Afabicin, a First-in-Class Antistaphylococcal Antibiotic, in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Clinical Noninferiority to Vancomycin/Linezolid

Abstract

Afabicin (formerly Debio 1450, AFN-1720) is a prodrug of afabicin desphosphono, an enoyl-acyl carrier protein reductase (FabI) inhibitor, and is a first-in-class antibiotic with a novel mode of action to specifically target fatty acid synthesis in Staphylococcus spp. The efficacy, safety, and tolerability of afabicin were compared with those of vancomycin/linezolid in the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to staphylococci in this multicenter, parallel-group, double-blind, and double-dummy phase 2 study. Randomized patients (1:1:1) received either low-dose (LD) afabicin (intravenous [i.v.] 80 mg, followed by oral 120 mg, twice a day [BID]), high-dose (HD) afabicin (i.v. 160 mg, followed by oral 240 mg, BID), or vancomycin/linezolid (i.v. vancomycin 1 g or 15 mg/kg, followed by oral linezolid 600 mg, BID). The most frequent baseline pathogen was Staphylococcus aureus (97.5% of microbiological intent-to-treat [mITT] population), and 50.4% of patients had methicillin-resistant S. aureus Clinical response rates at 48 to 72 h postrandomization in the mITT population were comparable among treatment groups (94.6%, 90.1%, and 91.1%, respectively). Both LD and HD afabicin were noninferior to vancomycin/linezolid (differences, -3.5% [95% confidence interval {CI}, -10.8%, 3.9%] and 1.0% [95% CI, -7.3%, 9.2%], respectively). Most common treatment-emergent adverse events were mild and were headache (9.1% and 16.8%) and nausea (6.4% and 8.4%) with LD and HD afabicin, respectively. Afabicin was efficacious and well tolerated in the treatment of ABSSSI due to staphylococci, and these data support further development of afabicin for the treatment of ABSSSI and potentially other types of staphylococcal infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02426918.).

Keywords: ABSSSI; FabI inhibitor; afabicin; efficacy; phase II; safety; staphylococcus.

Copyright © 2020 Wittke et al.

Figures

FIG 1

Patient disposition. a, For those indicated as “Non-completers,” reasons for noncompletion included adverse events (4 patients, including 3 patients who had a serious adverse event and 1 patient who died [see “Safety”]), physician decision (3 patients, including 1 patient who was not treated, 1 patient in the LD afabicin group who was withdrawn on day 2, and 1 patient in the vancomycin/linezolid group who was withdrawn on day 28), withdrawal by patient (14 patients), and other reasons (29 patients). b, For those indicated as having “Completed the study” and the “Per-protocol completer population,” these patients completed up to STFU. c, For those for which there was “No baseline staphylococcal pathogen,” the patients met the criteria for inclusion, but pathogenic staphylococcal species were not identified from baseline lesion or blood samples by the central laboratory.