Efficacy and safety of delafloxacin compared with vancomycin plus aztreonam for acute bacterial skin and skin structure infections: a Phase 3, double-blind, randomized study

Abstract

Background: Delafloxacin is an investigational anionic fluoroquinolone in development for oral or intravenous administration for the treatment of infections caused by Gram-positive (including MRSA), Gram-negative, atypical and anaerobic organisms.

Objectives: To establish the non-inferiority of delafloxacin compared with vancomycin plus aztreonam for the treatment of acute bacterial skin and skin structure infections and to compare the safety of the two antimicrobials.

Patients and methods: A Phase 3, multicentre, randomized, double-blind, active-controlled study with 660 patients compared delafloxacin 300 mg or vancomycin 15 mg/kg plus aztreonam 2 g each administered twice daily intravenously for 5-14 days. Non-inferiority was evaluated by objective response (≥20% erythema reduction) at 48-72 h after initiation of study drug, investigator subjective assessment of outcome and microbiological responses. Clinical Trials Registration: NCT01811732. EudraCT number: 2012-001767-71.

Results: In the ITT analysis set, the objective response was 78.2% in the delafloxacin arm and 80.9% in the vancomycin/aztreonam arm (mean treatment difference, -2.6%; 95% CI, -8.78% to 3.57%). Investigator-assessed cure was similar between the two groups at follow-up (52.0% versus 50.5%) and late follow-up (70.4% versus 66.6%). Bacterial eradication of MRSA was 100% and 98.5% in the delafloxacin group and the vancomycin/aztreonam group, respectively. Frequency of treatment-emergent adverse events in the delafloxacin and vancomycin/aztreonam groups was similar. Treatment-emergent adverse events leading to study drug discontinuation were higher in the vancomycin/aztreonam group compared with the delafloxacin group (4.3% versus 0.9%).

Conclusions: Delafloxacin, an anionic fluoroquinolone, was statistically non-inferior to vancomycin/aztreonam at 48-72 h following the start of therapy and was well tolerated as monotherapy in the treatment of acute bacterial skin and skin structure infections.

Figure 1.

CONSORT diagram of patient disposition. ITT analysis set included all patients who were randomly assigned to treatment. CE analysis set included all patients in the ITT population who: (i) received ≥80% of the total expected doses of the assigned study drug or were clinical failures and received ≥4 doses of study drug; (ii) did not receive any concomitant, systemic antibacterial therapy with activity against the identified pathogen; and (iii) had no major protocol deviations. MITT analysis set consisted of all patients in the ITT analysis set that had bacterial pathogens known to cause ABSSSI at baseline. ME analysis set included all patients in the MITT population who met the criteria established for the CE analysis set. SAF, safety; TC, telephone call.

Figure 2.

Objective response and investigator-assessed response at FU and LFU by analysis set, MRSA infection at baseline and BMI category. *Primary endpoint. Cure = no remaining signs and symptoms. Improved = some remaining signs and symptoms, but no further antibiotics required. Success = cure + improved. ITT, all patients randomized; MITT, ITT patients with eligible pathogen; CE patients who completed activities as defined in the protocol; ME, CE patients with eligible pathogen. BMI was calculated as body weight (in kg)/h (in m²).

Figure 3.

Percentage change from baseline in reduction of erythema (digital planimetry) at each visit (ITT population).

Figure 4.

Box-plot of glucose concentrations (mmol/L): intense glucose analysis set. Note: the lower fence reflects the actual minimum value or 1.5× IQR below quartile 1, whichever is bigger; the upper fence reflects the actual maximum value or 1.5× IQR above quartile 3, whichever is smaller.