Effect of Antibiotic Choice On ReNal Outcomes (ACORN)

Sponsor

Vanderbilt University Medical Center (Other)

Overall Status

Enrolling by invitation

CT.gov ID

NCT05094154

Collaborator

(none)

2,500

Enrollment

Location

Arms

26.7

Anticipated Duration (Months)

93.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Sepsis is one of the most common causes of acute illness and death in the United States. Early, empiric broad-spectrum antibiotics are a mainstay of sepsis treatment. Two classes of antibiotics with activity against Pseudomonas, anti-pseudomonal cephalosporins and anti-pseudomonal penicillins, are commonly used for acutely ill adults with sepsis in current practice. Recent observational studies, however, have raised concern that anti-pseudomonal penicillins may cause renal toxicity. Anti-pseudomonal cephalosporins, by comparison, may be associated with a risk of neurotoxicity. Rigorous, prospective data regarding the comparative effectiveness and toxicity of these two classes of medications among acutely ill patients are lacking. The investigator propose a randomized trial comparing the impact of anti-pseudomonal cephalosporins and anti-pseudomonal penicillins on renal outcomes of acutely ill patients.

Condition or Disease	Intervention/Treatment	Phase
Sepsis AKI Neurotoxicity	Drug: anti-pseudomonal cephalosporin Drug: anti-pseudomonal penicillin	Phase 4

Detailed Description

Sepsis is a common condition associated with high mortality and morbidity. Antibiotics are an integral component of the management of patients with sepsis. Each hour delay in antibiotic administration in sepsis is associated with an increase in mortality. Clinical guidelines recommend early management bundles, including early broad-spectrum antibiotics, for patients with presumed sepsis in the emergency department and intensive care unit. Since the specific organism causing an infection is rarely known at clinical presentation, empiric broad-spectrum antibiotics are commonly prescribed. For patients at risk for resistant organisms, the most common regimens include vancomycin (to cover gram-positive organisms including methicillin-resistant Staphylococcus aureus) and an anti-pseudomonal cephalosporin or anti-pseudomonal penicillin (to cover gram-negative organisms including Pseudomonas).

Cephalosporins and penicillins are beta-lactam antibiotics that act by inhibiting the synthesis of the peptidoglycan layer of bacterial cell walls. They are commonly used for a variety of infections including empiric broad spectrum coverage for sepsis and suspected nosocomial infections. Several cephalosporins and penicillins have anti-pseudomonal activity, including cefepime, a fourth-generation cephalosporin, ceftazidime, a third-generation cephalosporin, and piperacillin-tazobactam, an extended-spectrum penicillin with beta-lactamase inhibitor. Anti-pseudomonal penicillins are the preferred agents for empiric broad spectrum coverage at many centers, and piperacillin-tazobactam, specifically, has the added benefit of treating anaerobic organisms.

Acute Kidney Injury (AKI) is a common complication of ICU admission. AKI is associated with a six to eight fold increase in mortality in ICU populations is therefore a common target of critical care trials. Sepsis is the most common cause of AKI and accounts for 40-50% of AKI in the intensive care unit (ICU). As the primary treatment for the underlying cause of sepsis, antibiotics are a critical treatment for acutely ill patients, but antibiotics may cause renal injury, and renally-cleared antibiotics may reach supratherapeutic levels in the setting of AKI. Vancomycin has long been associated with AKI. Recently, a number of retrospective observational analyses have examined a potential association between the concurrent administration of vancomycin and piperacillin-tazobactam and the development of AKI, compared with vancomycin alone. These data, however, are likely to be confounded by indication bias and studies evaluating whether piperacillin-tazobactam causes more AKI than other anti-pseudomonal antibiotics have been inconclusive.

Based on this preliminary, observational data, however, some institutions have elected to change their preferred broad spectrum antibiotic regimens from one including an anti-pseudomonal penicillin to one including an anti-pseudomonal cephalosporin. However, others have argued against this approach given the lack of randomized trials comparing the relative efficacy and safety of the two agents as well as observational data suggesting that cephalosporins may be associated with neuro-toxicity.

Tens of thousands of patients each year receive either anti-pseudomonal cephalosporins and penicillins, but no randomized trials have ever compared their relative effectiveness or safety. Each class of medications has been hypothesized to have toxicities that may be relevant for acutely ill patients. Because the relationship between antibiotic choice (anti-pseudomonal cephalosporins or anti-pseudomonal penicillins) and clinically relevant outcomes, such as AKI, are unknown, clinical trial data is urgently needed. Rigorous high-quality evidence that anti-pseudomonal cephalosporins, compared to anti-pseudomonal penicillins, decreases, increases or has no impact on the risk of AKI would have the potential to change the care received by thousands of acutely ill adults each year.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

2500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This study will be performed as a pragmatic, randomized controlled clinical trial with parallel group assignment.This study will be performed as a pragmatic, randomized controlled clinical trial with parallel group assignment.

