Outcomes with Cefiderocol Treatment in Patients with Bacteraemia Enrolled into Prospective Phase 2 and Phase 3 Randomised Clinical Studies

David L Paterson; Masahiro Kinoshita; Takamichi Baba; Roger Echols; Simon Portsmouth

doi:10.1007/s40121-022-00598-9

Outcomes with Cefiderocol Treatment in Patients with Bacteraemia Enrolled into Prospective Phase 2 and Phase 3 Randomised Clinical Studies

Infect Dis Ther. 2022 Apr;11(2):853-870. doi: 10.1007/s40121-022-00598-9. Epub 2022 Feb 20.

Authors

David L Paterson¹, Masahiro Kinoshita², Takamichi Baba², Roger Echols³, Simon Portsmouth⁴

Affiliations

¹ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Royal Brisbane and Women's Hospital Campus, Brisbane, Australia.
² Shionogi & Co., Ltd., Osaka, Japan.
³ Infectious Disease Drug Development Consulting, LLC, Easton, CT, USA.
⁴ Shionogi Inc., 300 Campus Park, Florham Park, NJ, 07932, USA. Simon.Portsmouth@shionogi.com.

Abstract

Introduction: A post hoc, descriptive analysis of three prospective, randomised, controlled clinical studies investigating cefiderocol in gram-negative bacterial infections was conducted to assess its efficacy in patients with baseline bacteraemia.

Methods: Data from APEKS-cUTI (NCT02321800), APEKS-NP (NCT03032380) and CREDIBLE-CR (NCT02714595) studies were assessed individually. Patients received cefiderocol 2g, q8h, for 7-14 days or comparators (imipenem/cilastatin [APEKS-cUTI], meropenem [APEKS-NP] or best available therapy [BAT; CREDIBLE-CR]). Bacteraemia and clinical outcomes were assessed at early assessment (EA), end of treatment (EOT) and test of cure (TOC) for patients in the intention-to-treat populations with baseline blood samples positive for aerobic gram-negative species. Eradication, persistence or recurrence of baseline blood pathogen was confirmed from follow-up blood cultures; in the absence of follow-up blood cultures, clinical response, administration of additional antibiotics and vital status were used to assess bacteraemia outcome.

Results: Of 885 patients randomised, 84 had bacteraemia and 89 (cefiderocol: 55, comparators: 34) gram-negative pathogens were isolated, namely Enterobacterales (n = 62) and non-fermenters (n = 27). At EA, on-therapy bacteraemia eradication rates in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 50.0% (4/8) and 72.0% (18/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 100% (10/10) and 69.2% (9/13), respectively. Persistence in blood at EA was seen in six patients overall (cefiderocol: 3, comparators: 3); indeterminate responses were common (cefiderocol: 8, comparators: 3), usually due to lack of blood cultures. Clinical cure/improvement rates at EA in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 100% (19/19), 62.5% (5/8) and 64.0% (16/25) with cefiderocol. Corresponding rates for comparators were 77.8% (7/9), 90.0% (9/10) and 30.8% (4/13), respectively. Bacteraemia eradication rates with cefiderocol in APEKS-cUTI, APEKS-NP and CREDIBLE-CR were 89.5%, 37.5% and 60.0% at EOT and 78.9%, 12.5% and 44.0% at TOC.

Conclusion: This descriptive analysis suggests that cefiderocol may be a useful treatment option for gram-negative bacteraemia, including pathogens resistant to other antibiotics.

Keywords: Bloodstream infection; Carbapenem resistance; Cefiderocol; ESBL; Eradication; Gram-negative bacteraemia; Metallo-beta-lactamase; Multidrug resistance.