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Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 g/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.Staphylococcus aureus is a leading cause of healthcare-associated and community-onset bacteremia in the United States and abroad (15,23,24). A recent study showed that S. aureus infection was reported as a discharge diagnosis for 0.8% of all hospital inpatients, or an average of 292,045 inpatients per year (19). Infections caused by methicillin-resistant S. aureus (MRSA) in hospitalized patients as well as in otherwise healthy patients with no obvious risk factors are an emerging problem (3,8,18). Current therapy for S. aureus bacteremia (SAB), particularly for MRSA bacteremia, is less than adequate. This fact is supported by the high rates of complications, including mortality, relapsing infection, and metastatic infections (infective endocarditis, bone and joint infections, and suppurative abscesses), associated with SAB (1,2,6,7,11,14,22). Taken together, these observations indicate that novel therapies for SAB are urgently needed.One potential strategy to improve clinical outcomes of SAB is adjunctive therapy using passive immunization with monoclonal antibodies that target S. aureus. Tefibazumab (Aurexis) is a humanized immunoglobulin G1 monoclonal antibody that specifically recognizes clumping factor A (ClfA) with a high affinity. ClfA, a surface adhesin protein found on virtually all strains of S. aureus, is an MSCRAMM (microbial surface components recognizing adhesive matrix molecules) protein that mediates the adhesion of S. aureus to fibrinogen (10,16,17). In preclinic...

Objective.To evaluate the humoral immune response to pneumococcal and influenza vaccination in adults with rheumatoid arthritis (RA) receiving certolizumab pegol (CZP).Methods.In this 6-week, single-blind, placebo-controlled trial with optional 6-month open-label extension (NCT00993668), patients were stratified by concomitant methotrexate (MTX) use and randomized to receive CZP 400 mg (loading dose; according to CZP label) or placebo at weeks 0, 2, and 4. Pneumococcal (polysaccharide 23) and influenza vaccines were administered at Week 2. Satisfactory humoral immune response, defined as ≥ 2-fold titer increase in ≥ 3 of 6 pneumococcal antigens and ≥ 4-fold titer increase in ≥ 2 of 3 influenza antigens, were assessed independently 4 weeks after vaccination.Results.Following pneumococcal vaccination, 62.5% of placebo patients and 54.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions was −8.0 percentage points; 95% CI −22.5 to 6.6%). Following influenza vaccination, 61.4% of placebo and 53.5% of CZP patients without effective titers at baseline achieved a humoral response (difference in proportions: −8.0 percentage points; 95% CI −22.9 to 7.0%). In all patients, including those with effective titers at baseline, 58.2% of placebo and 53.3% of CZP patients developed satisfactory pneumococcal titers, and 54.1% of placebo and 50.5% of CZP patients developed satisfactory influenza antibody titers. Vaccine responses to pneumococcal and influenza antigens were reduced similarly in both treatment groups with concomitant MTX use.Conclusion.Humoral immune responses to pneumococcal and influenza vaccination are not impaired when given during the loading phase of CZP treatment in patients with RA. (ClinicalTrials.govNCT00993668).

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Summary. The rationale, trial design, and statistical aspects of QUIET, the QUinapril Ischemic Event Trial, are described. QUIET is a prospective, double-blind placebocontrolled study that will assess the ability of the angiotensin-converting enzyme (ACE) inhibitor quinapril to reduce the rate of cardiac ischemic events and to slow or prevent the development of coronary artery atherosclerosis as assessed by serial angiography in a normolipidemic population without left ventricular dysfunction. The study began in September 1991 and has completed recruitment with 1740 patients across 38 centers (28 U.S., 4 Canada, 6 Europe) by the end of 1992. Patients are randomized to 20 mg of quinapril or placebo once daily and continue in the study for 3 years. Study completion is projected for 1995.