BMY 28100, a new oral cephalosporin.

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.

Aminoglycoside antibiotics. 7. Dihydrostreptomycin analogues.

Dihydrostreptomycin analogues with structural variations in their guanidino groups were prepared. The analogue with a methyl group on the guanidine at C-1 was nearly as active as dihydrostreptomycin against bacteria. However, the 2-imidazolin-2-ylamino substituent at C-1 eliminated activity. No analogue with a substituent on the C-3 guanidino group was active.

Antibacterial activity of phosphanilic acid, alone and in combination with trimethoprim.

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.

Comparison of a new cephalosporin, BMY 28142, with other broad-spectrum beta-lactam antibiotics.

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.

Aminoglycoside antibiotics. 3. Epimino derivatives of neamine, ribostamycin, and kanamycin B.

2',3'-Epimino analogues of neamine, ribostamycin, and kanamycin B possessing little or no intrinsic antimicrobial activity were designed to enhance the activity of kanamycin A against bacterial strains that elaborate aminoglycoside 3'-phosphotransferases. Routes were devised for their synthesis from the parent antibiotics and the 2'',3''-epimino analogue of kanamycin B also was prepared. None of these analogues was active against phosphotransferase-producing bacteria, although the kanamycin B derivatives showed very weak activity against nonresistant strains. At 8 and 32 microgram/mL, the 2',3'-epimino analogue of neamine produced a small synergistic effect on the activity of kanamycin A against a strain of Escherichia coli that produces aminoglycoside 3'-phosphotransferase II. The N3-(carbobenzyloxy) derivative of this analogue produced a small effect against the same strain, and it, as well as the 2'',3''-epimino analogue of kanamycin B, slightly enhanced the activity of kanamycin A against a strain of Proteus rettgeri that elaborates a similar enzyme.

Amikacin, an aminoglycoside with marked activity against antibiotic-resistant clinical isolates.

A total of 319 clinical isolates known to be resistant to one or more aminoglycoside antibiotics were tested for their susceptibility to 10 aminoglycosides. The percentages of isolates found by an agar dilution method to be susceptible were: amikacin, 83.7%; tobramycin, 41.4%; butirosin A, 33.2%; dideoxykanamycin B, 32.6%; gentamicin C, 27.3%; lividomycin A, 17.6%; neomycin B, 10.7%; paromomycin, 10.3%; kanamycin A, 10.0%; and ribostamycin, 7.2%. The effectiveness of the antibiotics was related to their degree of resistance to bacterial enzymes; e.g., of the nine enzymes known to inactivate antibiotics containing 2-deoxystreptamine, amikacin was affected by one enzyme, tobramycin by five, and gentamicin and kanamycin by six. Examination of cell-free extracts from the 52 strains resistant to amikacin revealed that only four contained the amikacin-inactivating enzyme aminoglycoside-6'-acetyltransferase, a finding indicating that this mechanism of resistance is rare. Other experiments suggest that most amikacin-resistant strains, which are almost invariably resistant to all aminoglycosides, lack the ability to accumulate effectively either amikacin or presumably the other antibiotics intracellularly.

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-S 640, a cephalosporin with a broad spectrum of antibacterial activity: properties in vitro.

BL-S 640 was evaluated in vitro by comparison with cephalothin, cephaloridine, cefazolin, and cephalexin. The new compound was more active than the control cephalosporins against most major gram-negative and some gram-positive species. Moreover, its antibacterial spectrum included strains of Enterobacter, Proteus morganii, P. rettgeri, and Providencia stuartii, species generally resistant to the other cephalosporins. BL-S 640 was an effective bactericidal agent for strains of various species of Enterobacteriaceae. In human plasma, the compound was 58% protein bound.

Activity of BB-K8 (amikacin) against clinical isolates resistant to one or more aminoglycoside antibiotics.

