Daptomycin and Rifampin Alone and in Combination Prevent Vascular Graft Biofilm Formation and Emergence of Antibiotic Resistance in a Subcutaneous Rat Pouch Model of Staphylococcal Infection

AbstractObjectiveTo investigate the efficacy of daptomycin and rifampin either alone or in combination in preventing prosthesis biofilm in a rat model of staphylococcal vascular graft infection.DesignProspective, randomised, controlled animal study.MaterialsGraft infections were established in the back subcutaneous tissue of adult male Wistar rats by implantation of Dacron prostheses followed by topical inoculation with 2×107 colony forming units of Staphylococcus aureus, strain Smith diffuse.MethodsThe study included a control group, a contaminated group that did not receive any antibiotic prophylaxis and three contaminated groups that received intra-peritoneal daptomycin, rifampin-soaked graft and daptomycin plus rifampin-soaked graft, respectively. Each group included 15 animals. The infection burden was evaluated by using sonication and quantitative agar culture. Moreover, an in vitro antibiotic susceptibility assay for S. aureus biofilms was performed to elucidate the same activity.ResultsWhen tested alone, daptomycin and rifampin showed good efficacies. Their combination showed efficacies significantly higher than that of each single compound. The in vitro studies showed that Minimum Inhibitory Concentration and Minimum Bactericidal Concentration values for daptomycin were lower in presence of rifampin. Daptomycin prevented the emergence of rifampin resistance.ConclusionDaptomycin is an important candidate for prevention of staphylococcal biofilm-related infection and rifampin could serve as an interesting anti-staphylococcal antibiotic enhancer

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial

Background In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. Methods We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4\u20136 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2\ub75 mg/day orally for 5 years) or intermittent use of letrozole (2\ub75 mg/day orally for 9 months followed by a 3-month break in years 1\u20134 and then 2\ub75 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. Findings Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53\u201372), disease-free survival was 85\ub78% (95% CI 84\ub72\u201387\ub72) in the intermittent letrozole group compared with 87\ub75% (86\ub70\u201388\ub78) in the continuous letrozole group (hazard ratio 1\ub708, 95% CI 0\ub793\u20131\ub726; p=0\ub731). Adverse events were reported as expected and were similar between the two groups. The most common grade 3\u20135 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3\u20135 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3\u20135 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3\u20135 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). Interpretation In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them