Synergistic Activity of Carbenicillin and Gentamicin in Experimental Pseudomonas Bacteremia in Neutropenic Rats

The activities of azlocillin, cefotaxime, and amikacin alone and in combination were evaluated in in vitro checkerboard studies, in infected neutropenic mice, and in human volunteers. The combination of cefotaxime plus amikacin was more synergistic in vitro than the others against the Enterobacteriaceae tested, and the combination of azlocillin plus amikacin was more synergistic against Pseudomonas aeruginosa and Staphylococcus aureus. Survival of neutropenic mice infected with Escherichia coli and Klebsiella pneumoniae, respectively, was greater with azlocillin plus amikacin (24 of 40 and 11 of 40) and with cefotaxime plus amikacin (21 of 40 and 17 of 40) than with azlocillin plus cefotaxime (22 of 40 and 3 of 40; P < 0.05). Median serum bactericidal activity in volunteers receiving these antibiotics alone and in combination was -1:8 with most agents and with all combinations tested against 10 strains each of E. coli, K. pneumoniae, P. aeruginosa, and S. aureus. These data suggest that clinical trials with combinations of azlocillin or cefotaxime plus amikacin deserve further study in febrile neutropenic patients.Overwhelming infections with gram-negative bacteria and Staphylococcus aureus occur frequently in granulocytopenic patients (7, 9, 24). Early empiric combination antibiotic therapy is widely used in this clinical situation (7,10,18,24). Most therapeutic regimens include an aminoglycoside, such as gentamicin, tobramycin, or amikacin, and a broad-spectrum beta-lactam, such as carbenicillin or ticarcillin, or a cephalosporin. However, there is need for combinations with even broader activity and less toxicity than the above. The studies recorded in this report on the comparative activities of combinations of amikacin with azlocillin, a new broad-spectrum ureidopenicillin (29), and cefotaxime, a new broad-spectrum cephalosporin (26), were a response to that need. The studies were pursued collaboratively in three laboratories using (i) in vitro susceptibility testing, (ii) infected neutropenic mice, and (iii) serum from human volunteers who had received each drug alone and in combination.

Section: Resultsmentioning

confidence: 99%

In vitro and in vivo studies of three antibiotic combinations against gram-negative bacteria and Staphylococcus aureus

Zinner¹,

Klastersky²,

Gaya³

et al. 1981

“…Because animal and human synergism data are sparse, in vitro data are often used to select optimal combinations for clinical use. Although the data are inconclusive, several studies have reported an association between the in vitro synergistic activity of combinations and the therapeutic outcome in both animals (2,13,21,24) and humans (1,9,10,14,19,25).…”

Section: Discussionmentioning

confidence: 99%

Synergism at clinically attainable concentrations of aminoglycoside and beta-lactam antibiotics

Hooton¹,

Blair²,

Turck³

et al. 1984

We evaluated the in vitro synergistic activity at clinically attainable concentrations of combinations of aminoglycoside and ,-lactam antibiotics against 30 gentamicin-resistant clinical isolates of gram-negative bacilli. All 56 pairs of 4 aminoglycosides and 14 1-lactams were evaluated. Combinations with amikacin demonstrated inhibitory synergistic activity in 29% of the assays, as compared with 22% for netilmicin (P = 0.018), 17% for gentamicin (P < 0.001), and 13% for tobramycin (P < 0.001 Antimicrobial synergism is said to occur when two or more antibiotics in combination exert an inhibitory effect on microorganisms that is greater than the additive effects of the individual antibiotics. Several animal (2,3,16,18,24) and human (1, 17) studies have demonstrated that certain antibiotic combinations are more effective than single antibiotics in eradicating serious infections and preserving life. Moreover, those combinations resulting in a successful therapeutic outcome are more likely to demonstrate in vitro synergism against infecting strains than less successful combinations (1,9,10,14,19,25). Thus, it seems rational to use such in vitro data in selecting optimal combinations of antibiotics for the empirical therapy of serious bacterial infections. Most previous investigations of in vitro synergism have involved small numbers of different antibiotic combinations and bacterial species. In this study, we compared the in vitro synergistic activity of a large number of combinations of aminoglycoside and ,-lactam antibiotics against a group of 30 gram-negative bacilli. Because synergism obtained at concentrations higher than those achieved with usual dosage regimens probably has little practical value, we expressed our results in terms of synergism obtained at clinically attainable concentrations of antibiotics.(These studies were presented in part at the 13th International Congress of Chemotherapy, Vienna, Austria, 1983.) MATERIALS AND METHODS We selected for study 30 isolates of gentamicin-resistant (MIC, >8 pug/ml) gram-negative bacilli of several species from clinical specimens submitted to microbiology laboratories at the Seattle Veterans Administration Hospital and Harborview Medical Center in Seattle, Wash. Among the 30 isolates were (number of isolates in parentheses) species of Achromobacter (1), Acinetobacter (1), Citrobacter (2), Enterobacter (2), Escherichia (3), Klebsiella (5), Providencia (1), Pseudomonas (9), and Serratia (6). All isolates were identified by standard microbiological methods. We evaluated 4 aminoglycoside and 14 P-lactam antibiotics, including * Corresponding author. 8 cephalosporins and 6 non-cephalosporins. The antibiotics evaluated were amikacin, gentamicin, netilmicin, tob--ramycin, cefoperazone, ceforanide, cefotaxime, cefpiramide (SM-1652), cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, imipenem, moxalactam, Sch 29482, apalcillin, mezlocillin, and piperacillin. Standard powders for these antibiotics were supplied by their manufacturers (see Acknowledgments).Antimicrobial su...

