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

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Abstract

Purpose

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.

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Most cited references 26

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A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

Samir S Awad, Alejandro Rodríguez, Kenneth Chuang … (2014)

Ceftobiprole, the active moiety of ceftobiprole medocaril, is a novel broad-spectrum cephalosporin, with bactericidal activity against a wide range of gram-positive bacteria, including Staphylococcus aureus (including methicillin-resistant strains) and penicillin- and ceftriaxone-resistant pneumococci, and gram-negative bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa.

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A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections.

Karen Bush, Juliana Ianus, Devika P. Bagchi … (2008)

A randomized, double-blind, multicenter trial involving patients with a broad range of complicated skin and skin-structure infections due to either gram-positive or gram-negative bacteria was conducted to compare ceftobiprole monotherapy with treatment with vancomycin plus ceftazidime. Patients were randomized 2:1 to receive ceftobiprole or to receive vancomycin plus ceftazidime. Outcomes were determined at a test-of-cure visit (7-14 days after completion of therapy) and were analyzed for all patients with complicated skin and skin-structure infections, as well as for subgroups, on the basis of major types of infections and severity of disease. Among the clinically evaluable and the intent-to-treat populations, clinical cure rates at the test-of-cure visit were similar in the ceftobiprole and comparator treatment arms (clinical cure rate, 90.5% [439 of 485 patients] and 90.2% [220 of 244 patients] in the clinically evaluable population, respectively; 81.9% [448 of 547 patients] and 80.8% [227 of 281 patients] in the intent-to-treat population, respectively). Clinical cure rates in ceftobiprole-treated patients ranged from 86.2% (125 of 145 patients) among those with diabetes who had foot infections to 93.0% (80 of 86 patients) among those with cellulitis. Among patients treated with ceftobiprole, clinical cure rates were similar among patients from whom gram-negative bacteria were isolated (87.9% [109 of 124 patients]) and among patients from whom gram-positive bacteria were isolated (91.8% [292 of 318 patients]) and were not statistically different from the clinical cure rates among comparator-treated patients (89.7% [61 of 68 patients] and 90.3% [149 of 165 patients], respectively). Rates of adverse events and serious adverse events in the 2 treatment groups were similar. Ceftobiprole monotherapy is as effective as vancomycin plus ceftazidime for treating patients with a broad range of complicated skin and skin-structure infections and infections due to gram-positive and gram-negative bacteria.

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A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation.

Susan Nicholson, Tobias Welte, Thomas File … (2012)

Community-acquired pneumonia (CAP) is a serious infection requiring hospitalisation in 20% of cases. The novel cephalosporin ceftobiprole has microbiological activity against the major bacterial pathogens causing CAP, including Streptococcus pneumoniae, Haemophilus influenzae and Klebsiella pneumoniae, as well as against Staphylococcus aureus, including meticillin-resistant S. aureus (MRSA). This was a multicentre, double-blind study in which 706 patients with CAP severe enough to require hospitalisation were randomised to ceftobiprole or to an expert-recommended course of ceftriaxone ± linezolid (comparator group). Clinical and microbiological outcomes were determined 7-14 days after completion of therapy (test-of-cure visit). For the 469 clinically evaluable patients, cure rates were 86.6% vs. 87.4% for ceftobiprole and comparator, respectively [95% confidence interval (CI) of the difference, -6.9% to 5.3%]; in the intention-to-treat (ITT) analysis of 638 CAP patients, these cure rates were 76.4% vs. 79.3%, respectively (95% CI of the difference, -9.3% to 3.6%). A typical bacterial pathogen was identified in 29% of the ITT population. Microbiological eradication rates in the 144 microbiologically evaluable patients were 88.2% and 90.8% for the respective treatment groups (95% CI of the difference, -12.6% to 7.5%). Both study drugs were well tolerated, with but a minority of patients requiring premature discontinuation due to an adverse event (6% in the ceftobiprole group and 4% in the comparator group). The overall incidence of treatment-related adverse events was higher in the ceftobiprole group, primarily owing to differences in rates of self-limited nausea (7% vs. 2%) and vomiting (5% vs. 2%). In summary, ceftobiprole was non-inferior to the comparator (ceftriaxone ± linezolid) in all clinical and microbiological analyses conducted, suggesting that ceftobiprole has a potential role in treating hospitalised patients with CAP. [ClinicalTrails.gov identifier: NCT00326287]. Copyright © 2011 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

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Author and article information

Journal

Journal ID (nlm-ta): Infect Drug Resist

Journal ID (iso-abbrev): Infect Drug Resist

Journal ID (publisher-id): idr

Journal ID (pmc): idr

Title: Infection and Drug Resistance

Publisher: Dove

ISSN (Electronic): 1178-6973

Publication date (Electronic): 16 September 2020

Publication date Collection: 2020

Volume: 13

Pages: 3209-3215

Affiliations

[1 ]Basilea Pharmaceutica International Ltd ., Basel, Switzerland

Author notes

Correspondence: Kamal Hamed Basilea Pharmaceutica International Ltd ., Grenzacherstrasse 487, Basel4005, SwitzerlandTel +41 61 567 1588Fax +41 61 606 1216 Email kamal.hamed@basilea.com

Author information

Kamal Hamed http://orcid.org/0000-0003-1896-9736

Article

Publisher ID: 268269

DOI: 10.2147/IDR.S268269

PMC ID: 7502402

SO-VID: 925a1805-a6ce-4ff8-b8a4-1bfddaae0094

License:

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

History

Date received : 18 June 2020

Date accepted : 29 August 2020

Page count

Figures: 1, Tables: 6, References: 29, Pages: 7

Funding

Funded by: Preparedness and Response, Biomedical Advanced Research and Development Authority;

Funded by: Basilea Pharmaceutica International Ltd;

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

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Abstract

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Patients and Methods

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Conclusion

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Pan African Medical Journal: COVID-19

Most cited references 26

A phase 3 randomized double-blind comparison of ceftobiprole medocaril versus ceftazidime plus linezolid for the treatment of hospital-acquired pneumonia.

A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections.

A randomised, double-blind trial comparing ceftobiprole medocaril with ceftriaxone with or without linezolid for the treatment of patients with community-acquired pneumonia requiring hospitalisation.

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