The avermectins are a complex of chemically related agents which exhibit extraordinarily potent anthelmintic activity. They are produced by a novel species of actinomycete, NRRL 8165, which we have named Streptomyces avermitilis . The morphological and cultural characteristics which differentiate the producing organism from other species are described. The avermectins have been identified as a series of macrocyclic lactone derivatives which, in contrast to the macrolide or polyene antibiotics, lack significant antibacterial or antifungal activity. The avermectin complex is fully active against the gastrointestinal nematode Nematospiroides dubius when fed to infected mice for 6 days at 0.0002% of the diet. Fermentation development, including medium modification and strain selection, resulted in increasing the broth yields from 9 to 500 μg/ml.

Phosphonomycin is a newly discovered antibiotic produced by streptomycetes. It is effective, when administered by the oral route, to mice infected with Gram-positive or Gram-negative microorganisms. The antibiotic is bactericidal and inhibits cell-wall synthesis.

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.

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

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