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...

Amoxycillin was significantly more active than ampicillin in the treatment of intraperitoneal mouse infections when administered by oral and parenteral routes, although the causal bacteria were equally susceptible in vitro to the two penicillins. Amoxycillin produced higher antibiotic blood concentrations in mice than ampicillin after oral administration, and this was a possible explanation for the superior oral activity of amoxycillin. In contrast, antibiotic blood concentrations were the same for both compounds after subcutaneous injection, but it was demonstrated that amoxycillin was more effective than ampicillin by this route in reducing bacterial counts in the peritoneal cavity and in the blood of mice infected with Escherichia coli. Amoxycillin was also significantly more active than ampicillin in the treatment of infection by intraperitoneal dosing as a result of greater bactericidal activity in infected mice together with the production of higher antibiotic blood levels. The results of these studies on the effects of parental treatment of experimental infections with the two penicillins show that the superior chemotherapeutic activity of amoxycillin was associated with the greater bactericidal activity of amoxycillin in vivo and with differences in the distribution of the two penicillins in the infected animal.Although amoxycillin is similar to ampicillin with respect to antibacterial spectrum and general level of antibacterial activity in vitro (4, 5), initial chemotherapeutic studies showed that the compound was more active than ampicillin against a variety of mouse infections by oral and parenteral routes (1). The superior activity of amoxycillin by the oral route might be explained largely by the better oral absorption characteristics of amoxycillin compared with ampicillin, resulting in higher serum concentrations of amoxycillin, but this would not be the explanation for the results obtained by subcutaneous injection where the blood levels produced by amoxycillin were no different from those of ampicillin (1). Further investigations of the activity of amoxycillin after parenteral treatment of an experimental mouse thigh lesion infection showed that amoxycillin produced greater bactericidal effects than ampicillin in vivo and suggested that this was the explanation for the superior chemotherapeutic activity of amoxycillin (2).The data reported here were derived from studies designed to investigate differences between amoxycillin and ampicillin in the treatment of experimental intraperitoneal mouse infections and involved measurement of antibiotic levels and bacterial counts in the blood and peritoneal cavity of infected mice and correlation of these parameters with effectiveness of treatment. MATERIALS AND METHODSAntibiotics. The penicillins were used as commer-

Amoxycillin was significantly more active than ampicillin in the treatment of intraperitoneal mouse infections when administered by oral and parenteral routes, although the causal bacteria were equally susceptible in vitro to the two penicillins. Amoxycillin produced higher antibiotic blood concentrations in mice than ampicillin after oral administration, and this was a possible explanation for the superior oral activity of amoxycillin. In contrast, antibiotic blood concentrations were the same for both compounds after subcutaneous injection, but it was demonstrated that amoxycillin was more effective than ampicillin by this route in reducing bacterial counts in the peritoneal cavity and in the blood of mice infected with Escherichia coli. Amoxycillin was also significantly more active than ampicillin in the treatment of infection by intraperitoneal dosing as a result of greater bactericidal activity in infected mice together with the production of higher antibiotic blood levels. The results of these studies on the effects of parental treatment of experimental infections with the two penicillins show that the superior chemotherapeutic activity of amoxycillin was associated with the greater bactericidal activity of amoxycillin in vivo and with differences in the distribution of the two penicillins in the infected animal.