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Antimicrobial Agents and Chemotherapy, August 1998, p. 1996-2001, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

In Vivo Activity and Pharmacokinetic Evaluation of a Novel Long-Acting Carbapenem Antibiotic, MK-826 (L-749,345)

Charles J. Gill,* Jesse J. Jackson, Lynn S. Gerckens, Barbara A. Pelak, Randall K. Thompson, Jon G. Sundelof, Helmut Kropp, and H. Rosen

Antibiotic Discovery and Development, Merck Research Laboratories, Rahway, New Jersey 07065

Received 14 October 1997/Returned for modification 14 April 1998/Accepted 3 June 1998

MK-826 (formerly L-749,345), is a potent 1-beta -methyl carbapenem with a long half-life and broad spectrum of activity. This compound is presently in phase-II clinical trials. Its activity against a number of gram-positive and gram-negative organisms was compared to those of imipenem (IPM) and eight other beta -lactam agents in two in vivo murine infection models. The distribution in tissue and pharmacokinetic properties of MK-826 and ceftriaxone (CTRX) were also evaluated in CD-1 mice following a single intraperitoneal dose (10 mg/kg of body weight). In addition, concentrations in plasma as well as biliary and urinary recovery of MK-826 were compared to that of CTRX in a cannulated rat model. In a localized murine thigh infection model, MK-826 and IPM were superior to a variety of beta -lactam antibiotics in reduction of Staphylococcus aureus CFU compared with results from nontreated controls (eliminating >= 4 log10 CFU). Similar activities of IPM and MK-826 were observed in a gram-positive bacterial murine systemic infection model. While IPM demonstrated greater efficacy than MK-826 against Enterobacter cloacae (50% effective doses [ED50s] of 0.062 and 0.227 mg/kg, respectively) and Pseudomonas aeruginosa (ED50s of 0.142 and 3.0 mg/kg, respectively) systemic infections, MK-826 was 8- to 350-fold more efficacious than IPM against all other gram-negative organisms in this infection model. In mice, MK-826 demonstrated a higher peak concentration in serum (62.8 versus 42.6 µg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 µg · hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 µg/ml remaining, respectively, at 6 h posttreatment. The rat pharmacokinetic model showed the average AUC of MK-826 to be greater than that of CTRX (284 versus 142 µg · hr/ml) following a single 10-mg/kg dose. Also, a half-life of MK-826 longer than that of CTRX (3.2 versus 2.3 h) was observed in this species. The total amount of drug excreted in the bile in 8 h was greater for CTRX (55 to 64% of the dose) than for MK-826 (6 to 12.5% of the dose). Urinary recovery was similar for both antibiotics, with 16 to 18% of the dose recovered over an 8-h period. This excellent broad-spectrum in vivo efficacy of MK-826, together with advantageous pharmacokinetics, supports the argument for its further clinical development.

* Corresponding author. Mailing address: Antibiotic Discovery and Development (80T-100), Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900. Phone: (732) 594-6053. Fax: (732) 594-5700. E-mail: charles_gill{at}merck.com.

Antimicrobial Agents and Chemotherapy, August 1998, p. 1996-2001, Vol. 42, No. 8
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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