Synthesis and structure-activity relationships of some 6 beta-acrylamido penicillins.

Syntheses are described for penicillins (4b approximately 4i, 5a and 5b) which possess a 6 beta-(2-heteroaryl-3-substituted)-propenamido side-chain of fixed geometry. In vitro results for these compounds against a range of Gram-positive and Gram-negative bacteria showed in most cases good stability against both penicillinase and TEM-1 beta-lactamase; analogues (4b approximately 4i) bearing a 2-(2-aminothiazol-4-yl) unit showed the best intrinsic activity, the cyclohexyl compound (4b) being the most promising. The 1-acetoxyethyl ester (6) of 4b was also prepared; in experimental animal studies the in vivo properties of this compound compared favourably with cefuroxime axetil and are reported together with selected in vivo data for the other compounds.

BRL 20330, an oral prodrug of temocillin: bioavailability studies in man.

BRL 20330 is the o-methyl phenyl ester of temocillin which is well absorbed after oral administration and converted to temocillin in the body. BRL 20330 was administered to healthy subjects in a three-part cross-over study with single doses equivalent to 400, 600 and 800 mg of temocillin. Peak serum concentrations of temocillin were 9.8, 12.8 and 15.8 mg/l respectively and concentrations of 3.0-6.0 mg/l were measured at 12 h after dosing. High and prolonged concentrations of temocillin were measured in the urine. The mean urinary recovery was 22-25% and only 0.2% of unhydrolyzed BRL 20330 was detected in the urine. Little difference in the extent of absorption was noted when BRL 20330 was administered with food although the peak levels of temocillin were delayed and reduced slightly. Urinary concentrations of temocillin, even after 24 h, were bactericidal for a number of Gram-negative bacteria including multi-resistant strains. BRL 20330 was well tolerated and there was no evidence of gastro-intestinal adverse effects.

Effect of protein binding on antibiotic activity in vivo.

Using a group of penicillins all belonging to the same chemical class, antibacterial activity against Staphylococcus aureus was determined in vitro and also in vivo by use of an intraperitoneal infection in mice. The compounds all showed essentially the same level of activity in vitro but differed markedly in their activity in vivo. This activity in vivo could be correlated directly with the extent of binding in mouse serum.

BRL 17421, a novel beta-lactam antibiotic, highly resistant to beta-lactamases, giving high and prolonged serum levels in humans.

BRL 17421 is a new semisynthetic beta-lactam antibiotic with an unusual spectrum of antibacterial activity. The compound exhibits exceptional stability to a wide range of bacterial beta-lactamases and is active against the majority of Enterobacteriaceae, including strains highly resistant to many of the penicillins and cephalosporins currently available. Among the clinical isolates of Enterobacteriaceae tested, the frequency of strains resistant to BRL 17421 was found to be low, and there was a slow rate of emergence of resistance during in vitro studies. BRL 17421 was highly active against Haemophilus influenzae and Neisseria gonorrhoeae, including beta-lactamase-producing strains. The compound was markedly less active against Pseudomonas aeruginosa and Bacteroides fragilis than against the Enterobacteriaceae. Against the gram-positive bacteria, BRL 17421 showed a very low level of activity. BRL 17421 was found to be 85% bound to human serum, and the antibacterial activity was diminished two- to fourfold in the presence of human serum. Against experimental infections in mice, the activity of BRL 17421 reflected the properties observed in vitro. Studies in human volunteers showed unusually high and prolonged serum concentrations of the compound after parenteral dosage, with a serum half-life of about 5 h, and approximately 85% of the dose was recovered unchanged in the urine. BRL 17421 was poorly absorbed after oral administration. The compound was well tolerated after intramuscular and intravenous administration in volunteers, with no adverse side effects.

Antibacterial activity and synergy, in vitro and in vivo, of a combination of amoxycillin and flucloxacillin.

The antibacterial activity of a combination of equal parts of amoxycillin and flucloxacillin was compared in vitro and in vivo with that of amoxycillin and flucloxacillin against a range of gram-positive and gram-negative bacteria. The combination generally showed additive effects against bacteria sensitive to the individual penicillins and there was no evidence of antagonism, but synergistic effects were observed between amoxycillin and flucloxacillin against certain amoxycillin-resistant gram-negative bacilli. The extent of synergism varied according to the particular bacterial species under test and synergy was observed only against bacteria with chromosomally-mediated beta-lactamases and not against bacteria with R-factor-mediated beta-lactamases. In general, amoxycillin + flucloxacillin demonstrated activity against experimental mouse infections in good agreement with demonstrated activity against experimental mouse infections in good agreement with its in vitro activity, and synergy was produced against a range of gram-negative bacilli in vivo. The data suggest that clinical trial with amoxycillin + flucloxacillin in the treatment of selected infections including those due to some amoxycillin-resistant bacteria may well be justified.

Use of pyocin 78-C2 in the treatment of Pseudomonas aeruginosa infection in mice.

Purified pyocin, administered parenterally to mice infected with sensitive strains of Pseudomonas aeruginosa, afforded significant protection against two of the three strains studied.