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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.

BMY 28100, a new oral cephalosporin with a (Z)-propenyl side chain at the 3 position and a p-hydroxyphenylglycyl substituent at the 7 position, was evaluated in comparison with cefaclor and cephalexin and, when appropriate, ampicillin and vancomycin. In vitro, BMY 28100 was more active than the reference cephalosporins against streptococci, Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, Haemophilus influenzae, Propionibacterium acnes, Clostridium perfringens, and Clostridium difficile. BMY 28100 was comparable to cefaclor and more active than cephalexin against Staphylococcus saprophyticus and ampicillin-susceptible strains of Branhamella catarrhalis; but against ampicillin-resistant strains of B. catarrhalis, BMY 28100 was comparable to cephalexin and more active than cefaclor. Against Neisseria gonorrhoeae, BMY 28100 was comparable to cephalexin, but less active than cefaclor. Members of the family Enterobacteriaceae overall were equally susceptible to BMY 28100 and cefaclor but were less susceptible to cephalexin. In human serum, BMY 28100 was 45% protein bound. After an oral dose to mice, 82% of the drug was recovered in urine. The oral therapeutic efficacy of BMY 28100 in systemically infected mice reflected its activity in vitro.

The therapeutic efficacies of cefadroxil and cephalexin were compared in a Streptococcus pyogenes-induced lung infection in rats. Although MICs, rates of in vitro killing in rat serum, and antibiotic serum levels after oral administration were similar for both drugs, cefadroxil was about eight times more effective than cephalexin in reducing the number of viable streptococci at the site of infection. This excellent in vivo bactericidal activity of cefadroxil in lung tissue and bronchial secretions was reflected in the 50% protective dose (PD50) after single or multiple oral treatments. A single treatment given 24 h after infection resulted in a PD50 of 2.8 mg of cefadroxil per kg, compared with 21 mg of cephalexin per kg. When treatment was administered three times, at 24, 27, and 30 h postinfection, the PD50s of cefadroxil and cephalexin were 0.7 and 8.0 mg/kg, respectively. In infected animals, treated 24 h postinfection, the area under the lung tissue concentration versus time curve for cefadroxil was significantly greater than that of cephalexin. This difference in pharmacokinetic behavior may account, at least in part, for the superior therapeutic results obtained with cefadroxil in this experimental pulmonary infection.

BMY 28142, a new broad-spectrum semisynthetic cephalosporin, was evaluated in vitro and in vivo in comparison with ceftazidime, cefotaxime, moxalactam, and cefoperazone. The activity of BMY 28142 compared favorably with the activities of the other compounds against both Pseudomonas aeruginosa and Staphylococcus aureus and was somewhat greater against members of the family Enterobacteriaceae. The influence of inoculum size on MICs of BMY 28142 was small for most of the isolates tested, except Enterobacter species. With Enterobacter strains, a marked inoculum effect was found with all of the compounds, and the effect was more pronounced in broth than agar. Still, MICs of BMY 28142 in broth did not exceed 16 micrograms/ml. Of 37 Enterobacteriaceae strains resistant to one or more of the comparison beta-lactams, none were resistant, at a low inoculum size (10(4) CFU), to BMY 28142, compared with 3 for moxalactam, 18 for ceftazidime, 23 for cefotaxime, and 34 for cefoperazone; at an inoculum size of 10(6) CFU, the number of resistant strains was 12, 17, 25, 34, and 37, respectively. Binding to human serum proteins approximated 19%. Recovery of 73% of the drug in mouse urine indicated good bioavailability. The in vitro profile was sustained in vivo by the results obtained with experimental infections in mice. BMY 28142 was as effective as ceftazidime against systemic infection with P. aeruginosa and as effective as cefotaxime against systemic infection with S. aureus. Overall, infections with 18 of 20 strains representing nine genera were responsive to BMY 28142 at doses equivalent to or lower than those of the most effective of the comparison compounds.

We explored the antibacterial activity of phosphanilic acid (P), an analog of sulfanilic acid, alone and in combination with trimethoprim (T; TP, 1:5) with sulfamethoxazole (S) and co-trimoxazole, the combination of this sulfonamide with trimethoprim (TS, 1:5) as the reference. P resembled S in spectrum but, in addition, had significant activity against Pseudomonas aeruginosa. The overall frequency and degree of synergism with TP were lower than with co-trimoxazole. P, like S, was strongly affected by changes in inoculum size and was not bactericidal. P was well absorbed parenterally but not orally in mice. Despite low (but prolonged) blood levels, P, given orally to mice, was effective in treating infections caused by P. aeruginosa. However, against most experimental infections the therapeutic effectiveness of P, as well as that of TP, administered either intramuscularly or orally was unimpressive. Based on in vivo data, the therapeutic application of P or TP would appear to be limited.

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.

The relative antimicrobial activity of a large series of semisynthetic coumermycins has been determined. Most of the derivatives, which were 3-substituted-4-hydroxy-8-methyl-7-[3-O-(5-methyl-2-pyrrolylcarbonyl) noviosyloxy] coumarins, had an in vitro antibacterial spectrum similar to that of the parent compound, coumermycin A1, but were generally less potent in minimal inhibitory concentration (MIC) tests. Derivatives with an alkylcarboxamido, arylcarboxamido, or arylsulfonamido group in the 3 position had considerably greater in vitro activity than those possessing an amino-, aryl-, or alkyureido substituent. Efficacy in Staphylcoccous aureusSmith infections of mice was greater for those compounds with branched-chain alkylcarboxamido, unsubstituted, mono- or disubstituted aryl- and heteroaryl-carboxamido groups than for derivatives having an n-alkylcarboxamido, aralkyl-carboxamido, arylsulfonamido, or trisubstituted arylcarboxamido substituent. Significant in vitro activity against Klebsiella pneumoniaeand other gram-negative species was restricted to those compounds having a 3-(3-n-alkyl-4-hydroxy-phenyl-carboxamido) group. Only the n-hexyl homologue demonstrated in vivo activity in a K. pneumoniaeinfection. Many derivatives were two- to threefold more active than coumermycin A1in orally treated mouse infections, despite the fact that their MIC values were considerably higher. This result was undoubtedly a reflection of the markedly greater oral absorbability possessed by many of the derivatives. Although peak oral mouse blood levels of some compounds were > 25 times higher than those of coumermycin A1, their toxicity for the host was no greater. In addition, the semisynthetic coumermycins caused much less local irritation than coumermycin A1when administered parenterally.

A series of penicillins characterized by the presence of a sulfoamino or a modified sulfoamino group in the side chain was subjected to in vitro antimicrobial screening tests. Although the most potent members of the series were less active than benzylpenicillin against gram-positive bacteria and comparably active against most gram-negative bacteria, they were, on the average, 8 to 16 times more effective against strains of Pseudomonas aeruginosa.In other comparative laboratory tests against P. aeruginosa,these compounds were about as active as carbenicillin and four to eight times more active than ampicillin. An examination of structure-activity relationships indicated that maximal potency was obtained with penicillins having an α-(aromatic or heteroaromatic)-α-sulfoaminoacetamido side chain. The compound with an α-phenyl group was comparable in activity to those having an α-(2- or 3-thienyl) group, whereas any modification in position or structure of the α-sulfoamino group reduced activity. Results of studies with a cell-free P. aeruginosaβ-lactamase suggest that the marked inhibitory effects of α-sulfoamino penicillins for P. aeruginosacan be attributed, at least in part, to their high degree of resistance to this enzyme. Some derivatives, however, had weak antipseudomonal activity, despite possessing a high degree of β-lactamase resistance.