There are few well-documented cases of infective endocarditis due to highly aminoglycoside-resistant enterococci reported to date. Nevertheless, strains with high-level resistance to both streptomycin and gentamicin are now sufficiently common that the number of cases of endocarditis due to these organisms will undoubtedly continue to increase. Serious efforts to develop appropriate alternative treatment strategies are now clearly necessary. All high-level gentamicin-resistant bloodstream isolates from patients with suspected or proven endocarditis should be screened for high-level streptomycin resistance. Because these two resistance traits are mediated by distinct genetic elements, a significant minority of highly gentamicin-resistant enterococci will be susceptible to synergistic killing by combinations of cell wall-active antibiotics with streptomycin. For strains highly resistant to both aminoglycosides, there is no evidence of benefit from use of these toxic antimicrobials, and treatment with a cell wall-active agent alone is warranted. Based on older literature and animal models, perhaps as many as 40% to 50% of cases of enterococcal endocarditis might be curable by such regimens. Alternative combinations using a cell wall-active antibiotic together with a fluoroquinolone or rifampin cannot be specifically recommended based on any firm data from the literature, but possible merits of such combinations can be explored in vitro under appropriate circumstances. For ampicillin- and vancomycin-susceptible strains, ampicillin would seem preferable because this drug typically demonstrates greater bactericidal activity in vitro as a single agent. Consideration could be given to administration of ampicillin by continuous intravenous infusion. Several animal studies indicating effectiveness of penicillins for enterococcal endocarditis have used dosing regimens resulting in sustained serum levels. It is unknown whether these observations are relevant to human enterococcal infections. Testing for beta-lactamase production should be undertaken if penicillins are to be used. For strains that are resistant to achievable concentrations of penicillins, or when the patient is intolerant of beta-lactams, vancomycin can be used. In animal models, teicoplanin has appeared to be superior to vancomycin, but high concentrations must be attained. This drug is not yet approved for clinical use, however, and it is unclear if any advantage would exist in treatment of human infections. The recent emergence of enterococci which are resistant to glycopeptides has introduced another potential complicating factor; some of these are also substantially resistant to beta-lactams as well. In some reports, favorable interactions between vancomycin and beta-lactams have been observed against vancomycin-resistant strains.(ABSTRACT TRUNCATED AT 400 WORDS)