In vitro activity of DU-6681a, an active form of the new oral carbapenem compound DZ-2640, in comparison with that of R-95867, faropenem and oral cephalosporins
Jun Okuda*,
Masako Otsuki,
Takanori Oh and
Takeshi Nishino
Department of Microbiology, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8414, Japan
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Abstract
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We compared the in vitro antibacterial activity of DU-6681a against Gram-positive and Gram-negative bacteria with that of R-95867, faropenem and oral cephalosporins such as cefcapene, cefotiam and cefpodoxime. DU-6681a is an active form of the new oral carbapenem compound DZ-2640, which is an ester-type prodrug, and R-95867 is an active form of the oral carbapenem CS-834. Against most Gram-positive bacteria, DU-6681a was as active as or two- to 16-fold more potent than R-95867 and faropenem in terms of MIC90, and comparable to or two- to 64-fold more effective than the cephalosporins. Against most Gram-negative bacteria, the activity of DU-6681a was the same as or two- to 16-fold more potent than that of R-95867, and comparable to or two- to 2048-fold higher than that of faropenem and the cephalosporins.
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Introduction
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Carbapenem antibiotics have extremely potent activities against a wide range of aerobic and anaerobic bacteria. These potent activities depend on resistance to hydrolysis by most ß-lactamases, and high affinity for penicillinbinding proteins. Three carbapenems, i.e. imipenem, panipenem and meropenem, are available for clinical use at the present time. Although imipenem is stable to hydrolysis by most ß-lactamases, it is hydrolysed by renal dehydropeptidase, and therefore requires co-administration with cilastatin, a dehydropeptidase inhibitor, for in vivo efficacy.1 Meropenem contains the 1ß-methyl group, which confers stability to renal dehydropeptidase, and eliminates the requirement for co-administration with cilastatin.2 DZ-2640 is a new oral carbapenem, synthesized and developed by Daiichi Pharmaceutical Co., Ltd, Tokyo, Japan. DZ-2640 is a pivaloyloxymethyl (POM) ester prodrug and becomes de-esterified to produce an active form, DU-6681a.3 DZ-2640 bears a bicyclic imidazole ring as a side chain, which affects both its in vitro activity and its pharmacokinetics after oral administration.3 DZ-2640 administered orally was rapidly absorbed in mice, rats, monkeys and dogs as the active form, DU-6681a.4 In this study, we compared the in vitro antimicrobial activity of DU-6681a with that of R-95867,5 (which is an active form of the recently developed oral carbapenem, CS-834), faropenem6 and oral cephalosporins such as cefcapene, cefotiam and cefpodoxime,7 against a broad range of clinical isolates including enteropathogenic bacteria.
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Materials and methods
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DU-6681a was synthesized at the New Product Research Laboratories I, Daiichi Pharmaceutical Co. (Tokyo, Japan). R-95867, its parent compound CS-834 and cefpodoxime were obtained from Sankyo Co., Ltd, Tokyo, Japan. Cefotiam was purchased from Takeda Chemical Industries, Osaka, Japan; cefcapene from Shionogi & Co., Ltd, Osaka, Japan; and faropenem from Suntory Co., Ltd, Osaka, Japan. Ampicillin and methicillin were from Banyu Pharmaceutical Co., Ltd, Tokyo, Japan.
The bacterial strains used in this study were standard strains and clinical isolates maintained in our laboratory. MICs were determined by the agar dilution method as recommended by the Japan Society of Chemotherapy.8 Sensitivity test agar (STA; Eiken Chemical Co., Ltd, Tokyo, Japan) was used as the test medium for staphylococci, enterococci and Gram-negative enteric bacteria. STA supplemented with 5% horse blood was used for streptococci; STA supplemented with 5% Fildes enrichment (Difco Laboratories, Detroit, MI, USA) for Haemophilus influenzae, chocolated STA for Moraxella catarrhalis and GAM agar (Nissui Seiyaku Co., Ltd, Tokyo, Japan) for anaerobic bacteria. One loopful (5 µL) of an inoculum corresponding to 5 x 103 cfu/spot was inoculated on to drug-containing agar plates, which were then incubated at 37°C for 18 h. Anaerobic bacteria were incubated in an anaerobic chamber (Forma Scientific, Marietta, OH, USA).
