IN-VITRO SYNERGISM OF CEFTRIAXONE COMBINED WITH AMINOGLYCOSIDES AGAINST PSEUDOMONAS-AERUGINOSA

The antipseudomonal activities of ceftriaxone (CEF) or ceftazidime (CA Z), each combined with tobramycin (TOB) or netilmicin (NET), against 9 0 clinically significant Pseudomonas aeruginosa isolates were examined both by checkerboard and time-kill assays. As expected, susceptibilit y testing of single antibiotics by agar dilution demonstrated good act ivity for CAZ (89% susceptible), TOB (94%), and NET (58%), but poor ac tivity for CEF (15%). Checkerboard studies revealed striking synergy ( FIC indices less than or equal to 0.5) for CEF, however, in combinatio n with either TOB (72%) or NET (81%), compared with CAZ-TOB (44%) or C AZ-NET (60%) (P < 0.01, respectively). No antagonism (FIC indices grea ter than or equal to 4) was found in any of these combinations. The MI C(90)s of CEF, CAZ, or aminoglycosides in the combinations were reduce d at least fourfold: CEF, from >128 to 32 mg/liter; CAZ, from 16 to 4 mg/liter; TOB, from 4 to 0.5 mg/liter; and NET, from 32 to 4 mg/liter. With CEF and NET, the percentage of strains sensitive to less than or equal to 8 mg/liter of both drugs alone and in combination increased from 9% to 69%. Results of the time-kill assay for CEF-NET agreed reas onably well with the checkerboard method (Spearman rank correlation co efficient, 0.40, P less than or equal to 0.01), and generated a bacter icidal outcome in 60% (24 of the 40 isolates), when tested with combin ations at 1/4 MBC of either antibiotic alone. Importantly, concentrati ons of CEF and aminoglycoside combinations that demonstrated synergy b y either checkerboard or time-kill assays were achievable in serum cli nically. These data suggest a unique interaction of CEF-amino-glycosid e combinations against P. aeruginosa. The precise mechanism of synergy and the clinical implication of these in vitro results remain to be d etermined.