In vitro activity of piperacillin, ticarcillin, and mezlocillin alone and in combination with aminoglycosides against Pseudomonas aeruginosa

Abstract

A total of 103 isolates of Pseudomonas aeruginosa were studied to compare the in vitro effectiveness of three beta-lactam antibiotics (piperacillin, ticarciflin, and meziocillin) when used alone and in combination with four aminoglycosides (tobramycin, gentamicin, amikacin, and netilmicin). All drugs were tested as single agents against a standard inoculum (5 x 105 CFU/ml). The three antipseudomonal penicillins were also tested against the isolates at a higher inoculum concentration (107 CFU/ml). Synergy testing was performed by the two-dimensional checkerboard method and was defined by (i) a fractional bactericidal index of -0.5 and (ii) bacterial killing accomplished at antibiotic concentrations no greater than those achievable in serum. All combinations were assessed for synergy. The degree of synergy was further'analyzed by dividing the isolates into groups based on their susceptibility and resistance to the individual agents in the combination. The overall effectiveness of the various aminoglycoside-antipseudomonal penicillin combinations was assessed regarding their ability to kill the isolates either as single agents or through synergy. Piperacillin was the most active antipseudomonal penicillin, and tobramycin and amikacin were the most active aminoglycosides when used as single agents. When tested against isolates at a higher inoculum concentration, ticarcillin was significantly more active than the other beta-lactams. The highest degree of overall synergy was noted with gentamicin-ticarcillin (78.2% of strains) and amikacin-piperacillin (77% of strains). When assessed for overall effectiveness, all combinations containing amikacin were the most active. The combination of amikacin-piperacillin was the most effective, with activity against 96% of all isolates.The newer semisynthetic penicillins have been shown by previous investigators to demonstrate increased antibacterial activity against a wide range of organisms (3,17,26,29), including strains of members of the family Enterobacteriaceae and Pseudomonas aeruginosa that are multiply resistant to other antimicrobial agents (3, 10). Moreover, these antimicrobial agents have been found to be especially useful when combined with an aminoglycoside (AMG) in the treatmnent of severe infections with gram-negative bacilli (1, 2), perhaps reflecting their in vitro synergistic activity (10,11,13,15,16,19,24).The purpose of this study was to compare the in vitro synergistic activity of the four most commonly used AMGs with that of three of the newer semisynthetic antipseudomonal penicillins (APP) against 103 hospital strains of P. aeruginosa. Only results demonstrating synergy at clinically attainable concentrations in serum of both antimicrobial agents were considered to be synergistic. In addition, we examined each drug combination for overall effectiveness in vitro. Analyses of these results took into consideration synergistic responses as well as single-drug activities.MATERIALS AND METHODS Organisms. Altogether, 103 P. aeruginosa strains were obtained from th...

Combination Antibiotic Therapy for Empiric and Definitive Treatment of Gram‐Negative Infections: Insights from the Society of Infectious Diseases Pharmacists

“…␤-Lactam-aminoglycoside combinations have been studied extensively in vitro for P. aeruginosa, and to a lesser extent for A. baumannii. 37,[48][49][50][51] More than 2 decades ago, the effect of adding gentamicin, tobramycin, amikacin, or netilmicin to piperacillin for 103 clinical P. aeruginosa isolates was evaluated with use of the checkerboard method. 48 Amikacin and tobramycin were more active when combined with piperacillin, compared with gentamicin or netilmicin.…”

“…37,[48][49][50][51] More than 2 decades ago, the effect of adding gentamicin, tobramycin, amikacin, or netilmicin to piperacillin for 103 clinical P. aeruginosa isolates was evaluated with use of the checkerboard method. 48 Amikacin and tobramycin were more active when combined with piperacillin, compared with gentamicin or netilmicin. Many investigators have since produced similar results using different antipseudomonal ␤-lactams and aminoglycoside combinations in vitro against MDR P. aeruginosa and A. baumannii.…”

Antibiotic combinations: should they be tested?

“…Finally, direct evidence has now been presented that beta-lactam-aminoglycoside synergism against P. aeruginosa can occur by mechanisms directly analogous to those previously documented in E. coli, enterococci, and Staphylococcus aureus. Miller (117). The main conclusion that can be drawn from such studies is that it is difficult to predict from strain characteristics and in vitro susceptibility to individual agents whether a particular combination will exhibit synergistic activity against any one clinical isolate at pharmacologically relevant concentrations.…”