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

• Published in: Diagnostic microbiology and infectious disease 1999-11, Vol.35 (3), p.219-225
• Main Authors: Dressel, Dana C., Tornatore-Reuscher, Michelle A., Boschman, Cynthia R., Stosor, Valentina, Zembower, Teresa, Postelnick, Michael J., Noskin, Gary A., Peterson, Lance R.
• Format: Article
• Language: English
• Subjects: Ampicillin - pharmacology; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Clinical Laboratory Techniques - standards; Drug Synergism; Enterococcus - drug effects; Enterococcus - growth & development; Gentamicins - pharmacology; Gram-Positive Bacterial Infections - microbiology; Guidelines as Topic; Humans; Medical sciences; Microbial Sensitivity Tests; Penicillins - pharmacology; Pharmacology. Drug treatments; Time Factors
• ISSN: 0732-8893; 1879-0070
• DOI: 10.1016/S0732-8893(99)00088-7

Between December 1, 1993, and December 1, 1996, we tested 4,411 isolates of Enterococcus sp. at gentamicin concentrations of 500 μg/mL and 2000 μg/mL using agar dilution to phenotypically categorize them into 3 groups: those with a MIC ≤500 μg/mL (n = 3,132; 71%); a MIC >500, but ≤2000 μg/mL (n = 441; 10%); and those with a MIC >2000 μg/mL (n = 838; 19%). Ten unique strains of each phenotype were tested to determine which gentamicin concentration was the best in vitro predictor of synergy with ampicillin. Testing was done by a time-kill method using clinically achievable levels of ampicillin and gentamicin. We found that for the gentamicin MIC ≤500 μg/mL group, 7 of 10 isolates demonstrated synergy with ampicillin as manifested by a ≥2 log 10 increase in killing versus the effect of ampicillin alone (at 1 2 the MIC for ampicillin). In the group sensitive to a gentamicin MIC range between >500 and ≤2,000 μg/mL, none of the 10 isolates demonstrated synergy. Absence of synergy was also found in the group resistant to 2,000 μg/mL of gentamicin. Assessment of eight additional enterococcal isolates with reduced sensitivity to ampicillin (MIC from 32–256 μg/mL) found no correlation between gentamicin sensitivity at 500 μg/mL and any in vitro test for synergy, nor with clinical therapeutic outcome. Gentamicin at 2μg/mL combined with ampicillin was as effective in enhancing killing as a higher level of 4 μg/mL. These findings validate the current NCCLS guideline for predicting synergistic activity against enterococci in strains with usual susceptibility to ampicillin, and suggest that a therapeutic level less than maximal recommended dosing is sufficient when using gentamicin in this setting .