Cefoxitin, a Semisynthetic Cephamycin Antibiotic: In Vivo Evaluation

Abstract

Cefoxitin, 3-carbamoyloxymethyl-7-a-methoxy-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid, a semisynthetic cephamycin antibiotic shown to have broad-spectrum activity in vitro, is active also in vivo against a wide variety of bacteria including penicillin-resistant staphylococci. It is, however, particularly effective against gram-negative organisms including strains of indole-positive Proteus against which cephalothin and cephaloridine are ineffective. When cefoxitin is given subcutaneously, concentrations in mouse blood, urine, and other tissues are higher than those seen for cephalothin. Higher concentrations in the blood and greater therapeutic efficacy are achieved with cefoxitin when it is given with probenecid. For this reason it is believed that cefoxitin is excreted mainly by way of the renal tubules. The data indicate that cefoxitin has potential as a therapeutically useful antibiotic.Two naturally occurring 7-methoxylated cephalosporins were described by Nagarajan et al. (10). One of these was among the three described independently by Stapley et al. (13) who designated this class of compounds cephamycins. To produce agents of greater activity and a broader spectrum, these naturally occurring antibiotics have been modified chemically (1, 5). In one analogue of cephamycin C, the aminoadipoyl sidechain at C-7 is replaced with a thienylacetyl group. This antibiotic, cefoxitin, 3 -carbamoyloxymethyl -7 -a -methoxy -7 -[2 -(2-thienyl)acetamido] -3 -cephem -carboxylic acid was shown to have broad antibacterial activity in vitro (14). The present paper describes some of the pharmacological properties of cefoxitin and its therapeutic efficacy in mice against a number of systemic infections. MATERIALS AND METHODSCrystalline cefoxitin sodium salt and a laboratory sample of cephamycin C sodium, of approximately 70% purity, were used as water solutions in these tests. Commercial samples of cephalothin, (Keflin, Lilly), cephaloridine (Loridine, Lilly), ampicillin (Penbritin-S, Ayerst), and methicillin (Staphcillin, Bristol) were solubilized aseptically with sterile water.Efficacy studies. As a standard procedure, Charles River CD1 female mice, weighing 18 to 20 grams, were infected intraperitoneally with 3 to 100 times the number of organisms that should kill 50% of the infected, nontreated animals (LD,0). Five mice were used at each of the fourfold drug concentrations tested. Therapy was given by the indicated route at the time of infection and again 6 h later. The test was terminated 7 days after infection, and the survival records of that day were used to calculate the number of organisms in the challenge LD,0 and also the ED50, i.e., the amount of antibiotic that should protect 50% of the infected, treated animals (7).For most of the test organisms the challenge preparation consisted of appropriate dilutions in brain heart infusion of broth cultures of the test strain. Some organisms, however, were used as suspensions in 5% hog gastric mucin. These were strains of Enterobacter, Proteus vulgaris, and P...

Metabolic fate of SCE-1365, a new broad-spectrum cephalosporin, after parenteral administration to rats and dogs

“…SCE-1365 crosses the placenta of rats rather poorly, the result being smilar to that with other cephalosporins such as cefazolin (7), cefatrizine (10), and cephacetrile (13). The lacteal concentration of SCE-1365, like that of other cephalosporins (23,26), was also low ( served (4,6,12,18 …”

Cefoxitin, a Semisynthetic Cephamycin Antibiotic: Antibacterial Spectrum and Resistance to Hydrolysis by Gram-Negative Beta-Lactamases

“…The studies of Miller et al (4) have shown that cefoxitin protects mice against E. cloacae. However, further clinical investigation of cefoxitin is clearly indicated.…”

Comparative Study of Seven Cephalosporins: Susceptibility to Beta-Lactamases and Ability to Penetrate the Surface Layers of Escherichia coli

“…These mutant strains (DC2 and DC3) have now been used, in conjunction with the parental E. coli strain (UB1005), to assess the properties of cefazolin (10), cefoxitin (9,11,22), cefamandole (23), and cefuroxime (C. H (8,16). This paper compares the properties of the seven cephalosporins examined here against these four types of (8-lactamase.…”