The antimicrobial susceptibility of 339 isolates from the otorhinolaryngological infections at the otorhinolaryngological departments at 27 universities in Japan, as well as their 108 affiliated hospitals and practitioners during January 2007 to June 2007 was determined to garenoxacin (GRNX), levofloxacin, moxifloxacin, azithromycin, cefditoren, and cefcapene applicable for otorhinolaryngological infections. The in vitro activities of these drugs against the isolates were compared. The quinolones including GRNX were potently active against Streptococcus pneumoniae including penicillin-intermediate and -resistant strains (PISP and PRSP), Streptococcus pyogenes and methicillin-susceptible Staphylococcus aureus, except for MRSA, a major causative pathogens for otorhinolaryngological infection. When MIC ranges, MIC₅₀, MIC₈₀ and MIC₉₀ of three quinolones were compared, it was considered that GRNX was the most active of them. GRNX was potently active against Haemophilus influenzae and Moraxella catarrhalis same as that of other quinolones tested.

In conclusion, GRNX exhibits a potently active against fresh isolates from otorhinolaryngological infections, and has an effective potential in the treatment of otorhinolaryngological infections.

We studied the usefulness of Mycospor^® Cream 1% (hereinafter referred to as “bifonazole cream”), which was approved 20 years ago in Japan, with once-daily application in 16 patients with tinea pedis (plantar tinea pedis, n=8; interdigital tinea pedis, n=8). One of them discontinued after 2 weeks of study treatment due to aggravation of skin symptoms. This subject was excluded from assessment of mycological activity and skin-symptom improvement at 4 weeks after initiation of treatment, but included in overall clinical efficacy rating and usefulness rating as an “ineffective” and “useless” case. The mean (±SD) duration of study treatment among the 15 subjects (excluding the discontinued subject) was 26.5±2.3 days (range: 21 to 28 days). The mycological eradication rate at Week 4 was 100% (15/15 subjects). The scores on all skin symptoms (itching, redness, papules, blisters, pustules, maceration, and scaling) at Week 4 significantly improved from the respective baseline scores (p<0.05), and almost all skin symptoms disappeared. The skin-symptom improvement rate was 93% (14/15 subjects). The overall clinical efficacy rate, which was assessed based on mycological efficacy and skin-symptom improvement rating, was 81% (13/16 subjects). No adverse reaction was observed in any of the subjects. The usefulness rate, which was assessed based on overall clinical efficacy and safety rating, was 88% (14/16 subjects). In this study, we confirmed that the usefulness of bifonazole cream for the treatment of tinea pedis was consistent with the results of studies performed before approval and 10 years after approval. About 20 years have passed since its launch, but bifonazole cream still remains a useful antifungal drug for topical treatment of tinea pedis.

Four major causative bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pyogenes) of pediatric respiratory infections, 295 clinical isolates in total, were isolated at general practitioners’ clinics in Sendai city, and evaluated the drug susceptibility to seven antibiotics for pediatric.

Penicillin-resistant S. pneumoniae and penicillin-intermediate S. pneumoniae (PRSP-PISP) were 55.8% of all S. pneumoniae isolates. The MIC₉₀ of penicillin and cephalosporin antibiotics in S. pneumoniae were good, 0.5～1𝜇g/mL, however, macrolide-resistant strains remarkably increased. As for H. influenzae, 50.0% of all isolates were ampicillin-intermediate and -resistant (MIC: ≧2𝜇g/mL), the MIC₉₀s of cephalosporin antibiotics had large differences between 0.5 to 8𝜇g/mL, and generally less susceptibility was shown to other antibiotics. M. catarrhalis showed less susceptibility to amoxicillin which behaved unstably to penicillinase, on the other hand, the MIC₉₀s of other antibiotics were relatively good, 0.25～1𝜇g/mL. S. pyogenes remarkably tend to be resistant to macrolide antibiotics, however, the MIC₉₀s of penicillin and cephalosporin antibiotics were very good, 0.03～0.06𝜇g/mL.

Pediatric respiratory infections are required a treatment which results in inhibition of drug-resistant bacteria. Based on the results of drug susceptibility testing, we should make a proper selection of antibiotics by reference to disposition such as drug concentration in serum and transfer into cells.

In Japan, as a measure to prevent puerperal infection, oral antimicrobial prophylaxis has been conducted after delivery in many maternity clinics. However, there are only a few reports on the evidence supporting the validity of antimicrobial prophylaxis following normal delivery. There is concern that unnecessary antimicrobial administration may be conducted in such clinics.

In the present study, the puerperal females after normal delivery were placed on different treatments. A group of females received no oral antimicrobial administration. The remaining females were given cefteram pivoxil (CFTM-PI) in the two different doses. In this manner, we evaluated usefulness of antimicrobial prophylaxis.

