Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

Superselective intraarterial cerebral infusion of cetuximab after osmotic blood/brain barrier disruption for recurrent malignant glioma: phase I study

Methods A total of 15 patients with recurrent malignant glioma were included in the current study. The starting dose of Cetuximab was 100 mg/m(2) and dose escalation was done to 250 mg/m(2). All patients were observed for 28 days post-infusion for any side effects. Results There was no dose-limiting toxicity from a single dose of SIACI of Cetuximab up to 250 mg/m(2) after osmotic BBB disruption with mannitol. A tolerable rash was seen in 2 patients, anaphylaxis in 1 patient, isolated seizure in 1 patient, and seizure and cerebral edema in 1 patient. Discussion SIACI of mannitol followed by Cetuximab (up to 250 mg/m(2)) for recurrent malignant glioma is safe and well tolerated. A Phase I/II trial is currently underway to determine the efficacy of SIACI of cetuximab in patients with high-grade glioma

Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury

<div><p>The pathophysiology of myocardial injury that results from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT C57BL/6 mice, a manipulation that resulted in marked myocardial necrosis associated with activation of fB protein and myocardial deposition of C3 activation products. In contrast, in fB^-/- mice, the same procedure resulted in significantly reduced myocardial necrosis (% ventricular tissue necrotic; fB^-/- mice, 20 ± 4%; WT mice, 45 ± 3%; <i>P</i> < 0.05) and diminished deposition of C3 activation products in the myocardial tissue (fB^-/- mice, 0 ± 0%; WT mice, 31 ± 6%; <i>P</i><0.05). Reconstitution of fB^-/- mice with WT serum followed by cardiac I/R restored the myocardial necrosis and activated C3 deposition in the myocardium. In translational human studies we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, and the levels were directly correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis (Spearman coefficient = 0.465, <i>P</i> < 0.01). Taken together, our results support the conclusion that circulating fB is a crucial pathophysiological amplifier of I/R-induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury.</p></div

Factor B knockout mice experienced reduced myocardial necrosis and complement C3 deposition.

<p>fB^-/- mice and WT were used in a myocardial I/R model. The left anterior descending (LAD) coronary artery was occluded for 1 hr then reperfused for 24 hrs. Propidium iodide and blue fluorescent microspheres (BFM) (the latter after re-occlusion of the LAD) were injected <i>in vivo</i> just prior to heart harvesting to delineate the necrotic tissue and the tissue lacking circulation and therefore at risk for necrosis, respectively. <b><i>(a)</i></b> Circulating fB in the blood was significantly activated in WT mice (n = 4) but not in fB^-/- mice (n = 4). Serum obtained from cardiac puncture at the end of reperfusion was analyzed by Western blotting as described in Materials and Methods, Section 3. Each lane in the blot represented a separate mouse. Arrows indicate fB and Bb fragments. <b><i>(b)</i></b> The bar chart summarizes the relative intensities of Bb fragments. Bars represent Means ± SEM (* indicates <i>P</i><0.05 compared with WT controls). <b><i>(c)</i></b> Cryosections prepared from the heart slices were stained with a FITC-tagged anti-C3 antibody. <b><i>(d)</i></b> Bar graph: bars indicate the percentage of total area that is C3 positive. <b><i>(e)</i></b> Necrotic tissue (bright red fluorescence) was visualized under a fluorescent microscope immediately after the harvest of hearts, using a 2x objective lens, in slices obtained by dividing the heart into four (top and bottom of each slice are adjacent in the figure). Non-ischemic tissue was defined by the blue fluorescence of BFM, the non-fluorescing tissue constituting weight of tissue at risk (WAR) (n = 7 per group). <b><i>(f)</i></b> Bar graph: Necrotic area expressed as % WAR as defined in the Materials and Methods, Section 2.</p

Demographics and baseline data for the 56 patients in the study who underwent open heart surgery.

<p>Demographics and baseline data for the 56 patients in the study who underwent open heart surgery.</p

mRNA expression of fB in the WT hearts after IR.

<p>RNA were isolated from WT hearts without surgery (naïve group; n = 3), or sham operation (n = 10), or I/R operation (n = 12). cDNA were synthesized, reverse transcribed, and real-time RT-PCR were performed as described in Method Section.</p

Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury - Fig 5

<p><i>(a)</i> The increases in coronary blood Bb levels immediately after AXCL correlated significantly with postoperative increases in cTn1 levels. <b><i>(b)</i></b> The increases in postoperative increases in cTn1 levels correlated significantly with AXCL time. Univariate analyses were carried out as described in Method. * indicates statistical significance.</p

Levels of the myocardial necrosis marker cTnI in the peripheral blood increased significantly following cardiac surgery.

<p>Levels of the myocardial necrosis marker cTnI in the peripheral blood increased significantly following cardiac surgery.</p