We compared the antimicrobial activities of oral quinolones, ciprofloxacin (CPFX), gatifloxacin (GFLX), garenoxacin (GRNX), levofloxacin (LVFX), moxifloxacin (MFLX), norfloxacin (NFLX), prulifloxacin (PUFX), and tosufloxacin (TFLX) using Streptococcus pneumoniae, Haemophilus influenzae, Streptococcus agalactiae, Streptococcus pyogenes, extended spectrum 𝛽-lactamase(ESBL) producing Klebsiella pneumoniae, and methicillin-susceptible Staphylococcus aureus (MSSA) isolated from clinical materials. Based on the pharmacokinetics-pharmacodynamics theory, the target attainment rate at the area under the curve (AUC)/MIC of 120 or more for Gram-negative and 30 or more for Gram-positive bacteria was calculated using Monte Carlo simulation (MCS), and was assessed as the efficacy. GRNX showed the lowest MIC₅₀ and MIC₉₀ values (0.03 and 0.06𝜇g/ml, respectively) against S. pneumoniae, suggesting its potent antimicrobial activity. GRNX also exhibited the most potent antimicrobial activity against Gram-positive bacteria (S. agalactiae, S. pyogenes, MSSA) other than S. pneumoniae. The antimicrobial activity of CPFX against H. influenzae was most potent. The MIC₅₀ and MIC₉₀ values were 0.016𝜇g/ml each. However, the MIC₅₀ and MIC₉₀ values of the other agents were also favorable. PUFX showed the most potent antimicrobial activity against ESBL-producing K. pneumoniae. Both of MIC₅₀ and MIC₉₀ values were 0.06 and 1𝜇g/ml, respectively. On efficacy assessment using MCS, GRNX, GFLX, and MFLX showed a probability of 90% or more against S. pneumoniae and S. pyogenes. Against S. agalactiae, GRNX, MFLX, and GFLX showed a probability of approximately 60%. All agents showed a low probability against ESBL-producing K. pneumoniae; PUFX showed a maximum (43.63%). GRNX, MFLX, GFLX, and LVFX showed a probability of 90% or more against MSSA. Furthermore, we investigated the probability that the target value of resistance inhibition, an AUC/MIC of more than 200 against S. pneumoniae, is achieved. GRNX showed the highest probability (95.05%). It also exhibited a similar probability even when the target value was established as 250. Recently, the widespread use of quinolones has increased the number of quinolone-resistant bacteria. In the future, antimicrobial agents should be selected with respect to more potent therapeutic effects and resistance inhibition, and an appropriate dose and administration method must be employed.

Sensitivity to 𝛽-lactam antibiotics of isolates clinically obtained from respiratory infection sites in adults on the second survey on sensitivity of isolates conducted by the Japanese Society of Chemotherapy in 2007 was investigated according to the classification of the “Guideline for treatment for adult nosocomial pneumonia in 2008”. Among the primary antibacterial drugs for mild (A) and moderate (B) nosocomial pneumonia in adults, 𝛽-lactam antibiotics; ceftriaxone (CTRX), sulbactam/ampicillin (SBT/ABPC), panipenem/betamipron (PAPM/BP), tazobactam/piperacillin (TAZ/PIPC), imipenem/cilastatin (IPM/CS), meropenem (MEPM), doripenem (DRPM), biapenem (BIPM) were studied to evaluate their clinical efficacy. The covering rate was analyzed using the minimal inhibitory concentration (MIC) and break point of pharmacokinetics/pharmacodynamics (PK/PD).

Consequently, the results with methicillin-susceptible Staphylococcus aureus (MSSA), Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Klebsiella pneumoniae revealed the MIC₉₀ of all antibacterial drugs to be at low levels, while almost 100% of isolates were within the range of PK/PD break points except BIPM and SBT/ABPC to H. influenzae, and SBT/ABPC to K. pneumoniae. However, the analysis of P. aeruginosa didn’t reach 100% for the covering rates of isolates, indicating that these drugs did not have a complete inhibitory action to restrict bacterial proliferation. The analysis of all 5 carbapenem drugs showed superiority to TAZ/PIPC in MIC₉₀ while covering rates of isolates at PK/PD break points showed inferiority to TAZ/PIPC.

This tendency was found to be more significant in covering the rates of isolates on the regular dose with maximal bactericidal action and on the maximum dose. This is because the maximum dose approved in Japan is as low as half that in IPM/CS and 1/3 that in MEPM in Western countries.

