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

Abstract

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...

Synergism of the combinations of imipenem plus ciprofloxacin and imipenem plus amikacin against Pseudomonas aeruginosa and other bacterial pathogens

“…In contrast to studies reported previously (9,12), we have shown a significant incidence of synergy (45%) when imipenem and amikacin were combined and tested against imipenem-susceptible isolates of P. aeruginosa. These findings would support previous observations of increased rate of killing of P. aeruginosa by the combination of imipenem and amikacin (19).…”

Efficacy of ceftazidime and aztreonam alone or in combination with amikacin in experimental left-sided Pseudomonas aeruginosa endocarditis

“…To our knowledge, experience with P. aeruginosa endocarditis is lacking. On the other hand, in comparison with the other aminoglycosides, amikacin has been found in some studies to be less nephrotoxic (10,20), more often resulting in synergism when it is combined in vitro with the newer antipseudomonal ,B-lactams against P. aeruginosa, including multiresistant strains (13,16,17). (16-39; 10) a After 5 h, none of the antibiotics was detected in serum (n = 8 tests).…”

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

“…The definition of synergy was established with the follow- (15). For the purpose of this study, antibiotic concentrations approximating clinically achievable ranges were mezlocillin, '64 ,ug/ml; piperacillin, .64 jig/ml; ticarcillin, c64 ,ug/ml; amikacin s16 jig/ml; gentamicin, c4 ,ug/ml; netilmicin, .8 ,ug/ml; and tobramycin, c4 ,ug/ml (21).…”

“…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).…”