Publications by authors named "G Ralph Corey"

278 Publications

Clinical Presentation, Timing, and Microbiology of CIED Infections: An Analysis of the WRAP-IT Trial.

JACC Clin Electrophysiol 2021 01 28;7(1):50-61. Epub 2020 Oct 28.

Heart and Vascular Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Objectives: This study characterized the microbiology of major cardiac implantable electronic device (CIED) infections that occurred during the WRAP-IT (Worldwide Randomized Antibiotic Envelope Infection Prevention Trial) study.

Background: The WRAP-IT study offers a unique opportunity for further understanding of the pathogens involved in major CIED infections in a prospective dataset, with implications for clinical practice and infection management.

Methods: A total of 6,800 patients randomized 1:1 to receive an antibacterial envelope or not (control subjects) were included in this analysis. Patient characteristics, infection manifestation (pocket vs. systemic), and infection microbiology were evaluated through all follow-up (36 months). Data were analyzed using Cox proportional hazards regression.

Results: A total of 3,371 patients received an envelope, and 3,429 patients were control subjects. Major CIED infection occurred in 32 patients who received an envelope and 51 control subjects (36-month Kaplan-Meier estimated event rate, 1.3% and 1.9%, respectively; p = 0.046). A 61% reduction in major pocket infection was observed within 12 months of the procedure in the envelope group (hazard ratio: 0.39, 95% confidence interval: 0.21 to 0.73; p = 0.003). Among 76 patients with major infections who had a sample taken, causative pathogens were identified in 47 patients. Staphylococcus species were the predominate pathogen (n = 31) and envelope use resulted in a 76% reduction in Staphylococcus-related pocket infections (n = 4 vs. 17; p = 0.010). Envelope use was not associated with delayed onset of pocket infections and did not affect the presentation of infections.

Conclusions: Antibacterial envelope use resulted in a significant reduction of major CIED pocket infections and was particularly effective against Staphylococcus species, the predominant cause of pocket infections. (Worldwide Randomized Antibiotic Envelope Infection Prevention Trial [WRAP-IT]; NCT02277990).
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http://dx.doi.org/10.1016/j.jacep.2020.07.021DOI Listing
January 2021

Cost-Effectiveness of an Antibacterial Envelope for Cardiac Implantable Electronic Device Infection Prevention in the US Healthcare System From the WRAP-IT Trial.

Circ Arrhythm Electrophysiol 2020 10 11;13(10):e008503. Epub 2020 Sep 11.

Cleveland Clinic, OH (B.L.W., K.G.T.).

Background: In the WRAP-IT trial (Worldwide Randomized Antibiotic Envelope Infection Prevention), adjunctive use of an absorbable antibacterial envelope resulted in a 40% reduction of major cardiac implantable electronic device infection without increased risk of complication in 6983 patients undergoing cardiac implantable electronic device revision, replacement, upgrade, or initial cardiac resynchronization therapy defibrillator implant. There is limited information on the cost-effectiveness of this strategy. As a prespecified objective, we evaluated antibacterial envelope cost-effectiveness compared with standard-of-care infection prevention strategies in the US healthcare system.

Methods: A decision tree model was used to compare costs and outcomes of antibacterial envelope (TYRX) use adjunctive to standard-of-care infection prevention versus standard-of-care alone over a lifelong time horizon. The analysis was performed from an integrated payer-provider network perspective. Infection rates, antibacterial envelope effectiveness, infection treatment costs and patterns, infection-related mortality, and utility estimates were obtained from the WRAP-IT trial. Life expectancy and long-term costs associated with device replacement, follow-up, and healthcare utilization were sourced from the literature. Costs and quality-adjusted life years were discounted at 3%. An upper willingness-to-pay threshold of $150 000 per quality-adjusted life year was used to determine cost-effectiveness, in alignment with the American College of Cardiology/American Heart Association practice guidelines and as supported by the World Health Organization and contemporary literature.

Results: The base case incremental cost-effectiveness ratio of the antibacterial envelope compared with standard-of-care was $112 603/quality-adjusted life year. The incremental cost-effectiveness ratio remained lower than the willingness-to-pay threshold in 74% of iterations in the probabilistic sensitivity analysis and was most sensitive to the following model inputs: infection-related mortality, life expectancy, and infection cost.

Conclusions: The absorbable antibacterial envelope was associated with a cost-effectiveness ratio below contemporary benchmarks in the WRAP-IT patient population, suggesting that the envelope provides value for the US healthcare system by reducing the incidence of cardiac implantable electronic device infection. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02277990.
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http://dx.doi.org/10.1161/CIRCEP.120.008503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566304PMC
October 2020

Impact of Cardiac Implantable Electronic Device Infection: A Clinical and Economic Analysis of the WRAP-IT Trial.

Circ Arrhythm Electrophysiol 2020 05 12;13(5):e008280. Epub 2020 Apr 12.

Department of Cardiovascular Medicine and Heart and Vascular Institute, Cleveland Clinic, OH (B.L.W., K.G.T.).

Background: Current understanding of the impact of cardiac implantable electronic device (CIED) infection is based on retrospective analyses from medical records or administrative claims data. The WRAP-IT (Worldwide Randomized Antibiotic Envelope Infection Prevention Trial) offers an opportunity to evaluate the clinical and economic impacts of CIED infection from the hospital, payer, and patient perspectives in the US healthcare system.

Methods: This was a prespecified, as-treated analysis evaluating outcomes related to major CIED infections: mortality, quality of life, disruption of CIED therapy, healthcare utilization, and costs. Payer costs were assigned using medicare fee for service national payments, while medicare advantage, hospital, and patient costs were derived from similar hospital admissions in administrative datasets.

Results: Major CIED infection was associated with increased all-cause mortality (12-month risk-adjusted hazard ratio, 3.41 [95% CI, 1.81-6.41]; <0.001), an effect that sustained beyond 12 months (hazard ratio through all follow-up, 2.30 [95% CI, 1.29-4.07]; =0.004). Quality of life was reduced (=0.004) and did not normalize for 6 months. Disruptions in CIED therapy were experienced in 36% of infections for a median duration of 184 days. Mean costs were $55 547±$45 802 for the hospital, $26 867±$14 893, for medicare fee for service and $57 978±$29 431 for Medicare Advantage (mean hospital margin of -$30 828±$39 757 for medicare fee for service and -$6055±$45 033 for medicare advantage). Mean out-of-pocket costs for patients were $2156±$1999 for medicare fee for service, and $1658±$1250 for medicare advantage.

