263Gastrointestinal Safety Profile of Tedizolid: Pooled Results from Two Phase 3 Trials in Acute Bacterial Skin and Skin Structure Infections

Introduction. Iclaprim is a diaminopyrimidine antibiotic for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to Gram-positive pathogens. Aim. This analysis evaluates patients with wound infections from two Phase 3 trials of ABSSSI. Methodology. Six-hundred-two patients with wound infections from two Phase 3, double-blinded, randomized, multicenter, active controlled trials (REVIVE-1/–2) were evaluated in a post hoc analysis of iclaprim 80 mg compared with vancomycin 15 mg kg–1 administered intravenously every 12 h for 5–14 days. The primary endpoint was to determine whether iclaprim was non-inferior (10 % margin) to vancomycin in achieving a ≥20 % reduction from baseline in lesion size 48–72 h after starting study drug (early clinical response [ECR]). Safety was assessed. Results. In REVIVE-1, ECR was 83.5 % with iclaprim versus 79.7 % with vancomycin (treatment difference 3.77%, 95 % CI −4.50%, 12.04%). In REVIVE-2, ECR was 82.7 % with iclaprim versus 76.3 % with vancomycin (treatment difference 6.38%, 95 % CI −3.35%, 16.12%). In the pooled dataset, iclaprim had similar ECR rates compared with vancomycin among wound infection patients (83.2 % vs 78.2 %) with a treatment difference of 5.01 % (95 % CI −1.29%, 11.32%). The safety profile was similar in iclaprim- and vancomycin-treated patients, except for a higher incidence of diarrhea with vancomycin (n=17) compared with iclaprim (n=6) and fatigue with iclaprim (n=17) compared with vancomycin (n=8). Conclusion. Based on early clinical response, iclaprim achieved non-inferiority to vancomycin with a similar safety profile in patients with wound infections suspected or confirmed as caused by Gram-positive pathogens. Iclaprim may be a valuable treatment option for wound infections.

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Telavancin for Acute Bacterial Skin and Skin Structure Infections, aPost HocAnalysis of the Phase 3 ATLAS Trials in Light of the 2013 FDA Guidance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00471-15 ◽

2015 ◽

Vol 59 (10) ◽

pp. 6170-6174 ◽

Cited By ~ 5

Author(s):

Richard Pushkin ◽

Steven L. Barriere ◽

Whedy Wang ◽

G. Ralph Corey ◽

Martin E. Stryjewski

Keyword(s):

Clinical Response ◽

Lesion Size ◽

Phase 3 ◽

Two Phase ◽

Skin Structure ◽

Fda Guidance ◽

Complicated Skin ◽

Clinical Responses ◽

Cure Rates ◽

Post Hoc

ABSTRACTTwo phase 3 ATLAS trials demonstrated noninferiority of telavancin compared with vancomycin for complicated skin and skin structure infections. Data from these trials were retrospectively evaluated according to 2013 U.S. Food and Drug Administration (FDA) guidance on acute bacterial skin and skin structure infections. Thispost hocanalysis included patients with lesion sizes of ≥75 cm2and excluded patients with ulcers or burns (updated all-treated population;n= 1,127). Updated day 3 (early) clinical response was defined as a ≥20% reduction in lesion size from baseline and no rescue antibiotic. Updated test-of-cure (TOC) clinical response was defined as a ≥90% reduction in lesion size, no increase in lesion size since day 3, and no requirement for additional antibiotics or significant surgical procedures. Day 3 (early) clinical responses were achieved in 62.6% and 61.0% of patients receiving telavancin and vancomycin, respectively (difference, 1.7%, with a 95% confidence interval [CI] of −4.0% to 7.4%). Updated TOC visit cure rates were similar for telavancin (68.0%) and vancomycin (63.3%), with a difference of 4.8% (95% CI, −0.7% to 10.3%). Adopting current FDA guidance, this analysis corroborates previous noninferiority findings of the ATLAS trials of telavancin compared with vancomycin.

