BL-S640, a Cephalosporin with a Broad Spectrum of Antibacterial Activity: Bioavailability and Therapeutic Properties in Rodents

The bioavailability and therapeutic properties of BL-S 640 in rodents were compared with those of cephalothin, cephaloridine, and cefazolin after parenteral administration, and cephalexin after oral administration. When given intramuscularly in dosages of 5 to 40 mg/kg, peak concentrations of BL-S 640 in the blood of mice were proportional to dose, but when given orally, they were proportional only up to a dose of 25 mg/kg. After either route of administration, the concentration of BL-S 640 in the blood declined at a slower rate than that of the control compounds. Rats receiving BL-S 640 orally excreted an average of 39% of the drug in the urine. BL-S 640 was highly effective in the treatment of mice infected systemically with a variety of pathogenic bacteria, its therapeutic efficacy in comparison with that of other cephalosporins being frequently in excess of what would have been predicted on the basis of comparative activities in vitro.     

In Vitro Evaluation of BL-S640 Cephalosporin Antibiotic

BL-S640, a new oral cephalosporin analogue, was evaluated in vitro against 102 gram-negative and 80 gram-positive bacteria. The antimicrobial spectrum was similar to that of previous cephalosporin analogues. Good antimicrobial activity against strains of Escherichia coli, Klebsiella, staphylococci, and streptococci was demonstrated. Relatively poor activity and/or resistance was noted among most strains of Proteus, Providencia, Pseudomonas, and Serratia. In comparative studies BL-S640 had better activity against strains of Hemophilus influenzae, Staphylococcus aureus, and Enterobacteriaceae than many cephalosporin analogues. Variation of susceptibility results was dependent upon the type of media and inoculum size. Cross-resistance between BL-S640 cephalexin, cephalothin, and cefazolin was demonstrated. Among strains of Klebsiella the more rapid selection of resistance ot other cephalosporins was in contrast to BL-S640. Experience in vitro with BL-S640 has documented its antimicrobial activity,and further studies of pharmacokinetics and therapeutic efficacy are indicated.     

In Vitro Evaluation of a New Oral Cephalosporin, Cefatrizine (BL-S640)

The activity of cefatrizine (BL-S640), a semisynthetic orally absorbed cephalosporin, was studied and found to have in vitro activity at least comparable to that previously reported for cephalexin.     

Laboratory Evaluation of BL-S786, a Cephalosporin with Broad-Spectrum Antibacterial Activity

Biological and physicochemical properties of BL-S786 were compared with those of cephalothin, cephaloridine, and cefazolin. With few exceptions, BL-S786 was more active than the reference compounds against major gram-negative pathogenic species and its antibacterial spectrum was broader than that of cephalosporins currently available for clinical use. Although BL-S786 was generally less active than the control cephalosporins against gram-positive pathogens, it inhibited their growth at concentrations that should readily be achieved in humans after standard parenteral dosage. Streptococcus faecalis, a species relatively unsusceptible to cephalosporins in general, was an exception. BL-S786 was an effective bactericidal agent for strains of various gram-negative organisms. After intramuscular administration to mice, BL-S786 achieved high concentrations in blood, and its biological half-life was longer than that of the other three cephalosporins.     

BL-S786 (Ceforanide), a New Parenteral Cephalosporin: In Vitro Studies

BL-S786 (ceforanide) is a new cephalosporin which showed broad-spectrum activity in vitro against 453 clinical isolates. At a concentration of 3.12 mug/ml, it inhibited greater than 75% of isolates of Escherichia coli, Klebsiella spp., Proteus mirabilis, Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumoniae. Essentially no activity was observed against isolates of Serratia marcescens, and only minimal activity was observed against Enterobacter spp. Its activity was directly related to the size of the inoculum. The minimal bactericidal concentrations were similar to the minimal inhibitory concentrations for isolates of all organisms except S. aureus and S. pyogenes. The minimal bactericidal concentrations were considerably higher than the minimal inhibitory concentrations for these organisms.     

