Human Pharmacology of Cefotaxime (HR 756), a New Cephalosporin

Abstract

Cefotaxime (HR 756) is a new senisynthetic parenteral cephalosporin with exceptional activity against gram-negative organisms and considerable stability against their f,-lactamases. To study its pharmacokinetic properties, 0.5-, 1-, and 2-g doses were administered to each of six volunteers intravenously over 15 mi, followed by a sustaining infusions of 0.5, 1, and 2 g/h, respectively, for 3 consecutive hours. The loading doses produced mean peak levels of 41, 93, and 160 .g/ ml, and mean steady-state serum concentrations were 27, 64, and 138 ,ug/ml, respectively. The mean terminal half-life was 75 ± 7 min. The total volume of distribution averaged 0.22 ± 0.03 liters/kg of body weight. Total body and renal clearances were 232 ± 30 and 145 ± 24 ml/nnin per 1.73 m2, respectively; 63 ± 9% of the administered dose was excreted through the kidneys in 24 h. To determine the effect of cefotaxime on the renal tubules, urinary alanine aminopeptidase excretion was measured before, during, and after the infusions. It remained within the normal range in all instances; however, 48 ± 14% of the total daily alanine aminopeptidase output was recovered during the infusion period. Side effects were dose related and included fatigue, loose stools, and night sweats. No significant changes in hematology, serum chemistry, or urinalysis were recorded.Cefotaxime (proposed generic name of 3-acetoxymethyl-7-[(2-(2-amino-4 thiazolyl)-2-methoxy-iminoacetyl)amino]-ceph-3-eme-4-carboxylic acid, sodium salt) is a novel parenteral cephalosporin with remarkable activity against gram-negative organisms, including indole-positive Proteus species, Serratia, and, to some extent, Pseudomonas aeruginosa (5,11, 12, 28, 29). Its resistance to hydrolysis by gram-negative ,8-lactamase Richmond types I, III, IV, and V is of the same order as that of cefoxitin and cefuroxime (8). In experimental animal infections, cefotaxime appeared to be superior to cefazolin (12).We conducted a pharmacokinetic study with this compound to evaluate the following aspects of this new cephalosporin: (i) determination of the pharmacokinetic parameters during steadystate infusions at three different dose levels; (ii) effect of cefotaxime on the urinary excretion of alanine aminopeptidase (AAP) as a possible indicator of tubular toxicity; and (iii) evaluation of the local and systemic tolerances of high doses.(These results were presented in part at the 18th Interscience Conference on Antimicrobial Agents and Chemotherapy, Atlanta, Ga., [1][2][3][4] October 1978.) MATERIAIS AND MErHODSSix healthy, young male volunteers took part in the study. Informed consent was obtained from each participant. At intervals of 1 week 0.5-, 1-, and 2-g doses of cefotaxime were administered to each volunteer over 15 min, followed by sustaining infusions of 0.5, 1, and 2 g/h, respectively, for 3 consecutive hours (Fig. 1). The infusion rate was controlled with an infusion pump (Perfior E+2; Braun Melsungen, West Germany).A total of 28 serum samples were drawn from the contralateral forearms at 0,...

Clinical evaluation of cefotaxime for therapy of lower respiratory tract infections

“…The serum levels after 1 g (Table 3) are in agreement with previously published findings, including the presence of residual antimicrobial activity up to 6 h after dosing (8,14,19 levels for up to 6 h after i.v. or i.m.…”

“…The human pharmacology of cefotaxime is similar to that of most currently available cephalosporins, but its half-life of approximately 1 h is twice as long as that of cephalothin (7,14,19). The serum levels after 1 g (Table 3) are in agreement with previously published findings, including the presence of residual antimicrobial activity up to 6 h after dosing (8,14,19 levels for up to 6 h after i.v.…”

“…(8,18,19). Like cephalothin, cefotaxime is converted in vitro to a biologically less active desacetyl derivative, which accounts for the fact that only 60% of this drug is excreted unaltered in the urine (8,14,19 764,1980). Although the incidence of adverse clinical reactions observed in our study is encouraging (Table 4), the incidence of superinfection is noteworthy.…”

Comparative pharmacokinetics of cefoperazone, cefotaxime, and moxalactam

“…The major route of elimination for moxalactam is via the kidneys. We found a mean of 61% in the urine, which is similar to the 55 to 76% reported by others (24,29,32,35 (7,9,10,12,22) and 76.1 min calculated from our own data, is much more rapid than that of cefoperazone (1,6,33,34) and moxalactam (19,29,35,36 Elimination of cefotaxime is rapid, with about 90% of the dose recovered in urine by HPLC, of which two-thirds is detected as unchanged cefotaxime and one-third as the major metabolite desacetyl cefotaxime. Bax et al (2) reported a total urine recovery of 87% with 35% as desacetylated metabolite, compared with a total recovery rate of 89.6% with 29.1% as metabolite in our study.…”

Cefotaxime: in vitro activity and tentative interpretive standards for disk susceptibility testing

“…Cefotaxime (formerly HR 756) is a new cephalosporin agent much acclaimed for its broad spectrum of in vitro antimicrobial activity (2,3,5,(11)(12)(13) and its beta-lactamase resistance and beta-lactamase inhibitory activity (5,6,8). Interpretive zone standards for the disk diffusion susceptibility testing of cefotaxiime have been recently proposed (1) and include the use of 5-or 30-,ug disks, depending on the organism being tested.…”