Antimicrobial activity of DU-6681a, a parent compound of novel oral carbapenem DZ-2640

Tanaka, Mayumi; Hohmura, Masato; Nishi, T.; Sato, Kenichi; Hayakawa, Isao

doi:10.1128/aac.41.6.1260

Cited by 17 publications

(6 citation statements)

References 12 publications

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“…The MIC of LJC 11,036 is 0.025 g/ml, and that of cefdinir is 1.56 g/ml. (14), and CL 191,121 (MIC 100 , 1.0 g/ml) (17), LJC 11,036 appears to have the most potent antipneumococcal activity, which is one of its noteworthy features. As with imipenem, no significant inoculum effect was detected with LJC 11,036 against any of the strains tested.…”

Section: Discussionmentioning

confidence: 99%

In Vitro Antibacterial Activity of LJC 11,036, an Active Metabolite of L-084, a New Oral Carbapenem Antibiotic with Potent Antipneumococcal Activity

Hikida¹,

Itahashi²,

Igarashi³

et al. 1999

Antimicrob Agents Chemother

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LJC 11,036 is the active metabolite of L-084, a novel oral carbapenem that exhibits potent broad-spectrum activity. Antibacterial activities of LJC 11,036 against clinical isolates from respiratory infections, such as Streptococcus pneumoniae(n = 52), Streptococcus pyogenes(n = 19), Haemophilus influenzae(n = 50), Klebsiella pneumoniae(n = 53), and Moraxella catarrhalis(n = 53), and from urinary-tract infections, such asEscherichia coli (n = 53) (MICs at which 90% of the isolates were inhibited [MIC90s], 0.1, ≤0.006, 0.39, 0.05, 0.05, and 0.05 μg/ml, respectively), were 2- to 64-fold higher than those of imipenem, cefdinir, and faropenem. Moreover, against these bacterial species, except for H. influenzae, the MIC90s of LJC 11,036 were 4- to 512-fold lower than those of levofloxacin. LJC 11,036 showed bactericidal activity equal or superior to that of imipenem. Bactericidal activity against penicillin-resistant S. pneumoniae (PRSP) did not vary with the phase of growth. LJC 11,036 had potent activity against various β-lactamase-producing strains, excluding carbapenemase producers. Against renal dehydropeptidase-I, LJC 11,036 was more stable than imipenem. Furthermore, LJC 11,036 produced in vitro postantibiotic sub-MIC effects against PRSP HSC-3 (6.0 h at one-fourth the MIC) andH. influenzae LJ5 (9.2 h at one-half the MIC). LJC 11,036 showed high binding affinities for PBP1A, -1B, -2A/2X, -2B, and -3 of PRSP and for PBP1B, -2, -3A, and -3B of H. influenzae.

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Section: Discussionmentioning

confidence: 99%

In Vitro Antibacterial Activity of LJC 11,036, an Active Metabolite of L-084, a New Oral Carbapenem Antibiotic with Potent Antipneumococcal Activity

Hikida¹,

Itahashi²,

Igarashi³

et al. 1999

Antimicrob Agents Chemother

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“…The use of a specific transport system is suggested by the increased efficacies of the CL 191,121 derivatives with the L-form amino acids of alanine and phenylalanine after oral administration but the decreased activities of the D-form amino acids. The novel peptidic prodrugs of this THF carbapenem demonstrated efficacies comparable to those of other investigational oral carbapenems (5,18), ester prodrugs of active carbapenems (16), esters of tribactam antibiotics (15,20), the orally bioavailable oxazolidinones (4) and ketolides (1), and ester-type cephalosporins (6,13,17) against infections caused by both gram-negative and gram-positive isolates. The peptidic prodrugs of these novel aminomethyl THF-1␤-methylcarbapenems are promising new agents for the treatment of infections caused by a variety of gram-positive and gram-negative bacteria.…”