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Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥5.5 mmol/L: pooled analysis from two phase 3 trials

10.21203/rs.2.10962/v2 ◽

2019 ◽

Author(s):

Alpesh N. Amin ◽

Jose Menoyo ◽

Bhupinder Singh ◽

Christopher S. Kim

Keyword(s):

Serum Potassium ◽

Safety Profile ◽

Potassium Level ◽

Serum Potassium Level ◽

Efficacy And Safety ◽

Phase 3 ◽

Two Phase ◽

Baseline Serum ◽

Sodium Zirconium ◽

Sodium Zirconium Cyclosilicate

Abstract Background: Reliable, timely-onset, oral treatments with an acceptable safety profile for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤48 hours in patients with baseline serum potassium level ≥5.5 mmol/L. Methods: Data were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤5.5 and ≤5.0 mmol/L, and proportion achieving potassium level ≤5.5 and ≤5.0 mmol/L at 4, 24, and 48 hours. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated. Results: At baseline, 125 of 170 patients (73.5%) had potassium level 5.5–<6.0, 39 (22.9%) had potassium level 6.0–6.5, and 6 (3.5%) had potassium level >6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1-hour post-initial dose. By 4 and 48 hours, 37.5% and 85.0% of patients achieved potassium level ≤5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤5.5 and ≤5.0 mmol/L were 2.0 (1.1–2.0) and 21.6 (4.1–22.4) hours, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious. Conclusions: SZC 10 g three times daily achieved serum potassium reduction and normokalemia, with a favorable safety profile. ClinicalTrials.gov identifiers: NCT01737697 and NCT02088073

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In Vitro Activity of Iclaprim against Isolates in Two Phase 3 Clinical Trials (REVIVE-1 and -2) for Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02239-18 ◽

2019 ◽

Vol 63 (4) ◽

Cited By ~ 2

Author(s):

Stephanie Noviello ◽

Sophie Magnet ◽

Stephen Hawser ◽

David B. Huang

Keyword(s):

Susceptibility Testing ◽

In Vitro Activity ◽

Phase 3 ◽

Gram Positive ◽

Two Phase ◽

Content Type ◽

Skin Structure ◽

Streptococcus Anginosus ◽

Antibacterial Susceptibility

ABSTRACT Iclaprim, a selective bacterial dihydrofolate reductase inhibitor, and other antibiotics were tested against Gram-positive isolates from two phase 3 studies of acute bacterial skin and skin structure infections (ABSSSIs) (REVIVE-1 and -2). Seven hundred ninety baseline isolates, including Staphylococcus aureus, β-hemolytic streptococci, and Streptococcus anginosus group, underwent antibacterial susceptibility testing. Iclaprim had an MIC90 of 0.12 μg/ml for S. aureus (0.12 μg/ml for methicillin susceptible, 0.25 μg/ml for methicillin resistant), 0.25 μg/ml for β-hemolytic streptococci, and 0.008 μg/ml for S. anginosus group. Iclaprim demonstrated potent activity against these Gram-positive ABSSSI isolates.

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Tedizolid and Linezolid for Treatment of Acute Bacterial Skin and Skin Structure Infections of the Lower Extremity versus Non–Lower-Extremity Infections

Journal of the American Podiatric Medical Association ◽

10.7547/15-218 ◽

2017 ◽

Vol 107 (4) ◽

pp. 264-271 ◽

Cited By ~ 4

Author(s):

Warren S. Joseph ◽

Darren Culshaw ◽

Steven Anuskiewicz ◽

Carisa De Anda ◽

Philippe Prokocimer

Keyword(s):