We compared three treatment groups with respect to the incidence of infection for the period until the first week after discharge, and obtained the following results: non-antimicrobial prophylaxis group (group A), 5.83%; antimicrobial prophylaxis group (group B), 1.77%; antimicrobial prophylaxis group (group C), 0%. In group B, the puerperal females were orally given CFTM-PI in a total daily dose of 300mg, three times daily for three days. In group C, the puerperal females were orally given CFTM-PI in a total daily dose of 300mg, three times daily for five days. The incidence of infection was the lowest in group C which was followed by group B and group A in this order and the significant intergroup difference was recognized (p=0.004).

We also compared the total counts of bacteria, aerobes and anaerobes in lochia on the fifth day during the puerperal period with those on the first day in each treatment group. The decrease in bacterial count was the largest in group C, which was followed by group B and group A in this order. Compared with the total bacterial counts obtained on the first day, those obtained on the fifth day decreased significantly (p<0.001).

The results of the present study showed usefulness of antimicrobial prophylaxis after normal delivery. As one of the factors, a significant decrease in the count of bacteria in lochia seems to contribute toward producing the satisfactory outcome.

Tebipenem is the active metabolite of ME1211, tebipenem pivoxil, a novel oral carbapenem that possesses potent activity against almost pathogens except for Pseudomonas aeruginosa. In this study, we compared the susceptibility of tebipenem with current antibiotics against various organisms isolated from various specimen, mainly urinary tract. Tebipenem had a potent activity against Neisseria gonorrhoeae; its activity was comparable to it of cefixime that has most potent activity among oral antibiotics. Against Enterococcus faecalis, the activity of tebipenem was comparable to the activities of ampicillin and amoxicillin, and superior to it of faropenem. Against Citrobacter freundii, Escherichia coli , Klebsiella pneumoniae, and Enterobacter spp. including extended-spectrum 𝛽-lactamase producers, tebipenem had a potent activity with or without ceftazidime-resistance.

Tebipenem pivoxil (TBPM-PI) is a novel oral carbapenem antibiotic. It has been developed as a pro-drug of tebipenem (TBPM), to increase absorption. We assessed the distribution of TBPM to aural discharge and tissues after administration of TBPM-PI to adult patients who underwent otolaryngological surgical tissue resection and pediatric patients with acute otitis media or acute sinusitis.

Following the administration of single oral doses of 150 and 250mg (potency) of TBPM-PI to adult patients who underwent otolaryngological surgical tissue resection, tissue TBPM concentrations for the respective doses were 0.38 to 1.76𝜇g/g and 0.17 to 0.91𝜇g/g in mucous membranes of the maxillary sinus, 0.26 to 0.94𝜇g/g and 0.14 to 0.45𝜇g/g in mucous membranes of the ethmoid sinus, and 0.12 to 0.13𝜇g/g and 0.14 to 0.47𝜇g/g in palatine tonsil tissues, as well as 0.29𝜇g/g in mucous membranes of the middle ear for the dose of 250mg. The percentages of these tissue concentrations to plasma concentrations for the respective doses were 14.3% to 61.0% and 18.4% to 54.6% in mucous membranes of the maxillary sinus, 34.3% to 52.1% and 9.9% to 54.6% in mucous membranes of the ethmoid sinus, and 10.3% to 15.0% and 6.5% to 17.4% in palatine tonsil tissues, as well as 16.8% in mucous membranes of the middle ear for the dose of 250mg.

Following the administration of TBPM-PI at doses of 4mg (potency) /kg and 6mg (potency) /kg twice daily to pediatric patients with acute otitis media or acute sinusitis, TBPM concentrations in the aural discharge for these doses were 0.03 to 2.00𝜇g/g and 1.07 or 1.18𝜇g/g, respectively. The percentage of aural discharge concentrations to plasma concentrations for these doses was 0.3% to 86.1% and 40.5% or 83.6%, respectively.

These results indicate a favorable distribution profile of TBPM to tissues affected by otitis media or sinusitis after the administration of TBPM-PI and can support the high efficacy of TBPM-PI.

Tebipenem pivoxil (TBPM-PI), a novel oral carbapenem antibiotic, is a prodrug of tebipenem (TBPM). We assessed the pharmacokinetics of TBPM-PI fine granules at 250 mg as potency in healthy male volunteers in fasting and non-fasting states.

C_max of TBPM in the non-fasting state was lowered to approximately 60% of that in the fasting state, however AUC_0–∞ and urinary excretion of TBPM in the non-fasting state were almost equivalent to those in the fasting state when TBPM-PI fine granules were administered.

In conclusion, the absorption rate of TBPM-PI was reduced in the non-fasting state after the administration of TBPM-PI fine granules, but intake of food had little influence on the absorption amount of TBPM. Thus the effect of diets on the pharmacokinetics of TBPM-PI would raise no problem in clinical use of TBPM-PI.

