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Agar minimal inhibitory concentrations and mouse protection test effective doses were determined for each of four beta-lactam antibiotics against each of 12 Gram-negative and 3 Gram-positive bacterial cultures. The beta-lactamase activity of these cultures also was studied. The data were examined to determine whether relative in vivo efficacies could be predicted from relative in vitro activities. Although such predictions were quite accurate for cefoxitin and cefazolin, this was not true for cefamandole or for cephalothin. Such poor predictability was not necessarily associated with the susceptibility of these cephalosporins to hydrolysis by bacterial beta-lactamases. Although the clinical significance of these observations is not known, these data emphasize that relative in vitro activities should be used only with caution to estimate in vivo efficacies, since not all compounds show the excellent predictability observed here for cefazolin and cefoxitin. [ABSTRACT FROM AUTHOR]

The maximum yield for the production of L-681,110 by Streptomyces sp. MA-5038 (ATCC 31587) was observed after 5 days' incubation at 28 degrees C and pH about 8.3. L-681,110 was isolated from the fermentation broth by acetone extraction of the mycelia, absorption to Amberlite XAD-2 resin and two separations by thin-layer chromatography. The structure of L-681,110 was found to consist of a sixteen-membered lactone with a new type of substitution. The inhibition of ATPase, activity against Caenorhabditis elegans and stimulation of gamma-aminobutyric acid release indicate that L-681,110 possesses some characteristics of both oligomycin and avermectin. L-681,110 was also active against tapeworm and ticks in an in vivo assay.

The cephamycins are a family of beta-lactam antibiotics that are produced by actinomycetes and are structurally similar to the cephalosporins. They are characterized by the presence of a 7-alpha-methoxyl group, which confers unusually high resistance to beta-lactamases. Cefoxitin, the first semisynthetic cephamycin, is resistant to almost all beta-lactamases. Cefoxitin retains the 3-carbamoyl group of cephamycin C and thus has excellent metabolic stability. Cefoxitin is bactericidal and almost devoid of any inoculum effect. Active against many cephalothin-resistant gram-negative bacteria, cefoxitin demonstrates a very broad spectrum that includes indole-positive Proteus and many strains of Serratia. In contrast to that of the cephalosporins, cefoxitin's spectrum of activity against anaerobic pathogens includes Bacteroides fragilis. The therapeutic effectiveness of cefoxitin in experimental infections in mice confirms the excellent characteristics of this semisynthetic cephamycin and indicates that it should be a very valuable agent for treatment of bacterial infections.

The novel beta-lactam, L-640,876, exhibited excellent therapeutic activity when administered parenterally but not orally to mice infected with a variety of pathogenic bacteria. In this respect, the compound was as potent as cefotaxime against representative Gram-positive and Gram-negative organisms, in most cases, equal to or more potent than cefoxitin, and more effective than mecillinam. When administered subcutaneously to normal mice at dose levels ranging from 10 to 50 mg/kg, L-640,876 provided an adequate dose response, recovery of ca. 45% of biological activity in the urine, and excellent distribution at the highest dose level into liver, lung, kidney, heart muscle, but not brain.

Cefoxitin is a new, cephalosporin-like antibiotic which is highly resistant to hydrolysis by beta-lactamase. Ninety-one cultures were selected either for their general resistance to cephalosporin antibiotics or for their ability to produce beta-lactamase. Some of these cultures were resistant to cefoxitin. The capacity of each of the 91 strains to hydrolyze cefoxitin with beta-lactamase was determined. Only seven of the cultures degraded the antibiotic as determined by a general assay for beta-lactamase. Several others were able to hydrolyze cefoxitin after enzyme was induced by low concentrations of the antibiotic. The role of the constitutive and inducible enzyme in bacterial resistance to the antibiotic was investigated. Enzymatic destruction of cefoxitin was found to be an important factor contributing to bacterial resistance. However, the complete and rapid degradation of cefoxitin is not essential to resistance since one strain, Enterobacter cloacae 1316, hydrolyzed the antibiotic very slowly but was able to grow unaffected in the presence of cefoxitin. The presence of the enzyme is not necessarily sufficient to confer resistance since another culture, Klebsiella D535, readily hydrolyzed the antibiotic but was susceptible to it.

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 mug/ml.

The authors review the procedure utilized for the naming of a new antibiotic. The cephamycins are taken as an example. Cefoxitin, derivative of the cephamycin C through an original chemical reaction is described. This antibiotic possesses a high degree of resistance to beta-lactamases due to the presence of a methoxy group in the 7alpha position of the beta-lactam ring. The results of extensive in-vitro trials are given, they indicate that cefoxitin has a unique antibacterial activity.