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Results
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The antibacterial activities of DU-6681a, cefcapene, cefotiam, cefpodoxime, faropenem and R-95867 were determined against 706 clinical isolates. The MIC ranges, MIC50s and MIC90s of the clinical isolates tested are summarized in the Table
. The MIC90s of DU-6681a against penicillinsusceptible and penicillin-non-susceptible Streptococcus pneumoniae were comparable to or at least two-fold lower than those of R-95867 and faropenem, respectively, and four- to at least 64-fold higher than those of cefcapene, cefotiam and cefpodoxime. The MIC90 of DU-6681a against H. influenzae including ß-lactamase-producing strains was comparable to that of R-95867, and almost comparable to or two- to 32-fold lower than those of faropenem and cephalosporins. For M. catarrhalis, the MIC90 of DU-6681a was two- to 32-fold lower than those of the other reference compounds. The MIC90s of DU-6681a for methicillinsusceptible Staphylococcus aureus and Staphylococcus epidermidis (MSSA and MSSE) were 0.06 and 0.12 mg/L, respectively. The activities against MSSA and MSSE were two- to 64-fold and four- to 64-fold higher than those of the other reference compounds at the MIC90 levels. The MIC90s of DU-6681a for methicillin-resistant S. aureus and S. epidermidis (MRSA and MRSE) were 32 and 8 mg/L, respectively. DU-6681a showed the highest activity against MRSA of the antibiotics tested. The activity of DU-6681a against MRSE was four- to at least 16-fold greater than that of the other reference compounds except for cefotiam, and two-fold less than that of cefotiam, at the MIC90 levels. The MIC90 of DU-6681a against Streptococcus pyogenes was comparable to or at least two- to eight-fold lower than those of the reference compounds. For Enterococcus avium, the MIC90 of DU-6681a was 16 mg/L, the lowest among the antibiotics tested. The activity of DU-6681a against Enterococcus faecalis was comparable to or greater than that of the reference compounds except for faropenem. DU-6681a was inactive against Enterococcus faecium (MIC90 > 128 mg/L), as were the reference compounds. The MIC90s of DU-6681a for Escherichia coli, Serratia marcescens, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii and Morganella morganii ranged from 0.015 mg/L to 0.25 mg/L, and DU-6681a showed the highest activity against those strains. The activity of DU-6681a was comparable to or greater than that of the reference compounds against Klebsiella pneumoniae, Proteus vulgaris, Proteus rettgeri, Proteus mirabilis (except for cefcapene and cefpodoxime) and Acinetobacter baumannii (except for R-95867). For Pseudomonas aeruginosa, the MIC90 of all compounds tested was
64 mg/L. The antibacterial activities of DU-6681a and reference antibiotics against clinical isolates of enteropathogenic bacteria are also shown in the Table
. The MIC90 of DU-6681a for E. coli O157 was
0.008 mg/L, and DU-6681a showed by far the highest activity against that strain of all compounds tested. The activity of DU-6681a against Vibrio cholerae O1 and O139, and Vibrio parahaemolyticus was comparable to that of R-95867, and greater than that of faropenem and the cephalosporins. Against Salmonella spp. and Shigella spp., the activity of DU-6681a was greater than that of the other compounds tested.
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Table. Antibacterial activities of DU-6681a and reference antibiotics against Gram-positive and Gram-negative bacteria
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The MIC range of DU-6681a against anaerobic bacteria was
0.0080.12 mg/L, which was lower than that of any of the other compounds tested (Table
). Against Bacillus spp., the activity of DU-6681a was comparable to or greater than that of the other compounds tested.
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Discussion
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This study showed that DU-6681a possesses a broadspectrum and potent antibacterial activity against the majority of Gram-positive and Gram-negative bacteria tested. We compared the in vitro antimicrobial activity of DU-6681a with that of R-95867 rather than that of either meropenem or imipenem, because DU-6681a and R-95867 are oral carbapenems, but meropenem and imipenem are parenteral carbapenems. Sakagawa et al.5 reported that the most important feature of R-95867 was its potent activity against S. pneumoniae, H. influenzae and M. catarrhalis, which are the major causes of community-acquired pneumonia. The activity of DU-6681a against S. pneumoniae, H. influenzae and M. catarrhalis was comparable to or greater than that of R-95867. DU-6681a also showed activity against MRSA and MRSE: the MIC90s of DU-6681a against those strains were four-fold and eight-fold, respectively, lower than those of R-95867.
In this study, we also investigated the antibacterial activity against enteropathogenic bacteria such as E. coli O157, V. cholerae O1 and O139, V. parahaemolyticus, Salmonella spp. and Shigella spp. When DZ-2640 was administered orally to starving rats, 8.7% of DU-6681a was excreted into the bile up to 48 h after administration (unpublished data). Therefore, it is suggested that DZ-2640 administered orally may be effective against infections caused by enteropathogenic bacteria.
Recently, the use of fluoroquinolones against a wide range of pathogenic species has been increasing; however, the general use of fluoroquinolones is restricted because of their side-effects and the limitation of bacterial resistance. For instance, the use of new quinolones in children is not recommended.9 Therefore, DU-6681a may be useful in cases in which fluoroquinolones are contraindicated.
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Notes
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* Corresponding author. Present address: New Product Research Laboratories I, Daiichi Pharmaceutical Co. Ltd, 16-13 Kita-kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan; Tel: +81-3-3680-0151, ext. 5810; Fax: +81-3-5696-8344; E-mail: okudao2e{at}daiichipharm.co.jp 
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Received 9 September 1999;
returned 19 January 2000; revised 8 February 2000;
accepted 28 February 2000