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Antimicrobial Agents and Chemotherapy, August 2005, p. 3526-3528, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3526-3528.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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

Jun Nagura,* Koji Kijima, Mizuyo Kurazono, Sho Takahata, Toshie Sugano, Yukari Tanaka, Yoko Hirai, Keiko Yamada, Yoshihiro Takayama, Eiki Shitara, and Minoru Yonezawa

Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan

Received 23 August 2004/ Returned for modification 30 November 2004/ Accepted 20 April 2005


   ABSTRACT
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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.


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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 x 106 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 µg/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 log10 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 ± 0.89 log10 CFU/g (mean ± standard derivation). ME1036 at 10 and 20 mg/kg/dose reduced the bacterial counts to 3.15 ± 1.57 log10 CFU/g (P < 0.01) and 2.58 ± 0.68 log10 CFU/g (P < 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 ± 3.37 and 3.94 ± 2.69 log10 CFU/g (P < 0.01), respectively.



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  		FIG. 1. Comparative efficacies of ME1036 and vancomycin (VAN) in a 5-day treatment of endocarditis caused by S. aureus CR1434 in rabbits. The bacterial counts in the vegetations after treatment with ME1036 (10 and 20 mg/kg/dose) or vancomycin (20 and 40 mg/kg/dose) at 12-h intervals twice a day are shown. The bacterial counts in control (Cont) animals were measured at the start of therapy (18 h after bacterial challenge). Open squares, the mean log10 number of CFU. Values in parentheses indicate the number of sterile vegetations/number of animals treated; e.g., (6/9) means that the bacterial counts in vegetations from six rabbits were lower than the limit of detection in all nine treated rabbits. **, P < 0.01 versus the results for the control (Steel's test).

 
To ascertain whether residual MRSA CR1434 isolates from ME1036-treated animals were resistant to ME1036, the bacteria were plated onto MHA containing 4 µg/ml of ME1036. No resistant clone was detected. The efficacies of ME1036 and vancomycin as part of 1-, 3-, and 5-day treatments are shown in Fig. 2. For the control, the bacterial count in the cardiac vegetation was 8.94 ± 0.61 log10 CFU/g. The 3-day treatment with ME1036 and vancomycin reduced the bacterial counts to 3.12 ± 1.14 log10 CFU/g (P < 0.01) and 5.63 ± 2.72 log10 CFU/g, respectively. Steel's test for multiple comparisons or the Mann-Whitney U test was used for statistical analysis. The treatment with ME1036 showed sufficient efficacy in reducing the bacterial counts, and the treatment period required to exhibit efficacy in vivo was shorter for ME1036 than for vancomycin.



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  		FIG. 2. Efficacies of ME1036 and vancomycin in the successive 1-, 3-, and 5-day treatments of endocarditis caused by S. aureus CR1434 in rabbits. Values in parentheses indicate the number of sterile vegetations/number of animals treated. *, P < 0.05 versus the results for the controls; **, P < 0.01 versus the results for the controls (Steel's test).

 
Pharmacokinetic studies were performed with uninfected rabbits by using a single intravenous injection of drugs. The concentrations of ME1036 and vancomycin in plasma were determined by high-performance liquid chromatography and bioassay, and the detection limits were 0.5 and 0.75 µg/ml, respectively. The concentrations of ME1036 and vancomycin in plasma are shown in Fig. 3, and the values of the pharmacokinetic parameters are presented in Table 1. The protein binding of ME1036 and vancomycin in rabbit serum was measured by an ultrafiltration method, and the rates were 21.3 and 46.7%, respectively.



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  		FIG. 3. Plasma concentration-time profiles after intravenous administration of ME1036 (followed by administration of cilastatin sodium at 20 mg/kg/dose) and vancomycin in healthy rabbits.

 

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  		TABLE 1. Values of pharmacokinetic parameters for ME1036 and vancomycin in rabbitsa

 
In the time-kill curves against MRSA in vitro, the sub-MICs of ME1036 had a transient inhibitory or modest killing effect over the first 4 h of exposure, while similar sub-MICs of vancomycin exhibited no effect (4).

The MICs of ME1036 and vancomycin against S. aureus CR1434 at various inoculum sizes were measured by the agar dilution method with MHA, as recommended by CLSI (formerly NCCLS) (7). The strain was inoculated onto agar plates at 1.6 x 102 to 1.6 x 107 CFU/spot. The MICs (previously shown) of ME1036 and vancomycin increased twofold at an inoculum of 1.6 x 106 CFU/spot, but the MIC of vancomycin increased another fourfold at an inoculum of 1.6 x 107 CFU/spot.

Use of the rabbit endocarditis model is considered appropriate for determination of the efficacies of antimicrobial agents against serious infections (5). In this study, we have shown that ME1036 was more effective than vancomycin in a 5-day treatment. Our judgment was based on the reduced bacterial counts and the improved bacterial eradication rate in cardiac vegetations. In addition, no ME1036-resistant mutant was isolated from the vegetations during the ME1036 treatment, which was supported by in vitro studies (4). Moreover, following the 1-, 3-, and 5-day treatments, ME1036 reduced the bacterial counts and sterilized the cardiac vegetations more rapidly than vancomycin.

When the level of protein binding is taken into account, the free-fraction areas under the concentration-time curve from 0 h to infinity of the two drugs were comparable. The data obtained from these pharmacokinetic studies, however, cannot account for the superior efficacy of ME1036 over that of vancomycin in the endocarditis model.

We therefore compared the in vitro activities of ME1036 and vancomycin under different conditions. The titers of bacteria in cardiac vegetations are particularly high and often exceed 108 CFU/g in bacterial endocarditis models (3). In the present rabbit model, the bacterial counts in the controls were in the same range. The MIC for the inoculum size (1.6 x 107 CFU/spot) was comparable to the bacterial counts within the vegetation in this model. The MIC of ME1036 at the larger inoculum size was lower than that of vancomycin. 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.

In conclusion, the efficacy of ME1036 in the rabbit endocarditis model is superior to that of vancomycin, and ME1036 may be a promising candidate for the treatment of serious endocarditis infections caused by MRSA.


   FOOTNOTES
 
* Corresponding author. Mailing address: Pharmaceutical Research Department, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan. Phone: 81-45-545-3178. Fax: 81-45-541-2359. E-mail: jun_nagura{at}meiji.co.jp. Back


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Antimicrobial Agents and Chemotherapy, August 2005, p. 3526-3528, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3526-3528.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.




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