Background The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. Methods We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. Results Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of −1.4 percentage points (90% confidence interval [CI], −4.9 to 2.2; 95% CI, −5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P = 0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). Conclusions Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927.)

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The frequencies of human cytomegalovirus (HCMV) protein‐specific CD8 T cells, identified by the presence of intracellular IFN‐γ, were measured by flow cytometry following stimulation of freshly isolated peripheral blood mononuclear cells (PBMC) with comprehensive peptide pools. These pools spanned the entire amino acid sequences of the HCMV pp65 and major immediate early (IE‐1) proteins and consisted of 15‐amino acid peptides with at least nine overlaps between neighboring peptides. As a result all potential CD8 T cell epitopes contained in these proteins were provided by the complete pools and, therefore, unlike with single epitopes, testing was independent of donor HLA type. Individual stimulating peptides from the same pools were identified in parallel experiments. Thus we found that our results with the complete pools using PBMC from 26 healthy HCMV‐seropositive donors were 100 % sensitive and specific with respect to predicting the presence of recognized epitopes in the respective proteins. In addition, cells from 15 renal transplant patients were tested with complete pools alone. While our results confirmed our previous contention that HCMV IE‐1 is an important CD8 T cell target, the technical improvement we made in order to address this question has clearly wider implications. Similar pools may be applied to examine the role of proteins from other pathogens, in autoimmune disease or following vaccination.

Antigen-specific, cytokine flow cytometry was used to analyze the prevalence and frequency of CD4 and CD8 memory T cells specific for the abundantly expressed cytomegalovirus (CMV) phosphoprotein 65 (pp65) in healthy CMV IgG-seropositive individuals. Stimulation of peripheral blood mononuclear cells with peptide pools and individual peptides derived from the pp65 amino acid sequence in 40 donors revealed that 63% of donors had a detectable CD4 T cell response and that 83% of donors had a detectable CD8 T cell response against this protein. The overall frequencies of T cells directed against pp65 were analyzed for 20 donors by stimulation with peptide pools covering the complete pp65 protein and were as high as 2 in 1000 and 9 in 1000 (median) peripheral blood CD4 and CD8 T cells, respectively. In addition, a comparison between CD4 responses to a CMV lysate containing various CMV proteins and pp65-specific responses in 9 donors indicated that pp65 was a dominant target of the CMV-specific CD4 T cell response in some, but not all, donors. Several new T cell epitopes were identified.