Lower Extremity ◽

Clinical Response ◽

The United States ◽

The European Union ◽

Phase 3 ◽

Two Phase ◽

Once Daily ◽

Therapy Evaluation ◽

Skin Structure ◽

Post Therapy

Background: Tedizolid phosphate, the prodrug of the oxazolidinone tedizolid, has been approved in a number of countries, including the United States, those in the European Union, and Canada, for treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Two phase 3 trials demonstrated the noninferior efficacy of tedizolid (200 mg once daily for 6 days) to linezolid (600 mg twice daily for 10 days) in patients with ABSSSI. Because of the challenges of treating lower-extremity ABSSSI, the efficacy and safety of tedizolid and linezolid for treating lower-extremity versus non–lower-extremity infections were compared. Methods: This was a post hoc analysis of pooled data from patients with lower-extremity infections enrolled in two phase 3 studies, ESTABLISH-1 (NCT01170221) and ESTABLISH-2 (NCT01421511), comparing tedizolid to linezolid in patients with ABSSSI. Results: Lower-extremity ABSSSI were present in 40.7% of tedizolid-treated and 42.2% of linezolid-treated patients. Methicillin-resistant Staphylococcus aureus (MRSA) was present in 34.7% of all patients with a baseline causative pathogen. Early clinical responses at 48 to 72 hours and investigator-assessed responses at the post-therapy evaluation were similar between tedizolid and linezolid, regardless of ABSSSI type. With both treatments, the early clinical response was slightly higher in patients with non–lower-extremity infection than in those with lower-extremity ABSSSI (tedizolid, 84.8% versus 77.0%; linezolid, 81.4% versus 76.6%, respectively); however, by the post-therapy evaluation visit, response rates were similar (tedizolid, 87.1% versus 86.3%; linezolid, 86.6% versus 87.2%, respectively). Gastrointestinal adverse events and low platelet counts were observed more frequently with linezolid treatment. Conclusions: Post-therapy evaluations showed that the clinical response of lower-extremity ABSSSI to tedizolid and linezolid was comparable to that of ABSSSI in other locations. A short 6-day course of once-daily tedizolid was as effective as a 10-day course of twice-daily linezolid in treating patients with lower-extremity ABSSSI.

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Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥ 5.5 mmol/L: pooled analysis from two phase 3 trials

BMC Nephrology ◽

10.1186/s12882-019-1611-8 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 3

Author(s):

Alpesh N. Amin ◽

Jose Menoyo ◽

Bhupinder Singh ◽

Christopher S. Kim

Keyword(s):

Serum Potassium ◽

Safety Profile ◽

Potassium Level ◽

Serum Potassium Level ◽

Efficacy And Safety ◽

Phase 3 ◽

Two Phase ◽

Baseline Serum ◽

Sodium Zirconium ◽

Sodium Zirconium Cyclosilicate

Abstract Background Reliable, timely-onset, oral treatments with an acceptable safety profile for patients with hyperkalemia are needed. We examined the efficacy and safety of sodium zirconium cyclosilicate (SZC; formerly ZS-9) treatment for ≤ 48 h in patients with baseline serum potassium level ≥ 5.5 mmol/L. Methods Data were pooled from two phase 3 studies (ZS-003 and HARMONIZE) among patients receiving SZC 10 g three times daily. Outcomes included mean and absolute change from baseline, median time to potassium level ≤ 5.5 and ≤ 5.0 mmol/L, and proportion achieving potassium level ≤ 5.5 and ≤ 5.0 mmol/L at 4, 24, and 48 h. Outcomes were stratified by baseline potassium. Safety outcomes were evaluated. Results At baseline, 125 of 170 patients (73.5%) had potassium level 5.5–< 6.0, 39 (22.9%) had potassium level 6.0–6.5, and 6 (3.5%) had potassium level > 6.5 mmol/L. Regardless of baseline potassium, mean potassium decreased at 1 h post-initial dose. By 4 and 48 h, 37.5% and 85.0% of patients achieved potassium level ≤ 5.0 mmol/L, respectively. Median (95% confidence interval) times to potassium level ≤ 5.5 and ≤ 5.0 mmol/L were 2.0 (1.1–2.0) and 21.6 (4.1–22.4) h, respectively. Fifteen patients (8.8%) experienced adverse events; none were serious. Conclusions SZC 10 g three times daily achieved serum potassium reduction and normokalemia, with a favorable safety profile. Trial registration ClinicalTrials.gov identifiers: ZS-003: NCT01737697 and HARMONIZE: NCT02088073.

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In Vitro Activity of Delafloxacin and Microbiological Response Against Fluoroquinolone Susceptible and Non-Susceptible S. aureus Isolates from Two Phase 3 Studies of Acute Bacterial Skin and Skin Structure Infections (ABSSSIs)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofw172.1587 ◽

2016 ◽

Vol 3 (suppl_1) ◽

Author(s):

Sandra Mccurdy ◽

Laura Lawrence ◽

Leah N. Woosley ◽

Robert K. Flamm ◽

Carol Tseng ◽

...

