Synergistic effect of gentamicin plus ampicillin on enterococci with differing sensitivity to gentamicin: A phenotypic assessment of NCCLS guidelines

Between December 1, 1993, and December 1, 1996, we tested 4,411 isolates of Enterococcus sp. at gentamicin concentrations of 500 mu g/mL and 2000 mu g /mL using agar dilution to phenotypically categorize them into 3 groups: th ose with a MIC less than or equal to 500 mu g/mL (n = 3,132; 71%); a MIC >5 00, but less than or equal to 2000 mu g/mL (n = 441; 10%); and those with a MIC >2000 mu g/mL (n = 838; 19%). Ten unique strains of each phenotype wer e tested to determine which gentamicin concentration was the best in vitro predictor of synergy with ampicillin. Testing was done by a time-kill metho d using clinically achievable levels of ampicillin and gentamicin. We found that for the gentamicin MIC less than or equal to 500 mu g/mL group, 7 of 10 isolates demonstrated synergy with ampicillin as manifested by a greater than or equal to 2 log(10) increase in killing versus the effect of ampici llin alone (at 1/2 the MIC for ampicillin). In the group sensitive to a gen tamicin MIC range between >500 and less than or equal to 2,000 mu g/mL, non e of the 10 isolates demonstrated synergy. Absence of synergy was also foun d in the group resistant to 2,000 mu g/mL of gentamicin. Assessment of eigh t additional enterococcal isolates with reduced sensitivity to ampicillin ( MIC from 32-256 mu g/mL) found no correlation between gentamicin sensitivit y at 500 mu g/mL and any in vitro test for synergy, nor with clinical thera peutic outcome. Gentamicin at 2 mu g/mL combined with ampicillin was as eff ective in enhancing killing as a higher level of 4 mu g/mL. These findings validate the current NCCLS guideline for predicting synergistic activity ag ainst enterococci in strains with usual susceptibility to ampicillin, and s uggest that a therapeutic level less than maximal recommended dosing is suf ficient when using gentamicin in this setting. (C) 1999 Elsevier Science In c.