A54145 complex is made up of eight factors; A, A1? B, B1? C, D, E, and F which were active in vitro (MIC 0.25~> 32/ig/ml) against Gram-positive aerobic organisms. The complex, factors B and Bj were found to be active against two strains of Clostridium perfringens. A calcium dependence study on someof the factors showed that their in vitro antibacterial activity was greatly enhanced by the presence of calcium (50mg/liter) in the media. Resistance build-up was seen when Staphylococcus sp. and Streptococcus sp. were passed seven times in the presence of sublethal concentrations of A54145antibiotics. This resistance disappeared immediately when the resistant organisms were passed in the absence of the antibiotics. Factor A was very effective against Staphylococcus aureus and Streptococcuspyogenes infections in mice (sc ED5Osof 3.3~2.4 mg/kg x 2, respectively). Factor B was more active against S. pyogenes in vivo (sc ED50, 0.9mg/kg x 2). Acute mousetoxicities were determined with these antibiotics. Semisynthetic derivatives were evaluated.

No abstract

Dirithromycin is a 9-N-ll-O-oxazine derivative which is formed by condensation of 9(S)-erythromycylamine with 2-(2-methoxyethoxy)acetaldehyde. Dirithromycin is hydrolyzed, either under acidic conditions or in vivo, to its major active metabolite, 9(S)-erythromycylamine. The antimicrobial spectrum of dirithromycin is similar to that of erythromycin; both antibiotics are active against gram-positive bacteria, Legionella spp., Helicobacter pylori, and Chlamydia trachomatis. Comparable results were obtained for each antibiotic in MIC and MBC determinations and in the potential development of resistance in vitro. The effects of human serum, bacterial growth media, test methodology, and inoculum size on MICs were similar for each antibiotic. In standard mouse protection studies, dirithromycin was more efficacious than erythromycin against experimental infections after subcutaneous administration of antibiotic. These results were consistent with pharmacokinetic studies in rodents, which showed that dirithromycin gave more persistent concentrations of antibiotic in serum and tissues than were achieved with erythromycin. These studies indicate that dirithromycin possesses antimicrobial activity comparable to that of erythromycin in vitro but is more active than erythromycin in vivo, which may be attributable to the persistence of antimicrobial activity in the tissue(s) of the test animals.Erythromycin is an important antimicrobial agent whose role in chemotherapy is well established. It has now assumed even greater importance because of its activity against such increasingly prevalent pathogens as Legionella, Helicobacter (formerly Campylobacter), Mycoplasma, and Chlamydia species (5,25,35). During the past decade, substantial efforts have been devoted to structural modifications of erythromycin in order to improve upon its biological properties (10, 18). Dirithromycin ( Fig. 1) is a novel derivative of erythromycin which was initially discovered at Karl Thomae GmbH (22). Although its spectrum of antimicrobial activity is similar to that of erythromycin, dirithromycin exhibits higher and more prolonged concentrations in tissues than does erythromycin (6). This report describes our initial results of the synthesis and antimicrobial evaluation of dirithromycin.(These results were presented in part at the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy, Los Angeles, Calif., 23 to 26 October 1988 [7a, 7b].) MATERIALS AND METHODS Synthesis of dirithromycin. 9(S)-Erythromycylamine (Fig. 2, compound 7) (18.5 g, 25.2 mmol) and 2-(2-methoxyethoxy) acetaldehyde (Fig. 2, compound 4) (4.4 g, 37 mmol) were dissolved in acetonitrile (55 ml). The reaction mixture was stirred for 18 h and cooled to 0 to 5°C. The solid was filtered, washed with cold acetonitrile, and dried to yield 16.6 g (79%) of dirithromycin (Fig. 2, compound 8). Dirithromycin was recrystallized from ethanol-water by dissolving it (3.0 g) in ethanol (12 ml) at 30°C and slowly adding water (28 ml). The mixture was cooled, and the solid was filter...

53SYNOPSIS. Experimental observation of the pathogenicity of some strains of Hartmannelkz plus the observation of human meningoencephalitis due to small amebas which had a structure compatible with that of Hartmannella in the tissues has suggested the concept af respiratory amebiasis followed by cerebral and other complica- tions.Until recently no cultural evidence was available to identify positively the amebas in the human cases. This report summarizes the isolation of Naegleria sp. (HB-I) from human spinal fluid by mouse inoculation followed by tissue culture of the infected mouse brain. C. Butt and his associates, who submitted this material to us, iso-OME stirains of free-living amebas of the family Hart-s mannellidae can grow in and destroy many different types of tissue culture; many of these isolates are pathogenic for animals. This report presents strong evidence (that another common free-living ameba of the family Schizopyrenidue, genus Naegleria, is similarly endowed with pathogenic capabilities.The spinal fluid from which the isolate was recovered was made available to us by Dr. Cecil Butt and his colleagues(1) who performed the autopsy and who also recovered the ameba in culture. Their findings are reported elsewhere. MATERIALS 1. Escherichia coli. This culture, used by Dr. B. N. Singh as nutrient for soil amebas, was obtained from him in 195T and maintained on Trypticase soy agar slants (transfer several times each week). This organism was originally referred to by Dr Singh and by us as Aerohacter yp. 2 . Naegleria gruheri. Known strains of this ameba growing with associated Gram-negative bacteria were obtained thru the courtesy of Dr. S. L. C h a w of Cincinnati, Ohio, and Prof William Balamuth of Berkeley, California. 3 . Tetramitw rostratus. Cysts of culture No. B 15811'1 were kindly supplied to us by Dr. J. L. Griffin of the Armed Forces Institute of Pathology. 4. Mice. SPF (Lilly) mice of the ND-4 line, caesarian-derived from germ-free animals, were used thruout these tests. 5. Tissue Culture. MK, (Lilly) continuous cell line of monkey kidney cells was utilized in roller tubes, Leighton tubes, or tissue culture bottles with Medium 199 containing 100 unilts of penicillin G and 100 Ng of streptomycin per ml. METHODS Direct microscopic examination.Both phase and ordinary microscopy should be utilized for preliminary examination of all specimens for these amebas. Since some strains of free-living amebas are only sluggbhly motile at 20 C, it is desirable to keep the slide at 37 C during examination. Ordinary clean, sterile slides and cover slips are used to make relatively thin preparations of exudates of body fluids or tissue emulsions. Sealing the cover slip edges with sterile mineral oil applied with a small camel's hair brush will preserve the preparation against drying. lated the N a e g l e k on agar medium with Escherichia coli without antibiotics tat 37 C.The new isolate failed to grow on the medium previously suggested by us for Hartmannella. HB-1 is virulent for laboratory animals and has ...

A novel low-molecular weight inhibitor of an aminoglycoside-inactivating enzyme, initially THE JOURNAL OF ANTIBIOTICS