Cephamycins, a New Family of β-Lactam Antibiotics. IV. In Vivo Studies

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The susceptibility to some cephalosporin antibiotics and to cephamycin C, a member of a new family of #-lactam antibiotics, was evaluated for 466 cultures representing 11 different genera or species of gram-negative clinical isolates. The susceptibility of 39 gram-negative cultures known to produce ,B-lactamase was also determined. The ,-lactamase activity of a representative group of the clinical isolates and the 39 enzyme producers was studied with the cephalosporins (cephalothin and cephaloridine) and cephamycin C as substrates and was related to the in vitro disc susceptibility to these same antibiotics. The significant resistance to #-lactamase displayed by the cephamycins is reflected in the kinetics of enzyme activity (Km and V..mx) that are reported for the cephalosporins and the cephamycins. Resistance to (3-lactamase is probably one of the reasons that many cephalosporin-resistant cultures are susceptible to cephamycin C.Stapley et al. (22) described the production of cephamycins A, B, and C from fermentation broths of various species of Streptomyces. In spite of their resemblance to the cephalosporins (1, 19), the cephamycins demonstrate markedly greater resistance to microbial degradation by fB-lactamase (EC 3.5.2.6 penicillin [cephalosporin] amido-Blactam hydrolase) than is normally displayed by the cephalosporins. Although cephamycins A and B are endowed with broad-spectrum activity, they are limited from the standpoint of sufficient potency in many instances. Cephamycin C has been found to be particularly effective versus gram-negative bacteria of clinical importance and relatively ineffective versus gram-positive organisIns.Our efforts were conicenitrated on the investigationi of the relative merits of cephamycin C with respect to its in vitro efficacy and stability to microbial f3-lactamase degradation vis-&-vis those same l)rol)erties of some cephalosporin antibiotics. Pa. 19486. pital, Seattle, Wash.). These cultures represent 11 different genera or species of gram-negative bacteria that were obtained randomly from various infectious disease states (urinary tract, postsurgical, wound and respiratory infections, etc.) and not selected on the basis of antibiotic resistance.

Section: S S Smentioning

confidence: 99%

Cephamycins, a New Family of β-Lactam Antibiotics: Antibacterial Activity and Resistance to β-Lactamase Degradation

Daoust

Ōnishi

Wallick

et al. 1973

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“…Cephamycin C is active against bacterial species resistant to cephalothin and cephaloridine, such as Proteus vulgaris (13). In animals, cephamycin C is therapeutically effective against systemic infections; high doses failed to reveal gross evidence of nephrotoxicity (12). Cefoxitin is an analogue of cephamycin C, with considerably heightened antibacterial potency (18) and greater resistance to cephalosporinase inactivation (14).…”

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confidence: 99%

Effects of Rate of Infusion and Probenecid on Serum Levels, Renal Excretion, and Tolerance of Intravenous Doses of Cefoxitin in Humans: Comparison with Cephalothin

Goodwin

Raftery

Goldberg

et al. 1974

Using a randomized crossover design, 1-g intravenous doses of cephalothin and cefoxitin, a cephalosporinase-resistant cephamycin, were infused into 12 normal adult males over periods of 120, 30, and 3 min, the last with and without prior intravenous infusions of probenecid (1 g). Mean peak serum concentrations of antibiotic activity after cephalothin infusions were 23, 56, 103, and 102 gg/ml, respectively, and after cefoxitin infusions they were 27, 74, 115, and 125 Ag/ml, respectively. Probenecid treatment prolonged the terminal serum half-life of cephalothin-like activity from 0.52 to 1.0 h, and of cefoxitin from 0.68 to 1.4 h. In contrast to cephalothin, which was found to be metabolized about 25% to the less active desacetyl form, cefoxitin was metabolized less than 2% to the virtually inactive descarbamyl form, as judged from urinary recoveries. Neither antibiotic displayed detectable organ toxicity. Of 300 recent clinical isolates of gram-negative bacilli other than Pseudomonas spp., 83% were susceptible to cephalothin but 95% were susceptible to cefoxitin. Organisms resistant to cephalothin but susceptible to cefoxitin included strains of Escherichia coli, Proteus vulgaris, Klebsiella spp., Serratia marcescens, Enterobacter spp., and Bacteroides spp.

“…Recently, the discovery of a new family of antibiotics, the cephamycins, has been reported (1,3,(6)(7)(8)(9)11). These 7-methoxylated cephalosporins possess marked resistance to the action of ,@-lactamases from gram-positive and gramnegative organisms (10).…”

mentioning

confidence: 99%

Cefoxitin, a Semisynthetic Cephamycin Antibiotic: Susceptibility Studies

Wallick

Hendlin

1974

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Cefoxitin, 3-carbamoyloxymethyl-7-a-methoxy-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid, is a new semisynthetic cephamycin with broad antibacterial activity. It is highly active against gram-negative microorganisms including indole-positive Proteus and Serratia strains, which are ordinarily resistant to the cephalosporins. Cefoxitin is also highly active against many strains of Escherichia coli and Proteus mirabilis which are resistant to the cephalosporins. Furthermore, E. coli and Klebsiella strains which are susceptible to the cephalosporins are generally more susceptible to the cephamycin analog. The susceptibility of the gram-positive bacteria falls well within the effective range of the antibiotic for gram-negative organisms, but cefoxitin is less active than cephalothin or cephaloridine. As is the case with the cephalosporins, strains of Pseudomonas and group D streptococci are resistant to cefoxitin. Changes in pH, inoculum density, and growth medium have no significant effect on the activity of the antibiotic.Recently, the discovery of a new family of antibiotics, the cephamycins, has been reported (1, 3, 6-9, 11). These 7-methoxylated cephalosporins possess marked resistance to the action of ,@-lactamases from gram-positive and gramnegative organisms (10). One of these, cephamycin C, has broad gram-negative activity but lacks significant activity against gram-positive organisms. Cefoxitin, 3-carbamoyloxymethyl-7-a -methoxy -7 -[2 -(2 -thienyl)acetamido] -3 -cephem-4-carboxylic acid (Fig. 1) A second group of 174 gram-negative microorganisms which were selected for their resistance to cephalothin were also tested.Disk susceptibility testing. The zone of inhibition obtained with each bacterial culture with the respective antibiotics was determined by means of the Kirby-Bauer disk susceptibility testing method (2). Mueller-Hinton (MH) agar (BBL) medium was used for these studies. When isolates of Streptococcus and Diplococcus pneumoniae were tested, the medium was supplemented with 5% defibrinated sheep blood and the tubes or plates were incubated in the presence of 10% CO2.All