Meropenem

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P264：Nach Gebrauch gründlich waschen.

  P264：Nach Gebrauch gründlich waschen.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

  P302+P352：BEI BERÜHRUNG MIT DER HAUT: Mit viel Wasser/... (Hersteller kann, falls zweckmäßig, ein Reinigungsmittel angeben oder, wenn Wasser eindeutig ungeeignet ist, ein alternatives Mittel empfehlen) waschen.

  P305+P351+P338：BEI KONTAKT MIT DEN AUGEN: Einige Minuten lang behutsam mit Wasser spülen. Eventuell vorhandene Kontaktlinsen nach Möglichkeit entfernen. Weiter spülen.

  P321：Besondere Behandlung

  P332+P313：Bei Hautreizung: Ärztlichen Rat einholen/ärztliche Hilfe hinzuziehen.

  P362：Kontaminierte Kleidung ausziehen und vor erneutem Tragen waschen.

Meropenem Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.
  S37/39:Bei der Arbeit geeignete Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.

• Beschreibung

  Meropenem is a new carbapenem antibiotic introduced to market for the i.v. treatment of a wide variety of hospital infections such as lower respiratory tract, urinary tract, intraabdominal, gynecological and polymicrobial infections. Meropenem has a broad spectrum of antibacterial activity against most clinically important Gram-positive and Gramnegative aerobic and anaerobic bacteria with especially high potency against multiresistant Enterobacteriaceae and Pseudornonas aeruginosa. Compared with imipenem, the only other available carbapenem antibiotic, meropenem has the advantage of being dehydropeptidase 1 (DHP-1) stable and therefore does not need to be administered in conjunction with the DHP-1 inhibitor cilastatin. Meropenem is also being evaluated for treatment of resistant pseudomonal infections in cystic fibrosis patients.

• Chemische Eigenschaften

  1KG;

• Originator

  Sumitomo (Japan)

• Verwenden

  Meropenem, is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia.

• Verwenden

  antineoplastic, PDGF receptor blocker, immunomodulator

• Definition

  ChEBI: Meropenem is a carbapenemcarboxylic acid in which the azetidine and pyrroline rings carry 1-hydroxymethyl and in which the azetidine and pyrroline rings carry 1-hydroxymethyl and 5-(dimethylcarbamoyl)pyrrolidin-3-ylthio substituents respectively. It has a role as an antibacterial drug, an antibacterial agent and a drug allergen. It is a carbapenemcarboxylic acid, a pyrrolidinecarboxamide, an alpha,beta-unsaturated monocarboxylic acid and an organic sulfide.

• Manufacturing Process

  3.10 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline and 1.10 g of triethylamine were dissolved in 40 ml of dried tetrahydrofuran, and a solution of 1.20 g of ethyl chloroformate in 10 ml of dried tetrahydrofuran was added dropwise thereto at -25-35°C. After stirring at the same temperature for 50 min, 10 ml of concentrated aqueous ammonia was added dropwise to the mixture at -25-40°C. The temperature was then gradually elevated to room temperature, and the reaction mixture was stirred for 1 hour, followed by concentration under reduced pressure. To the residue were added 20 ml of water and 50 ml of diethyl ether. After ice-cooling, the thus formed white crystals were separated by filtration, washed successively with cool water and cool diethyl ether, and dried under reduced pressure to yield trans-1-(pnitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide. Melting point: 163.3-164.0°C.
  A solution of 1.89 g of methanesulfonyl chloride in 10 ml of dried tetrahydrofuran was added dropwise to a suspension of 2.32 g of trans-1-(pnitrobenzyloxycarbonyl)-4-hydroxy-L-prolineamide and 1.67 g of triethylamine in 40 ml of dried tetrahydrofuran at room temperature. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure, and to the residue were added 30 ml of water and 30 ml of diethyl ether. After cooling, the resulting white crystals were separated by filtration, washed successively with cool water and cool diethyl ether and dried under reduced pressure to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxyL-prolineamide. Melting point: 149.5-151°C.
  A solution of 642 mg of thioacetic acid in 14 ml of dried dimethylformamide was added to a suspension of 374 mg of 50% sodium hydride in 13 ml of dried dimethylformamide in a nitrogen stream, followed by stirring at room temperature for 25 minutes. To the mixture were added 975 mg of sodium iodide and then a solution of 2.52 g of trans-1-(p-nitrobenzyloxycarbonyl)-4- methanesulfonyloxy-L-prolineamide in 12 ml of dried dimethylformamide, and the resulting mixture was heated to 70°C for 6 hours while stirring. The reaction mixture was poured into a cool aqueous solution of sodium chloride and extracted with benzene. The extract was washed successively with a 10% aqueous solution of sodium sulfate and a sodium chloride aqueous solution, dried over sodium sulfate and distilled off to remove the solvent. The resulting crude crystals were washed with a warm mixed solvent of tetrahydrofuran and benzene to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)- 2-carbamoyl-4- acetylthio-L-prolineamide. Melting point: 168.5-169.5°C.
  950 mg of (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4- acetylthiopyrrolidine was dissolved in 95 ml of methanol, and 2.59 ml of a 1 N aqueous solution of sodium hydroxide was added thereto at room temperature in an argon stream, followed by stirring at that temperature for 15 min. The reaction mixture was neutralized with 2.59 ml of a 1 N aqueous solution of hydrochloric acid and distilled off under reduced pressure to remove the methanol. The thus precipitated crystals were filtered and washed with water to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4- mercaptopyrrolidine. Melting point: 158-162°C.
  To 1.33 g (20 mM) of activated zinc was added 20 ml of dried tetrahydrofuran, and 8.8 ml of a 15% n-hexane solution of diethylaluminium chloride was added thereto in a nitrogen stream under ice-cooling. A solution prepared by dissolving 1.49 g (5.2 mM) of (3R,4R)-4-acetoxy-3-[(R)-1-(tbutyldimethylsilyloxy)ethyl]-2-azetidinone and 3.73 g (15.3 mM) of benzyl-αbromopropionate in 13.3 ml of dried tetrahydrofuran was added dropwise to the mixture over a period of 30 to 40 min, followed by stirring for 1 hours. Under ice-cooling, 2.8 ml of pyridine, 13.2 ml of water, 26.5 ml of ethyl acetate and 13.2 ml of a 1 N hydrochloric acid aqueous solution were successively added thereto, and the resulting mixture

