title: Synergistic effect of gentamicin plus ampicillin on enterococci with differing sensitivity to gentamicin: a phenotypic assessment of NCCLS guidelines.
abstract: Between December 1, 1993, and December 1, 1996, we tested 4,411 isolates of Enterococcus sp. at gentamicin concentrations of 500 micrograms/mL and 2000 micrograms/mL using agar dilution to phenotypically categorize them into 3 groups: those with a MIC < or = 500 micrograms/mL (n = 3,132; 71%); a MIC > 500, but < or = 2000 micrograms/mL (n = 441; 10%); and those with a MIC > 2000 micrograms/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 < or = 500 micrograms/mL group, 7 of 10 isolates demonstrated synergy with ampicillin as manifested by a > or = 2 log10 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 < or = 2,000 micrograms/mL, none of the 10 isolates demonstrated synergy. Absence of synergy was also found in the group resistant to 2,000 micrograms/mL of gentamicin. Assessment of eight additional enterococcal isolates with reduced sensitivity to ampicillin (MIC from 32-256 micrograms/mL) found no correlation between gentamicin sensitivity at 500 micrograms/mL and any in vitro test for synergy, nor with clinical therapeutic outcome. Gentamicin at 2 micrograms/mL combined with ampicillin was as effective in enhancing killing as a higher level of 4 micrograms/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.
authors.affiliation: Clinical Microbiology Division, Northwestern Memorial Hospital, Chicago, Illinois 60611, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Dressel
authors.forename: M A
authors.initials: MA
authors.lastname: Tornatore-Reuscher
authors.forename: C R
authors.initials: CR
authors.lastname: Boschman
authors.forename: V
authors.initials: V
authors.lastname: Stosor
authors.forename: T
authors.initials: T
authors.lastname: Zembower
authors.forename: M J
authors.initials: MJ
authors.lastname: Postelnick
authors.forename: G A
authors.initials: GA
authors.lastname: Noskin
authors.forename: L R
authors.initials: LR
authors.lastname: Peterson
mesh_terms: D000667:Ampicillin / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019411:Clinical Laboratory Techniques / Q000592:standards*; D004357:Drug Synergism; D016983:Enterococcus / Q000187:drug effects* / Q000254:growth & development; D005839:Gentamicins / Q000494:pharmacology*; D016908:Gram-Positive Bacterial Infections / Q000382:microbiology; D017408:Guidelines as Topic; D006801:Humans; D008826:Microbial Sensitivity Tests; D010406:Penicillins / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D005839:Gentamicins; D010406:Penicillins; D000667:Ampicillin