Antimicrobial spectrum of Ro 15-8074/001, a new oral cephalosporin

Abstract

The activity of Ro 15-8074/001 was compared with that of cefaclor, amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, norfloxacin, and ceftriaxone against 225 clinical isolates. It was more active than cefaclor, amoxicillin-clavulanic acid, and trimethoprim-sulfamethoxazole against members of the family Enterobacteriaceae and Haemophilus influenzae and had activity similar to that of cefaclor against nonenterococcal streptococci. It was not usefully active against Pseudomonas aeruginosa, Streptococcusfaecalis, or most isolates of staphylococci.Ro 15-8075 (Fig. 1A) is the pivaloylomethoxyester of an aminothiazolyl cephalosporin. After oral administration and absorption the ester group is enzymatically split to produce the free acid Ro 15-8074 (Fig. 1B). Peak levels in serum of 5 ,ug of Ro 15-8074 per ml are achieved following oral administration of 1 g of Ro 15-8075, and 80 to 100% of the free acid is excreted in the urine over the first 24 h. When administered to mice with experimental infections due to a range of gram-positive or -negative organisms, curative doses for 50% (of mice) of Ro 15-8075 were 5 to 100 times lower than those of cephalexin (data on file, F. Hoffmann-La Roche and Co. Ltd., Basel, Switzerland). We used the sodium salt (Ro 15-8074/001) of the free acid to compare the activity of this compound with that of four other oral antibiotics and ceftriaxone against a variety of bacteria.Ro 15-8074/001 was a gift from F. Hoffman-La Roche. All other antibiotics were donated by their respective manufacturers. Antimicrobial activity was determined by an agar dilution method with fresh serial dilutions of compounds prepared according to the instructions of the manufacturer. The inoculum was prepared from a fresl overnight broth culture adjusted to a McFarland 0.5 standard and then diluted to deliver 105 CFU with a replicating spot device. Haemophilus influenzae and nonenterococcal streptococci were tested on Mueller-Hinton agar supplemented with 5% chocolatized horse blood and 1% IsoVitaleX (BBL Microbiology Systems, Cockeysville, Md.) incubated in 8% C02 at 37°C for 18 h. All other isolates were tested on MuellerHinton agar incubated in air at 37°C for 18 h. Serial dilutions of trimethoprim-sulfamethoxazole (TMP-SMX) were supplemented with 5% lysed horse blood. Susceptibility to amoxicillin-clavulanic acid was determined by using a constant ratio of amoxicillin to clavulanic acid of 2:1.The

Comparable Evaluation of Orally Active Beta-Lactam Compounds in Ampicillin-Resistant Gram-Positive and Gram-Negative Rods: Role of Beta-Lactamases on Resistance

“…Recently, two cephem derivatives chemically related to other third-genera tion cephalosporins were developed, sug gesting good antibacterial activity not only against grampositive but also against gram-negative isolates [9,10,16,18]. This was why we studied the antibacterial activ ity of these new compounds against a var iety of gram-positive and gram-negative pathogens in comparison with other orally active agents such as cefuroxime-axetil, cefaclor, ampicillin, and amoxycillin + clavulanic acid.…”

Comparative in vitro antibacterial activities of two new oral cephalosporins, ceftetrame (Ro 19-5247) and cefetamet (Ro 15-8074)

“…The activities of ceftetrame and cefetamet were, however, relatively weak and inconsistent against strains of Aeromonas hydrophila, Serratia marcescens, Enterobacter cloacae, Morganella morganii, Pseudomonas cepacia, and Pseudomonas pseudomallei, with variedproportions of isolates of these bacterial species being resistant (requiring concentrations of .8 p.g/ml for inhibition). Neither ceftetrame nor cefetamet was active against the following bacterial species (numbers of tested strains in parentheses): A. anitratus (128), C. jejuni (25), Flavobacterium meningosepticum (6), Pseudomonas aeruginosa (96), Pseudomonas fluorescens (11), Pseudomonas maltophilia (7), and Pseudomonas putida (7). It is of interest to note that although the activities of ceftetrame and cefetamet against gram-negative bacteria were generally comparable, ceftetrame was 8 to 16 times more active than cefetamet against H. influenzae, M. Continued on following page b Including 10 Shigella flexneri and 11 Shigella sonnei isolates.…”

Cefetamet Pivoxil Clinical Pharmacokinetics

“…From a pharmacokinetic point of view, the protein binding is such that disease states and drug interactions are not likely to affect Table I. In vitro activity of cefetamet against various Gram-positive and Gram-negative pathogens in comparison with related orally available cephalosporins and cefotaxime (data from Aldridge et al 1987;Angehrn et al 1989;Bowie et al 1987;Chau et al 1987;Cullmann & Dick 1990;Cullmann et al 1988;Easmon et al 1987;Fass & Helsel 1986;Hohl et al 1987;LeSaux et al 1987;Machka et al 1988;Mittermayer 1986;Neu et al 1986;Ng et al 1985;Peeters & Piot 1985;Rozgonyi et al 1989;Stobberingh et al 1987;Then 1987; Thomas & Lang 1986;Wise et al 1986). All studies used broth or agar dilution techniques, at least 10 strains of clinical isolates and an inoculum size of 10 4 to 106 colony-forming units per millilitre a Including bla+ strains.…”