Cefuroxime, a Beta-Lactamase-Resistant Cephalosporin with a Broad Spectrum of Gram-Positive and -Negative Activity

The in vitro activity of cefuroxime, a cephalosporin antibiotic, was investigated against 604 isolates and compared with the activity of other beta-lactam compounds. Cefuroxime had activity comparable to that of other cephalosporins, including cefamandole and cefoxitin, against streptococcal and staphylococcal species; most streptococci were inhibited by 0.1 mug or less per ml, and staphylococci were inhibited by 1.6 mug or less per ml. Enterococci were relatively resistant. Cefuroxime inhibited beta-lactamase-producing Neisseria gonorrhoeae and Haemophilus influenzae. Cefuroxime had excellent activity against members of the Enterobacteriaceae; 83% of beta-lactamase-producing Escherichea coli, 100% of Salmonella, 100% of Klebsiella, 90% of Proteus mirabilis, 95% of Citrobacter, 56% of Enterobacter, and 58% of Shigella were inhibited by 12.5 mug/ml. Cefuroxime had activity comparable to that of cefamandole and cefoxitin; it inhibited isolates of E. coli and Klebsiella resistant to cefamandole and inhibited Enterobacter and Citrobacter resistant to cefoxitin. Many isolates of Serratia, some indole-positive strains of Proteus, and Bacteroides fragilis were resistant to cefuroxime. Resistance of cefuroxime to hydrolysis by beta-lactamases played a major role in its activity against both gram-positive and gram-negative organisms.     

Susceptibility of Clinical Isolates of Enterobacteriaceae to BL-S640, a New Oral Cephalosporin

The in vitro activity of BL-S640, a 7-(2-aryl-2-aminoacetamido)-3-(heterocyclic-thiomethyl) cephalosporin, was evaluated against 338 clinical isolates of Enterobacteriaceae in comparison with ampicillin, cephalothin, cefazolin, and cephalexin. Against Escherichia coli, BL-S640 was as active as cefazolin and more active than ampicillin, cephalothin, and cephalexin. BL-S640 was as effective as the other cephalosporins tested and far more active than ampicillin against Klebsiella and was more active than cephalexin against Proteus mirabilis and the indole-positive Proteus. The majority of Enterobacter, Serratia, and Citrobacter were resistant to ampicillin and all the cephalosporins tested. With rare exceptions, the zone of inhibition by the BL-S640 30-mug disk was either larger or the same as the zone obtained by the cephalothin 30-mug disk in the Kirby-Bauer disk susceptibility test.     

In Vitro Activity of BL-S640 Against Gram-Negative Bacilli and Staphylococcus aureus Compared with Activity of Four Other Semisynthetic Cephalosporins

The in vitro activity of BL-S640 (cefatrizine) was determined against 674 recent clinical isolates of Staphylococcus aureus and Enterobacteriaceae. Activity against S. aureus was less than that of cephapirin, cephalothin, and cefazolin, but greater than that of cephalexin. Activity against gram-negative isolates was variable: BL-S640 was slightly less potent than cefazolin against Escherichia coli and Klebsiella, but more active than the other compounds. As for the more resistant gram-negative genera, BL-S640 was significantly superior to the control cephalosporins. The effect of inoculum size on the antibacterial activity was moderate for most organisms except Enterobacter, Providencia stuartii, and indole-positive Proteus, the median minimal inhibitory concentrations of which were 6 to 27 times lower when determined with a 10(-4)-diluted culture compared with the undiluted one. The stability in aqueous solution at 37 C was remarkably high at the lower pH values, but low at the neutral point.     

Cefuroxime, a New Cephalosporin Antibiotic: Activity In Vitro

Cefuroxime is a new broad-spectrum cephalosporin antibiotic with increased stability to beta-lactamases. This stability, although no absolute in all cases, has the effect of widening the antibacterial spectrum of the compound so that many organisms resistant to the established cephalosporins are susceptible to cefuroxime. It is active against gram-positive organisms, including penicillinase-producing staphylococci, but it is less active against methicillin-resistant strains. In addition to its high activity against non-beta-lactamase-producing gram-negative bacteria, cefuroxime effectively inhibits the growth of many beta-lactamase-producing strains, including Enterobacter, Klebsiella, and indole-positive Proteus spp. It is highly active against Neisseria gonorrhoeae, Neisseria meningitidis, and also Haemophilus influenzae, including ampicillin-resistant strains. Cefuroxime is rapidly bactericidal and induces the formation and subsequent lysis of filamentous forms over a small concentration range.     