Conclusions: This large, prospective analysis corroborates and extends understanding of the impact of CIED infections as seen in real-world datasets. CIED infections severely impact mortality, quality of life, healthcare utilization, and cost in the US healthcare system. Registration: URL: https://www.clinicaltrials.gov Unique Identifier: NCT02277990.
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http://dx.doi.org/10.1161/CIRCEP.119.008280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237027PMC
May 2020

Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis.

J Clin Invest 2020 07;130(7):3750-3760

ContraFect Corporation, Yonkers, New York, USA.

BACKGROUNDNovel therapeutic approaches are critically needed for Staphylococcus aureus bloodstream infections (BSIs), particularly for methicillin-resistant S. aureus (MRSA). Exebacase, a first-in-class antistaphylococcal lysin, is a direct lytic agent that is rapidly bacteriolytic, eradicates biofilms, and synergizes with antibiotics.METHODSIn this superiority-design study, we randomly assigned 121 patients with S. aureus BSI/endocarditis to receive a single dose of exebacase or placebo. All patients received standard-of-care antibiotics. The primary efficacy endpoint was clinical outcome (responder rate) on day 14.RESULTSClinical responder rates on day 14 were 70.4% and 60.0% in the exebacase + antibiotics and antibiotics-alone groups, respectively (difference = 10.4, 90% CI [-6.3, 27.2], P = 0.31), and were 42.8 percentage points higher in the prespecified exploratory MRSA subgroup (74.1% vs. 31.3%, difference = 42.8, 90% CI [14.3, 71.4], ad hoc P = 0.01). Rates of adverse events (AEs) were similar in both groups. No AEs of hypersensitivity to exebacase were reported. Thirty-day all-cause mortality rates were 9.7% and 12.8% in the exebacase + antibiotics and antibiotics-alone groups, respectively, with a notable difference in MRSA patients (3.7% vs. 25.0%, difference = -21.3, 90% CI [-45.1, 2.5], ad hoc P = 0.06). Among MRSA patients in the United States, median length of stay was 4 days shorter and 30-day hospital readmission rates were 48% lower in the exebacase-treated group compared with antibiotics alone.CONCLUSIONThis study establishes proof of concept for exebacase and direct lytic agents as potential therapeutics and supports conduct of a confirmatory study focused on exebacase to treat MRSA BSIs.TRIAL REGISTRATIONClinicaltrials.gov NCT03163446.FUNDINGContraFect Corporation.
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http://dx.doi.org/10.1172/JCI136577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7324170PMC
July 2020

A pooled analysis of patients with wound infections in the Phase 3 REVIVE trials: randomized, double-blind studies to evaluate the safety and efficacy of iclaprim versus vancomycin for treatment of acute bacterial skin and skin structure infections.

J Med Microbiol 2020 Apr;69(4):625-630

Motif BioSciences, Princeton, New Jersey, USA.

Iclaprim is a diaminopyrimidine antibiotic for the treatment of acute bacterial skin and skin structure infections (ABSSSI) due to Gram-positive pathogens. This analysis evaluates patients with wound infections from two Phase 3 trials of ABSSSI. 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 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. 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 (=17) compared with iclaprim (=6) and fatigue with iclaprim (=17) compared with vancomycin (=8). 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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http://dx.doi.org/10.1099/jmm.0.001177DOI Listing
April 2020

Activity of Eravacycline against Gram-Negative Bacilli Isolated in Clinical Laboratories Worldwide from 2013 to 2017.

Antimicrob Agents Chemother 2020 02 21;64(3). Epub 2020 Feb 21.

Tetraphase Pharmaceuticals, Watertown, Massachusetts, USA.

Eravacycline is a novel, fully synthetic fluorocycline antibiotic developed for the treatment of serious infections, including those caused by multidrug-resistant (MDR) pathogens. Here, we evaluated the activities of eravacycline and comparator antimicrobial agents against a global collection of frequently encountered clinical isolates of Gram-negative bacilli. The CLSI broth microdilution method was used to determine MIC data for isolates of ( = 13,983), ( = 2,097), ( = 1,647), and ( = 1,210) isolated primarily from respiratory, intra-abdominal, and urinary specimens by clinical laboratories in 36 countries from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. Multidrug-resistant (MDR) isolates were defined by resistance to agents from ≥3 different antimicrobial classes. The MICs ranged from 0.25 to 1 μg/ml for and were 1 μg/ml for and 2 μg/ml for , , and Eravacycline's potency was up to 4-fold greater than that of tigecycline against genera/species of , , and The MICs for five of six individual genera/species of and were within 2-fold of the MICs for their respective subsets of MDR isolates, while the MDR subpopulation of spp. demonstrated 4-fold higher MICs. Eravacycline demonstrated potent activity against the majority of clinical isolates of Gram-negative bacilli, including MDR isolates, collected over a 5-year period. This study further underscores the potential benefit of eravacycline in the treatment of infections caused by MDR Gram-negative pathogens.
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http://dx.doi.org/10.1128/AAC.01699-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038303PMC
February 2020

Activity of Eravacycline against Gram-Positive Bacteria Isolated in Clinical Laboratories Worldwide from 2013 to 2017.

Antimicrob Agents Chemother 2020 02 21;64(3). Epub 2020 Feb 21.

Tetraphase Pharmaceuticals, Watertown, Massachusetts, USA.

