Therapeutic Effect of ME1036 on Endocarditis Experimentally Induced by Methicillin-Resistant Staphylococcus aureus

Abstract

The efficacy of ME1036, a novel parenteral carbapenem, was compared with that of vancomycin by using a rabbit model of methicillin-resistant Staphylococcus aureus (MRSA) endocarditis. Compared with vancomycin, ME1036 reduced the bacterial counts in the vegetations at a lower dosage or over a shorter period of administration when it was used for the treatment of MRSA endocarditis.Recently, methicillin-resistant Staphylococcus aureus (MRSA) has become increasingly prevalent worldwide as both a nosocomial and a community-acquired pathogen (11). Furthermore, nosocomial MRSA infections increase the risk of mortality and prolonged hospitalization. Endocarditis caused by MRSA is a serious infectious disease (1), and MRSA continues to make up a growing share of organisms that cause endocarditis (6, 9). Vancomycin is the most reliable antimicrobial agent for the treatment endocarditis caused by MRSA, but drug tolerance has been correlated with treatment failure (2, 10). ME1036, a novel parenteral carbapenem synthesized at Meiji Seika Kaisha, Ltd., possesses potent activities against gram-positive bacteria (including MRSA and penicillin-resistant Streptococcus pneumoniae) and gram-negative bacteria (4).Rabbit endocarditis was produced by the method of Perlman and Freedman (8). Female New Zealand White rabbits (weight, 1.9 to 2.6 kg) were anesthetized with ketamine and xylazine. A polyethylene catheter was placed across the aortic valves. S. aureus CR1434 (1.3 to 2.9 ϫ 10 6 CFU in 1 ml) was injected into the vein. This strain was isolated from clinical samples in a hospital in Japan. The MICs of methicillin, ME1036, and vancomycin for S. aureus CR1434 are 400, 0.5, and 1 g/ml, respectively. Eighteen hours after bacterial challenge, the antimicrobial treatment was initiated. Either ME1036 (coadministered with cilastatin sodium at 20 mg/kg of body weight/dose) or vancomycin was administered intravenously every 12 h for 5 days. Another experiment was conducted by following the same procedure but for durations of 1, 3, and 5 days. Untreated control animals were killed at the initiation of therapy. Twelve hours after the last treatment, the animals were killed. The vegetations were weighed wet under sterile conditions, homogenized in saline, and serially diluted. The dilutions were plated on Muller-Hinton agar (MHA), and the plates were incubated at 37°C for 24 h. The lower limit of detection was 2.04 to 2.93 log 10 CFU/g.The efficacies of ME1036 and vancomycin in the MRSA endocarditis model are shown in Fig. 1. The cardiac vegetations from controls had a bacterial count of 8.83 Ϯ 0.89 log 10 CFU/g (mean Ϯ standard derivation). ME1036 at 10 and 20 mg/kg/dose reduced the bacterial counts to 3.15 Ϯ 1.57 log 10 CFU/g (P Ͻ 0.01) and 2.58 Ϯ 0.68 log 10 CFU/g (P Ͻ 0.01), respectively. The vegetations were rendered sterile by consecutive treatment with ME1036. Vancomycin at 20 and 40 mg/ kg/dose reduced the bacterial counts to 6.91 Ϯ 3.37 and 3.94 Ϯ 2.69 log 10 CFU/g (P Ͻ 0.01), respectively.To ascertain whether residual MRSA CR1434 i...

Molecular Basis and Phenotype of Methicillin Resistance in Staphylococcus aureus and Insights into New β-Lactams That Meet the Challenge

“…Real-time bioluminescent imaging demonstrated a greater reduction in the cardiac bioluminescence signal with ME1036 therapy than with vancomycin (120 mg/kg twice daily) and daptomycin (10 mg/kg once daily) therapy (183). Likewise, the efficacy of ME1036 in a rabbit model of endocarditis was superior to that of vancomycin (129). The in vivo pharmacokinetic activity of ME1036 in a murine thigh infection model against multiple bacteria (including MRSA) showed that the correlations of the time with drug levels above the MIC and efficacy were similar to those of other carbapenems (4).…”

Efficacy of ME1036 against meticillin-resistant Staphylococcus aureus and vancomycin-insensitive S. aureus in a model of haematogenous pulmonary infection

“…The sub-MIC effect and the MIC observed at large inoculum sizes may contribute to the better in vivo efficacy of ME1036 compared to that of vancomycin. [4].…”

“…ME1036, a novel parenteral carbapenem, was developed to combat MRSA or VISA [3][4], and it is expected to be useful for the treatment of severe staphylococcal infections such as pneumonia, bacteremia, and pulmonary abscesses.…”