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. 1998 Aug;42(8):1996-2001.
doi: 10.1128/AAC.42.8.1996.

In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345)

C J Gill  1 , J J Jackson, L S Gerckens, B A Pelak, R K Thompson, J G Sundelof, H Kropp, H Rosen
Affiliations

In vivo activity and pharmacokinetic evaluation of a novel long-acting carbapenem antibiotic, MK-826 (L-749,345)

C J Gill et al. Antimicrob Agents Chemother. 1998 Aug.

Abstract

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 microg/ml) and a larger area under the curve (AUC) (150.8 versus 90.0 microg . hr/ml) than CTRX. The concentrations of MK-826 and CTRX in serum declined slowly, with levels of 3.6 and 2.0 microg/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 microg . 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.

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Figures

FIG. 1
FIG. 1
Chemical structure of MK-826.
FIG. 2
FIG. 2
Efficacy of MK-826 and other agents in the mouse thigh model: experiment 1. DBA/2 mice were challenged (0.2 ml; i.p.) with S. aureus MB2985 in the right thigh at 0 h. Antibiotic treatment (0.5 ml; s.c.) was given at 2, 6, 10, 24, 48, 72, 96, and 120 h after challenge. Circles show individual values for mouse 1 to 5; bars show geometric means.
FIG. 3
FIG. 3
Efficacy of MK-826 and other agents in the mouse thigh model: experiment 2. DBA/2 mice were challenged (0.2 ml; i.p.) with S. aureus MB2985 in the right thigh at 0 h. Antibiotic treatment (0.5 ml; s.c.) was given at 2, 6, 10, 24, 48, 72, 96, and 120 h after challenge. Cilastatin was used except where noted. Circles show individual values for mouse 1 to 5; bars show geometric means.
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References

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