• Trademarks

  Merrem I.V. (AstraZeneca).

• Therapeutic Function

  Antibiotic

• Clinical Use

  Meropenem is a synthetic carbapenem possessing a complex side chain at C-3. It also has a chiral methyl group at C-4. This methyl group conveys intrinsic resistance to hydrolysis by dehydropeptidase-1. As a consequence, it can be administered as a single agent for the treatment of severe bacterial infections.

• in vitro

  the meropenem mics for penicillin-resistant streptococcus pneumoniae were higher than for the penicillin-susceptible strains but the organisms remained susceptible. clinical susceptibility in vitro to meropenem was defined by mics of ≤4 mg/l, intermediate susceptibility by mics of 8 mg/l and mics of ≥16 mg/l define resistance; equivalent figures for zones of growth inhibition were ≥14 (susceptible), 12-13 (intermediate) and ≤11 (resistant) mm [1].meropenem was 2- to 4-fold more active than imipenem against gram-negative organisms and its spectrum of antimicrobial activity was wider than those of all other drugs tested.meropenem inhibited all anaerobic bacteria at less than or equal to 8 mg/l and 0.25 mg/l inhibited 50% of strains. meropenem mics were not significantly influenced by high inocula and the drug was generally bactericidal [2]. meropenem bound most strongly to penicillin-binding protein 2 of escherichia coli and pseudomonas aeruginosa, and to penicillin-binding proteins 1 of staphylococcus aureus [3].meropenem had one identified metabolite, a β-lactam ring-opened form which is devoid of microbiological activity [4].

• in vivo

  in rabbits, meropenem significantly increased the plamsa total clearance of valproate to about 1.5 times compared to the control (6.09 ml/min/kg vs. 4.28 ml/min/kg). meropenem significantly increased the urinary excretion of valproate- glucuronide in rabbits [5].

• Einzelnachweise

  [1] edwards j r. meropenem: a microbiological overview [j]. journal of antimicrobial chemotherapy, 1995, 36 (suppl a): 1-17.
  [2] jones r n, barry a l, tbornsberry c. in-vitro studies of meropenem [j]. journal of antimicrobial chemotherapy, 1989, 24 (suppl a): 9-29.
  [3] yang y, bhachech n, bush k. biochemical comparison of imipenem, meropenem and biapenem: permeability, binding to penicillin-binding proteins, and stability to hydrolysis by β-lactamases [j]. journal of antimicrobial chemotherapy, 1995, 35 (1): 75-84.
  [4] drusano g l, hutchison m. the pharmacokinetics of meropenem [j]. scandinavian journal of infectious diseases.supplementum, 1994, 96: 11-16.

Meropenem Upstream-Materialien And Downstream Produkte

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