HR 756, a Highly Active Cephalosporin: Comparison with Cefazolin and Carbenicillin

The in vitro activity of Ro 13-9904, a new cephalosporin derivative, was compared with the activities of cephalothin, cefamandole, cefoxitin, cefotaxime, and moxalactam against 591 clinical isolates of gram-negative and gram-positive organisms. The spectra of activity and potency of Ro and cefotaxime were quite similar; they were the most active agents against Enterobacteriaceae, Streptococcus pyogenes, Haemophilus influenzae, Neisseria gonorrhoeae, and Neisseria meningitidis. Moxalactam was only slightly less active against these organisms. Ro 13-9904, cefotaxime, and moxalactam were approximately equal in activity against Pseudomonas aeruginosa; concentrations of 50 to 100 ,Ig/ml inhibited over 90% of the strains tested. Cefamandole and cephalothin were the most active drugs tested against staphylococci. Moxalactam demonstrated the highest intrinsic activity against Bacteroides fragilis; a concentration of 1.6 yg/ ml inhibited over 50% of the strains. All six of the antibiotics were essentially inactive against group D streptococci. The action of all of the antibiotics was bactericidal, with minimal bactericidal concentrations generally being no more than twofold greater than miniimal inhibitory concentrations. The only exception to this was found when large inocula of Staphylococcus aureus were tested. Increased inoculum size generally sharply reduced the activity of Ro 13-9904, cefotaxime, and moxalactam against Enterobacteriaceae and P. aeruginosa.The chemotherapy of serious bacterial infections, particularly those which are hospital acquired, is a continuing clinical challenge. Organisms such as Serratia, Acinetobacter, Pseudomonas cepacia, and others once thought to cause disease only rarely, if at all, are now recognized as common pathogens. The need for antimicrobial agents with broad spectra of activity and resistance to the /3-lactamases of gramnegative organisms associated with nosocomial infection has motivated research resulting in the development of a great number of cephalosporin derivatives. Since the discovery of the fungus Cephalosporium acremonium in Sardinian sewage in 1945 (1), the cephalosporins have evolved into a complex group of antibiotics with significant differences in potency and antibacterial spectrum. Ro 13-9904 (Fig. 1) is a new product of the chemical manipulation of side chains joined to the 7-amino-cephalosporanic acid nucleus. It has been reported to be highly active against common gram-negative organisms and relatively resistant to inactivation by cephalosporinases; preliminary data also suggest that the expanded spectrum of activity includes Pseudomonas aeruginosa, Serratia marcesens, and most strains of Enterobacter (compound Ro 13-9904 preliminary data, Hoffmann-La Roche, Inc., 1979).The purpose of this study was to compare the in vitro activity of Ro 13-9904 with the activities of other drugs representing the three major generations of cephalosporin development. The first generation was represented by cephalothin, the second was represented by cefamandole and cefoxit...

Section: Discussionmentioning

confidence: 98%

Comparative in vitro studies of Ro 13-9904, a new cephalosporin derivative

Eickhoff¹,

Ehret²

1981

“…The novel cephalosporin, cefotaxime (HR756; CEF) has been shown by in vitro studies to be a potent antimicrobial agent (1,2,4) and is at present under clinical evaluation. It is known that CEF, like cephalothin, undergoes desacetylation in vivo ( Fig.…”

mentioning

confidence: 99%

Activity of the cefotaxime (HR756) desacetyl metabolite compared with those of cefotaxime and other cephalosporins

Wise¹,

Wills²,

Andrews³

et al. 1980

The desacetyl metabolite (DES) of cefotaxime (HR756) is formed in vivo to a significant extent. The in vitro activities of DES, the parent compound, and cefazolin, cefoxitin, and cefuroxime were compared against 70 (4) with two inocula (103 and 106 colony-forming units per I ,l of inoculum). Table 1 summarizes the results obtained from the five antimicrobial agents when tested at an inoculum of 103 colony-forming units.The high activity of CEF against the Enterobacteriaceae was confirmed. It is interesting to note that DES was consistently more active than cefoxitin, cefuroxime, or cefazolin against these strains but about 1/10th as active as the parent compound. In particular, DES was 10-to 20-fold more active than cefazolin, cefoxitin, and cefuroxime against Proteus mirabilis. The susceptibility of the indole-positive Proteus spp. to DES was more variable, the minimum inhibitory concentration for one strain of Proteus morganii being 128 pg/ml but that of another being 0.5 ,ug/ml. Two strains of Enterobacter spp. (minimum inhibitory concentrations of DES, 0.5 and 1 ug/ml), three strains Providencia stuartii (miniimum inhibitory concentration of DES 2, 0.06 and 0.06 ,ug/ml), and two strains of Serratia marcescens (minimum inhibitory concentration of DES, 0.5 and 1 pg/ml) were more susceptible to DES than cefoxitin, cefuroxime, and cefazolin. The 10 strains ofPseudomonas aeruginosa were uniformly resistant to DES yet were moderately susceptible to CEF.

“…Ongoing surveillance in our hospital did not identify an epidemic of nosocomial infections due to pseudomonas in association with the instances of superinfection with this organism which we observed. Whether the emergence of resistance to cefotaxime and other cephalosporins by serial in vitro passage of pseudomonas and other clinical isolates, as observed by Wise et al (26), has any relevance to our observations of superinfections with cefotaxime-resistance gram-negative bacilli during therapy with this drug awaits further study. Furthermore, the adequacy of monotherapy with cefotaxime for serious pseudomonas and other gram-negative bacillary infections requires additional observations, despite the 70% response rate of the 10 gram-negative bacillary pneumonias which we observed.…”

Section: Discussionmentioning

confidence: 84%

Clinical evaluation of cefotaxime for therapy of lower respiratory tract infections

Schleupner¹,

Engle²

1982

A clinical trial was designed to evaluate the efficacy and safety of cefotaxime, a new semisynthetic, broad-spectrum cephalosporin, in the therapy of communityand hospital-acquired pneumonias. Thirty-nine males (mean age, 65 years) were treated for 41 episodes of pneumonia. Only five patients did not have a serious underlying disease; 15 had two or more significant disorders. Sixty-six percent of these pneumonias were due to Streptococcus pneumoniae or Haemophilus influenzae. The minimal inhibitory concentrations for all bacterial isolates ranged from 0.008 to 4 ,ug/ml. Peak serum cefotaxime levels during therapy ranged from 12 to 124 ,ug/ml 1 h after a 1-g dose. Satisfactory bacteriological and clinical responses were observed in 85% of the cases. Four episodes of pulmonary superinfections due to cefotaxime-resistant gram-negative bacilli were noted, each in a patient being mechanically ventilated. Pseudomonas was involved in each of these superinfections, and three were fatal. No serious toxicity or adverse reaction to cefotaxime was seen. The results of this study suggest that cefotaxime is an effective and well-tolerated new cephalosporin antimicrobial agent for the therapy of pneumonia due to susceptible organisms.