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

Abstract

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...

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

“…There have been previous studies purporting to show synergistic killing by combinations of AMGs and betalactams for strains which were resistant to one or the other agent of the combination or, in some cases, to both agents when used alone (19). Our data indicate that synergistic killing was more likely when the isolate was susceptible to one or both of the agents and was less likely when it was resistant to both antimicrobial agents.…”

“…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).…”

Antibiotic combinations: should they be tested?

“…Similarly, comparison of beta-lactam-aminoglycoside interactions against P. aeruginosa by checkerboard MIC testing and 6-or 24-h time-kill curves results in concordance rates of <50% between any pair of methods (35,36). On the other hand, several studies examining small numbers of strains have suggested rough correlations between results obtained by different methods (110,191). Klastersky et al (101) found agreement between time-kill and MBC checkerboard assessment of cefazolin-amikacin interactions for 60% (13 of 20) of Klebsiella isolates.…”

“…Beta-lactam combinations may also exhibit antagonistic effects (2,75). Unlike beta-lactam-aminoglycoside combinations (with which antagonism has been reported but appears to be distinctly uncommon), antagonism of one beta-lactam by another is not rare (59,95,109,110,138,179). For example, Neu and Fu (138) detected antagonism between azlocillin and cefazolin against 16% of gram-negative bacilli tested.…”

Clinical evaluation of moxalactam: evidence of decreased efficacy in gram-positive aerobic infections

“…Assuming that an MIC of 32 ,ug/ml to be the upper limit of susceptibility, only 16% of these organisms were resistant. As has been the experience in other studies, many (40%) of our P. aeruginosa strains were resistant (2,(6)(7)(8)(9)21 (2,6,7,9), Streptococcus pyogenes (2,6,7,9,20), and Listeria monocytogenes (7). The resistance of moxalactam to hydrolysis by ,-lactamase elaborated by Staphylococcus aureus (4) and the infrequent production of this enzyme type by other gram-positive organisms argue against a ,-lactamase enzymatic mechanism as an explanation of relative moxalactam insusceptibility in this population.…”