Keyword(s):

Vitro Activity ◽

In Vitro Activity ◽

Phase 3 ◽

Two Phase ◽

Skin Structure

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CANVAS 1 and 2: Analysis of Clinical Response at Day 3 in Two Phase 3 Trials of Ceftaroline Fosamil versus Vancomycin plus Aztreonam in Treatment of Acute Bacterial Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05738-11 ◽

2012 ◽

Vol 56 (5) ◽

pp. 2231-2236 ◽

Cited By ~ 52

Author(s):

H. David Friedland ◽

Tanya O'Neal ◽

Donald Biek ◽

Paul B. Eckburg ◽

Douglas R. Rank ◽

...

Keyword(s):

Clinical Response ◽

Retrospective Analysis ◽

Response Rates ◽

Time Interval ◽

Phase 3 ◽

Two Phase ◽

Ceftaroline Fosamil ◽

Content Type ◽

Skin Structure ◽

Complicated Skin

ABSTRACTScientific and regulatory interest in assessing clinical endpoints after 48 to 72 h of treatment for acute bacterial skin and skin structure infections (ABSSSI) has increased. Historical, pre-antibiotic-era data suggest that a treatment effect relative to untreated controls can be discerned in this time interval. Ceftaroline fosamil, a broad-spectrum bactericidal cephalosporin with activity against Gram-positive organisms, including methicillin-resistantStaphylococcus aureus(MRSA), and Gram-negative organisms was efficacious in two phase 3 trials of complicated skin infections (CANVAS 1 and 2) using clinical cure rates at the test-of-cure visit. To assess an early clinical response in the CANVAS trials, a retrospective analysis using a day 3 clinical endpoint was conducted. Adults with ABSSSI received intravenous ceftaroline fosamil at 600 mg every 12 h (q12h) or vancomycin at 1 g plus aztreonam at 1 g (V/A) q12h for 5 to 14 days. Clinical response at day 3, defined as cessation of infection spread and absence of fever, was analyzed in patients with a lesion size of ≥75 cm2and either deep and/or extensive cellulitis, major abscess, or an infected wound. Day 3 integrated CANVAS clinical response rates were 74.0% (296/400) for ceftaroline and 66.2% (263/397) for V/A (difference, 7.8%; 95% confidence interval [CI], 1.3% to 14.0%). In the individual studies, absolute treatment differences of 9.4% (CANVAS 1) and 5.9% (CANVAS 2) favoring ceftaroline were observed. For ABSSSI due to MRSA, response rates were 81.7% and 77.4% in the ceftaroline and V/A groups, respectively. In this retrospective analysis, ceftaroline fosamil monotherapy had a numerically higher clinical response than V/A at day 3 in the treatment of ABSSSI.

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In Vitro Activity of Ceftobiprole against Pathogens from Two Phase 3 Clinical Trials of Complicated Skin and Skin Structure Infections

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00336-08 ◽

2008 ◽

Vol 52 (9) ◽

pp. 3418-3423 ◽

Cited By ~ 27

Author(s):

Karen M. Amsler ◽

Todd A. Davies ◽

Wenchi Shang ◽

Michael R. Jacobs ◽

Karen Bush

Keyword(s):

Pseudomonas Aeruginosa ◽

Clinical Trials ◽

In Vitro Activity ◽

Phase 3 ◽

Two Phase ◽

Gram Negative ◽

Skin Structure ◽

Complicated Skin ◽

Resistant Strains

ABSTRACT In phase 3 clinical trials for ceftobiprole treatment of complicated skin and skin structure infections, 1,219 gram-positive and 276 gram-negative aerobic baseline pathogens were identified. Ceftobiprole inhibited all staphylococcal isolates, including methicillin-resistant strains, at MICs of ≤4 μg/ml. Against Enterobacteriaceae and Pseudomonas aeruginosa isolates, the potency of ceftobiprole was similar to that of cefepime.

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