A blinded, randomized, multicenter study of an intravenous Staphylococcus aureus immune globulin

Abstract

Objectives: Very low birth weight (VLBW) infants are vulnerable to nosocomial infections and subsequent morbidity; including infections caused by Staphylococcus aureus: 85% of nosocomial S. aureus infections are caused by capsular polysaccharide (CPS) types 5 and 8. Altastapht is a polyclonal investigational human immunoglobulin G (IgG) with high levels of opsonizing S. aureus CPS types 5 and 8 IgG.Methods: A Phase 2 clinical trial to assess the safety and kinetics of Altastaph in VLBW infants. Neonates in this multicenter study were randomized to receive two identical 20 ml/kg i.v. infusions of either 0.45% NaCl placebo or 1000 mg Altastaph/kg. Each infant was followed for 28 days after the second infusion or until discharge. Serum S. aureus CPS types 5 and 8 IgG levels were measured preinfusion and at various times after each infusion.Results: Of 206 neonates, 158 received both infusions. Adverse events were similar in the two treatment groups. Six subjects (3% in each group) discontinued owing to an adverse event. Geometric mean anti-type 5 IgG levels were 402 and 642 mcg/ml 1 day following infusion of the first (day 0) and Second (day 14) doses, respectively, in neonates p1000 g and slightly higher in neonates 1001 to 1500 g. Trough levels before second infusion were 188 mcg/ml. Type 8 IgG levels were similar. Geometric mean IgG levels among placebo recipients were consistently <2 and <5 mcg/ml for types 5 and 8 in both weight groups. Three episodes of S. aureus bacteremia occurred in each arm.Conclusions: Infusion of Altastaph in VLBW neonates resulted in high levels of specific S. aureus types 5 and 8 CPS IgG. The administration of this anti-staphylococcal hyperimmune globulin was well tolerated in this population.

Does IVIg administration yield improved immune function in very premature neonates?

“…10 IVIg preparations aimed at reducing the incidence of infection with specific pathogens 66 seem to be safe in the study populations tested, 67 but larger studies have not shown efficacy. 68,69 At present, the available data are incomplete or do not support the suggested immunoenhancements attributed to IVIg in very premature neonates. Evaluation of IVIg-mediated effects on immune function should be performed using homogenous (exclusively very premature immune components) ex vivo and in vitro systems.…”

Antibodies toStaphylococcus aureuscapsular polysaccharides 5 and 8 perform similarlyin vitrobut are functionally distinctin vivo

“…In a phase 2 study, low-birth-weight neonates were given two intravenous (IV) doses of AltaStaph or placebo. 18 The rates of adverse events between the two arms of the study were similar, and the rates of S. aureus bacteremia were nearly identical (»3%) in both groups. Another phase 2 trial enrolled patients with documented S. aureus bacteremia who received standard therapy plus Altastaph or placebo, 19 but the vaccineinduced CP antibodies were insufficient to significantly reduce S. aureus bacteremia in this at-risk population.…”

Why antibodies disobey the Hippocratic Oath and end up doing harm: a new clue

“…Similar obstacles have been encountered with attempts to use hepatocytes for in vitro drug toxicology assays and to model human liver diseases (3,4). Human embryonic and fetal stem cells can be propagated for extended periods in culture and can be differentiated to hepatocyte-like cells that are able to survive in vivo (5)(6)(7)(8). However, the ethical issues associated with their use and their limited availability have reduced enthusiasm for this approach.…”

“…Clinical trials with an investigational CP5-and CP8-based conjugate vaccine for S. aureus (StaphVAX) have been notable for largely negative results, in that the vaccine did not induce sustained protection against the development of disease (5,6). In addition, phase II trials with CP-specific immunoglobulin did not demonstrate an adjunctive therapeutic effect in adults (7) or prevent bacteremia in neonates (8). Although a vaccine for strains that do not express CP8 or CP5 (PentaStaph) is in clinical trials, disappointing results with existing investigational CP-based vaccines and immunotherapy highlight the fact that the mechanisms behind their lack of efficacy against S. aureus-associated disease are vexing and mysterious.…”