The in vitro activity of carbapenems is variable, with imipenem being most active. Because there are few therapeutic alternatives to amino- glycoside-containing regimens, combinations of -lactams were tested in vitro and in animal models of enterococcal experimental IE. The combination of ampicillin and imipe- nem acted synergistically in vitro and was effective therapy of multidrug-resistant enterococcal experimental IE.198 This study led to additional studies of experimental IE that dem- onstrated that the combination of ampicillin-ceftriaxone was effective therapy for gentamicin-susceptible or high-level gentamicin-resistant E faecalis experimental IE.199 The likely mechanism of double -lactam combinations against entero- cocci is saturation of different penicillin-binding proteins. These in vitro and in vivo studies provided the rationale for double -lactam therapeutic trials in humans with E faecalis IE caused by gentamicin-susceptible or high-level gentami- cin-resistant strains. A large, multicenter study by Spanish and Italian investigators compared ampicillin-ceftriaxone with ampicillin-gentamicin therapy of E faecalis IE.191 Patients with high-level aminoglycoside-resistant strains were not treated with ampicillin-gentamicin. A smaller study by this group compared ceftriaxone-ampicillin therapy of aminogly- coside-susceptible with high-level aminoglycoside-resistant E Both of these studies had significant limitations: They were observational, largely retrospective, and nonran- domized; the regimens were not standardized among the dif- ferent centers; discontinuation of gentamicin therapy was at the discretion of the investigators and not always the result of gentamicin-associated nephrotoxicity; and the serum con- centrations of gentamicin were not assessed or reported in all study sites. Despite these limitations, these 2 studies provide impor- tant data. First, these are the largest series of E faecalis IE reported to date, 43 patients in 1 study190 and 272 in the other Second, high-level aminoglycoside-resistant E faeca- lis IE treated with ampicillin-ceftriaxone therapy was present in 50% of the patients in the smaller study and 33% of patients in the larger study. 