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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.

SUBMITTER: O'Riordan W

PROVIDER: S-EPMC6093995 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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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.

O'Riordan William W McManus Alison A Teras Juri J Poromanski Ivan I Cruz-Saldariagga Maria M Quintas Megan M Lawrence Laura L Liang ShuJui S Cammarata Sue S

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20180801 5

<h4>Background</h4>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.<h4>Met ...[more]

PMID: 29518178

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Project description:BackgroundDelafloxacin 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.ObjectivesTo 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 methodsA 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.ResultsIn 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%).ConclusionsDelafloxacin, 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.

Project description:BackgroundThe development of novel broad-spectrum antibiotics, with efficacy against both gram-positive and gram-negative bacteria, has the potential to enhance treatment options for acute bacterial skin and skin structure infections (ABSSSIs). Ceftobiprole is an advanced-generation intravenous cephalosporin with broad in vitro activity against gram-positive (including methicillin-resistant Staphylococcus aureus) and gram-negative pathogens.MethodsTARGET was a randomized, double-blind, active-controlled, parallel-group, multicenter, phase 3 noninferiority study that compared ceftobiprole with vancomycin plus aztreonam. The Food and Drug Administration-defined primary efficacy endpoint was early clinical response 48-72 hours after treatment initiation in the intent-to-treat (ITT) population and the European Medicines Agency-defined primary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit. Noninferiority was defined as the lower limit of the 95% CI for the difference in success rates (ceftobiprole minus vancomycin/aztreonam) >-10%. Safety was assessed through adverse event and laboratory data collection.ResultsIn total, 679 patients were randomized to ceftobiprole (n = 335) or vancomycin/aztreonam (n = 344). Early clinical success rates were 91.3% and 88.1% in the ceftobiprole and vancomycin/aztreonam groups, respectively, and noninferiority was demonstrated (adjusted difference: 3.3%; 95% CI: -1.2, 7.8). Investigator-assessed clinical success at the TOC visit was similar between the 2 groups, and noninferiority was demonstrated for both the ITT (90.1% vs 89.0%) and clinically evaluable (97.9% vs 95.2%) populations. Both treatment groups displayed similar microbiological success and safety profiles.ConclusionsTARGET demonstrated that ceftobiprole is noninferior to vancomycin/aztreonam in the treatment of ABSSSIs, in terms of early clinical response and investigator-assessed clinical success at the TOC visit.Clinical trials registrationNCT03137173.

Project description:AimExploratory analyses evaluated patient characteristics and outcomes among patients with complicated skin and soft tissue infection (cSSTI) in the phase 3 COVERS study who were admitted to an intensive care unit (ICU).MethodsAdults with cSSTI (surface area ≥ 75 cm2) and evidence of systemic inflammation and/or underlying comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h [q8h]) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g q8h) for 5-14 days. Clinical response and ICU length of stay (LOS) within first hospitalization were evaluated in the modified intent-to-treat (MITT) and clinically evaluable (CE) populations; a Cox proportional hazards model identified factors associated with increased hospital LOS.ResultsOverall, 42 of 761 randomized patients were admitted to the ICU (ceftaroline fosamil, n = 32; vancomycin plus aztreonam, n = 10) prior to, or at start of, study treatment. Baseline differences between the ICU and non-ICU populations were indicative of more severe disease in ICU patients; within this subset, there were also some notable imbalances between treatment groups. Clinical cure rates at test-of-cure (ceftaroline fosamil vs. vancomycin plus aztreonam) were generally similar in the non-ICU and ICU subsets (MITT population 79% vs. 79% and 69% vs. 90.0%, respectively; CE population 87% vs. 85% and 80% vs. 89%, respectively). Median ICU LOS was 8 vs. 13 days, respectively. ICU admission was a risk factor predicting increased hospital LOS (P < 0.001).ConclusionsClinical outcomes for patients admitted to the ICU were generally similar to non-ICU patients, despite more severe baseline disease, with shorter median treatment duration in the ceftaroline fosamil group. ICU admission was associated with longer hospital LOS. Given the small sample size and unbalanced patient and disease characteristics within the ICU subgroup, differences between treatment groups should be interpreted with caution.Trial registrationClinicalTrials.gov identifier, NCT01499277.