“…Moxalactam plus amikacin was the combination most often synergistic for amikacinsusceptible P. aeruginosa, and piperacillin plus amikacin was the combination most frequently synergistic for amikacin-resistant P. aeruginosa and amikacinsusceptible S. marcescens. These results demonstrate frequent in vitro synergistic activity between the new beta-lactam agents and amikacin (especially moxalactam or piperacillin with amikacin), but comparative clinical trials are needed to establish the relative efficacy and toxicity of these combinations.Although well-controlled, definitive clinical studies are lacking, several animal and human studies suggest that Pseudomonas aeruginosa and Serratia marcescens infections may be favorably influenced by treatment with synergistic antimicrobial combinations consisting of an aminoglycoside plus carbenicillin or ticarcillin (1,9,16,17,22). However, the usefulness of these specific combinations has been recently curtailed by the increasing resistance of P. aeruginosa and S. marcescens to carbenicillin and ticarcillin and even to some of the aminoglycosides (18,20,21).…”

mentioning

confidence: 99%

“…Although well-controlled, definitive clinical studies are lacking, several animal and human studies suggest that Pseudomonas aeruginosa and Serratia marcescens infections may be favorably influenced by treatment with synergistic antimicrobial combinations consisting of an aminoglycoside plus carbenicillin or ticarcillin (1,9,16,17,22). However, the usefulness of these specific combinations has been recently curtailed by the increasing resistance of P. aeruginosa and S. marcescens to carbenicillin and ticarcillin and even to some of the aminoglycosides (18,20,21).…”

mentioning

confidence: 99%

Comparative in vitro synergistic activity of new beta-lactam antimicrobial agents and amikacin against Pseudomonas aeruginosa and Serratia marcescens

Kurtz¹,

Winston²,

Bruckner³

et al. 1981

The in vitro synergistic activities of moxalactam, cefoperazone, or cefotaxime in combination with amikacin or piperacillin were compared against aminoglycoside-susceptible and aminoglycoside-resistant isolates of Pseudomonas aeruginosa and Serratia marcescens by the checkerboard agar dilution method. All antimicrobial combinations demonstrated some synergy, and no antagonism was observed. Moxalactam plus amikacin and piperacillin plus amikacin were most frequently synergistic (two-thirds of the isolates inhibited synergistically by each combination), whereas combinations of moxalactam, cefotaxime, or cefoperazone with piperacillin were synergistic against only 18 to 25% of the isolates. Moxalactam plus amikacin was the combination most often synergistic for amikacinsusceptible P. aeruginosa, and piperacillin plus amikacin was the combination most frequently synergistic for amikacin-resistant P. aeruginosa and amikacinsusceptible S. marcescens. These results demonstrate frequent in vitro synergistic activity between the new beta-lactam agents and amikacin (especially moxalactam or piperacillin with amikacin), but comparative clinical trials are needed to establish the relative efficacy and toxicity of these combinations.Although well-controlled, definitive clinical studies are lacking, several animal and human studies suggest that Pseudomonas aeruginosa and Serratia marcescens infections may be favorably influenced by treatment with synergistic antimicrobial combinations consisting of an aminoglycoside plus carbenicillin or ticarcillin (1,9,16,17,22). However, the usefulness of these specific combinations has been recently curtailed by the increasing resistance of P. aeruginosa and S. marcescens to carbenicillin and ticarcillin and even to some of the aminoglycosides (18,20,21). Furthermore, a history of a severe allergic reaction to penicillin usually prohibits the use of carbenicillin or ticarcillin.Moxalactam, cefoperazone, and cefotaxime are three new beta-lactam antimicrobial agents with remarkably wide spectra of in vitro antibacterial activity that include most P. aeruginosa and S. marcescens isolates as well as Escherichia coli, Klebsiella spp., Enterobacter spp., Proteus mirabilis, indole-positive Proteus spp., and Bacteroides fragilis (10). These drugs also have inhbitory activity for many strains resistant to carbenicillin, ticarcillin, and the aminoglycosides (6,11,12). Whereas numerous previous studies have focused on the in vitro effectiveness of moxalactam, cefoperazone, and cefotaxime as single agents and their enhanced antibacterial activity over presently available beta-lactam agents, there is a relative paucity of infornation on the relative synergistic activity of these drugs with aminoglycosides or other beta-lactam agents against recent clinically significant bacterial isolates. Thus, we compared the in vitro synergistic activity of moxalactam, cefoperazone, or cefotaxime in combination with amikacin or piperacillin against aminoglycoside-susceptible and aminoglycoside-resistant P. aerugino...