No Evidence for Ceftobiprole-Induced Immune Hemolytic Anemia in Three Phase 3 Clinical Trials

Kamal Hamed, Tatiana Wiktorowicz, Maziar Assadi Gehr Basilea Pharmaceutica International Ltd., Basel, SwitzerlandCorrespondence: Kamal HamedBasilea Pharmaceutica International Ltd., Grenzacherstrasse 487, Basel 4005, SwitzerlandTel +41 61 567 1588Fax +41 61 606 1216Email kamal.hamed@basilea.comPurpose: Drug-induced immune hemolytic anemia (DIIHA) is a rare but serious adverse event associated with a number of drugs, including second- and third-generation cephalosporins. A positive direct antiglobulin test (DAT) is a reliable finding in DIIHA, but positive results without evidence of hemolysis can occur, particularly in hospitalized patients. There have been no reports of hemolytic anemia in four previous Phase 3 trials or from post-marketing surveillance of the advanced-generation, broad-spectrum cephalosporin, ceftobiprole. The aim of this analysis was to review the incidence of positive DAT results and any evidence of hemolytic anemia from three recent Phase 3 trials of ceftobiprole.Patients and Methods: Patients were enrolled in three Phase 3 randomized controlled trials: 94 pediatric patients with pneumonia received ceftobiprole in the BPR-PIP-002 trial; 335 adults with acute bacterial skin and skin structure infections received ceftobiprole in the TARGET trial; and 201 adults with Staphylococcus aureus bacteremia have been randomized 1:1 to ceftobiprole or daptomycin ± aztreonam in the ongoing ERADICATE trial. In all three trials, DAT results were obtained at baseline, and follow-up tests were performed either at the test of cure (TOC) visit (BPR-PIP-002), end-of-treatment (EOT) visit (TARGET), or both EOT and post-treatment Day 70 visits (ERADICATE).Results: In the BPR-PIP-002 trial, five patients (all ceftobiprole treated) had a documented negative DAT result at baseline followed by a positive result at the TOC visit. One patient in the ongoing, blinded ERADICATE trial had a positive DAT result at both baseline and EOT. Results from other laboratory investigations showed no evidence of hemolytic anemia in these patients. No positive DAT results were reported in the TARGET trial.Conclusion: No evidence of hemolytic anemia associated with ceftobiprole was observed in either adults or children across several indications in this analysis of three large Phase 3 trials.Keywords: DIIHA, direct antiglobulin test, hemolysis, pneumonia, ABSSSIs, Staphylococcus aureus bacteremia