Section: Discussionmentioning

confidence: 80%

“…The carbapenem class of antibiotics has been shown to be effective against a broad spectrum of gram-positive and gram-negative bacteria and stable to most known resistance mechanisms. Presently, commercial carbapenems are effective only when they are administered by the parenteral route (3), while a few ester-type carbapenems are being developed for use as oral therapy (5,16). In addition, many ester-type prodrugs of cephalosporins and tribactams are in use or are under investigation for use as oral treatments (13,20).…”

mentioning

confidence: 99%

In Vivo Activities of Peptidic Prodrugs of Novel Aminomethyl Tetrahydrofuranyl-1β-Methylcarbapenems

Weiss¹,

Mikels²,

Petersen³

et al. 1999

Antimicrob Agents Chemother

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A series of novel aminomethyl tetrahydrofuranyl (THF)-1β-methylcarbapenems which have excellent broad-spectrum antibacterial activities exhibit modest efficacies against acute lethal infections (3.8 mg/kg of body weight against Escherichia coli and 0.9 mg/kg against Staphylococcus aureus) in mice when they are administered orally. In an effort to improve the efficacies of orally administered drugs through enhanced absorption by making use of a peptide-mediated transport system, several different amino acids were added at the aminomethyl THF side chains of the carbapenem molecules. The resulting peptidic prodrugs withl-amino acids demonstrated improved efficacy after oral administration, while the d forms were less active than the parent molecules. After oral administration increased (3 to 10 times) efficacy was exhibited with the alanine-, valine-, isoleucine-, and phenylalanine-substituted prodrugs against acute lethal infections in mice. Median effective doses (ED50s) of <1 mg/kg against infections caused by S. aureus, E. coli,Enterobacter cloacae, or penicillin-susceptibleStreptococcus pneumoniae were obtained after the administration of single oral doses. Several of the peptidic prodrugs were efficacious against Morganella morganii,Serratia marcescens, penicillin-resistant S. pneumoniae, extended-spectrum β-lactamase-producingKlebsiella pneumoniae, and E. coli infections, with ED50s of 1 to 14 mg/kg by oral administration compared with ED50s of 14 to >32 mg/kg for the parent molecules. In general, the parent molecules demonstrated greater efficacy than the prodrugs against these same infections when the drugs were administered by the subcutaneous route. The parent molecule was detectable in the sera of mice after oral administration of the peptidic prodrugs.

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“…This prodrug has been reported to be in Phase I clinical trials in Japan [133]. In vitro evaluation of DU-6681 against a variety of bacteria shows it to have broad spectrum activity [134]. It has comparable activity to imipenem against gram-positive organisms and is more potent than imipenem against gram-negative bacteria such as Enterobacteriacae, H. influenzae, and M. catarrhalis.…”

Section: Dz-2640mentioning

confidence: 98%

Quinolone, Everninomycin, Glycylcycline, Carbapenem, Lipopeptide and Cephem Antibacterials in Clinical Development

Bronson

Barrett²

2001

CMC

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The development of antibacterials was a very successful endeavor in the pharmaceutical company repertoire through the late 1970s, when interest in investing in antibiotic research and development temporarily waned. More recently, there have been a number of failures in late stage development or post-launch of human antibiotics. The answer to the dilemma of less-than-desired success may be the introduction of novel classes of agents, as well as development of new agents in traditional classes. This review provides an overview of the various "miscellaneous" antibacterials in development, excluding glycopeptides, macrolides, ketolides, and oxazolidinones. Among the agents highlighted in this review are the clinical candidates of quinolones, everninomycins, carbapenems, lipopeptides, glycylcyclines, and cephems. In several cases, certain quinolone agents described in this review will have been approved for marketing before press time.

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Antimicrobial activity of DU-6681a, a parent compound of novel oral carbapenem DZ-2640

Cited by 17 publications

References 12 publications

In Vitro Antibacterial Activity of LJC 11,036, an Active Metabolite of L-084, a New Oral Carbapenem Antibiotic with Potent Antipneumococcal Activity

In Vitro Antibacterial Activity of LJC 11,036, an Active Metabolite of L-084, a New Oral Carbapenem Antibiotic with Potent Antipneumococcal Activity

In Vivo Activities of Peptidic Prodrugs of Novel Aminomethyl Tetrahydrofuranyl-1β-Methylcarbapenems

Quinolone, Everninomycin, Glycylcycline, Carbapenem, Lipopeptide and Cephem Antibacterials in Clinical Development

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