Phase II, randomized, multicenter, double-blind, placebo-controlled trial of a polyclonal anti-Staphylococcus aureus capsular polysaccharide immune globulin in treatment of Staphylococcus aureus bacteremia

Abstract

New treatment modalities are needed for the treatment of infections due to multidrug-resistant Staphylococcus aureus. S. aureus capsular polysaccharide immune globulin (Altastaph) is a polyclonal immune globulin preparation that is being developed as adjunctive therapy for persons with S. aureus infections complicated by bacteremia. In a phase II, multicenter, randomized, double-blind, placebo-controlled trial, 40 subjects with documented S. aureus bacteremia received standard therapy plus either Altastaph at 200 mg/kg of body weight in each of two infusions 24 h apart or placebo. During the 42-day observation period, antibody pharmacokinetics and safety were the primary characteristics studied. Information regarding the resolution of bacteremia and fever was also analyzed. Anti-type-5 and anti-type-8 capsular antibody levels peaked after the second infusion at 550 mug/ml and 419 mug/ml, respectively, and remained above 100 mug/ml at day 28. A total of 316 adverse events were noted in 39 of 40 subjects. Infusion-related adverse events in Altastaph recipients were infrequent and similar to those among recipients of commercial intravenously administered immunoglobulin G products. Five of 21 (23%) subjects in the Altastaph group died, whereas 2 of 18 (11%) subjects in the placebo group died (P = 0.42). Compared to the control patients, the Altastaph recipients had a shorter median time to the resolution of fever (2 days and 7 days, respectively; P = 0.09) and a shorter length of hospital stay (9 days and 14 days, respectively; P = 0.03). However, these findings are exploratory, and there were few differences in the other variables measured. High levels of opsonizing antibodies were maintained for the initial 4 weeks. Although the study was not powered to show efficacy, these preliminary findings and safety profile suggest that Altastaph may be an effective adjunct to antibiotics and warrants further investigation (ClinicalTrials.gov number NCT00063089).

Figures

FIG. 1.

Subject disposition. Forty patients were enrolled in the study. One patient did not receive study drug and was excluded from further analysis. Among the subjects receiving Altastaph, 5 subjects died, 2 were noncompliant, and 1 withdrew consent, resulting in 13 per protocol subjects. Among the subjects in the placebo arm of the study, one subject died, resulting in 17 per protocol subjects (1 additional subject died 1 day after the 42-day follow-up period). All subjects in the mITT population were included in the safety analysis.

FIG. 2.

Pharmacokinetics of Altastaph. The geometric mean concentration (μg/ml) of anti-type 5 antibodies (A) and the mean concentration (μg/ml) of anti-type 8 antibodies (B) for Altastaph recipients versus time over the 42-day course of the study are indicated. The 95% upper and lower confidence (Conf.) intervals are also shown. The interrupted dashed line indicates the antibody levels for the placebo recipients.