Early synergistic interaction between semisynthetic penicillins and aminoglycosidic aminocyclitols against Enterobacteriaceae

Abstract

Time-kill curves were used to assess the relative in vitro efficacy of the early interaction of three semisynthetic penicillins with two aminoglycosides against 48 Enterobacteriaceae strains. The most efficacious combinations were piperacillin plus amikacin, which demonstrated synergism (>2 logs of increased kill after 7 h of incubation) against 43 of 48 (901%) strains, and piperacillin plus gentamicin, which exhibited synergism against 25 of 48 (52%) strains. With the combinations of carbenicillin or ticarcdillin plus amikacin or gentamicin, early synergistic killing was demonstrated against only 12 to 29% of the strains.Semisynthetic penicillins such as ampicillin, carbenicillin, and ticarcillin have been used for several years in the therapy of severe gramnegative baciliary infections. Piperacillin is a new semisynthetic penicillin which has demonstrated greater in vitro activity than carbenicillin or ticarcillin against Pseudomonas aeruginosa and members of the Enterobacteriaceae (1,5,13,15,16,19,20 Antibiotic synergism. The interaction between each of the three semisynthetic penicillins and each of the two aminoglycosides was evaluated by time-kill curves in Mueller-Hinton broth as described previously (6). A starting inoculum of 105 organisms per ml was prepared by appropriate dilution of an overnight broth culture. The concentrations of antibiotics in the flasks were selected to be at or below the MIC for each drug and within a clinically achievable range for each drug::125 pg/ml for each of the penicillins, s4 pg/ml for gentamicin, and <8 .g/ml for amikacin. The culture flasks (final volume, 20 ml) were incubated without agitation at 35°C, and 0.5-mi samples were removed at 0, 4, and 7 h for determination of colony counts with 10-fold serial dilutions. Early synergy is herein defined as a decrease of 100-fold or more in the number of 902 on May 11, 2018 by guest http://aac.asm.org/ Downloaded from

Early effects of beta-lactams on aminoglycoside uptake, bactericidal rates, and turbidimetrically measured growth inhibition in Pseudomonas aeruginosa

“…H+ demonstrates that aminoglycoside-associated killing is clearly apparent within minutes to hours (4,12,13,15,17,18,20,23; present data). These kinetic studies support the suggestion of others (6,7,11,14) that abbreviated time-kill studies may be preferable to conventional 24-h data in demonstrating synergy secondary to P-lactam-enhanced increased uptake of aminoglycosides. …”

Antibiotic combinations: should they be tested?

“…On the other hand, incorporation of clinically achievable (even if not necessarily subinhibitory) concentrations of both drugs would permit an estimate of the maximum killing rates expected. For penicillins which may be inactivated during prolonged incubation, sampling times at 6 to 7 h rather than 24 h may be preferable (66). An alternative approach, and one which is undoubtedly easier, is to choose therapy based on susceptibility studies and subsequently to use serum bactericidal titer determinations to assess the appropriateness of the selection.…”

“…Since that time, numerous studies utilizing various techniques and definitions have provided evidence for beta-lactam-aminoglycoside synergism against gram-negative bacilli (64). Although considerable attention has been given to the study of interactions against the Enterobacteriaceae (40,66,67,95,101), much attention has also been focused on activities of combination regimens against P. aeruginosa, no doubt due to difficulties in treating many such infections in seriously ill patients (19).…”

“…However, with agents used against gram-negative bacilli, incubation periods of that duration may result in almost complete inactivation of several betalactam antibiotics because of either enzymatic hydrolysis or chemical deterioration. As a result, shorter incubation periods before sampling have been recommended (66). Antagonism is often defined as a 100-fold reduction in killing by the combination compared with that seen with the most active drug alone (108).…”

Combination Therapy for Treatment of Infections with Gram-Negative Bacteria

“…For infections with Gram-negative bacteria, antimicrobial synergy has traditionally been seen with ␤-lactam-aminoglycoside combinations. The combination of a ␤-lactam and an aminoglycoside allows for different mechanisms of bacterial killing (8,66,98,237). ␤-Lactam-mediated disturbance of the cell walls of Gram-negative bacilli facilitates passage of aminoglycosides into the periplasmic space (105,169).…”