Project description:ObjectivesThe primary aim of the RELIEF study was to evaluate the efficacy and safety of two sequential intravenous (iv)/oral regimens: moxifloxacin iv/oral versus piperacillin/tazobactam (TZP) iv followed by oral amoxicillin/clavulanate (AMC).Patients and methodsThe study had a prospective, randomized, double-dummy, double-blind, multicentre design. Patients ≥18 years were prospectively stratified according to complicated skin and skin structure infection (cSSSI) subtype/diagnosis (major abscess, diabetic foot infection, wound infection or infected ischaemic ulcer), surgical intervention and severity of illness. Diagnoses and disease severity were based on predetermined criteria, documented by repeated photographs, and confirmed by an independent data review committee. Patients were randomized to receive either 400 mg of moxifloxacin iv once daily followed by 400 mg of moxifloxacin orally once daily or 4.0/0.5 g of TZP iv thrice daily followed by 875/125 mg of AMC orally twice daily for 7-21 days. The primary efficacy variable was clinical response at test of cure (TOC) for the per-protocol (PP) population. Clinical efficacy was assessed by the data review committee based on repeated photographs and case descriptions. Clinical trials registry number: NCT 00402727.ResultsA total of 813 patients were randomized. Clinical success rates at TOC were similar for moxifloxacin and TZP-AMC in the PP [320/361 (88.6%) versus 275/307 (89.6%), respectively; P = 0.758] and intent-to-treat (ITT) [350/426 (82.2%) versus 305/377 (80.9%), respectively; P = 0.632] populations. Thus, moxifloxacin was non-inferior to TZP-AMC. Bacteriological success rates were high in both treatment arms [moxifloxacin: 432/497 (86.9%) versus TZP-AMC: 370/429 (86.2%), microbiologically valid (MBV) population]. Moxifloxacin was non-inferior to TZP-AMC at TOC in both the MBV and the ITT populations. Both treatments were well tolerated.ConclusionsOnce-daily iv/oral moxifloxacin monotherapy was clinically and bacteriologically non-inferior to iv TZP thrice daily followed by oral AMC twice daily in patients with cSSSIs.

Project description:BackgroundDelafloxacin is a novel fluoroquinolone with broad antibacterial activity against pathogens causing acute bacterial skin and skin structure infections (ABSSSI). This network meta-analysis (NMA) was conducted to evaluate the relative efficacy of delafloxacin versus other comparators used for managing patients with ABSSSI.MethodsA systematic literature review was conducted to identify randomised controlled trials (RCTs) evaluating adults (≥ 18 years) with ABSSSI, complicated SSSI (cSSSI), complicated skin and soft tissue infections (cSSTI) or severe cellulitis with pathogen of gram-positive, gram-negative, or mixed aetiology. OVID MEDLINE®, Embase, Epub Ahead of Print, Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews were searched from inception through 12 April 2019. A feasibility assessment was conducted, followed by an NMA, which was run in a Bayesian framework. The interventions included in the NMA encompassed monotherapy or combination therapies of amoxicillin/clavulanate, ampicillin/sulbactam, ceftaroline, ceftobiprole, dalbavancin, daptomycin, delafloxacin, fusidic acid, iclaprim, linezolid, omadacycline, oxacillin + dicloxacillin, standard therapy, tedizolid, telavancin, tigecycline, vancomycin, vancomycin + aztreonam and vancomycin + linezolid.ResultsA feasibility assessment was performed and evidence networks were established for composite clinical response (n = 34 studies), early clinical response (n = 16 studies) and microbiological response (n = 14 studies) in the overall study population, composite clinical response (n = 4 studies) in obese subpopulation and for composite clinical response (n = 18 studies) and microbiological response (n = 14 studies) in patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. Delafloxacin performed significantly better than fusidic acid, iclaprim, vancomycin, and ceftobiprole for composite clinical response. Delafloxacin was comparable to dalbavancin, daptomycin, fusidic acid, iclaprim, linezolid, omadacycline, tedizolid, vancomycin, vancomycin + aztreonam and vancomycin + linezolid in the analysis of early clinical response, whereas for microbiological response, delafloxacin was comparable to all interventions. In the obese subpopulation, the results favoured delafloxacin in comparison to vancomycin, whilst the results were comparable with other interventions among the MRSA subpopulation.ConclusionsDelafloxacin is a promising new antibiotic for ABSSSI demonstrating greater improvement (composite clinical response) compared to ceftobiprole, fusidic acid, iclaprim, telavancin and vancomycin and comparable effectiveness versus standard of care for all outcomes considered in the study.

Dataset Information

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.

Publications

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.

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