Therapeutic use of cephaloridine, a beta-lactam antibiotic, in humans is associated with carnitine deficiency. A potential mechanism for the development of carnitine deficiency is competition between cephaloridine and carnitine for the renal reabsorptive process. OCTN2 is an organic cation/carnitine transporter that is responsible for Na(+)-coupled transport of carnitine in the kidney and other tissues. We investigated the interaction of several beta-lactam antibiotics with OCTN2 using human cell lines that express the transporter constitutively as well as using cloned human and rat OCTN2s expressed heterologously in human cell lines. The beta-lactam antibiotics cephaloridine, cefoselis, cefepime, and cefluprenam were found to inhibit OCTN2-mediated carnitine transport. These antibiotics possess a quaternary nitrogen as does carnitine. Several other beta-lactam antibiotics that do not possess this structural feature did not interact with OCTN2. The interaction of cephaloridine with OCTN2 is competitive with respect to carnitine. Interestingly, many of the beta-lactam antibiotics that were not recognized by OCTN2 were good substrates for the H(+)-coupled peptide transporters PEPT1 and PEPT2. In contrast, cephaloridine, cefoselis, cefepime, and cefluprenam, which were recognized by OCTN2, did not interact with PEPT1 and PEPT2. The interaction of cephaloridine with OCTN2 was Na(+)-dependent, whereas the interaction of cefoselis and cefepime with OCTN2 was largely Na(+)-independent. Furthermore, the Na(+)-dependent, OCTN2-mediated cellular uptake of cephaloridine could be demonstrated by direct uptake measurements. These studies show that OCTN2 plays a crucial role in the pharmacokinetics and therapeutic efficacy of certain beta-lactam antibiotics such as cephaloridine and that cephaloridine-induced carnitine deficiency is likely to be due to inhibition of carnitine reabsorption in the kidney.

01 Jan 1999·ChemotherapyQ4 · MEDICINE

In vitro Bactericidal Activities of Antimicrobial Agents and Morphologic Changes on Prevotella bivia

Q4 · MEDICINE

Article

Author: Satoh, Masaru ; Sato, Yasumasa ; Hayasaki, Yoh ; Tamaya, Teruhiko ; Kai, Jyunko ; Mikamo, Hiroshige ; Izumi, Koji ; Kawazoe, Kyoko

Prevotella bivia is common in pelvic inflammatory diseases. Parenteral antimicrobial agents have been widely used against those infections. We investigated the bactericidal activities of three cephalosporins, i.e. cefluprenam (CFLP), ceftazidime (CAZ) and cefotaxime (CTX) and of two other antimicrobial agents, i.e. clindamycin (CLDM) and imipenem (IPM) against P. bivia. We also investigated the in vitro morphological changes induced by these agents in P. bivia. Cephalosporins exhibited bactericidal activities against P. bivia and induced time- and concentration-dependent morphological changes in P. bivia (filamentation). CLDM and IPM also had bactericidal activities, but induced different morphologic alterations: formation of spheroblasts and lysis. These results confirm the fact that each antimicrobial agent has characteristic aspects.

01 Jan 1998·Journal of the Japanese Association for Infectious Diseases

Therapeutic Effect of Cefluprenam on Polymicrobial Urinary Tract Infection Associated with Enterococcus faecalis, Using the Infectious Urolithiasis Model in Rats

Article

Author: Takeuchi, H ; Satoh, M ; Munakata, K ; Yoshida, O

We examined the therapeutic effect of cefluprenam (CFLP) on the polymicrobial urinary tract infection associated with infectious stones as compared to that of ceftazidime (CAZ), using the experimental polymicrobial urinary tract infection caused by Proteus mirabilis (P. mirabilis), Pseudomonas aeruginosa (P. aeruginosa) and Enterococcus faecalis (E. faecalis). In order to form bladder stones in rats, a sterile zinc ring was implanted as a foreign body, followed by inoculating P. mirabilis E05106 transurethrelly. Thereafter, P. aeruginosa E030033 and E. faecalis 966 were inoculated according to the same way. CFLP or CAZ was administered intravenously twice a day for 5 days. The therapeutic effect was evaluated by the eradication of these bacteria from the urine, the kidney and stones, inhibition of growth of stones, and also a value of BUN. The urinary excretion rates of CFLP and CAZ was also determined (20 mg/kg). In result, CFLP significantly more effective in the eradication of P. mirabilitis, P. aeruginosa and E. faecalis from the urine, the kidney and stones than the control than the control (p < 0.05). Furthermore, CFLP significantly more effective in the eradication of P. aeruginosa from the urine and also E. facalis from the urine and stones (p < 0.05). Meanwhile, CAZ significantly more effective in the eradication of P. mirabilis from the urine, the kidney and stones and also P. aeraginosa from the kidney and stones than the control. However, CAZ did not show eradicative effect on E. faecalis. The urinary excretion rates of CFLP and CAZ at rats were 59.3% and 59.4%, respectively, within 8 hrs after administration, showing a similar excretion pattern. CFLP exhibited the prominent therapeutic effect on polymicrobial urinary tract infection associated with infectious stones caused by P. mirabilis, P. aeruginosa and E. faecalls. On the basis of these results, it has been strongly suggested that CFLP is highly beneficial in the management of intractable polymicrobial urinary tract infectious in clinic.

100 Deals associated with Cefluprenam

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Indication	Highest Phase	Country/Location	Organization	Date
Bacterial Infections	NDA/BLA	JP	-	-
Bacterial Infections	NDA/BLA	-	Eisai Co., Ltd.	-
Bacterial Infections	NDA/BLA	-	Eisai Co., Ltd.	-
Bacterial Infections	NDA/BLA	JP	-	-

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