Imipenem antibiotic

Pyrethroids are a category of insecticides that are remarkable because of tiieir high selectivity and low toxicity. Some members of this family, chrysantiiemic esters, are obtained by asymmetric cyclopropanation by diazoacetates in the presence of a Cu -Schiff-base catalyst. Among other applications, one of these esters subsequently affords access to cilastatine, an excellent stabilizer of the imipenem antibiotic in vivo. ... 

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). 

Furthermore, if the antibiotic passes membranes through a specific port of entry, its mutational loss leads to resistance. The lack of the outer membrane protein OprD in P. aeruginosa causes resistance to the (3-lactam antibiotic imipenem. Fosfomycin passes the cytoplasmic membrane via an L-a-glycerol phosphate permease. This transport system is not essential for bacterial growth and therefore mutants with a reduced expression are frequently selected under therapy. 

The 1-caibapenems (Fig. 5.5C) comprise a new family of fused /3-lactam antibiotics. They are analogues of penicillins or clavams, the snlphur (penicilhns) or o gen (calvams) atom being replaced by carbon. Examples are the olivanic acids (section 2.5.1) and thienamycin and imipenem (section 2.5.2). 

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. 

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... 

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-... 

Only patients with severe AP complicated by necrosis should receive infection prophylaxis with broad-spectrum antibiotics. Agents that cover the range of enteric aerobic gram-negative bacilli and anaerobic organisms should be started within the first 48 hours and continued for 2 to 3 weeks. Imipenem-cilastatin (500 mg every 8 hours) may be most effective a fluoroquinolone (e.g., ciprofloxacin, levofloxacin) with metronidazole should be considered for penicillin-allergic patients. 

Because human cases of glanders are rare, there is limited information shout antibiotic treatment of the organism in humans. Sulfadiazine has been found to be an effective in experimental animals and in humans SutfMderiente/fer is usually sensitive to tetracyclines, ciproflacacin, streptomycin, novobiocin, gentamicin, imipenem, ceftazidime, and the sulfonamides Resistance to chloramphenicol has been reported. 

Penicillin antibiotics must be used with caution because some strains of Bacillus anthracis possess an enzyme that inactivates penicillin. Other antimicrobial agents can be used as alternatives if the listed drugs are unavailable or in short supply. These include erythromycin, imipenem, clindamycin, vancomycin, and chloramphenicol.3... 

Transition metal ions cause a dramatic increase in the rate of hydrolysis of /Madam antibiotics [75][133][134], For example, copper(II) and zinc(II) ions increase the rate of alkaline hydrolysis ca. 108-fold and 104-fold, respectively [76], It has been suggested that the metal ion coordinates with both the carboxylate group and the /3-lactam N-atom of penicillins (A, Fig. 5.20). This complex stabilizes the tetrahedral intermediate and, thus, facilitates cleavage of the C-N bond catalyzed by the HO ion [74] [75], Such a model appears applicable also to clavulanic acid, imipenem, and monobactams, but it re-... 

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). 

Both of these antibiotics are notable. Imipenem is derived from a natural product, thienamycin. 

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). 

Infections resistant to other antibiotics (eg, cephalosporins, penicillins, aminoglycosides) have responded to treatment with imipenem. 

Pharmacology This product is a formulation of imipenem, a thienamycin antibiotic, and cilastatin sodium, the inhibitor of the renal dipeptidase, dehydropeptidase-1, which is responsible for the extensive metabolism of imipenem when it is administered alone. Cilastatin prevents the metabolism of imipenem, increasing urinary recovery and decreasing possible renal toxicity. The bactericidal activity of imipenem results from the inhibition of cell-wall synthesis, related to binding to penicillin-binding proteins (PBP). 

Resistance As with other -lactam antibiotics, some strains of P. aeruginosa may develop resistance fairly rapidly during treatment with imipenem-cilastatin. Pseudomembranous colitis Pseudomembranous colitis has occurred with virtually all antibiotics. 

Drugs that may affect cyclosporine include allopurinol, amiodarone, androgens (eg, danazol, methyltestosterone), anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin), azole antifungals (eg, fluconazole, ketoconazole), beta-blockers, bosentan, bromocriptine, calcium channel blockers, colchicine, oral contraceptives, corticosteroids, fluoroquinolones (eg, ciprofloxacin), foscarnet, HMG-CoA reductase inhibitors, imipenem-cilastatin, macrolide antibiotics, methotrexate, metoclopramide, nafcillin, nefazodone, orlistat, potassium-sparing diuretics, probucol, rifamycins (rifampin, rifabutin), serotonin reuptake inhibitors (SSRIs eg, fluoxetine, sertraline),... 

Action Monobactam, -1- cell wall S5mth Dose Adul. 1—2 g IV/EM q6-12h Peds. Premature 30 mg/kg/dose IV ql2h Term children 30 mg/kg/dose q6-8h X in renal impair Caution [B, +] Disp Inj SE NA /D, rash, pain at inj site Interac tions T Effects W/probenecid, aminoglycosides, i-lactam antibiotics X effects W7 cefoxitin, chloramphenicol, imipenem EMS Monitor for S/Sxs of super Infxn may cause aUCTgic Rxns rare cross-sensitivity Rxns to penicillins and cephalosporins have been rqwrted OD May cause Szs symptomatic and supportive... 

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... 

An antibiotic drug that is itself nontoxic may have metabolites that are toxic, diminishing its usefulness. For example, imipenem is hydrolyzed by renal dipeptidase to a metabohte that is inactive against bacteria but is toxic to humans. Coadministration of cilastatin inhibits the renal dipeptidase, which both prevents the formation of the toxic metabolite and decreases imipenem clearance, prolonging the half-life of the drug. 

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... 

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. 

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