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.

The antibacterial activities of ticarcillin, carbenicillin, tobramycin, and gentamicin and of combinations of these antibiotics were measured against Pseudomonas aeruginosa and other gram-negative bacilli in vitro and in experimental mouse infections. Synergistic effects were produced by the penicillin/aminoglycoside combinations in growth inhibition tests and in bactericidal tests against many of the bacteria tested. Combinations of ticarcillin + tobramycin were more active in vitro than carbenicillin + gentamicin against P. aeruginosa but were no more active than the latter against other gram-negative bacilli. Ticarcillin + tobramycin and carbenicillin + gentamicin also demonstrated synergistic activities against P. aeruginosa, Escherichia coli, and Enterobacter cloacae in experimental mouse infection models. Thus, the penicillin/aminoglycoside combinations produced greater protective effects than the individual antibiotics against lethal intraperitoneal infections and also were more effective in reducing kidney counts of viable bacteria and kidney abscess formation in experimental pyelonephritis infections. As was the case in vitro, ticarcillin + tobramycin was more effective than carbenicillin + gentamicin against the experimental P. aeruginosa infections. The results of these in vitro and in vivo studies suggest that combined therapy with ticarcillin and tobramycin may be warranted in the treatment of serious infections due to P. aeruginosa and Enterobacteriaceae.Combined therapy with carbenicillin and gentamicin is often recommended for the treatment of serious infections caused by gram-negative bacilli because of the synergy that can be demonstrated in vitro and in vivo against Pseudomonas aeruginosa and other gram-negative bacilli (2,3,10,12,18). A number of newer aminoglycosides with claims to being superior to gentamicin in some respect have become available, and combinations of carbenicillin with tobramycin (2, 7, 9, 21), amikacin (9,11,14), sisomicin (9, 14), and netilmicin (14) have been reported to be synergistic against P. aeruginosa. Similarly, ticarcillin, a semisynthetic penicillin analogue of carbenicillin, has been shown to produce synergy when combined with gentamicin (1,15,20,21), but no experimental data have been reported for combinations of ticarcillin with the newer aminoglycosides.The present study was designed to investigate the antibacterial effects produced by combining ticarcillin with tobramycin against P aeruginosa and other gram-negative bacilli. The combinations of antibiotics were examined for synergy in growth inhibition and bactericidal tests in vitro and against two experimental mouse infection models. In these tests the activity of ticarcillin + tobramycin was compared with that of carbenicillin + gentamicin.MATERIALS AND METHODS Bacteria. Most of the cultures tested in vitro and in vivo were clinical isolates from specimens of blood, urine, and wounds.Mice. Male and female albino mice, 18 to 22 g, were used for the intraperitoneal infection studies, and female mice, 18 to...

The rates of diffusion through purified extracellular alginate from Pseudomonas aeruginosa were measured for twelve beta-lactam antibiotics. The diffusion rate was reduced as the antibiotic molecular weight increased, but the range of diffusion rates exhibited by a common anti-pseudomonal penicillins was relatively small. The diffusion of ticarcillin through 1.0% w/v mixtures of alginate and purified mucus glycoprotein (mucin) from sputa of cystic fibrosis patients showed that, at equivalent concentrations, alginate represented the greater barrier to penetration. However if the mucin concentration was increased to 4.0% w/v, a more realistic physiological concentration, the diffusion of ticarcillin was retarded to a greater extent than in 1% w/v alginate, and the effect was compounded by other sputum components such as DNA. The results suggest that the antibiotic diffusion barrier represented by mucin may be significant in vitro, particularly for nebulized antibiotics.

The antibacterial activities of two ureidopenicillins, azlocillin and mezlocillin, were compared with those of the alpha-carboxypenicillins, carbenicillin and ticarcillin, against a large number of gram-positive and gram-negative bacteria. All four penicillins were active against a wide range of bacteria including Pseudomonas aeruginosa, but there were differences in the antibacterial spectra and in the antibacterial effects demonstrated by the two classes of penicillins. In particular, the minimum inhibitory concentrations of azlocillin and mezlocillin against Klebsiella aerogenes and against P. aeruginosa were greatly influenced by the size of bacterial inoculum tested whereas there was no significant inoculum effect with carbenicillin and ticarcillin. In stability tests, the ureidopenicillins were inactivated rapidly by the beta-lactamases of K. aerogenes and P. aeruginosa whereas the alpha-carboxypenicillins were stable. It seems probable that the inoculum effect seen with azlocillin and mezlocillin in antibacterial tests with K. aerogenes and P. aeruginosa is associated with the instability of the compounds to the beta-lactamases of these bacteria.

The aminoglycoside group of antibiotics is relatively inactive against enterococci and these compounds are not usually considered for the treatment of enterococcal infections. However, combinations of aminoglycosides with penicillins can be shown to produce bactericidal synergy against many strains of enterococci, and combined penicillin/aminoglycoside therapy is recommended for the treatment of severe infections, notably enterococcal endocarditis (Garrod et al., 1973). Synergism is not always demonstrated in vitro by combinations of penicillins and aminoglycosides and is dependent upon the level of resistance of the organism to the aminoglycoside. Thus a number of strains of enterococci are highly resistant to streptomycin or kanamycin, and combinations of penicillin and streptomycin or penicillin and kanamycin are not synergistic against these strains (Standiford et al., 1970;Moellering et al., 1971;Russell and Sutherland, 1975).The newer aminoglycosides, gentamicin and tobramycin, are more active in vitro than streptomycin and kanamycin against enterococci (Moeller-

In addition to their antibiotic activity, the olivanic acids inhibit a number of S-lactamases and enhance the activity of 1I-lactams such as amoxycillin against (3-lactamase-producing bacteria. Significant differences are observed both in antibacterial activities and in 11-lactamase inhibition properties when the olivanic acids are compared with the related thienamycin antibiotics which have (8R) rather than (8S) stereochemistry and trans-jS-lactam protons.

BRL 36650 is a new type of penicillin in which a formamido group has been introduced into the 6aL-position of the nucleus. The compound is highly active against aerobic gram-negative bacteria and is stable to a wide range of ,-lactamases produced by these organisms.

beta-Lactam antibiotics containing a catechol moiety show potent activity against Gram-negative bacteria, particularly organisms grown under iron-limited conditions, suggesting that the iron-regulated outer membrane proteins (IROMPs) play a role in antibiotic uptake. A catecholic C(7) alpha-formamido-substituted cephalosporin showed increased penetration into Escherichia coli cells grown in an iron-deficient medium compared with cells grown in a medium supplemented with iron. In contrast, penetration of the corresponding monohydroxyphenyl analogue was not influenced by iron concentration. Susceptibility studies with mutants of E. coli lacking one or more IROMPs suggested that the catecholic analogue was able to utilize the Fiu (83 kDa) and Cir (74 kDa) proteins, but not the enterobactin receptor FepA (81 kDa). Mutants lacking both Fiu and Cir showed a specific decreased susceptibility for catechol-containing cephalosporins. Radio-ligand binding studies with a Fe-catecholic cephalosporin confirmed an association with these proteins.