In vitro activity of L-627, a new carbapenem

Biapenem, formerly LJC 10,627 or L-627, a carbapenem antibiotic, was studied in its interactions with 12 ␤-lactamases belonging to the four molecular classes proposed by R. P. Ambler (Philos. Trans. R. Soc. Lond. Biol. Sci. 289:321-331, 1980). Kinetic parameters were determined. Biapenem was readily inactivated by metallo-␤-lactamases but behaved as a transient inhibitor of the active-site serine enzymes tested, although with different acylation efficiency values. Class A and class D ␤-lactamases were unable to confer in vitro resistance toward this carbapenem antibiotic. Surprisingly, the same situation was found in the case of class B enzymes from Aeromonas hydrophila AE036 and Bacillus cereus 5/B/6 when expressed in Escherichia coli strains.It has been clearly shown that bacterial resistance to ␤-lactam antibiotics is often a multifactorial event in which outer membrane impermeability and ␤-lactamase production by gram-negative bacteria play central roles (39).␤-Lactamase degradation of ␤-lactam antibiotics represents one of the most important biochemical mechanisms of resistance to these molecules in bacteria (19). These enzymes, which are bacterial hydrolases (EC 3.5.2.6), have been classified into four different molecular classes on the basis of their primary structures and catalytic mechanisms (1). Enzymes of classes A, C, and D exert their catalytic activity by a reactive serine residue in the active site, while class B ␤-lactamases are metalloproteins which require a divalent transition metal ion for their activity, most often Zn 2ϩ . Antibiotic pressure has often selected bacteria able to elaborate two or more specific chromosomally encoded or plasmidmediated ␤-lactamases which are active against a wide range of ␤-lactam compounds.An expanded spectrum of ␤-lactams has been developed over the past 20 years in order to overcome bacterial resistance to molecules previously developed for clinical use. Carbapenem antibiotics are reported to be very stable in the presence of active-site serine ␤-lactamases, with the exception of class C enzymes produced by members of the family Enterobacteriaceae which exhibit slow antibiotic hydrolysis (25). This phenomenon, combined with a reduced permeability of the bacterial outer membrane, leads to resistance in hyperproducing strains of Enterobacter cloacae and Pseudomonas aeruginosa. These novel antibiotics also show a broad range of activity against gram-negative and gram-positive bacteria (22,30), with the exception of Xanthomonas maltophilia, which produces a chromosomally encoded class B ␤-lactamase (4, 36) which is able to inactivate all ␤-lactam antibiotics except aztreonam (14). Moreover, carbapenem antibiotics have variable stability to hydrolysis by mammalian dehydropeptidase-I (18,20,21,34). For this reason, imipenem, the first carbapenem molecule to be introduced in the clinical setting, is administered in combination with cilastatin, a dehydropeptidase-I inhibitor. Despite the antimicrobial efficacy of imipenem, it is only relatively recently that reports ...

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confidence: 99%

Interactions of biapenem with active-site serine and metallo-beta-lactamases

Felici

Perilli

Segatore

et al. 1995

“…The carbapenem class of antimicrobial agents is highly active against the major bacterial pathogens causing meningitis, but in the first clinical trial of such an agent, the use of imipenem-cilastatin was terminated because of an excess of seizures in those receiving the drug (28). Meropenem, a carbapenem structurally related to imipenem, is stable to the majority of ␤-lactamases (23) and is active in vitro against a broad range of gram-negative and gram-positive aerobic and anaerobic bacteria, with several-fold-greater activity than that of imipenem against H. influenzae and N. meningitidis (4). Meropenem is also stable to human renal dehydropeptidase-I and, unlike imipenem, does not need to be combined with a dehydropeptidase inhibitor such as cilastatin (22).…”

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confidence: 99%

Randomized comparison of meropenem with cefotaxime for treatment of bacterial meningitis. Meropenem Meningitis Study Group

Klugman

Dagan

1995

159

Broad-spectrum cephalosporins are drugs of choice for the treatment of meningitis in communities which can afford them. The emergence of cephalosporin-resistant pneumococci demands the clinical trial of alternate agents. Carbapenems are active against the bacteria causing meningitis, but the use of imipenem-cilastatin was frustrated by drug-associated seizures. The safety and efficacy of meropenem, a new carbapenem, were compared to those of cefotaxime in a prospective randomized trial of 190 children with bacterial meningitis. Seizures occurred within 24 h before antibiotic therapy in 16 of 98 patients (16%) randomized to receive meropenem and in 6 of 92 patients (7%) randomized to receive cefotaxime. In patients without seizures before therapy, seizures occurred during therapy in 5 of 82 patients (6%) receiving meropenem and in 1 of 86 patients (1%) receiving cefotaxime (95% confidence interval: ؊0.7%, 10.6%). None were thought to be drug related. Twenty-four meropenem-treated patients (24%) and 11 cefotaxime-treated patients (12%) had neurological abnormalities before therapy. In patients without pretherapy neurological abnormalities, these abnormalities were present after treatment in 4 of 74 meropenem-treated patients (5%) and in 2 of 81 cefotaxime-treated patients (2%) (95% confidence interval: ؊3.2%, 9.1%). Of 75 meropenem-treated and 64 cefotaxime-treated patients with pretherapy positive cerebrospinal-fluid cultures, 68 and 59, respectively, had repeat lumbar punctures. Bacterial eradication was found to be 100% in both groups. Our data suggest that meropenem may be a carbapenem agent that is well tolerated and effective in the treatment of bacterial meningitis.

“…Imipenem, panipenem (formerly RS-533 or CS-533) (12,23), and biapenem (LJC-10,627 or L-627) (4,35,36) were also synthesized in our laboratories. Other antimicrobial agents were commercially available.…”

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confidence: 99%

Transient carbapenem resistance induced by salicylate in Pseudomonas aeruginosa associated with suppression of outer membrane protein D2 synthesis

Sumita

Fukasawa

1993

Pseudomonas aeruginosa PAO1 showed increased phenotypic resistance to imipenem, panipenem, and biapenem specifically in the presence of salicylate. The antipseudomonal activity of carbapenems was reduced in proportion to the concentration of salicylate. This resistance was transient and nonheritable. The synthesis of the outer membrane protein D2 (OprD or OprD2) in P. aeruginosa PAO1 was inhibited by 4 to 32 mM salicylate in the bacterial growth medium, whereas no changes in any other outer membrane proteins were observed. These results indicate that salicylate suppresses the synthesis of OprD and therefore reduces the antipseudomonal activity of carbapenems. Under these conditions, one carbapenem-meropenem-is still active against P. aeruginosa, which indicates that meropenem can pass through the outer membrane via both the D2 channel and another undefined route(s).