Synergism of aminoglycosides and carbenicillin against resistant strains of Serratia marcescens

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...

Section: Discussionsupporting

confidence: 92%

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

Hooton¹,

Blair²,

Turck³

et al. 1984

“…Approximately 40 to 70% of the isolates tested were inhibited synergistically by one or more of the beta-lactam-amikacin combinations (Table 1). This synergism compares favorably with the synergistic activity of the piperacillin-amikacin combination used in this study and of other aminoglycoside-penicillin combinations previously evaluated in vitro (4,5,14) as well as in patients (13,15,24). The specific mechanism of this in vitro VOL.…”

Section: Resultssupporting

confidence: 62%

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...

“…Gentamicin, netilmicin, and tobramycin were less effective. A total of 84% of the isolates were resistant to tobramycin, a frequency higher than that previously reported (6,15,18).…”

mentioning

confidence: 53%

“…Many combinations of antibiotics have been shown to be synergistic to various degrees (9,11,12,15,18,22,26,29). Few studies have evaluated the activities of moxalactam and cefotaxime in combination with other agents against S. marcescens and other bacteria (19).…”

mentioning

confidence: 99%

Comparative susceptibilities of clinical isolates of Serratia marcescens to newer cephalosporins, alone and in combination with various aminoglycosides

Markowitz¹,

Sibilla²

1980

We examined 100 clinically significant isolates of Serratia marcescens for susceptibility to newer cephalosporin and cephamycin antibiotics, alone and in combination with various aminoglycosides. Moxalactam and cefotaxime were the most effective agents; all isolates were inhibited by 25 and 50 ,ug/ml, respectively. All strains were susceptible to amikacin at concentrations safely achievable in serum, whereas gentamicin, netilmicin, and tobramycin inhibited 63, 63, and 16% of the isolates, respectively. Moxalactam, cefotaxime, and amikacin were active against gentamicin-susceptible and gentamicin-resistant strains. Studies of synergy revealed that moxalactam and cefotaxime, in combination with netilmicin or amikacin, were often synergistic and infrequently antagonistic against cephalothin-and gentamicin-resistant strains. These results suggest that moxalactam and cefotaxime, alone or in combination, may be efficacious in treating infections due to multiply antibiotic-resistant S. marcescens.Over the past decade, Serratia marcescens has achieved preeminence as a cause of serious nosocomial infections (6,21,23,30). Susceptibility to aminoglycoside antibiotics was, at one time, taken for granted, but the emergence of multiply antibiotic-resistant strains has been a cause for concern (23,30).Cephalosporin antibiotics have been notoriously ineffective against S. marcescens. However, newer generations of cephalosporins, most notably moxalactam (LY127935) and cefotaxime (HR756), have been shown to be extremely active in vitro against both cephalothin-susceptible and cephalothin-resistant strains and some gentamicin-resistant organisms (7,8,10,13,24,27 Only strains judged to be involved in clinically significant infections were studied, including: (i) urinary isolates (36 strains) at more than 100,000 organisms per ml of urine on two consecutive daily urine cultures; (ii) wound isolates (21 strains) when S. marcescens was the only organism cultured from an infected area; (iii) sputum isolates (23 strains) when S. marcescens was consistently isolated in pure culture from a patient with purulent sputum, fever, and pulmonary infiltrates; (iv) blood (17 strains