[Clinical efficacy, safety and PK-PD analysis of tebipenem pivoxil in a phase II clinical trial in otolaryngological infections].

Abstract 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 450 mg group (150 mg t.i.d), a 500 mg group (250 mg b.i.d), and a 900 mg group (300 mg 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 450 mg group, 88.6% (31/35 subjects) in the 500 mg group, and 85.3% (29/34 subjects) in the 900 mg group. Both the 500 mg and 900 mg 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 450 mg group, 94.7% (36/38 strains) in the 500 mg group, and 91.7% (33/36 strains) in the 900 mg 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 450 mg group, 100% in the 500 mg group, and 66.7% in the 900 mg 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, Cmaxf/MIC was 4. On the other hand, a clear relation was not found between T>MIC and the bacteriological efficacy. 4. The incidence of adverse reactions related to symptoms and signs was 28.8% (21/73 subjects) in the 450 mg group, 35.8% (24/67 subjects) in the 500mg group, and 30.6% (22/72 subjects) in the 900 mg group. The incidence of abnormal changes in laboratory test values was 8.2% (6/73 subjects) in the 450 mg group, 9.2% (6/65 subjects) in the 500 mg group, and 9.9% (7/71 subjects) in the 900 mg 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 250 mg b.i.d (500 mg/day) promises high clinical usefulness for the treatment of otolaryngological infections in adults.