Antimicrobial activity of amikacin combinations against Enterobacteriaceae moderately susceptible to third-generation cephalosporins

Abstract

Enterobacteriaceae strains having elevated minimal inhibitory concentrations (.2.0 to s32 ,ug/ml) of cefoperazone, cefotaxime, ceftazidime, and moxalactam were synergistically inhibited by amikacin combinations (54.1 to 69.6% occurrence). Indifference was rare (8.1% for moxalactam), and true antagonistic interactions were not observed. Strains resistant or susceptible to these new cephalosporins were also synergistically inhibited by the addition of amikacin, reducing resistant cephalosporin minimal inhibitory concentrations to clinically achievable levels.Amikacin has been recognized as the currently available aminoglycoside most refractory to bacterial enzyme inactivation (18). This stability has generally limited the use of amikacin to those clinical bacterial strains resistant to kanamycin, gentamicin, and tobramycin by enzyme plasmid-mediated mechanisms. Similarly, the recently introduced third-generation cephalosporins have substantial stability to bacterial plactamases and a potent antimicrobial activity (2, 3, 6-9, 15, 16). The bacteria most likely to harbor the higher minimal inhibitory concentrations (MICs) for these new ,B-lactams are the nonfermentative bacilli and the serogroup D Streptococcus spp.; however, a few strains of Enterobacteriaceae may have MICs of 2.0 to 32 ,ug/ml (3,(7)(8)(9). These latter organisms represent a very different population of enteric bacilli only moderately susceptible (MS) to these highly active new drugs. Very few Enterobacteriaceae are currently considered resistant (MICs, .64 ,g/ml) to cefoperazone,' cefotaxime, ceftazidime, or moxalactam.To determine the possibility of using antimicrobial combinations to treat infections caused by these MS strains of Enterobacteriaceae (cefoperazone, cefotaxime, ceftazidime, or moxalactam MICs, 2.0 to 32 ,ug/ml), we screened over 6,000 organisms to find strains having elevated MICs as described above. These recent clinical isolates from The Cleveland Clinic Foundation (Cleveland, Ohio), St. Francis Hospital (Wichita, Kans.), St. Vincent Hospital and Medical Center (Portland, Oreg.), and Northwestern Memorial Hospital (Chicago, Ill.) were collected and then retested for their susceptibility to the new ,-lactams singly and in combination with amikacin. Synergy analysis was determined by the checkerboard broth dilution technique, confirmed by a limited number of bactericidal concentration isobolograms and kill curves. Some additional organisms were tested, including several with resistance to one or more of the five broad-spectrum drugs to detect their possible conversion from resistantto-susceptible MIC results by the addition of another antimicrobial agent.MATERALS AND METHODS Antibiotics. The broad-spectrum drugs utilized in all phases of this study were supplied by the following manufacturers: amikacin, Bristol Laboratories, Syracuse, N.Y.; cefoperazone, Pfizer Inc., New York, N.Y.; cefotaxime, Hoechst-Roussel Pharmaceuticals Inc., Somerville, N.J.; ceftazidime, Glaxo Inc., Research Triangle Park, N.C.; moxalactam, Eli Lilly & Co., ...

Antibiotic combinations: should they be tested?

“…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.…”

“…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).…”

Antimicrobial activity of ceftriaxone, cefotaxime, desacetylcefotaxime, and cefotaxime-desacetylcefotaxime in the presence of human serum

“…This fact TABLE 2. Effect of adding human serum to broth in vitro susceptibility tests with 22 members of the Enterobacteriaceae, 6 Acinetobacter spp., and 6 Pseudomonas spp. seriously challenges the spectrum-class concept of the National Committee for Clinical Laboratory Standards that states that cefotaxime and ceftriaxone have similar antimicrobial coverages (11) and raises the question as to the most appropriate test medium for susceptibility assays of highly protein-bound antimicrobial agents.…”

“…The gram-negative coverage of ceftriaxone would also be reduced for the selected members of the family Enterobacteriaceae for which aminothiozolylmethoxyimino cephalosporin MICs range from 2 to 32 ;,jg/ml. These selected strains represent approximately 5% of all enteric bacilli (6). Cefotaxime activity, being unaffected by serum proteins, would have levels in serum (1 g intravenously) greater than the staphylococcal MIC9o for more than half the commonly used 8-h dosing interval (10).…”

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

“…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).…”