Eravacycline is a novel, fully synthetic fluorocycline antibiotic being developed for the treatment of serious infections, including those caused by resistant Gram-positive pathogens. Here, we evaluated the activities of eravacycline and comparator antimicrobial agents against a recent global collection of frequently encountered clinical isolates of Gram-positive bacteria. The CLSI broth microdilution method was used to determine MIC data for isolates of spp. ( = 2,807), spp. ( = 4,331), and spp. ( = 3,373) isolated primarily from respiratory, intra-abdominal, urinary, and skin specimens by clinical laboratories in 37 countries on three continents from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. There were no substantive differences (a >1-doubling-dilution increase or decrease) in eravacycline MIC values for different species/organism groups over time or by region. Eravacycline showed MIC and MIC results of 0.06 and 0.12 μg/ml, respectively, when tested against , regardless of methicillin susceptibility. The MIC values of eravacycline for and were equal (0.5 μg/ml). The eravacycline MICs for and were 0.06 μg/ml and were within 1 doubling dilution regardless of the vancomycin susceptibility profile. Eravacycline exhibited MIC results of ≤0.06 μg/ml when tested against and beta-hemolytic and viridans group streptococcal isolates. In this surveillance study, eravacycline demonstrated potent activity against frequently isolated clinical isolates of Gram-positive bacteria (, , and spp.), including isolates collected over a 5-year period (2013 to 2017), underscoring its potential benefit in the treatment of infections caused by common Gram-positive pathogens.
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http://dx.doi.org/10.1128/AAC.01715-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038300PMC
February 2020

International Society of Cardiovascular Infectious Diseases Guidelines for the Diagnosis, Treatment and Prevention of Disseminated Mycobacterium chimaera Infection Following Cardiac Surgery with Cardiopulmonary Bypass.

J Hosp Infect 2020 Feb 9;104(2):214-235. Epub 2019 Nov 9.

Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, College of Medicine and Science, Rochester, MN, USA.

Mycobacterial infection-related morbidity and mortality in patients following cardiopulmonary bypass surgery is high and there is a growing need for a consensus-based expert opinion to provide international guidance for diagnosing, preventing and treating in these patients. In this document the International Society for Cardiovascular Infectious Diseases (ISCVID) covers aspects of prevention (field of hospital epidemiology), clinical management (infectious disease specialists, cardiac surgeons, ophthalmologists, others), laboratory diagnostics (microbiologists, molecular diagnostics), device management (perfusionists, cardiac surgeons) and public health aspects.
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http://dx.doi.org/10.1016/j.jhin.2019.10.009DOI Listing
February 2020

A Pooled Analysis of the Safety and Efficacy of Iclaprim Versus Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections in Patients With Intravenous Drug Use: Phase 3 REVIVE Studies.

Clin Ther 2019 06 25;41(6):1090-1096. Epub 2019 Apr 25.

Duke University Medical Center, Durham, NC, USA.

Purpose: This analysis evaluates the efficacy and safety of iclaprim versus vancomycin for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in patients who were intravenous drug users (IVDUs).

Methods: A total of 621 patients who were IVDUs from 2 parallel Phase III, double-blind, randomized (1:1), active-controlled, multinational, multicenter trials (REVIVE-1 and REVIVE-2) were analyzed separately and pooled. This post hoc analysis summarizes the efficacy and safety profile of iclaprim 80 mg fixed dose compared with vancomycin 15 mg/kg administered intravenously during 2 h every 12 h for 5-14 days among this population. The primary end point of these studies was to determine whether iclaprim was noninferior (10% margin) to vancomycin in achieving a ≥20% reduction in lesion size at 48-72 h after initiation of treatment with the study drug (early clinical response) in the intent-to-treat population. The safety profile was assessed based on adverse events and laboratory parameters.

Findings: Iclaprim had higher early clinical response rates (85.8%; 95% CI, 81.5%-89.4%) compared with vancomycin (79.8%; 95% CI, 74.8%-84.2%) among patients with ABSSSIs who were IVDUs, with a treatment difference of +6.00% (95% CI, 0.06-12.0). The safety profile was similar in the iclaprim and vancomycin arms, with 3.7% and 5.0%, respectively, of patients discontinuing study therapy because of adverse events and 1.9% and 3.4%, respectively, of patients developing serious adverse events.

Implications: Iclaprim had a higher early clinical response rate and favorable safety profile compared with vancomycin for the treatment of ABSSSIs in patients who were IVDUs. Iclaprim may be a valuable treatment option for ABSSSIs in this patient population.
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http://dx.doi.org/10.1016/j.clinthera.2019.04.004DOI Listing
June 2019

Delafloxacin in Acute Bacterial Skin and Skin Structure Infections.

Clin Infect Dis 2019 04;68(Suppl 3):S191-S192

College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan.

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http://dx.doi.org/10.1093/cid/ciy1089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451998PMC
April 2019

Ceftaroline fosamil therapy in patients with acute bacterial skin and skin-structure infections with systemic inflammatory signs: A retrospective dose comparison across three pivotal trials.

Int J Antimicrob Agents 2019 Jun 1;53(6):830-837. Epub 2019 Feb 1.

Hampshire Hospitals NHS Foundation Trust, Winchester, UK. Electronic address:

This post-hoc analysis compared the pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h) in patients with acute bacterial skin and skin-structure infection (ABSSSI) and signs of sepsis. Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response syndrome (SIRS) as well as ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between the COVERS trial (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposure among patients in COVERS with or without markers of sepsis was compared using population pharmacokinetic modelling. In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic inflammatory sign or SIRS, respectively, compared with 55% (378/693) and 22% (155/693), respectively, in the CANVAS trials. Clinical cure rates for the modified intent-to-treat population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis [82% (255/312) and 85% (335/394)] and for those with SIRS [84% (168/199) and 85% (131/155)]. Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposure. Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposure was not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis [ClinicalTrials.gov ID: NCT01499277, NCT00424190, NCT00423657].
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http://dx.doi.org/10.1016/j.ijantimicag.2019.01.016DOI Listing
June 2019

Good Studies Evaluate the Disease While Great Studies Evaluate the Patient: Development and Application of a Desirability of Outcome Ranking Endpoint for Staphylococcus aureus Bloodstream Infection.

Clin Infect Dis 2019 05;68(10):1691-1698

Duke University Medical Center, Durham, North Carolina.

Background: Desirability of outcome ranking (DOOR) is an innovative approach in clinical trials to evaluate the global benefits and risks of an intervention. We developed and validated a DOOR endpoint for Staphylococcus aureus bloodstream infection (BSI) through a survey to infectious diseases clinicians and secondary analysis of trial data.

Methods: We administered a survey of 20 cases of S. aureus BSI, asking respondents to rank outcomes by global desirability. Correlations and percentage of pairwise agreement among rankings were estimated to inform development of a DOOR endpoint, which was applied to 2 prior S. aureus BSI trials. The probability that a patient randomly assigned to experimental treatment would have a better DOOR ranking than if assigned to control was estimated. Results were also analyzed using partial credit, which is analogous to scoring an academic test, assigning 100% to the most desirable outcome, 0% to the least, and "partial credit" to intermediate ranks.

