Stability of meropenem and effect of 1 beta-methyl substitution on its stability in the presence of renal dehydropeptidase I

Fukasawa, Masatomo; Sumita, Yoshihiro; Harabe, E T; Tanio, Tomoharu; Nouda, Hiroshi; Kohzuki, Tsuneo; Okuda, Takuo; Matsumura, Hideaki; Sunagawa, Makoto

doi:10.1128/aac.36.7.1577

Cited by 125 publications

(81 citation statements)

References 22 publications

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“…This activity of SM-17466 was consistent with its in vitro activity against methicillin-resistant strains. The stability of SM-17466 in the presence of mouse DHP-I was equivalent to that of meropenem (4). The coadministration of cilastatin with SM-17466 extended the serum half-life of this antibiotic in mice (about 27 min).…”

Section: Discussionmentioning

confidence: 77%

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Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus

Sumita

Nouda

Kanazawa

et al. 1995

Antimicrob Agents Chemother

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The in vitro and in vivo antibacterial activities of SM-17466, a new 1␤-methyl carbapenem, were evaluated against a wide range of clinical bacterial isolates and compared with the activities of meropenem, imipenem, vancomycin, and arbekacin. SM-17466 had a broad spectrum of action against gram-positive bacteria, showing especially potent activity against methicillin-resistant staphylococci. The MICs of SM-17466, meropenem, imipenem, vancomycin, and arbekacin at which 90% of clinical isolates of methicillin-resistant Staphylococcus aureus were inhibited were 3.13, 50, 100, 1.56, and 3.13 g/ml, respectively. This activity of SM-17466 was almost equivalent to those of the antibiotics used for the treatment of infections caused by this organism. SM-17466 also showed bactericidal activity against methicillin-resistant S. aureus. In contrast, SM-17466 was less active against gram-negative bacteria, especially against Pseudomonas aeruginosa, compared with the other carbapenems; however, of the carbapenems, SM-17466 exhibited the highest activity against Haemophilus influenzae and Bacteroides fragilis. SM-17466, at a 50% inhibitory concentration of less than 1 g/ml, bound to penicillin-binding proteins 1 to 4 in methicillin-susceptible S. aureus and also had good binding to penicillinbinding protein 2 in a methicillin-resistant strain (50% inhibitory concentration, 5.9 g/ml). This high affinity, which was 10 and 20 times greater than those for meropenem and imipenem, respectively, was reflected in the potent activity of SM-17466 against methicillin-resistant S. aureus. SM-17466 demonstrated excellent in vivo efficacy against methicillin-susceptible and -resistant S. aureus strains in a mouse peritoneal infection model: the efficacy of SM-17466 against methicillin-resistant strains was equal to or one-third that of vancomycin. This activity was comparable to the in vitro activity of SM-17466. The subcutaneous injection of SM-17466 in mice revealed that the half-life of SM-17466 in serum was about 18 min, intermediate between those of vancomycin and arbekacin and 1.5-fold that of imipenem-cilastatin. SM-17466 was resistant to hydrolysis by swine renal dehydropeptidase I, to an extent comparable to the resistance shown by meropenem.

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Section: Discussionmentioning

confidence: 77%

“…The stability of SM-17466 against renal DHP-I was determined with purified swine renal DHP-I, as reported previously (4). The activity of DHP-I was spectrophotometrically determined by measuring the hydrolysis of glycyldehydrophenylalanine as a substrate.…”

Section: Methodsmentioning

confidence: 99%

Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus

Sumita

Nouda

Kanazawa

et al. 1995

Antimicrob Agents Chemother

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“…Araki et al, Page 10 of 14 Carbapenems are hydrolyzed at the β-lactam ring by mammalian DHP-I [12,13].…”

Section: Discussionmentioning

confidence: 99%

In vivo efficacy of doripenem (DRPM) against Pseudomonas aeruginosa in murine chronic respiratory tract infection model

Araki

Yamada

Kamihira

et al. 2011

Journal of Infection and Chemotherapy

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Doripenem is a carbapenem antibiotic with broad-spectrum coverage of gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa, and is considered to be as effective as meropenem. The in vivo activity of doripenem was thus compared with that of meropenem in a chronic lower respiratory P. aeruginosa infection mouse model. The number of viable bacteria in the lungs after treatment with doripenem, meropenem, and saline mice was 2.01 ± 0.69, 2.03 ± 0.48 and 3.90 ± 1.40 log 10 CFU/lung, respectively. The number of viable bacteria in the lungs of mice treated with doripenem and meropenem was significantly lower than that in lungs of controls.Histopathological examination of lung specimens from the control group revealed promotion of the inflammatory response in chronic bronchial infection. However, the groups treated with doripenem and meropenem showed weaker inflammatory responses. These results suggest that doripenem treatment is effective against chronic airway infection with P. aeruginosa.

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“…The kinetic parameters and V max /K m ratios are summarized in Table 1. The V max /K m ratio for each substrate has been used as an index of the enzyme's preference for substrates (3,5). The V max /K m ratio decreased in the order of imipenem (6.24), meropenem (2.41), and DA-1131 (1.39), thus identifying DA-1131 as the least preferred substrate among the three, i.e., the most stable compound against RDPase.…”

Section: Imipenem (N-formimidoylthienamycin) Developed By Merckmentioning

confidence: 99%

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

Park

Kim

et al. 2002

Antimicrob Agents Chemother

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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...

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Stability of meropenem and effect of 1 beta-methyl substitution on its stability in the presence of renal dehydropeptidase I

Cited by 125 publications

References 22 publications

Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus

Antimicrobial activity of SM-17466, a novel carbapenem antibiotic with potent activity against methicillin-resistant Staphylococcus aureus

In vivo efficacy of doripenem (DRPM) against Pseudomonas aeruginosa in murine chronic respiratory tract infection model

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

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