In a phase IIb clinical study (dose-finding test, 450mg dosing group: 150mg t.i.d., 500mg dosing group: 250mg b.i.d., 900mg dosing group: 300mg t.i.d.) of tebipenem pivoxil (TBPM-PI) for treatment of otolaryngological infections in adults, TBPM concentrations in the patient plasma were quantified. The primary pharmacokinetic parameters such as ka, kel, Vd/F and Tlag were estimated by the Bayesian method and then the secondary pharmacokinetic parameters such as t_max, C_max, t_1/2 and AUC were calculated. As for the patients whose primary parameters were not properly estimated by the Bayesian method, the secondary parameters were calculated by the trapezoidal method. The primary pharmacokinetic parameters obtained by the Bayesian method in 450mg dosing group (150mg t.i.d.), 500mg dosing group (250mg b.i.d.), and 900mg dosing group (300mg t.i.d.) were 5.64±2.76, 5.11±3.06 and 2.51±1.13 hr^-1 for ka, 1.75±0.25, 2.03±0.10 and 1.34±0.27 hr^-1 for kel, 17.62±5.09, 15.83±6.14 and 19.34±8.80L for Vd/F, and 0.48±0.11, 0.38±0.03 and 0.39±0.26hr for Tlag, respectively. The secondary parameters obtained by the Bayesian method and the trapezoidal method were 0.85±0.29, 0.81±0.33 and 1.18±1.53 hr for t_max, 5.08±2.05, 7.92±4.02 and 8.69±4.01𝜇g/ml for C_max, 0.40±0.06, 0.34±0.01 and 0.54±0.10hr for t_1/2, 5.22±1.90, 7.93±4.04 and 13.62±6.29𝜇g・hr/ml for AUC after each dosing (AUC_0-8h or AUC_0-12h) and 15.65±5.70, 15.85±8.08 and 40.87±18.87𝜇g・hr/ml for AUC_0-24h, respectively.

As shown in the above, C_max and AUC after each dosing were increased with a rise in the dose level, and AUC_0-24h was increased with a rise in the total dose level per day. Regardless of the dosage, t_max was about 0.8-1.2hr and t_1/2 was about 0.3-0.5hr, showing almost constant values. Changes in the regimen and dosage did not influence the pharmacokinetic properties of TBPM-PI. Pharmacokinetics of TBPM-PI in adult patients with otolaryngological infection were similar to those in healthy subjects.

We conducted a double-blind intergroup comparative study investigating the efficacy, safety and PK-PD analysis of the new oral carbapenem antibacterial drug tebipenem pivoxil (TBPM-PI) for the treatment of otolaryngological infections in adults to establish the recommended clinical dosage.

The primary endpoint was the clinical effect of a 7-day oral administration of TBPM-PI to subjects with confirmed cases of infection by any of the 5 major bacterial species causative for otolaryngological infections (Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Moraxella catarrhalis, and Haemophilus influenzae) assigned to three groups set according to the TBPM-PI dosage, namely, a 450mg group (150mg t.i.d), a 500mg group (250mg b.i.d), and a 900mg group (300mg t.i.d).

1. Clinical efficacy : At the end of administration or at discontinuation, the efficacy rate for the 112 subjects in the efficacy analysis set was 72.1% (31/43 subjects) in the 450mg group, 88.6% (31/35 subjects) in the 500mg group, and 85.3% (29/34 subjects) in the 900mg group. Both the 500mg and 900mg groups showed a high efficacy rate of over 80%.

2. Bacteriological efficacy : The disappearance rate of the pre-administration causative bacteria (5 major bacterial species) at the end of administration (at discontinuation), it was 92.2% (47/51 strains) in the 450mg group, 94.7% (36/38 strains) in the 500mg group, and 91.7% (33/36 strains) in the 900mg group. All the groups showed a high disappearance rate, with no large differences among them. All strains of S. pneumoniae, including PRSP, as well as those of S. pyogenes and M. catarrhalis disappeared. The overall disappearance rate of H. influenzae was 78.6%, namely, 76.9% in the 450mg group, 100% in the 500mg group, and 66.7% in the 900mg group, showing differences among the groups.

3. PK-PD : The PK-PD analysis was executed in 124 strains isolated from 111 subjects in which the plasma TBPM concentration and the MIC of causative organism were measured. The target value of the PK-PD parameter was examined from the relation between PK-PD parameter and bacteriological efficacy. The presumed target value of AUCf/MIC was 10–20, C_maxf/MIC was 4. On the other hand, a clear relation was not found between T>MIC and the bacteriological efficacy.

4. Safety : The incidence of adverse reactions related to symptoms and signs was 28.8% (21/73 subjects) in the 450mg group, 35.8% (24/67 subjects) in the 500mg group, and 30.6% (22/72 subjects) in the 900mg group. The incidence of abnormal changes in laboratory test values was 8.2% (6/73 subjects) in the 450mg group, 9.2% (6/65 subjects) in the 500mg group, and 9.9% (7/71 subjects) in the 900mg group. There were no differences in either of these categories among the groups, and the incidence was considered not to be correlated with dose.

Based on the above, we considered that TBPM-PI at doses of 250mg b.i.d (500mg/day) promises high clinical usefulness for the treatment of otolaryngological infections in adults.