Multicenter in vitro evaluation of SM-7338, a new carbapenem

Meropenem was compared in vitro with imipenem as well as with several other contemporary beta-lactams, ciprofloxacin, and gentamicin against a group of highly antibiotic resistant members of the family Enterobacteriaceae and a collection of oxidase-positive and/or glucose-nonfermentative gram-negative bacilli. In this study, meropenem was more active than imipenem against isolates of Enterobacter, Klebsiella, Morganella, Providencia, Alcaligenes, Aeromonas, and Pasteurella.

supporting

confidence: 77%

mentioning

confidence: 99%

Activity of meropenem against antibiotic-resistant or infrequently encountered gram-negative bacilli

Jorgensen

Maher

Howell

1991

“…Meropenem is more active in vitro than imipenem against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Unlike imipenem, meropenem shows a good stability against human renal dehydropeptidase I and does not require the coadministration of a dehydropeptidase I enzyme inhibitor such as cilastatin (4,7,(9)(10)(11).…”

mentioning

confidence: 99%

Pharmacokinetics of meropenem (ICI 194,660) and its metabolite (ICI 213,689) in healthy subjects and in patients with renal impairment

Leroy

Fillastre

Borsa-Lebas

et al. 1992

The pharmacokinetics of meropenem (ICI 194,660) and its open-ring metabolite (ICI 213,689) were studied in 6 healthy volunteers and 16 patients with moderate to severe renal impairment after a single intravenous dose of 500 mg given as a 30-min infusion. Concentrations of unchanged meropenem in plasma and urine were measured by both microbiological and high-pressure liquid chromatographic (HPLC) assays. A good correlation was found between the two techniques. Pharmacokinetic parameters of unchanged meropenem were determined by using the HPLC data. The terminal half-lfe of unchanged meropenem increased in relation to the degree of renal impairment, being 1.2 h in subjects with normal renal function and 10 h in patients with end-stage renal failure. Total body clearance and renal clearance of unchanged meropenem are lnearly related to creatinine clearance. The concentrations of the metabolite in plasma, which are very low in healthy subjects, signcantl increased in uremic patients. The apparent half-life of ICI 213,689 increased in uremic patients and was about 35 h in patients with severe renal insufficiency. Meropenem and its metabolite are effectively removed by hemodialysis. The dialysis clearance of the unchanged drug was 81 J 22 ml/min. Dosage adjustments of meropenem will be necessary in patients with severe renal impairment.Meropenem (ICI 194,660) is a new parenteral carbapenem antibiotic characterized by a broad antibacterial spectrum. It has been shown to have activity against both gram-positive and gram-negative pathogens, including anaerobes such as Bacteroidesfragilis. Meropenem is more active in vitro than imipenem against members of the family Enterobacteriaceae and Pseudomonas aeruginosa. Unlike imipenem, meropenem shows a good stability against human renal dehydropeptidase I and does not require the coadministration of a dehydropeptidase I enzyme inhibitor such as cilastatin (4,7,(9)(10)(11).The purpose of this study was to investigate the pharmacokinetics of meropenem (ICI 194,660) and of its open-ring metabolite (ICI 213,689) in patients with moderate or severe renal impairment after a single intravenous (i.v.) dose of 500 mg given as a 30-min infusion.

“…Cilastatin, Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-butenoic acid, is a specific competitive inhibitor of RDPase and is well matched in its pharmacokinetic properties for coadministration with imipenem (8,22). Therefore, imipenem is designed to be coadministered with cilastatin to suppress RDPase for its clinical use, and they are now manufactured in a 1:1 combination.Meropenemhept-2-ene-2-carboxylic acid, which was introduced in the late 1980s, though relatively less active against gram-positive bacteria than imipenem (1,4,6,7), is stable in the presence of RDPase as judged by its V max /K m ratio. Thus, it is currently in clinical use without coadministration of an RDPase inhibitor.…”

mentioning

confidence: 99%

“…hept-2-ene-2-carboxylic acid, which was introduced in the late 1980s, though relatively less active against gram-positive bacteria than imipenem (1,4,6,7), is stable in the presence of RDPase as judged by its V max /K m ratio. Thus, it is currently in clinical use without coadministration of an RDPase inhibitor.…”

mentioning

confidence: 99%

Stability of New Carbapenem DA-1131 to Renal Dipeptidase (Dehydropeptidase I)

Park

Kim

et al. 2002

The stability of DA-1131 to renal dipeptidase (RDPase) (EC 3.4.13.19) was compared with that of imipenem and meropenem by V max /K m ratios as an index of the enzyme's preference for substrates. Our results showed a decreasing order of imipenem (6.24), meropenem (2.41), and DA-1131 (1.39). The biochemical evaluation of DA-1131 as the least preferred substrate of RDPase suggests its potential use as a novel ␤-lactam antibiotic which may be usable without coadministration of RDPase inhibitors once its clinical suitability is proven.Imipenem (N-formimidoylthienamycin), developed by Merck Sharp & Dohme, West Point, Pa., was highly effective against bacterial species resistant to most ␤-lactam antibiotics with unusually high potency against gram-positive as well as gramnegative bacteria (8,21,23). It is degraded, though, in the kidneys of various animals, resulting in a reduced antibacterial activity. The enzyme responsible for this metabolism was shown to be renal dipeptidase (RDPase, also called renal dehydropeptidase I) (EC 3.4.13.19) located in the brush-border membrane of renal proximal tubules (8,9,20). Cilastatin, Z-2-(2,2-dimethylcyclopropanecarboxamido)-2-butenoic acid, is a specific competitive inhibitor of RDPase and is well matched in its pharmacokinetic properties for coadministration with imipenem (8,22). Therefore, imipenem is designed to be coadministered with cilastatin to suppress RDPase for its clinical use, and they are now manufactured in a 1:1 combination.Meropenemhept-2-ene-2-carboxylic acid, which was introduced in the late 1980s, though relatively less active against gram-positive bacteria than imipenem (1,4,6,7), is stable in the presence of RDPase as judged by its V max /K m ratio. Thus, it is currently in clinical use without coadministration of an RDPase inhibitor.DA 237, 1996). DA-1131 has been examined in many aspects, including pharmacokinetics under various conditions in animals (10,12,13,16,17,18,19), in the renal excretion mechanism (14, 15), and in nephrotoxicity-related studies (11).We measured the kinetic parameters of imipenem, meropenem, and DA-1131 in relation to human RDPase and the RDPases of various animals to examine the stability of DA-1131 in reference to the two well-established ␤-lactam antibiotics, imipenem and meropenem.DA-1131 and meropenem were supplied by Dong-A Research Laboratory. Imipenem and cilastatin were obtained from Merck Sharp & Dohme. Human RDPase was purified to homogeneity with a 2,029-fold purification, and RDPases from animal sources were purified or partially purified according to the method previously described (24).RDPase-catalyzed hydrolysis of imipenem, meropenem, and DA-1131 was measured in the presence and absence of cilastatin (0.15 M) according to the method described by Kim and Campbell (9) by measuring the decrease in absorbance at 298 nm and 37°C as a function of time for 2.5 min. Substrate concentration was varied over a range of 1.25 to 3.3 mM in 3-(N-morpholino)propanesulfonic acid, pH 7.1. One microgram of purified RDPase was employ...