Results: Forty-two recipients (97%) completed the survey. The DOOR endpoint fitting these rankings (r = 0.89; 95% confidence interval, 0.67 to 0.94) incorporated survival plus cumulative occurrence of adverse events, cure, infectious complications, and ongoing symptoms. Tailored versions of this endpoint were applied to 2 S. aureus BSI trials, and both demonstrated no benefit of the experimental treatment using DOOR and partial credit analysis.

Conclusions: Using S. aureus BSI as an exemplar, we developed a DOOR endpoint that can be used as a template for development of DOOR endpoints for other diseases. Future trials can incorporate DOOR to allow for global assessment of patient experience.
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http://dx.doi.org/10.1093/cid/ciy766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495020PMC
May 2019

Iclaprim: a differentiated option for the treatment of skin and skin structure infections.

Expert Rev Anti Infect Ther 2018 11 23;16(11):793-803. Epub 2018 Oct 23.

c Department of Medicine , Duke University Medical Center , Durham , NC , USA.

Introduction: Iclaprim is a selective bacterial dihydrofolate reductase (DHFR) inhibitor. Although there are alternative options for the treatment of acute bacterial skin and skin structure infections (ABSSSI), iclaprim is differentiated from other available antibiotics. Areas covered: Iclaprim is under clinical development for ABSSSI. This review summarizes the mechanism of action, pharmacokinetics, microbiology, clinical development program, and the differentiation of iclaprim from other antibiotics. Expert commentary: Iclaprim has a different mechanism of action (DHFR inhibitor) compared to most other antibiotics, is active and rapidly bactericidal against Gram-positive pathogens including antibiotic-resistant pathogens, and suppresses bacterial exotoxins (alpha hemolysin, Panton Valentine leukocidin, and toxic shock syndrome toxin-1). Compared to trimethoprim, iclaprim has lower MIC, can be given without a sulfonamide, overcomes select trimethoprim resistance, and does not cause hyperkalemia. Iclaprim is administered as a fixed dose, does not require dose adjustment in renally-impaired or obese patients, and was not associated with nephrotoxicity in the Phase 3 pivotal REVIVE studies. Iclaprim represents a novel, alternative option for the treatment of severe skin and skin structure infections due to Gram-positive bacteria, particularly in patients at risk of acute kidney injury.
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http://dx.doi.org/10.1080/14787210.2018.1536545DOI Listing
November 2018

Surveillance of iclaprim activity: in vitro susceptibility of Gram-positive skin infection pathogens collected from 2015 to 2016 from North America and Europe.

Diagn Microbiol Infect Dis 2019 Feb 10;93(2):154-158. Epub 2018 Sep 10.

Leeds Teaching Hospitals & University of Leeds, Leeds, UK.

Iclaprim is a diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and surveillance data prior to 2006 suggested that iclaprim was active against Gram-positive pathogens including emerging drug-resistant pathogens. In an era of increasing antimicrobial resistance, we undertook testing iclaprim and comparators against 931 Gram-positive clinical isolates from the United States and Europe collected between 2015 and 2016. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing criteria. MIC/MIC was 0.03/0.12 for all Staphylococcus aureus, 0.06/0.06 for methicillin-susceptible S. aureus, 0.03/0.12 for methicillin-resistant S. aureus, 0.12/0.5 for Streptococcus agalactiae, ≤0.015/≤0.015 for Streptococcus anginosus, 0.03/0.06 for Streptococcus dysgalactiae, and ≤0.015 /0.03 μg/mL for Streptococcus pyogenes. Iclaprim was active against a contemporary collection (2015-2016) of Gram-positive bacteria isolated from the skin or soft tissue from patients with SSSI from the United States and Europe.
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http://dx.doi.org/10.1016/j.diagmicrobio.2018.09.002DOI Listing
February 2019

Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.

JAMA 2018 09;320(12):1249-1258

Duke University Medical Center, Durham, North Carolina.

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown.

Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events.

Design, Setting, And Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization.

Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care.

Main Outcomes And Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia.

Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]).

Conclusions And Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm.

Trial Registration: ClinicalTrials.gov Identifier: NCT01191840.
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http://dx.doi.org/10.1001/jama.2018.13155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233609PMC
September 2018

Considerations for Clinical Trials of Staphylococcus aureus Bloodstream Infection in Adults.

Clin Infect Dis 2019 02;68(5):865-872

Department of Medicine, Duke University Medical Center, Durham, North Carolina.

Clinical trials for Staphylococcus aureus bloodstream infections (SAB) are broadly grouped into 2 categories: registrational trials intended to support regulatory approval of antibiotics for the treatment of SAB and strategy trials intended to inform clinicians on the best treatment options for SAB among existing antibiotics. Both types of SAB trials are urgently needed but have been limited by cost, complexity, and regulatory uncertainty. Here, we review key SAB trial design considerations for investigators, sponsors, and regulators.
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http://dx.doi.org/10.1093/cid/ciy774DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376080PMC
February 2019

UK & Ireland Prostate Brachytherapy Practice Survey 2014-2016.

J Contemp Brachytherapy 2018 Jun 29;10(3):238-245. Epub 2018 Jun 29.

Department of Clinical Oncology, Northern Ireland Cancer Centre, Belfast City Hospital.

Purpose: To document the current prostate brachytherapy practice across the UK and Ireland and compare with previously published audit results.

Material And Methods: Participants from 25 centers attending the annual UK & Ireland Prostate Brachytherapy Conference were invited to complete an online survey. Sixty-three questions assessed the center's experience and staffing, clinician's experience, clinical selection criteria and scheduling, number of cases per modality in the preceding three years, low-dose-rate (LDR) pre- and post-implant technique and high-dose-rate (HDR) implant technique. Responses were collated, and descriptive statistical analysis performed.

