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...

Cephamycins A, B, and C are naturally produced cephalosporin-type antibiotics. Although A and B were found to be more active than C against gram-positive organisms, they were not so active against such strains as are cephalosporin C or the semisynthetic antibiotics cephaloridine and cephalothin. Against gram-negative organisms, cephamycin C was more active than A or B and, in general, was as active as the cephalosporins. In addition, cephamycin C was active in vitro against clinically isolated strains resistant to the cephalosporins, such as Proteus, Providencia , and Escherichia coli . The in vitro antibacterial activity of cephamycin C, cephalothin, and cephaloridine is primarily bactericidal. A 10,000-fold increase in inoculum of a strain of Proteus mirabilis resulted in 200-fold or greater increases in minimal inhibitory and minimal bactericidal end points of cephalothin and cephaloridine, but only 10- and 16-fold increases, respectively, for cephamycin C. After 15 passages through antibiotic-containing broths, during which time a culture of E. coli showed an increase in minimal inhibitory concentrations of streptomycin of >1,000-fold, end points for cephamycin C increased 4-fold, for cephalothin, 1.5-to 6-fold, and for cephaloridine, 128-fold.

Cephamycin A was found to be more active in vivo than cephamycin B. In comparison with cephamycin C, cephamycin A was more active against gram-positive organisms but less active against gram-negative organisms. Given subcutaneously, cephamycin C had good in vivo gram-negative activity, comparing favorably with cephalothin and cephaloridine against cephalosporin-susceptible organisms. In general, against the gram-negative organisms, it was more active than cephalothin or cephalosporin C and about as active as cephaloridine. In addition, cephamycin C protected mice against β-lactamase-producing Proteus cultures, including clinically isolated strains. The compound is remarkably nontoxic. Cephamycin C was detected in the serum and recovered from the urine of treated mice to about the same extent as cephaloridine. Like cephaloridine and cephalosporin C, cephamycin C must be excreted mainly by glomerular filtration, because the use of probenecid did not enhance the therapeutic effectiveness nor concentrations of these agents in the sera of treated mice.

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