One hundred fifty-two bacterial strains that possess resistance to kanamycin A, gentamicin, or tobramycin, or to more than one of these antibiotics, were collected from various sources in Canada, Europe, Japan, and the United States. This collection was composed of Staphylococcus aureus and Pseudomonas aeruginosa and members of the Enterobacteriaceae family. Their susceptibility to BB-K8 (amikacin), a new broad-spectrum semisynthetic derivative of kanamycin A, and to the other agents, was determined on Mueller-Hinton Medium by the twofold agar dilution method. Test results revealed that 60.5% of the isolates were resistant to 8 mug of tobramycin per ml, 67.1% to 8 mug of gentamicin per ml, 86.2% to 20 mug of kanamycin A per ml, and only 8.6% to 20 mug of amikacin per ml. Of interest is the fact that the amikacin-resistant strains were generally resistant to all of the other aminoglycosides. The broad spectrum of amikacin was not totally unexpected, because the compound has been shown to be a poor substrate for most enzymes that inactivate other aminoglycosides through O-phosphorylation, O-adenylylation, or N-acetylation. A number of susceptibility profiles were obtained when the organisms were tested against a series of nine aminoglycosides. The majority of these profiles resembled those found for organisms that possess known mechanisms of enzymatic inactivation.

Effect of assay medium on the antibacterial activity of certain penicillins and cephalosporins.

It is well known that the composition of the assay medium greatly affects the antimicrobial activity of aminoglycoside antibiotics. A similar response has now been observed with certain penicillins and cephalosporins. In the case of these compounds, this effect is apparently governed by the chemical nature of the penicillin 6- and cephalosporin 7-side chains. In comparison with their activity in Nutrient Broth, the activity of some of the beta-lactam antibiotics that have a weakly basic or basic group in their side chain was reduced as much as 40-fold in one or more of the following media: Mueller-Hinton, Trypticase soy, antibiotic assay, and heart infusion broths. In contrast, the assay medium had no effect on the activity of those compounds possessing an acidic or a nonionizable function in their side chain. The extent to which medium influences the antibacterial activity was also dependent upon the assay method and the organism, the effect being more pronounced in broth dilution than in agar dilution tests and occurring more frequently with gram-negative than with gram-positive organisms.

Microbiological properties of a new cephalosporin, BL-S 339: 7-(phenylacetimidoyl-aminoacetamido)-3-(2-methyl-1,3,4-thiadiazol-5-ylthiomethyl)ceph-3-em-4-carboxylic acid.

BL-S 339 is a new broad-spectrum, parenterally effective cephalosporin whose expression of antibacterial activity in vitro is markedly affected by the nature of the assay medium. When assayed in nutrient agar, BL-S 339 was more active than cephalothin against strains of Diplococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, Enterobacter, and indole-positive Proteus sp. However, when assayed in Mueller-Hinton medium, its activity, especially against gram-negative bacteria, was reduced substantially, whereas the activity of cephalothin was virtually unaffected by the assay medium. The in vivo activity of BL-S 339 correlated well with its activity in nutrient agar; when administered subcutaneously to mice, it was therapeutically more efficacious than cephalothin in infections caused by both gram-positive and gram-negative bacteria. When BL-S 339 was administered intramuscularly to mice, the concentrations achieved in the blood were three times those achieved with cephalothin. BL-S 339 was bound to human serum proteins to the same extent as cephalothin. Recovery of BL-S 339 in the urine within the 24-hr period after intramuscular administration to rats was three times that of cephalothin.

Structure-activity relationships among a group of 7-(alpha-(N,N'-substituted-amidinothio)-acetamido) cephalosphoranic acids.

Structure-activity relationships were examined for a number of 7-[alpha-(N,N'-substituted-amidinothio)-acetamido] cephalosporanic acids, including several wherein the amidino group was cyclized into six, seven, and eight-membered rings and a series wherein alkyl, cycloalkyl, alkenyl, and alkynyl radicals were substituted on the nitrogens of the noncyclized amidino group. Derivatives containing an unsubstituted cyclized amidino group had comparable antibacterial activity in vitro and in general had a spectrum of activity broader than that of cephalothin, especially against cephalothin-resistant strains of Escherichia, Klebsiella, and Proteus. When administered parenterally, the cephalosporin with the six-membered cyclized amidino group was as effective as cephalothin in experimental infections of mice produced by cephalothin-sensitive gram-negative organisms and more efficacious in infections caused by cephalothin-resistant strains. Among the cephalosporins with noncyclized amidino groups, those with an ethyl substituent on one of the nitrogens and a C(2)-C(4) alkyl radical, particularly propyl on the other, were the most active. They not only had a better profile of activity in vitro than cephalothin and the cephalosporin derivatives having a cyclized amidino group, but were also more efficacious in infections of mice.