A new, competitive, nonpeptide cholecystokinin (CCK) antagonist, asperlicin, was isolated from the fungus Aspergillus alliaceus. The compound has 300 to 400 times the affinity for pancreatic, ileal, and gallbladder CCK receptors than proglumide, a standard agent of this class. Moreover, asperlicin is highly selective for peripheral CCK receptors relative to brain CCK and gastrin receptors. Since asperlicin also exhibits long-lasting CCK antagonist activity in vivo, it should provide a valuable tool for investigating the physiological and pharmacological actions of CCK.

Haemophilus influenzae is an important pathogen in respiratory infections in children and often is implicated in otitis media. It is sensitive in vitro to a number of antibiotics, some of which are used clinically for the treatment of such infections. We have checked the in vitro sensitivity of a type b strain of H. influenzae. When tested in Levinthal's broth prepared with laked rabbit blood, the culture was most sensitive to tetracycline, ampicillin and penicillin and was somewhat less sensitive to cephalothin, fosfomycin, cephaloridine, and chloramphenicol. However, when this same strain was used to infect mice, fosfomycin was more active than ampicillin, tetracycline, chloramphenicol, penicillin or the cephalosporins.

Fosfomycin, a nontoxic broad-spectrum antibiotic, different in structure from all previously described antibiotics, acts selectively by inhibiting cell wall formation. It was overlooked during many years of screening because of antagonism by culture medium ingredients and frequent occurrence of resistant mutants. It is effective in many because the neutralizing substances are not present and resistant mutants of most species are avirulent. Fosfomycin has favorable pharmacologic characteristics. It is not cross resistant, does not show antagonism, and has been used successfully in combinations. An insoluble calcium salt is used in oral formulation and a sodium salt for parenteral administration. Overall success rates of 86% were reported with 1,000 patients in Spain and 79% in Japan.

A statistical technique has been employed to study the effects of various environmental factors in altering the actinomycete populations of soils located in the western part of Australia. Over 12,000 actinomycetes obtained at 28 different locations were included in the evaluation. Among factors that had a significant influence were the geographic area at which the sample was taken, the nature of plant rhizosphere, and a rainstorm. Seasonal changes in population did occur, but there was considerable stability of population with time. Although marked differences occurred in types of actinomycetes present among different geographic locations, multiple samples taken within a location at distances of 30 cm or greater showed marked similarity in populations. There were varied degrees of diversity among the populations studied. The population that developed after a rainstorm was low in diversity, whereas the populations of root rhizospheres were as diverse as those of plant-free soil-litter areas. In assessing the ecology of soil actinomycetes, it is important to consider the degree of change in population induced by an environmental factor and also its effect on diversity, since the effects may be complementary or may be opposite in nature.

Cefoxitin, a new semisynthetic cephamycin antibiotic, induced filament formation at subinhibitory concentrations with a beta-lactamaseless strain of Enterobacter cloacae (HSC 18410 M66). The extent of filament induction by cefoxitin was similar to that seen with cephalothin, cefazolin, and benzylpenicillin. Filament induction by cefoxitin was markedly less than that seen with cephalexin, carbenicillin, ticarcillin, cephradine, and cephapirin. Antibiotics which failed to induce filaments at any level tested included cephaloridine, cephacetrile, cephalosporin C, the cephamycins, 6-aminopenicillanic acid, 7-aminocephalosporanic acid, A16884, A16886, and FL-1060. Those antimicrobial agents tested which lacked an aromatic substituent in the 7-position (for cephems) or in the 6-position (for penams) did not induce filaments. These observations suggest a possible relationship between filament induction of the test organism and the molecular nature of constituents in the 7- or 6-position of beta-lactams.

Cefoxitin, 3-carbamoyloxymethyl-7-alpha-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.

The paw-licking response of rats to a subplantar injection of an antibiotic was used as an indicator of the pain caused by that antibiotic. Good agreement with clinical findings was obtained with cefoxitin, cephalothin, cephradine, cefazolin, cephaloridine, and carbenicillin. Incorporation of a local anesthetic into the diluent of an irritating antibiotic reduced the number of paw-licking episodes. This rat paw model offers a simple and rapid means of estimating pain-on-injection following intramuscular injection of antibiotics to humans and may be applicable to other drugs as well.

Albomycin and grisein were found to be composed of four antibiotically active substances of which A, a strongly active component, and D, a very weakly active component, appear to be stable to purification, while C has been observed to break down continually with concomitant appearance of more A. On the basis of published reports and of studies made in our laboratories, it is concluded that albomycin and grisein are chemically very similar and identical with respect to antimicrobial activity (5).