Guidelines for treatment of deep-seated P. acnes infections, including prosthetic joint infections, are few and are based mostly on anecdotal experience. In most reports, clindamycin and vancomycin are mentioned as the first drugs to consider for deep-seated P. acnes infections (15). Our data, like those in the study by Oprica et al. (11), suggest that penicillins and first-generation cephalosporins (cefazolin and cephalothin) show promise and should have an expanded role in studies of clinical efficacy. The variability in P. acnes susceptibility to clindamycin argues for routine antimicrobial susceptibility testing for clindamycin and other antibiotics. In addition, an expanded role for oral antibiotics should be considered in treatment of P. acnes infections, since many of the drugs that we found to be highly active in vitro, including amoxicillin, moxifloxacin, and linezolid, are also highly bioavailable. Levy et al. advocated for a greater use of oral antibiotics, such as an oral β-lactam plus rifampin, for treatment of P. acnes prosthetic infections (2), but actual practice has lagged behind these concepts, partly because of widely held biases in favor of intravenous treatment and also due to the lack of controlled clinical studies. Further work in this area may result in improved outcomes of P. acnes infections at substantially lower costs than with traditional approaches.