Cefotaxime metabolism

Parenterally administered cephalosporins that are metabolically stable and that are resistant to many types of jS-lactamases include eefuroxime, cefamandole, cefotaxime and cefoxitin, which has a 7a-methoxy group at R. Injectable cephalosporins with anti-pseudomonal activity include cefsulodin and cefoperazone. 

Urinary excretion is the major elimination path for most cephalosporins. When prescribing cephalosporins to patients with renal failure, practitioners must consider dose reduction or dose interval extension (Table 45.2). Renal tubular secretion contributes to the elimination of some cephalosporins, and an increase in cephalosporin plasma concentrations may occur when probenecid blocks renal tubular secretion of cephalosporins. Biliary elimination is important for some cephalosporins. Cefmetazole, cefoperazone (Cefobid), cefoxitin, and ceftriaxone achieve biliary concentrations greater than those in plasma. After parenteral administration of cefoperazone, 70% of the dose appears in the bile within 24 hours. Practitioners should decrease the dose of cefoperazone when prescribing for patients with hepatic failure or biliary obstruction. Metabolism is not a major elimination path for most cephalosporins. Cefotaxime is one of the few cephalosporins having an active metabolite, desacetyl cefotaxime. 

Among the semisynthetic derivatives, cephalothin (9.47) is the most widely used since it is a broad-spectrum antibiotic resistant to lactamase. Its main drawback is that it must be injected. Cefazolin (9.48) and cephaloridine (9.49) are metabolized to a lesser extent cephalexin (9.50, analogs to ampicillin) is orally active and has a much higher acid stability than the penicillins. Cefotaxime (9.51) and moxalactam (9.52) are highly active against meningitis. 

Piper nigrum and Piper longum 1. Amoxicillin 2. Cefotaxime 3. Rifampicin 4. Erythromycin 5. Telithromycin t blood levels of these antibiotics Attributed to inhibition of metabolism and of P-gp, e.g. Piper longum Be aware that toxic effects of antibiotics may occur, particularly when the prescriber/dispenser is unaware of the intake of herbal medicines... 

Desacetylation of cephalosporins occurs in liver and kidney via the activity of acetylesterases. Desacetylated cephalosporins all maintain some antibacterial activity. Desacetylcefotaxime penetrates well extra vascular body sites, achieves high tissue concentrations and acts synergistically with cefotaxime [94,95]. Desacetylation of cephaloglycin, cephalothin and cephapiiin resulted in formation of less active desacetyl forms [94] and less toxicity [64]. About 50% of cephaloglycin is metabolized to desacetylcephloglycin, which is less nephrotoxic at... 

Cefntaxime is metabolized in part to the less active desa-cctyl metabolite. Approximately 20% of the metabolite and 25% of the parent drug are excreted in the urine. The parent drug reaches the cerebrospinal fluid in sufEcient concentration tn be effective in the treatment of meningitis. Solutions nf cefotaxime sodium should be used within 24 hours. If stored, they. should be refrigerated. Refrigerated solutions maintain potency up to 10 days. 

The metabolite may have pharmacologic activity similar to that of the parent drug and thus contribute significantly to clinical response for example, oxypurinol and desacetyl cefotaxime. Alternatively, the metabolite may have qualitatively dissimilar pharmacologic action for example, normeperidine has central nervous system (CNS)-stimulatory activity that reportedly produces seizures, whereas meperidine has CNS-depressant actions. " Because of the multiplicity of potential interactions of compounds that are primarily metabolized, the practical consequences of metabolite accumulation are difficult to predict and are most often identified in those patients at risk by trial and error (Table 48-5). 

Cephalosporins such as cephalothin, cephalogly-cin, cephapirin, cephacetrile and cefotaxime share an acetoxymethyl group at the position 3 (Figure 2) and are all metabolically converted to desacetyl derivatives and to the antibacterially inactive lactone of these substances. 

Cefotaxime (Claforan) j—rt N-OCH3 —Cl OCCHg H 0 acetoxy group metabolized up to 25% metabolite... 

GENERAL FEATURES OF THE CEPHALOSPORINS Cephalosporins are excreted primarily by the kidney, and dosage should be decreased in patients with renal insufficiency. Cefpi-ramide (not available in U.S.) and cefoperazone are excreted predominantly in the bUe. Cefotaxime is deacetylated to a metabolite with less antimicrobial activity than the parent compound and excreted by the kidneys. The other cephalosporins do not undergo appreciable metabolism. 

Ceftizoxime has a spectrum of activity that is very similar to that of cefotaxime, except that it is less active against S. pneumoniae and more active against B. fragilis. The drug can be administered every 8—12 hours for serious infections. Ceftizoxime is not metabolized, and 90% is recovered in urine. 

In ceftizoxime, the whole C-3 side chain has been omitted to prevent deactivation by hydrolysis. It rather resembles cefotaxime in its properties however, not being subject to metabolism, its pharmacokinetic properties are much less complex. 

Ceftriaxone has the same C-7 side-chain moiety as cefotaxime and ceftizoxime, but the C-3 side chain consists of a metabolically stable and activating thiotriazinedione in place of the normal acetyl group. The C-3 side chain is sufficiently acidic that at normal pH, it forms an enolic sodium salt thus, the commercial... 

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