Effect of N-formimidoyl thienamycin (MK0787) on beta-lactamases and activity against beta-lactamase-producing strains

The in vitro synergistic activity of N-formimidoyl thienamycin and amikacin was determined against gentamicin-resistant enterobacteriaceae, Pseudomonas aeruginosa, and Staphylococcus aureus. N-Formimidoyl thienamycin showed synergism with amikacin against 19 of the gentamicin-resistant strains, 14 of the 49 strains of S. aureus, and only 1 strain of the 46 P. aeruginosa isolates.Thienamycin is a P-lactam antibiotic of novel structure produced by Streptomyces cattleya (4). The activity of this compound is characterized by its great intrinsic activity and broad antibacterial spectrum. The stability of thienamycin in the presence of P-lactamases and its activity against Pseudomonas sp. are of particular interest (6), although its potential utility was compromised by its lability in concentrated solutions and as a solid (4). Fortunately, this problem was partly solved with the development of the amidine derivate N-formimidoyl thienamycin (MK0787) (3, 6), a new analog of thienamycin that not only retains its great resistance against P-lactamases but is also capable of inhibiting them (3,7,14). The antibacterial activity of this thienamycin derivative is greater that that of thienamycin, especially against Pseudomonas, Bacteroides, and Enterococcus spp. (6,13). The purpose of this study was to evaluate the combined activity of N-formimidoyl thienamycin and amikacin.All the microorganisms studied, with the exception of Pseudomonas aeruginosa and Staphylococcus aureus isolates, were gentamicin resistant, with a minimum inhibitory concentration (MIC) of >8 ,ug/ml. The total number of isolates was 160; all of them were obtained from clinically significant specimens in a period of 6 months (from July to December 1981 (12). The concentrations used ranged between 0.01 and 32 ,ug/ml for N-formimidoyl thienamycin and between 0.25 and 32 ,ug/ml for amikacin. P-Lactamase activity of staphylococcal isolates was determined by using the Glaxo chromogenic cephalosporin, nitrocefin (9). S. aureus ATCC 25923 and Escherichia coli ATCC 25922 were utilized as control strains. The MICs obtained for these two control strains were 0.01 and 0.125 ,ug/ml with N-formimidoyl thienamycin and 1 and 2 ,ug/ml with amikacin. The evaluation of the N-formimidoyl thienamycin and amikacin combination was carried out in Mueller-Hinton agar by the simplified checkerboard method (5). Methodology and inoculum quantification were as described above. After 24 h of incubation at

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confidence: 99%

In Vitro Evaluation of N -Formimidoyl Thienamycin (MK0787) Combined with Amikacin Against Gram-Negative Bacilli and Staphylococcus aureus

Enciso¹,

Lindemann²,

Altés³

1982

“…inhibitory activity and their stability against most P-lactamases are expected to find wide clinical application in therapy for infections caused by P-lactamase-producing pathogens (12). However, carbapenems are rapidly metabolized in vivo, resulting in poor urinary recovery, because they are susceptible to renal dehydropeptidase I (4).…”

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confidence: 99%

Purification and characterization of human renal dehydropeptidase I

Mitsuhashi¹,

Fuse²,

Mikami³

et al. 1988

Self Cite

“…Other compounds were kindly provided by the following manufacturers: cefamandole from Eli Lilly & Co.; cefotetan (YM09330) (22) from Yamanouchi Pharmaceutical Co., Ltd.; cefbuperazone (T-1982) (21) from Toyama Chemical Co., Ltd.; clavulanic acid from Beecham Yakuhin Co., Ltd.; sulbactam (CP-45899) from Pfizer Inc.; and imipenem (formerly imipemide, N-formimidoyl thienamycin, or MK0787) (23) from Merck Banyu Co., Ltd.…”

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confidence: 99%

Properties of novel beta-lactamase produced by Bacteroides fragilis

Yotsuji¹,

Minami²,

Inoue³

et al. 1983

Self Cite

108

Bacteroidesfragilis strains were isolated from clinical specimens. B. fragilis G-237 was highly resistant to P-lactam antibiotics due to P-lactamase production.The purified enzyme from this strain gave a single protein band on polyacrylamide gel electrophoresis. The isoelectric point was 4.8, and the molecular weight was estimated to be 26,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The enzyme activity was inhibited by p-chloromercuribenzoate and iodine but not by clavulanic acid or sulbactam. The purified enzyme showed a unique substrate profile by hydrolyzing at a high rate most of the cephalosporins, including cephamycin derivatives, penicillins, and imipenem (formerly imipemide, N-formimidoyl thienamycin, or MK 0787).P-Lactamase production plays a significant role in resistance to P-lactam antibiotics (8, 14, 20). The enzymes from gram-positive bacteria are inducible, are extracellular, and have predominantly penicillinase activity (5, 10). The enzymes from gram-negative bacteria have been classified into several groups by substrate profile, inhibitory profile, and physicochemical and immunological properties (8,14,20).Bacteroidesfragilis strains have been isolated from clinical specimens with increasing frequency and are known to be moderately or highly resistant to penicillins and cephalosporins (4,19). Resistance has been ascribed to P-lactamase production by many investigators (1,9,(11)(12)(13)(16)(17)(18). Two kinds of P-lactamase from B. fragilis are known: cephalosporinases (1,11,12,16,18) and penicillinases (9,13,17).We selected two strains from B. fragilis that had been isolated due to their resistance levels against various P-lactam antibiotics and purified their ,-lactamases. This paper compares the properties of a novel P-lactamase produced by B. fragilis G-237 with those of a typical B. fragilis P-lactamase produced by strain G-242. Media. GAM agar and GAM broth (18) were the products of Nissui Pharmaceutical Co., Ltd.Antibiotic susceptibility testing. Drug resistance was determined by the agar dilution method described previously (17).Purification of ,B-lactamase. For the preparation of crude enzymes, we followed the method described previously (17). The P-lactamases were purified by absorption and elution on a DEAE-cellulose DE-52 column, gel filtration on a Sephadex G-150 column, and gel filtration on a Sephadex G-75 superfine column.Assay of P-lactamase and inhibition study. For the assay of P-lactamase and the inhibition study, we followed methods described previously (17). The millimolar absorbancy differences (Ac-) (7)