Imipenem, carbapenem antibiotic

Cilastatin (Sumitomo). Ethyl dimethylcyclopropane carboxylate is an intermediate for cilastatin, an inhibitor for dehydropeptidase I, which is administered in combination with the carbapenem antibiotic imipenem. It is produced by Sumitomo on a small scale via addition of a carbene to isobutene (lg,59). 

Meropenem (Merrem) is another carbapenem antibiotic with a broad spectrum of activity comparable to that of imipenem. A methyl group attached at the one-position on the five-member ring confers stability to dehydropeptidase 1. Consequently, meropenem does not require administration with cilastatin. When compared in human trials, imipenem-cilastatin and meropenem achieve similar clinical outcomes in patients with serious intraabdominal and soft tissue infections. Both imipenem-cilastatin and meropenem are used to treat infections caused by highly resistant Klebsiella pneumoniae producing ESBLs.The major cUnicaUy relevant distinction between imipenem-cilastatin and meropenem... 

Chromosomal metallo-beta-lactamases that hydrolyze carbapenem antibiotics, such as imipenem, meropenem, or biapenem, are present in some Stenotro-phomonas, Bacteroides, andAeromonas strains [26], Some clinical/5, aeruginosa and Serratia marcescens isolates have a plasmid that carries metallo-beta-lactamase genes [26], These enzymes are not inactivated by inhibitors of serine-based beta-lactamases such as clavulanic acid or sulbactam analogs. Enzyme-... 

The carbapenem antibiotics such as imipenem were developed to deal with the beta-lactamase-producing Gram-negative organisms resistant to the penicillins. 

Some cyclopropanes have proved to be useful as pharmaceutical intermediates. The compound, (-i-)-S-2,2-dimethylcyclopropanecarboxyHc acid, is a component of cilastatin (Fig. 3), which is administrated in combination with imi-penem, a carbapenem antibiotic [7]. In spite of its high and wide antibacterial activity, imipenem is found to be easily decomposed in the kidneys. This metabolism is suppressed by cilastatin, an enzyme inhibitor for dehydropeptidase I. 

The two most used carbapenems are the broad spectrum antibiotics imipenem and meropenem. 

Drug-Drug Interactions Simultaneous use of carbapenem antibiotics and VPA is known to result in decreased serum levels of VPA. A retrospective report of interactions with various antibiotics in this class foxmd a mean reduction in serum VPA levels of 88.7% in three patients taking meropenem, a mean reduction of 74% in two patients taking ertapenem, and a reduction of 73.3% in one patient taking imipenem [Wl ]. 

One of my favorite topics in process research is chemical lore, and we have all fallen victim to it. Years ago we were designing and developing the first practicable synthesis of imipenem, the first carbapenem antibiotic to reach the market.(3) As part of this synthesis lactone 1 (Scheme 1) was solvolyzed in benzyl alcohol, which afforded a 3 1 mixture of the desired benzyl ester and the... 

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). 

There are two additional important variations on the theme of p-lactam antibiotics. These are the carbapenems, of which imipenem (Primaxin) is the outstanding example, and the monobactams, of which aztreonam (Azactam) is the outstanding example (see figure 23.2). 

Carbapenems are representatives of another class of antibiotics that differ from penems in the absence of a sulfur atom in the penem ring. They include thienamicin (R = CH2CH2NH2), olivanic acid (R = CH=CHNH2>, and imipenem (R = CH2CH2NHC=NH). 

Mercaptopurine [6-MP] (Purinethol) [Antineoplastic/ Antimeta lite] Uses Acute leukemias, 2nd-line Rx of CML NHL, maint ALL in children, immunosuppressant w/ autoimmune Dzs (Crohn Dz) Action Antimetabolite, mimics hypoxanthine Dose Adults. 80-100 mg/mVd or 2.5-5 mg/kg/d maint 1.5-2.5 mg/kg/d Peds. Per protocol X w/ renal/hepatic insuff on empty stomach Caution [D, ] Contra Severe hepatic Dz, BM suppression, PRG Disp Tabs SE Mild hematotox, mucositis, stomatitis, D rash, fever, eosinophilia, jaundice. Hep Interactions T Effects W/ allopurinol T risk of BM suppression W/ trimethoprim-sulfamethoxazole X effects OF warfarin EMS May falsely T glucose OD May cause NA and liver necrosis symptomatic and supportive Meropenem (Merrem) [Antibiotic/Carbapenem] Uses lntra-abd Infxns, bacterial meningitis Action Carbapenem X cell wall synth, a [3-lactam Dose Adults. 1 to 2 g IV q8h Peds. >3 mo, <50 kg 10-40 mg/kg IV q 8h in renal insuff Caution [B, ] Contra [3-Lactam sensitivity Disp Inj 500 mg, 1 g SE Less Sz potential than imipenem D, thrombocytopenia Interactions T Effects W/ probenecid EMS Monitor for signs of electrolyte disturbances and... 

L B. The patient has complicated urinary tract infection and nonsevere sepsis syndrome caused by P. aeruginosa. Effective antibiotics for Pseudomonas spp. include mezlocillin, piperacillin, piperacillin-tazobactam, ticarcillin, and ticarciUin-clavulanate. The carbapenems (imipenem and meropenem) and the monobactam (aztreonam) are also active against P. aeruginosa. Ampicillin-sulbactam and cefazolin are ineffective against P. 

Carbapenems are synthetic p-lactam antibiotics that differ from the penicillins in that the sulfur atom of the thiazolidine ring (Figure 30.9) has been externalized and replaced by a carbon atom. Imipenem [i mi PEN em] is the only drug of this group currently available. 

Similarly, metallo- 3-lactamases share with metallo-proteases activation of a hydrolytic water molecule by interaction with an active-site Zn + ion. These lactamases have gained clinical prominence in the past few years as a result of their association with carbapenem resistance. The carbapenems, such as meropenem and imipenem, are fS-lactam antibiotics that have been introduced to circumvent Ser-fS-lactamase activity. The trans stereochemistry across the 6-5 bond rather than the cis geometry found in most other fS-lactams (Fig. 7) contributes to... 

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