In Vitro Antibacterial Activity and β-Lactamase Stability of SCE-129, a New Cephalosporin

SCE-129 [3-4-carbamoyl-1-pyridiniomethyl-7beta- (d-alpha-sulfophenylacetamido)-ceph-3-em-4-carboxylate] is a cephalosporin that inhibits Pseudomonas aeruginosa and Staphylococcus aureus. SCE-129 is tenfold more active than carbenicillin in inhibiting P. aeruginosa. SCE-129 has poor activity against Enterobacteriaceae compared with other cephalosporins and is 16-fold less active than the cephalosporins against streptococci. The activity of SCE-129 does not correlate with beta-lactamase stability, although SCE-129 is resistant to hydrolysis by gram-positive and gram-negative bacteria. The compound does not inhibit the hydrolysis of other cephalosporins. Although SCE-129 acts synergistically with gentamicin to inhibit some Pseudomonas, this cannot be predicted based on knowledge of resistance to one or more compounds.     

Cefamandole: Antimicrobial Activity In Vitro of a New Cephalosporin

Cefamandole, a new cephalosporin derivative, was found to have a broad spectrum of activity against a cross-section of both gram-positive and gram-negative bacteria isolated from clinical material. Gram-positive cocci, except for Streptococcus faecalis, were very susceptible. Penicillin G-resistant Staphylococcus aureus also was susceptible to cefamandole. Minimal bactericidal concentrations for gram-positive cocci approximated the minimal inhibitory concentrations. Strains of Haemophilus influenzae were very susceptible to the drug. Most strains of Escherichia coli, Klebsiella sp., and Proteus sp. were inhibited by low concentrations. Increasing resistance occurred with larger inocula. Strains of Pseudomonas sp. were resistant to cefamandole.     

SCE-129, Antipseudomonal Cephalosporin: In Vitro and In Vivo Antibacterial Activities

SCE-129 [3-(4-carbamoyl-1-pyridiniomethyl)-7beta-(d-alpha-sulfophenylacetamido)-ceph-3-em-4-carboxylate monosodium salt], a new semisynthetic cephalosporin, shows potent in vitro antibacterial activities against Pseudomonas aeruginosa and some gram-positive bacteria, whereas it shows lower activity against many gram-negative rods. Against clinical isolates of P. aeruginosa this cephalosporin exhibited higher activity than did carbenicillin, and against the strains of Staphylococcus aureus, SCE-129 had similar activity to carbenicillin. Variations in pH, addition of horse serum, and type of growth medium had no significant effects on the activity of the cephalosporin; however, the inoculum size had some effect on the activity. SCE-129 is an effective bactericidal agent against P. aeruginosa and S. aureus. The protective effects of SCE-129 in mice infected with P. aeruginosa and S. aureus were more potent than those of carbenicillin. The protective effects of SCE-129 on Pseudomonas infection in mice varied according to the dosage schedule and the challenge dose. In a multiple dose schedule, a smaller amount of SCE-129 was necessary than that in a single dose schedule. The effects of SCE-129 after subcutaneous or intraperitoneal administration were more potent than were those by intravenous administration. No protective effect was observed by oral administration.     

SCE-963, a New Broad-Spectrum Cephalosporin: In Vitro and In Vivo Antibacterial Activities

SCE-963 {7β-[2-(2-aminothiazol-4-yl)acetamido]-3-[({1-(2-dimethylaminoethyl)- 1H-tetrazol-5-yl}thio)methyl]-ceph-3-em-4-carboxylic acid}, a new semisynthetic cephalosporin, showed excellent antibacterial activity against gram-positive and gram-negative bacteria, including Haemophilus influenzae, indole-positive Proteus, Enterobacter species, and Citrobacter freundii. The minimum inhibitory concentrations of SCE-963 against most strains of clinically isolated Escherichia coli, Klebsiella pneumoniae, H. influenzae, and Proteus mirabilis were within the range of 0.2 to 0.78 μg/ml. These activities were about 10 times more potent than those of cefazolin, cephaloridine, and cephalothin. Variations in pH, addition of horse serum, and type of growth medium had no significant effect on the activity of the cephalosporin, but the inoculum size elicited a considerable effect on the activity of β-lactamase-producing strains of bacteria. SCE-963 exerted bactericidal and bacteriolytic effects on Staphylococcus aureus and E. coli. The pronounced in vitro activity was reflected in the remarkable protection in mice infected with a wide range of gram-negative bacteria, such as E. coli, K. pneumoniae, P. mirabilis, Proteus vulgaris, Proteus morganii, and Proteus rettgeri. The protective effects of SCE-963 in mice infected with E. coli, K. pneumoniae, and P. vulgaris varied according to the challenge dose. The activity of SCE-963 was far more potent when the drug was administered parenterally rather than orally.     

