Cilastatin

Extensive carbapenem and penem antibiotic research has been ongoing since thienamycin was discovered in 1978. However, only the imipenem-cilastatin combination has become a commercial product. Launched in 1985 in the United States as a broad-spectmm hospital product under the name Ptimaxin, this product had worldwide sales of some 300 million in 1988. Sales were predicted to rise to 345 million for the year ending 1989 (154). 

The catalytic asymmetric cyclopropanation of an alkene, a reaction which was studied as early as 1966 by Nozaki and Noyori,63 is used in a commercial synthesis of ethyl (+)-(lS)-2,2-dimethylcyclo-propanecarboxylate (18) by the Sumitomo Chemical Company (see Scheme 5).64 In Aratani s Sumitomo Process, ethyl diazoacetate is decomposed in the presence of isobutene (16) and a catalytic amount of the dimeric chiral copper complex 17. Compound 18, produced in 92 % ee, is a key intermediate in Merck s commercial synthesis of cilastatin (19). The latter compound is a reversible... 

Scheme 5. The Sumitomo Chemical Company s catalytic asymmetric synthesis of ethyl (+)-(1 S)-2,2-dimethylcyclopropanecarboxylate (18), an intermediate in Merck s commercial synthesis of cilastatin (19).

C7H,Bi03 107872-93-5) see Cilastatin (3/t)-3-[(2-bromo-l-oxooctyl)oxy]tetradecanoic acid metbyl ester... 

C3H7NO2S 52-90-4) see Carbocisteine Cilastatin Eptifibatide Letosteine Timonacic L-cysteine hydrochloride monohydrate... 

CjHf,N2 1467-79-4) see Azapropazone dimethyl cyanocarboimidodithioatc (C4HSN2S2 10191-60-3) see Cimetidine dimethyl cyclohexylidenemainnate (C11H14O4 94286-34-7) see Gabapentin (S )-2,2-dimethylcyclopropanecarboxamide (QH iNO 75885-58-4) see Cilastatin... 

Thienamycin (Fig. 5.5E) is a broad-spectrum /3-lactam antibiotic with high /3-lactamase resistance. Unfortunately, it is chemically unstable, although the TV-formimidoyl derivative, imipenem, overcomes this defect. Imipenem (Fig. 5.5E) is stable to most/3-lactamases but it readily hydrolysed by kidney dehydropeptidase and is administered with a dehydropeptidase inhibitor, cilastatin. Meropenem, which has yet to be marketed, is more stable than imipenem to this enzyme and may thus be administered without cilastatin. Its chemical structure is depicted in Fig. 5.5F. 

The chiral copper cataly.st (see Fig. 3.54) has been used to synthesize the drug Cilastatin. The desired biological activity is found in the stereoisomer derived from (-I-) 15-2,2-... 

Chiral copper catalyst Cyclopropanation Cilastatin Pharmaceutical 92... 

Adjust dose of imipenem/cilastatin based on body weight (refer to package insert). 

It is often difficult to narrow the spectrum of activity of the antibiotic choice since the infections are usually polymicrobial. As such, patients may receive long courses of broad-spectrum antibiotics such as imipenem/cilastatin and... 

Imipenem/cilastatin 500 mg every 6 hours 5% incidence of seizure nausea is also a concern... 

Piperacillin-tazobactam 3.375-4.5 g IV every 6 hours Imipenem-cilastatin 500 mg IV every 6 hours Ceftazidime 2 g IV + clindamycin 600 mg IV every 8 hours... 

General Imipenem/cilastatin, meropenem, ertapenem, or extended-spectrum penicillins with 3-lactamase inhibitor 1. Aztreonam with clindamycin or metronidazole 2. Ciprofloxacin with metronidazole 3. Aminoglycoside with clindamycin or metronidazole ... 

Gangrenous or Imipenem/cilastatin, meropenem, ertapenem, 1. Aztreonam with clindamycin or metronidazole... 

Insufficiency SO years) peripheral neuropathy Enterobacteriaceae, P. aeruginosa, Enterococcus spp., anaerobes Vancomycin PLUS (1) piperacillin/tazobactam (2) imipenem/cilastatin or meropenem (3) cefepime or ceftazidime and clindamycin or metronidazole (4) ciprofloxacin or levofloxacin and clindamycin or metronidazole... 

By screening 53 Rhodococcus and Pseudomonas strains, an NHase-amidase biocatalyst system was identified for the production of the 2,2-dimethylcyclopropane carboxylic acid precursor of the dehydropeptidase inhibitor Cilastatin, which is used to prolong the antibacterial effect of Imipenem. A systematic study of the most selective of these strains, Rhodococcus erythropolis ATCC25 544, revealed that maximal product formation occurs at pH 8.0 but that ee decreased above pH 7.0. In addition, significant enantioselectivity decreases were observed above 20 °C. A survey of organic solvent effects identified methanol (10% v/v) as the... 

Figure 8.6 Preparation of (S)-2,2-dimethylcyclopropane carboxylic acid, a precursor of Cilastatin...

S)-2,2-Dimethyl-cyclopro-panecarbox-amide 13 Cilastatin Dehydropeptide inhibitor Hydrolysis Comononas acidivorans and recombinant E. coli One-pot, two-step processes [7]... 

Animal and human studies support the use of antibiotics for the prevention of infectious morbidity and mortality in severe ANP. The most effective antimicrobial agents are the fluoroquinolones, imipenem-cilastatin, and metronidazole, which achieve adequate penetration into pancreatic juice and necrotic tissue and inhibit the growth of enteric bacteria. Although a recent meta-analysis [185] suggested that prophylactic antibiotic administration reduces sepsis and mortality and this approach has been recommended by recent guidelines and consensus state-... 

---