Carbapenems, such as panipenem and imipenem, showed better therapeutic efficacy against murine systemic infections caused by Pseudomonas aeruginosa than the activity expected from their MICs determined by using Mueller-Hinton medium. The mechanism was investigated and concluded that outer membrane permeability of P. aeruginosa played important role on carbapenem's antipseudomonal activity as well as existence of postantibiotic effect and strong bactericidal activity of carbapenem. Carbapenems showed 8 to 16 times lower MICs in low-nutritional media than those determined in Mueller-Hinton medium. Basic amino acids, such as L-lysine, L-histidine, and L-arginine, were responsible for the decreased antipseudomonal activity of carbapenems in Mueller-Hinton medium. Other amino acids had little effect on antipseudomonal activity. The effect of basic amino acids on antipseudomonal activity of carbapenem was concentration dependent. OprD-deficient mutants were isolated from P. aeruginosa PAO 1 and examined for their susceptibility to carbapenems with or without presence of basic amino acids. It is concluded that the decreased antipseudomonal activity of carbapenems was caused by competing permeation of carbapenems and basic amino acids through OprD channel of P. aeruginosa. Such influence by basic amino.acids was specific for carbapenems and it was not observed for cephems, penicillin, new quinolones, and aminoglycoside. Uptake of ¹⁴C-panipenem into P. aeruginosa PAO 1 was almost suppressed by 100mM L-lysine, and the inhibition of ¹⁴C-panipenem uptake was not observed in the OprD-deficient mutant. Concentrations of free basic amino acids are much lower in human serum than in Mueller-Hinton medium (less than 1/40). This is probably one main reason for carbapenem's stronger antipseudomonal activity than that expected from their MICs determined in Mueller-Hinton medium.

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The pharmacokinetic-based drug-drug interaction between a carbapenem antibiotic, panipenem (PAPM), and an acid antiepiletic drug valproic acid (VPA), was investigated in dogs, Elimination half-lives of VPA after oral and intravenous administration of VPA at 30mg/kg after concomitant intravenous injection of PAPM at 50mg/kg decreased to about 25% and 10%, respectively, of those after administration of VPA without PAPM. Absorption of VPA after oral administration was not affected by concomitant PAPM as indicated by the fact that the C_max and T_max values of VPA were unchanged. The in vivo plasma-free fraction of VPA varied between 7 and 36% depending on the total plasma level, and were not affected by concomitantly administered PAPM. Renal clearance tests at a constant rate of infusion of VPA were performed in two anesthetized dogs. The steady state plasma concentrations and the rates of renal excretion of the glucuronide metabolite of VPA during simultaneous infusion of PAPM and VPA were significantly higher than those in the control period (VPA alone). In vitro UDP-glucuronosyltransferase (UDPGT) activity toward VPA was found in dog hepatic microsomes, but not in renal microsomes. Concomitant injection of meropenem also enhanced the elimination of VPA from plasma, whereas cefozopran, flomoxef, cefmetazole and cephalexin did not affect VPA pharmacokinetics. These results indicate that the enhancement on VPA elimination was specific for the carbapenem antibiotics and some metabolic activation mechanism of hepatic UDPGT might contribute to this drug-drug interaction.

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We have reported that clarithromycin (CAM) treatment prolongs the survival time of patients with non-small cell lung cancer and improves various parameters in these patients. In the present study, CAM was administered to 33 patients with unresectable primary non-small cell lung cancer who had received prior chemotherapy, rediotherapy or both, and the levels of cachexia-inducing cytokine interleukin 6 (IL-6) and clinical parameters (body weight [BW], total protein [TP], albumin [Alb], cholinesterase [ChE] and hemoglobin [Hb]) were measured before and three months after CAM treatment. After three months of treatment, serum levels of IL-6 were significantly decreased, and BW, ChE and Hb were significantly increased. With regard to serum IL-6 levels, the changes in serum IL-6 levels (ΔL-6) were examined for correlation with the changes in the clinical parameters (ΔBW, TP, Alb, and Hb) and the survival time after the administration of CAM. ΔIL-6 was not correlated with ΔTP, ΔAlb, ΔChE, or ΔHb, but it was negatively correlated with ΔBW and survival time to a significant extent. These results suggest that CAM may decrease the progress of cancer-associated cachexia.

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Surgical site infection (SSI) is an important factor in prognosis after the operation. But techniques for diagnosing SSI and the selection of antimicrobial agents for therapeutic use have been depended on the surgeon in charge. We designed a prospecitive randomized study of sulbactam/ampicillin (SBT/ABPC) and cefotiam (CTM) for antibiotic prophylaxis against SSI after gastric cancer surgery and evaluated it as an early diagnostic system for SSI by the fuzzy set theory. The incidence of SSI was 13%(11/82 cases) in the SBT/ABPC group and 23%(18/77 cases) in the CTM group. The difference was not significant. The organisms isolated from SSI were Klebsiella and Pseudomonas in the SBT/ABPC group and Gram-positive cocci in the CTM group. We constructed an early diagnostic system by the fuzzy set theory with six details (blood loss and other resected organs during the operation, febrile pattern during days 2 to 4, differential counts of white blood cells on day 4, time sequential vector during days 1 to 4 and white blood cells and CRP value on day 4 after the operation). The sensitivity of this test in 137 patient with full data was 86%(24/28 cases) and the specificity was 90%(98/109 cases). We concluded that this system could be useful to judge the clinical effect of prophylactic antibiotics.

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