, which was the best antimicrobial activity in quinolones. We have detected 4 levofloxacin highly resistant S. pneumoniae, of which MIC value was over 32𝜇g/mL. Also, we have encountered the episode of the spread of S. pneumoniae in one family, which was clarified by scientific approach.

Yearly changes in the susceptibility of clinical isolates to ulifloxacin (UFX) and other fluoroquinolones were examined through surveys over 3 periods. In the first survey, 534 strains derived from 19 species were collected from clinical specimens during 6 months from December 2003 to May 2004. In the same way, 805 strains were collected from December 2005 to May 2006 in the second survey, and 863 strains were from December 2007 to May 2008 in the third survey.

Over these 3 study periods, the susceptibilities of fluoroquinolones against methicillin-susceptible Staphylococcus aureus and Escherichia coli were decreased. The isolation frequency of levofloxacin-nonsusceptible strain was increased from 0% to 11.8% and from 14.6% to 20.8%, respectively. MIC₉₀s of UFX against these pathogens were also increased, but its MIC₉₀ for E. coli was 2 to 4 times lower than that of levofloxacin. On the other hand, the susceptibility of strains of Klebsiella pneumoniae to UFX was increased. Among the fluoroquinolones tested, UFX showed the most potent activity against Pseudomonas aeruginosa, and no changes in the MIC₉₀s occurred during the surveillance. Although one strain of Streptococcus pneumoniae isolated in the third study period showed levofloxacin-resistance (MIC, 8𝜇g/mL), there were nearly no changes in the MIC₉₀s of any agents tested including UFX against S. pneumoniae during the surveillance. As for other bacterial species, a tendency to increase in resistance to UFX was not observed. The activity of UFX against Salmonella spp. and Shigella spp. was superior/equal to those of fluoroquinolones tested.

Three microsome enzymes are involved in voriconazole (VRCZ) metabolism, CYP2C19, CYP3A4 and CYP2C9, and subjects classified as poor metabolizers (PM), which would include about 20% of Japanese population, had higher serum VRCZ concentrations than other subjects. Also, because VRCZ appears hepatotoxicity and visual disturbance in side effect, VRCZ must be done therapeutic drug monitoring (TDM). This study evaluated the three cases which administered VRCZ to analysis for CYP2C19 gene. This study evaluated VRCZ trough concentration and side effect in the fifteen cases which administered VRCZ to analysis for TDM in Aichi University Hospital. Also, the administering design of VRCZ followed drug information in the three cases. Correlation of VRCZ trough concentration and dosage was weak in fifteen cases. In case 1, although patient is not PM, trough concentration of VRCZ showed high concentration (8.43𝜇g/mL) after 4 days of starting administration and appeared side effects of illusion and optical illusion. In case 2, although patient is PM, trough concentration of VRCZ showed 5.53𝜇g/mL and 8.61𝜇g/mL after 4 days and 7 days of starting administration, respectively, also liver function (AST, ALT and others) rised slightly. In case 3, although patient is not PM, trough concentration of VRCZ after the 5 days and 12 days of starting administration showed 3.2𝜇g/mL and 3.25𝜇g/mL, respectively, also maintained therapeutic trough lebel.

In this result, it was thought that pharmacokinetics of VRCZ was unstable comparatively and concentration of VRCZ varied generally among individuals regardless of the CYP2C19 genotype. Therefore, it was important to an individual patient to improve a clinical effect, and to decrease the adverse event from the initial administering design, and is necessary to do the administering design afterwards while doing TDM at many times.

This study evaluated the in vivo activity of liposomal amphotericin B (L-AMB) and deoxycholate amphotericin B (D-AMB) in a murine model of disseminated infection caused by Exophiala dermatitidis. Cyclophosphamide-treated neutropenic ddY mice were inoculated intravenously with conidial suspensions of E. dermatitidis IFM 4827 or IFM 53409. The maximum tolerated doses of L-AMB and D-AMB were set at 10mg/kg and 1mg/kg, respectively. Four hours after infection, a single dose of L-AMB (0.3 to 10mg/kg) or D-AMB (0.1 to 1mg/kg) was administered intravenously. The efficacy of the antifungal treatment was assessed by the survival time over two weeks and the tissue fungal burdens 4 days after infection. L-AMB at a dose of ≥1mg/kg significantly prolonged the survival time of mice infected with either strain compared with that of the control group. Percent survivals in the 10mg/kg L-AMB-treated group (100% and 75%) were higher than those in the 1mg/kg D-AMB-treated group (20% and 37.5%) in the IFM 4827 and IFM 53409 models, respectively. In the IFM 4827 model, 10mg/kg L-AMB exhibited greater efficacy than 1mg/kg D-AMB in terms of reducing the tissue fungal burdens (blood, lung, liver, spleen, and kidneys). These findings suggest that L-AMB was effective in the treatment of experimental disseminated E. dermatitidis infection, and the efficacy of L-AMB was superior to that of D-AMB.