Pharmacokinetics of tebipenem pivoxil (TBPM-PI), a novel oral carbapenem antibiotic, were known in various laboratory animal.

1) In mouse, rat, dog and monkey, TBPM-PI were absorbed quickly, and the bioavailability was 71.4, 59.1, 34.8 and 44.9%, respectively.

2) TBPM-PI was quickly converted to tebipenem (TBPM), an active form of TBPM-PI. Through blood circulation, TBPM was distributed into the kidney at a high concentration and eliminated quickly. There was no other tissue than the kidney, in which TBPM was highly distributed and remained for a long time. In addition, low penetration to the central nervous system was confirmed. The penetration ratio of TBPM to ELF, that is the ratio of ELF concentration to plasma concentration of TBPM, was 21.8±14.7%.

3) Serum protein bindings of TBPM in the range of 0.1–100𝜇g/ml were 90.4–98.3% for mouse, 78.5–90.0% for rat, 15.7–18.7% for dog, 35.3–39.3% for monkey and 59.7–73.9% for human.

4) In vitro metabolism was investigated in plasma, liver S9 fractions and small intestinal S9 fractions derived from infant and adult animals. TBPM-PI was transformed into TBPM quickly in any matrices. It was confirmed that absorbed TBPM-PI was quickly transformed into TBPM or LJC11,562 (opened ring TBPM) in the plasma after oral administration of ¹⁴C-TBPM-PI to infant or adult rat and monkey. TBPM-PI and opened ring TBPM-PI was not detected in plasma and urine samples. In rat and monkey, the oral absorption, distribution, metabolite and excretion of TBPM-PI were not so much different between infant and adult animals.

5) Liver metabolic enzyme system was little affected by 7-days repeated administration of 1–100mg/kg TBPM-PI. IC₅₀ values of TBPM-PI and TBPM for human CYP isoforms were estimated to be 100𝜇g/ml or higher.

6) After single oral administration of 10mg/kg ¹⁴C-TBPM-PI to rat, 36.9–42.7% and 58.3–62.2% of radioactivity was excreted to urine and feces, respectively, by 120 hours after administration. The majority of dosage was excreted out of body by 48 hours after administration. After single intravenous administration of 10mg/kg ¹⁴C-TBPM, 87.4% and 11.4% of radioactivity was excreted in urine and bile, respectively, by 24 hours after administration. The majority of dosage was excreted out of body by 4 hours after administration.

Tebipenem pivoxil (TBPM-PI), the first oral carbapenem antibiotic both in Japan and abroad, was examined on its convulsive liability. We used ICR male mice and Sprague-Dawley male rats to examine the pro-convulsive effect and anticonvulsive effect of TBPM-PI and its active metabolite, TBPM.

1. When mice were treated with TBPM-PI (30～1000mg/kg, p.o.) or TBPM (10～300mg/kg, i.v.), no convulsion was noted at any dose level. When rats were treated with TBPM (300mg/kg, i.v.), no convulsant effects were noted in electroencephalography or behavioral observation. In intraventricular injection of TBPM in mice, clonic convulsion was observed in 7/10 animals at 100𝜇g but no effect at 30𝜇g. On the other hand, the administration of 10/10𝜇g imipenem/cilastatin (IPM/CS) resulted in clonic convulsion in all animals and tonic convulsion in 3/10 animals, and 4/10 animals died. The administration of 100𝜇g meropenem did not cause any effects.

2. When mice were co-administered with pentylenetetrazole (45mg/kg: maximum dose level at which no convulsion is induced) and TBPM-PI (30～300mg/kg, p.o.) or TBPM (300mg/kg, i.v.), convulsion enhancing effect was not noted. On the other hand, the co-administration of pentylenetetrazole with IPM/CS (300/300mg/kg, i.v.) enhanced a convulsive effect of pentylenetetrazole.

3. When mice were treated with TBPM-PI (30～300mg/kg, p.o.) or TBPM (100mg/kg, i.v.), inhibitory effect was not noted on convulsions induced by electrostimulation, pentylenetetrazole or strychinine.

In conclusion, there were no pro-convulsive effects or anticonvulsive effect in the oral administration of TBPM-PI or intravenous administration of TBPM. Pro-convulsive effect was observed in the intraventricular injection of TBPM as in the case of other carbapenem antibiotics, but such action was weaker than that in IPM/CS administration. Accordingly, the risk of occurrence of convulsion related to TBPM-PI administration was low compared to IPM/CS administration, and TBPM-PI was considered to be less potential to induce convulsions in clinical use.