A Comparison of the Efficacy and Safety of Intravenous Followed by Oral Delafloxacin With Vancomycin Plus Aztreonam for the Treatment of Acute Bacterial Skin and Skin Structure Infections: A Phase 3, Multinational, Double-Blind, Randomized Study

Abstract

Background: Delafloxacin is an intravenous (IV)/oral anionic fluoroquinolone with activity against gram-positive (including methicillin-resistant Staphylococcus aureus [MRSA]), gram-negative, atypical, and anaerobic organisms. It is approved in the United States for acute bacterial skin and skin structure infections (ABSSSIs) caused by designated susceptible gram-positive and gram-negative organisms, and is in development for the treatment of community-acquired bacterial pneumonia.

Methods: A multicenter, randomized, double-blind trial of 850 adults with ABSSSI compared delafloxacin 300 mg IV every 12 hours for 3 days with a switch to 450 mg oral delafloxacin, to vancomycin 15 mg/kg IV with aztreonam for 5-14 days. The primary endpoint was objective response at 48-72 hours. Investigator-assessed response based on resolution of signs and symptoms at follow-up (day 14 ± 1), and late follow-up (day 21-28) were secondary endpoints.

Results: In the intent-to-treat analysis set, the objective response was 83.7% in the delafloxacin arm and 80.6% in the comparator arm. Investigator-assessed success was similar at follow-up (87.2% vs 84.4%) and late follow-up (83.5% vs 82.2%). Delafloxacin was comparable to vancomycin + aztreonam in eradication of MRSA at 96.0% vs 97.0% at follow-up. Frequency of treatment-emergent adverse events between the groups was similar. Treatment-emergent adverse events leading to study drug discontinuation was higher in the vancomycin + aztreonam group (1.2% vs 2.4%).

Conclusions: In ABSSSI patients, IV/oral delafloxacin monotherapy was noninferior to IV vancomycin + aztreonam combination therapy for both the objective response and the investigator-assessed response at follow-up and late follow-up. Delafloxacin was well tolerated as monotherapy in treatment of ABSSSIs.

Clinical trials registration: NCT01984684.

Figures

Figure 1.

Consolidated Standards of Reporting Trials (CONSORT) diagram of patient disposition. Intent-to-treat (ITT) analysis set included all patients who were randomly assigned to treatment. Clinically evaluable (CE) analysis set included all patients in the ITT population who (1) received ≥80% of the total expected doses of the assigned study drug or experienced clinical failure and received ≥4 doses of study drug; (2) did not receive any concomitant, systemic antibacterial therapy with activity against the identified pathogen; and (3) had no major protocol deviations. Microbiological ITT (MITT) analysis set consisted of all patients in the ITT analysis set who had bacterial pathogens known to cause acute bacterial skin and skin structure infections at baseline. Microbiologically evaluable analysis set included all patients in the MITT population who met the criteria established for the CE analysis set. Abbreviations: AE, adverse event; CE, clinically evaluable; FU, follow-up; ITT, intent-to-treat; LFU, late follow-up; ME, microbiologically evaluable; MITT, microbiological intent-to-treat; SAF, safety; TC, telephone call.

Figure 2.

Objective response and investigator-assessed response at follow-up and late follow-up by analysis set, methicillin-resistant Staphylococcus aureus (MRSA) infection at baseline. *Primary endpoint. **The primary efficacy endpoint for the European Medicines Agency submission, and a secondary efficacy endpoint for the US Food and Drug Administration submission. Cure = no remaining signs and symptoms; Improved = some remaining signs and symptoms but no further antibiotics required; Success = Cure + Improved. Abbreviations: CE, clinically evaluable (patients who completed activities as defined in the protocol); CI, confidence interval; DLX, delafloxacin; FU, follow-up; IA, investigator assessed; ITT, intent-to-treat (all patients randomized); LFU, late follow-up; ME, microbiologically evaluable (clinically evaluable patients with eligible pathogen); MRSA, methicillin-resistant Staphylococcus aureus; Van/AZ, vancomycin/aztreonam.