Additional or Adjunctive Therapies As discussed above, combination therapy with gentamicin therapy in S aureus NVE is discouraged because of the rela- tively high rates of intrinsic gentamicin resistance, a lack of clear-cut efficacy, and documented toxicity issues.149,153,161 Although most staphylococci are highly susceptible to rifampin, resistance develops rapidly when this agent is used alone. The in vivo efficacy of rifampin in combination with nafcillin, oxacillin, vancomycin, trimethoprim/sulfamethoxa- zole, or aminoglycosides is highly variable. Moreover, use of rifampin as adjunct therapy for S aureus NVE has been associ- ated with higher rates of adverse events (primarily hepatotox- icity) and a significantly lower survival rate.162 Thus, routine use of rifampin is not recommended for treatment of staphy- lococcal NVE. Of note, a prospective trial in patients with IE caused by MRSA failed to demonstrate that the addition of rifampin to vancomycin either enhanced survival or reduced the duration of bacteremia compared with treatment with Rifampin is often used in native valve S aureus IE when this infection is complicated by involvement of selected anatomic sites where rifampin penetrates effec- tively (eg, bone, joint, cerebrospinal fluid).164 No standard therapies exist for the treatment of S aureus IE caused by isolates that are not susceptible to vancomy- cin. Classification of these isolates has become complex and includes designations of reduced susceptibility (hVISA), intermediate resistance (VISA), and high-level resistance (VRSA). To date, the limited number of patients reported to have IE caused by these isolates precludes specific treatment recommendations. Thus, these infections should be managed in conjunction with an infectious diseases consultant. Although Markowitz et al165 showed that trimethoprim- sulfamethoxazole was inferior to vancomycin in the treat- ment of invasive S aureus infections, it is sometimes used in salvage situations. 