Results: Eighteen (72%) centers responded with 17 performing LDR only, 1 performing HDR only, and 6 performing both LDR and HDR. Seventy-one percent of centers have > 10 years of LDR brachytherapy experience, whereas 71% centers that perform HDR brachytherapy have > 5 years of experience. Thirteen centers have 2 or more clinicians performing brachytherapy with 61% of lead consultants performing > 25 cases (LDR + HDR) in 2016. The number of implants (range), that includes LDR and HDR, performed by individual practitioners in 2016 was > 50 by 21%, 25-50 by 38%, and < 25 by 41%. Eight centers reported a decline in LDR monotherapy case numbers in 2016. Number of center's performing HDR brachytherapy increased in last five years. Relative uniformity in patient selection is noted, and LDR pre- and post-implant dosimetry adheres to published quality guidelines, with an average post-implant D of > 145 Gy in 69% of centers in 2014 and 2015 compared to 63% in 2016. The median CT/US volume ratios were > 0.9 ≤ 1.0 ( = 4), > 1.0 ≤ 1.1 ( = 7), and > 1.1 ( = 2).

Conclusion: There is considerable prostate brachytherapy experience in the UK and Ireland. An apparent fall in LDR case numbers is noted. Maintenance of case numbers and ongoing compliance with published quality guidelines is important to sustain high quality outcomes.
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http://dx.doi.org/10.5114/jcb.2018.76839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052390PMC
June 2018

Pooled analysis of the phase 3 REVIVE trials: randomised, double-blind studies to evaluate the safety and efficacy of iclaprim versus vancomycin for treatment of acute bacterial skin and skin-structure infections.

Int J Antimicrob Agents 2018 Aug 19;52(2):233-240. Epub 2018 May 19.

Department of Pulmonology, Hospital Clinic of Barcelona, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomedica en red de Enfermedades Respiratorias, Barcelona, Spain.

Iclaprim, a diaminopyrimidine antimicrobial, was compared with vancomycin for treatment of patients with acute bacterial skin and skin-structure infections (ABSSSIs) in two studies (REVIVE-1 and REVIVE-2). Here, the efficacy and tolerability of iclaprim in a pooled analysis of results from both studies was explored. REVIVE-1 and REVIVE-2 were phase 3, double-blind, randomised, multicentre, active-controlled, non-inferiority (margin of 10%) trials, each designed to enrol 600 patients with ABSSSI using identical study protocols. Iclaprim 80 mg and vancomycin 15 mg/kg were administered intravenously every 12 h for 5-14 days. The primary endpoint was a ≥20% reduction from baseline in lesion size [early clinical response (ECR)] at the early time point (ETP) (48-72 h after starting study drug) in the intent-to-treat population. In REVIVE-1, ECR at the ETP was 80.9% with iclaprim versus 81.0% with vancomycin (treatment difference -0.13%, 95% CI -6.42% to 6.17%). In REVIVE-2, ECR was 78.3% with iclaprim versus 76.7% with vancomycin (treatment difference 1.58%, 95% CI -5.10% to 8.26%). The pooled ECR was 79.6% with iclaprim versus 78.8% with vancomycin (treatment difference 0.75%, 95% CI -3.84 to 5.35%). Iclaprim and vancomycin were comparable for the incidence of mostly mild adverse events, except for a higher incidence of elevated serum creatinine with vancomycin (n = 7) compared with iclaprim (n = 0). Iclaprim achieved non-inferiority compared with vancomycin for ECR at the ETP and secondary endpoints with a similar safety profile in two phase 3 studies for treatment of ABSSSI suspected or confirmed as caused by Gram-positive pathogens. [Clinical Trials Registration. NCT02600611 and NCT02607618.].
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http://dx.doi.org/10.1016/j.ijantimicag.2018.05.012DOI Listing
August 2018

A Phase 3, Randomized, Double-Blind, Multicenter Study To Evaluate the Safety and Efficacy of Intravenous Iclaprim versus Vancomycin for Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed To Be Due to Gram-Positive Pathogens (REVIVE-2 Study).

Antimicrob Agents Chemother 2018 05 26;62(5). Epub 2018 Apr 26.

Motif BioSciences, New York, New York, USA, and Rutgers New Jersey Medical School, Newark, New Jersey, USA

Iclaprim is a novel diaminopyrimidine antibiotic that may be an effective and safe treatment for serious skin infections. The safety and effectiveness of iclaprim were assessed in a global phase 3, double-blind, randomized, active-controlled trial. Six hundred thirteen adults with acute bacterial skin and skin structure infections (ABSSSIs) suspected or confirmed to be due to Gram-positive pathogens were randomized to iclaprim (80 mg) or vancomycin (15 mg/kg of body weight), both of which were administered intravenously every 12 h for 5 to 14 days. The primary endpoint was a ≥20% reduction in lesion size compared with that at the baseline at 48 to 72 h after the start of administration of study drug in the intent-to-treat population. Among patients randomized to iclaprim, 78.3% (231 of 295) met this primary endpoint, whereas 76.7% (234 of 305) of those receiving vancomycin met this primary endpoint (difference, 1.58%; 95% confidence interval, -5.10% to 8.26%). This met the prespecified 10% noninferiority margin. Iclaprim was well tolerated, with most adverse events being categorized as mild. In conclusion, iclaprim was noninferior to vancomycin in this phase 3 clinical trial for the treatment of acute bacterial skin and skin structure infections. On the basis of these results, iclaprim may be an efficacious and safe treatment for skin infections suspected or confirmed to be due to Gram-positive pathogens. (This trial has been registered at ClinicalTrials.gov under identifier NCT02607618.).
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http://dx.doi.org/10.1128/AAC.02580-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923167PMC
May 2018

Single Intravenous Dose of Oritavancin for Treatment of Acute Skin and Skin Structure Infections Caused by Gram-Positive Bacteria: Summary of Safety Analysis from the Phase 3 SOLO Studies.

Antimicrob Agents Chemother 2018 04 27;62(4). Epub 2018 Mar 27.

Sharp Chula Vista Medical Center, Chula Vista, California, USA.

