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The desacetyl metabolite (DES) of cefotaxime (HR756) is formed in vivo to a significant extent. The in vitro activities of DES, the parent compound, and cefazolin, cefoxitin, and cefuroxime were compared against 70 (4) with two inocula (103 and 106 colony-forming units per I ,l of inoculum). Table 1 summarizes the results obtained from the five antimicrobial agents when tested at an inoculum of 103 colony-forming units.The high activity of CEF against the Enterobacteriaceae was confirmed. It is interesting to note that DES was consistently more active than cefoxitin, cefuroxime, or cefazolin against these strains but about 1/10th as active as the parent compound. In particular, DES was 10-to 20-fold more active than cefazolin, cefoxitin, and cefuroxime against Proteus mirabilis. The susceptibility of the indole-positive Proteus spp. to DES was more variable, the minimum inhibitory concentration for one strain of Proteus morganii being 128 pg/ml but that of another being 0.5 ,ug/ml. Two strains of Enterobacter spp. (minimum inhibitory concentrations of DES, 0.5 and 1 ug/ml), three strains Providencia stuartii (miniimum inhibitory concentration of DES 2, 0.06 and 0.06 ,ug/ml), and two strains of Serratia marcescens (minimum inhibitory concentration of DES, 0.5 and 1 pg/ml) were more susceptible to DES than cefoxitin, cefuroxime, and cefazolin. The 10 strains ofPseudomonas aeruginosa were uniformly resistant to DES yet were moderately susceptible to CEF.

The pharmacology of cefotaxime and the metabolite desacetyl cefotaxime was studied in 40 patients with various degrees of renal and hepatic failure who received 0.5 or 1 g of cefotaxime intravenously. Patients with severe renal impairment (creatinine clearance, 3 to 10 ml/min) had a cefotaxiime serum halflife of 2.6 h and desacetyl cefotaxrime serum half-life of 10.0 h. The equivalent figures were 1.0 and 1.5 h, respectively, in subjects with normal renal function. The presence of an acute coexisting illness together with severe renal impairment was associated with a further prolongation of the serum half-lives. Hepatic dysfunction was accompanied by a reduction in desacetyl metabolite formation. A reduction of cefotaxime dosing to 0.5 g twice a day would appear prudent when the creatinine clearance is 5 ml/min or less to avoid accumulation of the parent compound and the metabolite.The novel cephalosporin cefotaxime combines a broad antibacterial spectrum with considerable antimicrobial potency (2, 10). This compound, like cephalothin and cephacetrile, possesses an acetoxy group on the 3 position of the cephem nucleus and undergoes desacetylation in animals and humans (7). Desacetyl cefotaxime has a good antibacterial spectrum and potency, being similar to cefamandole and cefuroxime (11). As little is known of the pharmacology of both the parent drug and the metabolite, this study was designed to investigate both cefotaxime and desacetyl cefotaxime in patients with various degrees of renal failure and also in patients with hepatic necrosis. A dosing regime is proposed. MATERIALS AND METHODSPatients. A total of 40 patients (19 males; mean age, 51.4 years) were studied after informed consent had been obtained. Thirty-four of these were under investigation for acute or chronic renal failure, and six patients had acute hepatocellular damage related to self-administered drugs such as acetaminophen and carbon tetrachloride. Thirty-eight patients received 1 g and 2 patients received 0.5 g of cefotaxime diluted in sterile water intravenously over 3 to 5 min. Creatinine clearance studies were performed during and after each investigation. Routine screening tests performed before and after the investigation consisted of a full blood count, blood urea, electrolytes, and liver function tests. In addition, the extent of the hepatocellular damage in five patients was gauged by the peak alanine-amino transferase activity measured daily. These six patients were all studied in the early recovery phase of their disease.

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