Imipenem

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H315：Verursacht Hautreizungen.

  H319：Verursacht schwere Augenreizung.

  H335：Kann die Atemwege reizen.

• Sicherheit

  P261：Einatmen von Staub vermeiden.

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

Imipenem 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.
  S27:Beschmutzte, getränkte Kleidung sofort ausziehen.
  S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.

• Beschreibung

  Imipenem is a chemically stable thienamycin derivative with an antibacterial activity that is broader in spectrum and of greater potency than most of the third generation cephalosporins. Combination with cilastatin, an inhibitor of renal brush-border dehydropeptidase-I, increases both urinary and plasma levels of imipenem.

• Chemische Eigenschaften

  White Crystals

• Originator

  Merck (USA)

• Verwenden

  Carbapenem antibacterial.

• Definition

  ChEBI: Imipenem is a broad-spectrum, intravenous beta-lactam antibiotic of the carbapenem subgroup. It has a role as an antibacterial drug. It is a beta-lactam antibiotic allergen and a member of carbapenems. It is a tautomer of an imipenem zwitterion.

• Manufacturing Process

  Preparation of N-formimidoyl thienamycin:
  Thienamycin (517 mg) is dissolved in pH 7 0.1 N phosphate buffer (25 ml) and cooled in an ice bath with magnetic stirring. The solution is adjusted to pH 8.5 using 2.5 N sodium hydroxide solution dispensed from an automatic burette. While maintaining a pH of 8.5, methyl formimidate hydrochloride (711 mg) is added portionwise over 2-3 minutes. After an additional 10 min, the pH of the solution is brought to 7.0 using 2.5 N hydrochloric acid. The solution is chromatographed on a column of XAD-2 resin (150 ml) which is eluted with water. The N-formimidoyl thienamycin derivative (imipenem) elutes in 1.5-2.0 column volumes (200-300 ml) and is lyophilized to a white solid (217 mg). UV (pH 7 0.1 N phosphate buffer); λmax297 nm (8,590); ir (Nujol mull) 1767 Cm-1(β-lactam).
  Another method preparation of imipenem:
  6-(1)-Hydroxyethyl-1-azabicyclo(3.2.0)heptane-3,7-dione-2-carboxylate is converted to the diphenoxyphosphate enol ester and this in turn reacted with N,S-bistrimethylsilyl-N-formimidoylcysteamine (use of the bistrimethylsilylated reagent is necessary in order to avoid side reactions caused by cyclization reactions). As a result the (PhO)2OPO-groups are converted to Me3SiN = CHNH-groups. Removal of the protecting groups complete the synthesis of 1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-(1-hydroxyethyl)-3-((2- ((iminomethyl)amino)ethyl)thio)-7-oxo-, (5R-(5-alpha,6-alpha(R*)))-.

• Trademarks

  ZIENAM

• Therapeutic Function

  Antibiotic

• Antimicrobial activity

  Imipenem shows potent activity against a wide range of Grampositive and Gram-negative aerobes and anaerobes, including many resistant to other agents.Concentrations (mg/L) inhibiting 50% of strains of other organisms are: Listeria monocytogenes, 0.03; Legionella pneumophila, 0.03; Enterococcus faecium, 4; Yersinia spp., 0.06. Mycobacterium fortuitum is inhibited by 6.25 mg/L. Imipenem is active against many Pseudomonas species, but not Sten. maltophilia. It is active against most anaerobes, with the exception of Cl. perfringens, which is only moderately susceptible. It is bactericidal at 2–4 times the MIC for most species, but some strains of Staph. aureus exhibit ‘tolerance’ . Bactericidal synergy with aminoglycosides, glycopeptides, fosfomycin and rifampicin (rifampin) has been observed against many strains of Staph. aureus and enterococci.
  Antibacterial activity is unaffected by the presence of cilastatin, which is itself devoid of antimicrobial activity.
  Imipenem is stable to hydrolysis by most serine β-lactamases, with the exception of the group 2f carbapenem-hydrolyzingenzymes hydrolyzingenzymes . Strains of B. fragilis, Aeromonas spp. and Sten. maltophilia can produce metallo-β-lactamases that hydrolyze the drug rapidly. These strains, in addition to occasional strains of enterobacteria, Acinetobacter baumannii and Ps. aeruginosa, show variable resistance to imipenem depending upon the level of carbapenem-hydrolyzing enzymes and the presence or absence of imipenem-specific porins. Efflux pumps also exist that may extrude imipenem from Gramnegative bacteria.

• Acquired resistance

  Some strains of Citrobacter, Enterobacter, Proteus vulgaris, Providencia, Ps. aeruginosa and Serratia spp. may be resistant to imipenem and other β-lactam agents, often because of the selection of stably derepressed mutants expressing high levels of group 1 β-lactamases coupled with decreased intracellular drug levels due to porin mutations or increased efflux.
  Induction of class 1 β-lactamases by imipenem in strains of Aeromonas, Pseudomonas and Serratia spp. is responsible for antagonism of β-lactamase-labile β-lactam agents in vitro. Imipenem resistance in Ps. aeruginosa can occur following selection of mutants that hyperproduce the group 1 cephalosporinase and which are also deficient in an outer membrane protein (OprD or D2) which specifically transports imipenem, but not cephalosporins or monobactams.

• Allgemeine Beschreibung

  Thienamycin was found in the culture broth of Streptomyces cattleya by Merck Sharp & Dohme in 1976, as a very unstable substance. It has a unique carbapenem structure, like that of the olivanic acids found in S. olivaceus by Beecham Research Laboratories in 1979. Thienamycin shows excellent activity against a variety of pathogenic bacteria, including Pseudomonas aeruginosa. Its chemical stability has been improved by derivatization with the formimidoyl group, and its biological stability has been improved by combining it with cilastatin, an inhibitor of kidney dihydropeptidase. The combination drug imipenem – cilastatin is now under study to evaluate its clinical efficacy and safety.

• Clinical Use

  Lower respiratory tract infections
  Urinary tract infections (complicated and uncomplicated)
  Intra-abdominal infections
  Gynecological infections
  Bacterial septicemia
  Bone and joint infections
  Skin and skin structure infections
  Endocarditis
  Polymicrobial infections

• Nebenwirkungen

  CNS effects such as confusional states and seizures have been reported, especially when recommended doses were exceeded, and in patients with renal failure or creatinine clearances of ≤20 mL/min/1.73 m2.
  Other reactions include phlebitis/thrombophlebitis (3.1%), nausea (2.0%), diarrhea (1.8%) and vomiting (1.5%).
  Increased hepatic enzymes may be seen in adults and children. Superinfection with Aspergillus, Candida and resistant Pseudomonas spp. have been described and pseudomembranous colitis has been reported.
  Patients with a history of hypersensitivity reactions to penicillins, cephalosporins or other β-lactam antibiotics should be treated cautiously with carbapenems.

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