Antibacterial Activity of a New Parenteral Cephalosporin—HR 756: Comparison with Cefamandole and Ceforanide

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: 97%

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

Eickhoff¹,

Ehret²

1981

“…Although secondgeneration cephalosporins-cefoxitin, cefamandole, and cefuroxime-inhibit the majority of Enterobacteriaceae, they have little or no activity against Pseudomonas aeruginosa. Third-generation compounds now being tested include cefoperazone (T1551) (5) and cefotaxime (HR756) (1,2,3,8). Moxalactam (LY127935) (4) and another new beta-lactam antimicrobial agent, thienamycin (11), though not cephalosporins, resemble them in that spectrum of activity and are currently under study.…”

mentioning

confidence: 99%

Comparison of cefoperazone, cefotaxime, and moxalactam (LY127935) against aerobic gram-negative bacilli

Lang¹,

Edwards²,

Durack³

1980

This study compares MATERIALS AND METHODSWe determined minimum inhibitory concentrations (MICs) by agar dilution by the procedure of Washington and Barry (9).Preparation of inoculum. Aerobic, gram-negative bacilli isolated by the Duke Clinical Microbiology Laboratory were streaked on nutrient agar (Difco Laboratories) to provide single colonies. After incubation and inspection for purity, plates were held at 4°C until used. Approximately five colonies were touched with a bacteriological loop and inoculated into tubes containing 2 to 5 ml of tryptic soy broth, which were incubated at 350C in air for 2 to 5 h. Turbidity was adjusted to that of a 0.5 MacFarlane standard by addition of further tryptic soy broth, the suspension was blended in a Vortex mixer, and a final dilution of 1:20 was made in tryptic soy broth. Plates were inoculated with a Steers replicator within 30 min of standardizing the inoculum. This method delivered approximately 104 colony-forming units CFU of each organism to the plates.Preparation of agar plates. LY127935 assay powder was supplied by Lilly Research Laboratories, cefoperazone was supplied by Pfizer, cefotaxime was supplied by Hoechst-Roussel, and thienamycin was supplied by Merck Sharp & Dohme. Cefoperazone and cefotaxime were dissolved in sterile, deionized water, LY127935 was dissolved in 0.1 M phosphate-buffered saline (PBS; pH 7.0), and thienamycin was dissolved in 0.01 M PBS. To make plates containing twofold dilutions, antibiotics were prepared in 50-ml, screwtopped tubes so that each held a final volume of 2.5 ml that contained 10 times the concentration of antibiotic required in each agar plate. A 22.5-ml amount of Mueller-Hinton agar from a single batch (control no. 656889) at a concentration of 1.5% at 50 to 550C was added to each tube to give a final volume of 25 ml. Antibiotic and agar were mixed by gentle inversion of the tube, which was then emptied into a 100-mm petri dish. Final concentrations of antibiotics in agar ranged from 64 jig to 0.03 ,ug of thienamycin. To test swarming Proteus, agar was prepared at a 3% concen-

“…In one instance, lesions were extensive and may have contributed to the death of the patient. The pathogenesis of the pseudomembranous changes could not be inferred from In vitro susceptibility testing (4,5,7,14,20,22,23,25,26) and results obtained in this study suggest that the greatest benefit of cefotaxime might occur in the treatment of multiply resistant, nosocomial, gram-negative pathogens. Fifteen courses of cefotaxime administered for infections caused by multiply resistant Serratia marcescens (13) (15).…”

Section: Resultsmentioning

confidence: 88%

“…One such agent, cefotaxime (Claforan, HR756; Hoechst-Roussel Pharmaceuticals, Sommerville, N.J.), has been shown to have excellent in vitro activity against Enterobacteriaceae and good activity against grampositive cocci (4,5,7,20,23). In vitro activity against strains of Pseudomonas aeruginosa has been comparable to that of ticarcillin, whereas the susceptibility of strains of Bacteroidesfragilis has been variable (2,4,14,22,25). Published information regarding the clinical efficacy of cefotaxime is limited.…”

mentioning

confidence: 99%

Clinical efficacy of cefotaxime in serious infections

Karakusis¹,

Feczko²,

Goodman³

et al. 1982

Thirty-five patients underwent 38 treatment courses with cefotaxime. Documented infections included 11 bacteremias, 7 cases of nosocomial pneumonia, 6 surgical wound infections, 3 bone infections, 1 biliary infection, and 1 urinary tract infection. Granulocytopenic patients with fever received 15 courses of empiric cefotaxime therapy alone; in 8 courses, no definite site of infection or pathogen was isolated. Broad-spectrum antibiotics had been administered to 23 patients before cefotaxime. Thirty-seven bacterial pathogens were isolated from 25 patients. Three such pathogens were resistant to cefotaxime and required alternative therapies. Pathogenic isolates included 13 Serratia marcescens, 12 Pseudomonas aeruginosa, 4 Escherichia coli, 2 Klebsiella pneumoniae, 2 Providencia stuartii, 1 Enterobacter cloacae, 1 Haemophilus influenzae, 1 Enterococcus, and 1 Staphylococcus aureus. Of the treatment courses, 25 of 38 resulted in a favorable response to cefotaxime, including 9 of 15 in granulocytopenic patients. Superinfection was seen in one patient. The emergence of resistance was documented in another patient. Of 15 patients with multiply resistant pathogens, 12 improved with cefotaxime. Of 12 patients with Pseudomonas aeruginosa, 6 favorably responded. Possible complications of cefotaxime were observed in 14 of 42 treatment courses. Cefotaxime is most useful in treatment of infections due to multiply resistant, gram-negative pathogens other than Pseudomonas aeruginosa.