Fig 3 - available via license: Creative Commons Attribution 4.0 International
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Flow chart with proposed criteria for DETOURS randomized, controlled trial. Note. DETOURS: De-escalating Empiric Therapy: Opting Out of Rx for Suspected Sepsis. Hashed box indicates the Opt-Out criteria sekected through the modified Delphi process.
Source publication
Background
Early administration of antibiotics in sepsis is associated with improved patient outcomes, but safe and generalizable approaches to de-escalate or discontinue antibiotics after suspected sepsis events are unknown.
Methods
We used a modified Delphi approach to identify safety criteria for an opt-out protocol to guide de-escalation or di...
Context in source publication
Context 1
... related to chest radiograph infiltrates plus additional findings were encompassed into the single parameter of "new chest x-ray infiltrate." The remaining 22 criteria were placed into a draft for the opt-out protocol safety checklist. The protocol was reviewed with the expert panel with a mock-up graphic to obtain final comments (Fig. ...
Citations
Several efforts to repurpose drugs for COVID-19 treatment have largely either failed to identify a suitable agent or agents identified did not translate to clinical use. Reasons that have been suggested to explain the failures include use of inappropriate doses, that are not clinically achievable, in the screening experiments, and the use of inappropriate pre-clinical laboratory surrogates to predict efficacy. In this study, we used an innovative algorithm, that incorporates dissemination and implementation considerations, to identify potential drugs for COVID-19 using iterative computational and wet laboratory methods. The drugs were screened at doses that are known to be achievable in humans. Furthermore, inhibition of viral induced cytopathic effect (CPE) was used as the laboratory surrogate to predict efficacy. Erythromycin, pyridoxine, folic acid and retapamulin were found to inhibit SARS-CoV-2 induced CPE in Vero cells at concentrations that are clinically achievable. Additional studies may be required to further characterize the inhibitions of CPE and the possible mechanisms.
Several efforts to repurpose drugs for COVID-19 treatment have largely either failed to identify a suitable agent or agents identified did not translate to clinical use; either because of demonstrated lack of clinical efficacy in trials, inappropriate dose requirements and probably use of inappropriate pre-clinical laboratory surrogates of effectiveness. In this study, we used an innovative algorithm, that incorporates dissemination and implementation considerations, to identify potential drugs for COVID-19 using iterative computational and wet laboratory methods that highlight inhibition of viral induced cytopathic effect (CPE) as a laboratory surrogate of effectiveness. Erythromycin, pyridoxine, folic acid and retapamulin were found to inhibit SARS-CoV-2 induced CPE in Vero cells at concentrations that are clinically achievable. Additional studies may be required to further characterize the inhibitions of CPE and the possible mechanisms.
Funding
TETFund Covid-19 Special Intervention Research grant(grant number TETFund/DR&D/CE/ SI/COVID-19/UDUS/VOL 1)
Background:
Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis.
Methods:
We evaluated non-ICU adults on broad-spectrum antibiotics despite negative blood cultures at ten U.S. hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs. usual care. The primary outcome was 30-day post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If antibiotics were continued, clinicians discussed rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided two measures: 1) the odds ratio of antibiotic continuation and 2) ratio of mean DOT among those who continued antibiotics.
Results:
Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs. 84%, OR 0.68, 95% confidence interval (CI) [0.47, 0.98]). DOT among those who continued antibiotics were similar (ratio of means 1.06, 95% CI [0.88-1.26]). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% v. 44%. Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar.
Conclusions:
An antibiotic opt-out protocol targeting patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm.
