Considerations for Clinical Trials of <i>Staphylococcus aureus</i> Bloodstream Infection in Adults

Holland, David; Chambers, Henry F.; Boucher, Helen W.; Corey, G. Ralph; Coleman, Ryan G.; Castaneda-Ruiz, Bibiana; Fowler, Vance G.

doi:10.1093/cid/ciy774

Cited by 36 publications

(20 citation statements)

References 46 publications

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“…Mortality and complications such as persistent bacteremia and infection relapse have been observed in >30% of cases despite appropriate antibiotic therapy, and patients with complicated tissue foci of infections are more likely to have poor outcomes [1, 2]. Risk stratification biomarkers offer a potential adjunctive tool for the identification of patients with S. aureus bacteremia at higher risk for poor outcomes, which could not only inform best management practices, but also facilitate clinical development of new drugs by identifying the patients who would most benefit from novel therapeutics [3].…”

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confidence: 99%

Prognostic Power of Pathogen Cell-Free DNA in Staphylococcus aureus Bacteremia

Guimaraes¹,

Gutierrez²,

Cao³

et al. 2019

Open Forum Infectious Diseases

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Background Staphylococcus aureus is a leading global cause of bacteremia that can cause invasive tissue infections with high morbidity and mortality despite appropriate antibiotic therapy. Clinicians lack sufficient tools to rapidly identify patients with a poor prognosis to guide diagnostic workup and treatment decisions. Host cell-free DNA provides prognostic value across a spectrum of critical illnesses, including S. aureus bacteremia and sepsis. Metrics of high bacterial load are associated with disease severity in S. aureus bacteremia, and the objective of this study was to evaluate whether incorporating quantitation of cell-free bacterial DNA would provide additive prognostic value when combined with biomarkers of the inflammatory response. Methods S. aureus cell-free DNA was measured by quantitative polymerase chain reaction (PCR) in baseline serum samples from an observational cohort of 111 patients with complicated S. aureus bacteremia and correlated with host inflammatory markers and clinical outcomes. Results High levels of S. aureus cell-free DNA at the time of positive index blood culture were prognostic for all-cause and attributable mortality and persistent bacteremia and were associated with infective endocarditis. However, they did not provide additive value to biomarkers of the host response to infection in multivariate analysis. Conclusions Measurements of bacterial load by PCR are a clinically feasible candidate biomarker for stratifying patients at higher risk for complications and poor outcomes. Their diagnostic and prognostic value for identifying foci of infection and influencing treatment remain to be evaluated in additional cohorts.

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confidence: 99%

Prognostic Power of Pathogen Cell-Free DNA in Staphylococcus aureus Bacteremia

Guimaraes¹,

Gutierrez²,

Cao³

et al. 2019

Open Forum Infectious Diseases

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“…Daptomycin, the newest drug developed for S. aureus BS I, is over 13 years old and was approved based on noninferiority to older antibiotics, with MRSA clinical success rates of 44.4% for daptomycin and 31.8% for vancomycin (18). Subsequent attempts to develop new antibiotics for S. aureus bacteremia have failed (19,20). The addition of adjunctive agents such as immunotherapeutics (21)(22)(23)(24) or antibiotics (e.g., gentamicin, rifampin, or β-lactams; refs.…”

Section: Discussionmentioning

confidence: 99%

“…Day 14 was selected as the primary efficacy endpoint because it was hypothesized that exebacase's novel, rapid mechanism of action and hallmark properties (9-12, 33) would lead to a more rapid resolution of clinical signs and symptoms of infection. The day 14 time point allowed for evaluation of the clinical rates in recent clinical trials of S. aureus bacteremia (18,20,27). This difference in mortality rates in cohort studies versus interventional trials reflects the intrinsic difference in the purpose of clinical medicine versus clinical trials.…”

Section: Methodsmentioning

confidence: 99%

Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis

Fowler

Das

Lipka-Diamond

et al. 2020

Journal of Clinical Investigation

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BACKGROUND. Novel 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. METHODS. In 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. RESULTS. Clinical 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. CONCLUSION. This 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 REGISTRATION. Clinicaltrials.gov NCT03163446. FUNDING. ContraFect Corporation.

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“…In the past several decades, there has been no significant improvement in morbidity or mortality in patients with complicated S. aureus infections (8,22,23). It is recognized that designing and executing clinical trials for S. aureus bacteremia is challenging (24). Daptomycin, approved in 2006, was the last antibiotic approved for the treatment of S. aureus bacteremia (8).…”

Section: Discussionmentioning

confidence: 99%

A Phase 1, Randomized, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S, an Anti- Staphylococcus aureus Thiomab Antibody-Antibiotic Conjugate, in Healthy Volunteers

Peck¹,

Rothenberg²,

Deng³

et al. 2019

Antimicrob Agents Chemother

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Staphylococcus aureus causes serious bacterial infections with high morbidity and mortality, necessitating the discovery of new antibiotics. DSTA4637S is a novel antibody-antibiotic conjugate designed to target intracellular S. aureus that is not adequately eliminated by current standard-of-care antibiotics. DSTA4637S is composed of an anti-S. aureus Thiomab human immunoglobulin G1 (IgG1) monoclonal antibody linked to a novel rifamycin-class antibiotic (4-dimethylaminopiperidino-hydroxybenzoxazino rifamycin [dmDNA31]) via a protease-cleavable linker. Phagocytic cells ingest DSTA4637S-bound S. aureus, and intracellular cathepsins cleave the linker, releasing dmDNA31and killing intracellular S. aureus. This first-in-human, randomized, double-blind, placebo-controlled, single-ascending-dose phase 1 trial analyzed the safety, pharmacokinetics, and immunogenicity of DSTA4637S in healthy volunteers. Thirty healthy male and female volunteers, 18–65 years old, were randomized into five cohorts receiving single intravenous (i.v.) doses of 5, 15, 50, 100, and 150 mg/kg of DSTA4637S or placebo (4 active:2 placebo). Subjects were followed for 85 days after dosing. No subject withdrew from the study, and no serious or severe adverse events occurred. One moderate infusion-related reaction (150 mg/kg DSTA4637S) occurred. No clinically meaningful or dose-related changes in laboratory parameters or vital signs occurred. Pharmacokinetics of plasma DSTA4637S conjugate and serum DSTA4637S total antibody were dose proportional. Systemic exposure of unconjugated dmDNA31 was low. No DSTA4637S-induced anti-drug antibody responses were observed. DSTA4637S was generally safe and well tolerated as a single i.v. dose in healthy volunteers. DSTA4637S has a favorable safety and pharmacokinetic profile that supports future development as a novel therapeutic for S. aureus infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02596399.)

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Considerations for Clinical Trials of Staphylococcus aureus Bloodstream Infection in Adults

Cited by 36 publications

References 46 publications

Prognostic Power of Pathogen Cell-Free DNA in Staphylococcus aureus Bacteremia

Prognostic Power of Pathogen Cell-Free DNA in Staphylococcus aureus Bacteremia

Exebacase for patients with Staphylococcus aureus bloodstream infection and endocarditis

A Phase 1, Randomized, Single-Ascending-Dose Study To Investigate the Safety, Tolerability, and Pharmacokinetics of DSTA4637S, an Anti- Staphylococcus aureus Thiomab Antibody-Antibiotic Conjugate, in Healthy Volunteers

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