Oritavancin is a lipoglycopeptide with bactericidal activity against Gram-positive organisms. Its rapid concentration-dependent bactericidal activity and long elimination half-life allow single-dose treatment of acute bacterial skin and skin structure infections (ABSSSI). SOLO I and SOLO II were randomized, double-blind studies evaluating the efficacy and safety of a single 1,200-mg intravenous (i.v.) dose of oritavancin versus twice-daily i.v. vancomycin for 7 to 10 days in ABSSSI patients. Safety data from both studies were pooled for safety analysis. The database comprised pooled safety data for 976 oritavancin-treated patients and 983 vancomycin-treated patients. The incidences of adverse events, serious adverse events, and discontinuations due to adverse events were similar for oritavancin (55.3, 5.8, and 3.7%, respectively) and vancomycin (56.9, 5.9, and 4.2%, respectively). The median time to onset (3.8 days versus 3.1 days, respectively) and the duration (3.0 days for both groups) of adverse events were also similar between the two groups. The most frequently reported events were nausea, headache, and vomiting. Greater than 90% of all events were mild or moderate in severity. There were slightly more infections and infestations, abscesses or cellulitis, and hepatic and cardiac adverse events in the oritavancin group; however, more than 80% of these events were mild or moderate. Subgroup analyses did not identify clinically meaningful differences in the incidence of adverse events attributed to oritavancin. A single 1,200-mg dose of oritavancin was well tolerated and had a safety profile similar to that of twice-daily vancomycin. The long elimination half-life of oritavancin compared to that of vancomycin did not result in a clinically meaningful delay to the onset or prolongation of adverse events. (This study has been registered at ClinicalTrials.gov under registration no. NCT01252719 and NCT01252732.).
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http://dx.doi.org/10.1128/AAC.01919-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5914007PMC
April 2018

Surveillance of iclaprim activity: In vitro susceptibility of gram-positive pathogens collected from 2012 to 2014 from the United States, Asia Pacific, Latin American and Europe.

Diagn Microbiol Infect Dis 2018 Apr 7;90(4):329-334. Epub 2017 Dec 7.

Leeds Teaching Hospitals & University of Leeds, Leeds, UK.

Iclaprim is a diaminopyrimidine, which inhibits bacterial dihydrofolate reductase, and it is highly active against Gram-positive pathogens including emerging drug-resistant pathogens. In vitro activity of iclaprim and comparators against 2814 Gram-positive clinical isolates from the United States, Asia Pacific, Latin American and Europe collected between 2012 and 2014 were tested. Susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Minimum inhibitory concentration (MIC) interpretations were based on CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. MIC/MIC for all S. aureus, methicillin susceptible S. aureus, methicillin resistant S. aureus, beta-hemolytic streptococci, and Streptococcus pneumoniae were 0.06/0.12, 0.06/0.12, 0.06/0.5, 0.06/0.25, and 0.06/2μg/mL, respectively. Iclaprim was 8 to 32-fold more potent than trimethoprim, the only FDA approved dihydrofolate reductase inhibitor, against all Gram-positive isolates including resistant phenotypes. The MIC of iclaprim was also lower than most of the comparators including linezolid and vancomycin against Gram-positive pathogens. Iclaprim demonstrated potent activity against a contemporary collection (2012-2014) of Gram-positive clinical isolates from the United States, Asia Pacific, Latin America and Europe.
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http://dx.doi.org/10.1016/j.diagmicrobio.2017.12.001DOI Listing
April 2018

A Phase 3, Randomized, Double-Blind, Multicenter Study to Evaluate the Safety and Efficacy of Intravenous Iclaprim Vs Vancomycin for the Treatment of Acute Bacterial Skin and Skin Structure Infections Suspected or Confirmed to be Due to Gram-Positive Pathogens: REVIVE-1.

Clin Infect Dis 2018 04;66(8):1222-1229

Duke University Medical Center, Durham, North Carolina.

Background: Our objective in this study was to demonstrate the safety and efficacy of iclaprim compared with vancomycin for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSIs).

Methods: REVIVE-1 was a phase 3, 600-patient, double-blinded, randomized (1:1), active-controlled trial among patients with ABSSSI that compared the safety and efficacy of iclaprim 80 mg fixed dose with vancomycin 15 mg/kg, both administered intravenously every 12 hours for 5-14 days. The primary endpoint of this study was a ≥20% reduction in lesion size (early clinical response [ECR]) compared with baseline among patients randomized to iclaprim or vancomycin at the early time point (ETP), 48 to 72 hours after the start of administration of study drug in the intent-to-treat population.

Results: ECR among patients who received iclaprim and vancomycin at the ETP was 80.9% (241 of 298) of patients receiving iclaprim compared with 81.0% (243 of 300) of those receiving vancomycin (treatment difference, -0.13%; 95% confidence interval, -6.42%-6.17%). Iclaprim was well tolerated in the study, with most adverse events categorized as mild.

Conclusions: Iclaprim achieved noninferiority (10% margin) at ETP compared with vancomycin and was well tolerated in this phase 3 clinical trial for the treatment of ABSSSI. Based on these results, iclaprim appears to be an efficacious and safe treatment for ABSSSI suspected or confirmed to be due to gram-positive pathogens.

Clinical Trials Registration: NCT02600611.
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http://dx.doi.org/10.1093/cid/cix987DOI Listing
April 2018

The effect of pulmonary surfactant on the in vitro activity of Iclaprim against common respiratory bacterial pathogens.

Diagn Microbiol Infect Dis 2018 Jan 20;90(1):64-66. Epub 2017 Sep 20.

Summa Health, Akron, OH.

The in vitro antimicrobial activity of iclaprim, a novel diaminopyrimidine, against common respiratory bacteria remained unchanged in the presence of pulmonary surfactant (Survanta®) at concentrations that greatly antagonized the antimicrobial activity of daptomycin. These results indicate that iclaprim could be a potential treatment for pneumonia caused by susceptible and multidrug resistant bacteria.
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http://dx.doi.org/10.1016/j.diagmicrobio.2017.09.011DOI Listing
January 2018

A Phase II Randomized, Double-blind, Multicenter Study to Evaluate Efficacy and Safety of Intravenous Iclaprim Versus Vancomycin for the Treatment of Nosocomial Pneumonia Suspected or Confirmed to be Due to Gram-positive Pathogens.

Clin Ther 2017 Aug 27;39(8):1706-1718. Epub 2017 Jul 27.

Duke University Medical Center, Durham, North Carolina.

Purpose: The primary objective of this Phase II study was to compare the clinical cure rates of 2 iclaprim dosages versus vancomycin in the treatment of patients with nosocomial pneumonia suspected or confirmed to be caused by gram-positive pathogens.