In Vitro Activity of Cefaclor, a New Orally Administered Cephalosporin Antibiotic

The in vitro antibacterial activity of cefaclor, cephalothin, and cephalexin against 261 clinical isolates of Staphylococcus aureus and Enterobacteriaceae was compared. Cefaclor and cephalexin were about equally active against S. aureus. Cefaclor was the most active cephalosporin against Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae. The effect on the antimicrobial activity using a relatively high and low inoculum was pronounced for cefaclor when compared with that of cephalothin.     

Silver Sulfadiazine: In Vitro Antibacterial Activity

Isolates (657) representing 22 bacterial species were tested for susceptibility to silver sulfadiazine. All of the strains tested were inhibited by concentration levels of the drug which are easily achieved topically. It is suggested that silver sulfadiazine may be useful as a broad-spectrum antimicrobial substance for the prevention and treatment of infections of burns and wounds.     

In Vitro Activity of Gepotidacin,a Novel Triazaacenaphthylene Bacterial Topoisomerase Inhibitor,against a Broad Spectrum of Bacterial Pathogens

Gepotidacin inhibits bacterial DNA replication through a mode different from that of fluoroquinolones. Gepotidacin and comparators were tested by broth and agar dilution against clinical isolates. The in vitro activities of gepotidacin were comparable against methicillin-susceptible and -resistant Staphylococcus aureus (MSSA and MRSA, respectively) isolates (MIC₉₀, 0.5 μg/ml). The gepotidacin MIC₉₀s were as follows (in micrograms per milliliter) for the indicated bacteria: Streptococcus pyogenes, 0.25; Escherichia coli, 2; Moraxella catarrhalis, ≤0.06; Streptococcus pneumoniae (0.25), Haemophilus influenzae, 1; Clostridium perfringens, 0.5; and Shigella spp., 1, including levofloxacin-resistant subsets. Gepotidacin warrants further investigation for clinical development.     

In Vitro Activity of HR 756, a New Cephalosporin, Against Neisseria gonorrhoeae

The in vitro activity of HR 756 was compared with penicillin, cefamandole, cefoxitin, and tetracycline against Neisseria gonorrhoeae. A total of 192 randomly selected isolates (of which 23 had minimal inhibitory concentrations of >/=0.5 mug/ml for penicillin) and three beta-lactamase-producing isolates were tested. HR 756 was the most active antibiotic tested, with more than 90% of the isolates inhibited by 0.008 mug/ml and all inhibited by 0.25 mug/ml.     

Antibacterial Activity of Cinoxacin In Vitro

Cinoxacin is a new synthetic compound similar chemically and in antimicrobial activity to oxolonic acid and nalidixic acid. It is most effective against Escherichia coli and Proteus mirabilis, but at concentrations expected in the urine it is inhibitory for all species of Enterobacteriaceae. Relative to nalidixic acid, cinoxacin has slightly greater inhibitory and bactericidal activity, less inoculum effect probably due to less heterogeneity in the susceptibility of bacterial cells, and less inhibition by high concentrations of serum protein. Both drugs are more active in an acid than an alkaline medium. Glucose can specifically antagonize the inhibitory effect against P. mirabilis. In urine the bactericidal rate and effect are decreased. Resistance to cinoxacin can be developed quickly by serial transfers in vitro. Some nonresistant organisms remained viable in bactericidal drug concentrations. The in vivo importance of the favorable features of cinoxacin must be determined by clinical trials.