Methods: This study was a double-blind, randomized, multicenter trial. A total of 70 patients were randomized 1:1:1 to receive iclaprim 0.8 mg/kg IV q12h (iclaprim q12h; n = 23), iclaprim 1.2 mg/kg IV q8h (iclaprim q8h; n = 24), or vancomycin 1 g IV q12h (vancomycin; n = 23) for 7 to 14 days. The primary end point was clinical cure in the intention-to-treat population at test of cure (TOC; 7 [1] days' posttreatment) visit.

Findings: The baseline and demographic characteristics of patients treated with either iclaprim or vancomycin were comparable. Cure rates in the intention-to-treat population were 73.9% (17 of 23), 62.5% (15 of 24), and 52.2% (12 of 23) at the TOC visit in the iclaprim q12h, iclaprim q8h, and vancomycin groups, respectively (iclaprim q12h vs vancomycin, P = 0.13; iclaprim q8h vs vancomycin, P = 0.47). The death rates within 28 days of the start of treatment were 8.7% (2 of 23), 12.5% (3 of 24), and 21.7% (5 of 23) for the iclaprim q12h, iclaprim q8h, and vancomycin groups (no statistically significant differences). The adverse event profile of both iclaprim dosing regimens was similar to that of vancomycin.

Implications: Iclaprim had clinical cure rates and a safety profile comparable with vancomycin among patients with nosocomial pneumonia. Iclaprim could be an important new therapeutic option for the treatment of nosocomial pneumonia, and a pivotal clinical trial is warranted to evaluate its safety and efficacy in this indication.
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http://dx.doi.org/10.1016/j.clinthera.2017.07.007DOI Listing
August 2017

Efficacy and Safety of Oritavancin Relative to Vancomycin for Patients with Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in the Outpatient Setting: Results From the SOLO Clinical Trials.

Open Forum Infect Dis 2017 19;4(1):ofw274. Epub 2017 Jan 19.

Duke University Medical Center, Durham, North Carolina.

Background: The objective of this analysis was to evaluate the efficacy and safety of oritavancin compared with vancomycin for patients with acute bacterial skin and skin structure infections (ABSSSIs) who received treatment in the outpatient setting in the Phase 3 SOLO clinical trials.

Methods: SOLO I and SOLO II were 2 identically designed comparative, multicenter, double-blind, randomized studies to evaluate the efficacy and safety of a single 1200-mg dose of intravenous (IV) oritavancin versus 7-10 days of twice-daily IV vancomycin for the treatment of ABSSSI. Protocols were amended to allow enrolled patients to complete their entire course of antimicrobial therapy in an outpatient setting. The primary efficacy outcome was a composite endpoint (cessation of spread or reduction in size of the baseline lesion, absence of fever, and no rescue antibiotic at early clinical evaluation [ECE]) (48 to 72 hours). Key secondary endpoints included investigator-assessed clinical cure 7 to 14 days after end of treatment (posttherapy evaluation [PTE]) and 20% or greater reduction in lesion area at ECE. Safety was assessed until day 60.

Results: Seven hundred ninety-two patients (oritavancin, 392; vancomycin, 400) received entire course of treatment in the outpatient setting. Efficacy response rates at ECE and PTE were similar (primary composite endpoint at ECE: 80.4% vs 77.5% for oritavancin and vancomycin, respectively) as was incidence of adverse events. Five patients (1.3%) who received oritavancin and 9 (2.3%) vancomycin patients were subsequently admitted to a hospital.

Conclusions: Oritavancin provides a single-dose alternative to multidose vancomycin for treatment of ABSSSI in the outpatient setting.
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http://dx.doi.org/10.1093/ofid/ofw274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414048PMC
January 2017

Gram-Positive Bacterial Infections: Research Priorities, Accomplishments, and Future Directions of the Antibacterial Resistance Leadership Group.

Clin Infect Dis 2017 Mar;64(suppl_1):S24-S29

Division of Infectious Diseases, Duke University School of Medicine, Durham, North Carolina.

Antimicrobial resistance in gram-positive bacteria remains a challenge in infectious diseases. The mission of the Gram-Positive Committee of the Antibacterial Resistance Leadership Group (ARLG) is to advance knowledge in the prevention, management, and treatment of these challenging infections to improve patient outcomes. Our committee has prioritized projects involving methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) due to the scope of the medical threat posed by these pathogens. Approved ARLG projects involving gram-positive pathogens include (1) a pharmacokinetics/pharmacodynamics study to evaluate the impact of vancomycin dosing on patient outcome in MRSA bloodstream infection (BSI); (2) defining, testing, and validating innovative assessments of patient outcomes for clinical trials of MRSA-BSI; (3) testing new strategies for "step-down" antibiotic therapy for MRSA-BSI; (4) management of staphylococcal BSIs in neonatal intensive care units; and (5) defining the impact of VRE bacteremia and daptomycin susceptibility on patient outcomes. This article outlines accomplishments, priorities, and challenges for research of infections caused by gram-positive organisms.
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http://dx.doi.org/10.1093/cid/ciw828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850444PMC
March 2017

Assessment of telavancin minimal inhibitory concentrations by revised broth microdilution method in phase 3 complicated skin and skin-structure infection clinical trial isolates.

Diagn Microbiol Infect Dis 2017 Mar 14;87(3):268-271. Epub 2016 Dec 14.

Theravance Biopharma US, Inc., South San Francisco, CA, USA.

The broth microdilution (BMD) MIC testing method for telavancin was recently revised BMD (rBMD) to improve accuracy and reproducibility. Staphylococcus aureus isolates from telavancin phase 3 complicated skin and skin-structure infection (cSSSI) studies were tested using the rBMD method. Retesting of 1132 isolates produced MICs ranging from ≤0.015 to 0.12μg/mL that were 8-fold lower than the original method. All isolates tested remained susceptible to telavancin at the revised susceptibility breakpoint of 0.12μg/mL. The clinical cure and microbiological eradication rates were 90% (368/409) and 89% (366/409) for telavancin-treated patients, and were similar for patients with methicillin-susceptible and -resistant S. aureus isolates and S. aureus isolates with elevated vancomycin MICs (≥1μg/mL). The data presented here are aimed to update the literature and better inform clinicians and clinical microbiologists about the revised telavancin MICs, as well as the corresponding clinical and microbiological cure rates for cSSSI patients.
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http://dx.doi.org/10.1016/j.diagmicrobio.2016.12.009DOI Listing
March 2017

A randomized, blinded, multicenter trial of a gentamicin vancomycin gel (DFA-02) in patients undergoing abdominal surgery.

Am J Surg 2017 Jun 18;213(6):1003-1009. Epub 2016 Nov 18.

Dr. Reddy's Laboratories, Inc., Princeton, NJ, USA.

Background: SI is a significant medical problem. DFA-02 is an investigational bioresorbable modified release gel consisting of both gentamicin (16.8 mg/mL) and vancomycin (18.8 mg/mL). A Phase 2a study, where the drug was applied during surgical incision closure, suggested safety and tolerability but was not designed to assess its efficacy.

Study Design: In a Phase 2b randomized, blinded trial patients undergoing abdominal, primarily colorectal, surgery were randomized (4:1:1) to one of three study arms: DFA-02, matching placebo gel, or standard of care (SOC) involving irrigation of the wound with normal saline. The DFA-02 and placebo gel groups received up to 20 mL of study drug inserted above the fascia during wound closure, and were treated in a double-blind manner; the SOC group was treated in a single-blind manner. The primary endpoint was SSI (adjudicated centrally by a blinded committee) through postoperative day 30.

Results: Overall, 445 subjects (intention-to-treat) were randomized at 35 centers with 425 subjects completing the study and being evaluable. There were 67 SSIs (15.8%): 64.2% superficial, 7.5% deep, and 28.4% organ space. The incidence of SSI was not statistically significantly different between the DFA-02 and the placebo gel/SOC arms combined, 42/287 = 14.6% vs 25/138 = 18.1% (p = 0.36), respectively. Rehospitalization within 30 days was also similar between study groups (DFA-02 28.6%, placebo gel 21.4%, SOC 27.3%).

Conclusion: In this multicenter, blinded, randomized trial with central adjudication, the gentamicin/vancomycin gel was not associated with a significant reduction in SSI.

Summary: Patients undergoing abdominal surgery were randomized to one of three study arms: DFA-02 gel consisting of both gentamicin and vancomycin, matching placebo gel, or standard of care (SOC). Of 425 patients completing the study at 35 sites the gentamicin/vancomycin gel was not associated with a significant reduction in SSI.
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http://dx.doi.org/10.1016/j.amjsurg.2016.10.007DOI Listing
June 2017

Pooled analysis of single-dose oritavancin in the treatment of acute bacterial skin and skin-structure infections caused by Gram-positive pathogens, including a large patient subset with methicillin-resistant Staphylococcus aureus.

Int J Antimicrob Agents 2016 Nov 13;48(5):528-534. Epub 2016 Sep 13.

Sharp Chula Vista Medical Center, 751 Medical Center Ct., Chula Vista, CA 91911, USA.

Oritavancin is a lipoglycopeptide antibiotic with bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). The phase 3 studies SOLO I and SOLO II demonstrated comparable efficacy and safety of a single dose of oritavancin compared with 7-10 days of twice-daily vancomycin in adults with acute bacterial skin and skin-structure infections (ABSSSIs). The present analysis assessed clinical responses by pathogen at 48-72 h and at study days 14-24 in SOLO patients within the pooled data set. Of the 1959 patients in the pooled SOLO studies, 1067 had at least one baseline Gram-positive pathogen and 405 had MRSA. Clinical response rates were similar for oritavancin- and vancomycin-treated patients by pathogen, including Staphylococcus aureus with or without the Panton-Valentine leukocidin (pvl) gene and from different clonal complexes, and were similar for pathogens within each treatment group. Oritavancin exhibited potent in vitro activity against all baseline pathogens, with MIC values (minimum inhibitory concentration required to inhibit 90% of the isolates) of 0.12 µg/mL for Staphylococcus  aureus, 0.25 µg/mL for Streptococcus pyogenes and 0.06 µg/mL for Enterococcus faecalis. Whereas both oritavancin and vancomycin achieved similarly high rates of clinical response by pathogen, including methicillin-susceptible and -resistant Staphylococcus aureus, oritavancin provides a single-dose alternative to 7-10 days of twice-daily vancomycin to treat ABSSSIs.
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http://dx.doi.org/10.1016/j.ijantimicag.2016.07.019DOI Listing
November 2016

Assessment of Minimum Inhibitory Concentrations of Telavancin by Revised Broth Microdilution Method in Phase 3 Hospital-Acquired Pneumonia/Ventilator-Associated Pneumonia Clinical Isolates.

Infect Dis Ther 2016 Dec 7;5(4):535-544. Epub 2016 Oct 7.

Theravance Biopharma US, Inc., South San Francisco, CA, USA.

Introduction: The broth microdilution method (BMD) for testing telavancin minimum inhibitory concentrations (MICs) was revised (rBMD) in 2014 to improve the accuracy, precision, and reproducibility of the testing method. The aim of this study was to determine the effect of the revised method on telavancin MIC values for Staphylococcus aureus (S. aureus) clinical isolates obtained from hospital-acquired pneumonia (HAP) patients.

Methods: Isolates from patients who participated in the phase 3 Assessment of Telavancin for Treatment of HAP Studies were retested using the rBMD method.

Results: Retesting of 647 isolates produced a range of telavancin MIC values from 0.015 µg/mL to 0.12 µg/mL with MIC values of 0.06/0.06 µg/mL for the total pool of samples. For methicillin-resistant S. aureus (MRSA), MIC values were 0.06/0.12 µg/mL. These values are up to 4-fold lower than MIC values obtained using the original method. These results were used in part to justify lowering the telavancin breakpoints. All tested isolates remained susceptible to telavancin at the revised susceptibility breakpoint of ≤0.12 µg/mL. Overall, the clinical cure rate for microbiologically evaluable telavancin-treated patients was 78% for S. aureus, 76% for patients with MRSA, and 79% for patients with isolates with reduced susceptibility to vancomycin (MIC ≥1 µg/mL).

Conclusion: Results from the rBMD method support the in vitro potency of telavancin against S. aureus.

Trial Registration: ATTAIN (NCT00107952 and NCT00124020).

Funding: Theravance Biopharma Antibiotics, Inc.
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http://dx.doi.org/10.1007/s40121-016-0133-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5125136PMC
December 2016