Masking:

Single (Outcomes Assessor)

Masking Description:

Patients and providers will necessarily be unblinded, but outcomes will be analyzed by a blind assessor.

Primary Purpose:

Treatment

Official Title:

Effect of Antibiotic Choice On ReNal Outcomes (ACORN)

Actual Study Start Date :

Nov 10, 2021

Anticipated Primary Completion Date :

Feb 1, 2024

Anticipated Study Completion Date :

Feb 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: anti-pseudomonal cephalosporin Participants in the anti-pseudomonal cephalosporin arm will receive at least one dose of an anti-pseudomonal cephalosporin.	Drug: anti-pseudomonal cephalosporin Providers will be prompted to order an anti-pseudomonal cephalosporin, such as cefepime with a dose range of 500 mg, 1,000 mg, or 2,000 mg, and frequency every 6, 8, 12, or 24 hours based on provider discretion.
Active Comparator: anti-pseudomonal penicillin Participants in the anti-pseudomonal penicillin arm will receive at least one dose of an anti-pseudomonal penicillin.	Drug: anti-pseudomonal penicillin Providers will be prompted to order anti-pseudomonal penicillin, such as piperacillin-tazobactam with a dose range of 3.375 g or 4.5 g and frequency every 6, 8, or 12 hours based on provider discretion.

Arm

Intervention/Treatment

Active Comparator: anti-pseudomonal cephalosporin

Participants in the anti-pseudomonal cephalosporin arm will receive at least one dose of an anti-pseudomonal cephalosporin.

Drug: anti-pseudomonal cephalosporin

Providers will be prompted to order an anti-pseudomonal cephalosporin, such as cefepime with a dose range of 500 mg, 1,000 mg, or 2,000 mg, and frequency every 6, 8, 12, or 24 hours based on provider discretion.

Active Comparator: anti-pseudomonal penicillin

Participants in the anti-pseudomonal penicillin arm will receive at least one dose of an anti-pseudomonal penicillin.

Drug: anti-pseudomonal penicillin

Providers will be prompted to order anti-pseudomonal penicillin, such as piperacillin-tazobactam with a dose range of 3.375 g or 4.5 g and frequency every 6, 8, or 12 hours based on provider discretion.

Outcome Measures

Primary Outcome Measures

Acute Kidney Injury (AKI) Ordinal Scale [14 days post-enrollment]
Acute Kidney Injury Score between randomization and day 14. The acute kidney injury score is an ordinal outcome containing the stages of AKI as defined by Kidney Disease: Improving Global Outcomes (KDIGO) creatinine criteria, new renal replacement therapy (RRT), and death: 0 = No AKI = Stage 1 AKI (Creatinine increase by 1.5-1.9 times baseline OR increase by >= 0.3 mg/dL) = Stage 2 AKI (Creatinine increase by 2.0-2.9 times baseline) = Stage 3 AKI (Creatinine increase by >= 3.0 times baseline OR increase to >= 4.0 mg/dL OR New RRT) = Death

Secondary Outcome Measures

Major Adverse Kidney Events within 14 days (MAKE14) [14 days post-enrollment]
Composite outcome of death within 14 days, new renal replacement therapy within 14 days, or stage 2 or higher AKI at day 14
Delirium and Coma-Free Days to day 14 [14 days post-enrollment]
The number of days alive and free of coma and delirium in the 14 days after enrollment

Other Outcome Measures

Post-Emergency Department Disposition [14 days post-enrollment]
Patient disposition (ex. floor unit or intensive care unit) at day 14 post-enrollment from the emergency department.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years old
Located in a participating emergency department or medical intensive care unit
Less than 12 hours from presentation to study hospital
Treating clinician initiating an order for an anti-pseudomonal cephalosporin or anti-pseudomonal penicillin

Exclusion Criteria:

Known receipt of > 1 dose of an anti-pseudomonal cephalosporin or anti-pseudomonal penicillin during the last 7 days
Current documented allergy to cephalosporins or penicillin
Known to be a prisoner
Treating clinicians feel that either an anti-pseudomonal cephalosporin or anti-pseudomonal penicillin is required or contraindicated for the optimal treatment of the patient, including for more directed antibiotic therapy against known prior resistant infections or suspected sepsis with an associated central nervous system infection

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

Vanderbilt University Medical Center

Investigators

Principal Investigator: Edward T Qian, MD, Vanderbilt University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

Responsible Party:

EDDIE QIAN, Principal Investigator, Clinical Fellow, Vanderbilt University Medical Center

ClinicalTrials.gov Identifier:

NCT05094154

Other Study ID Numbers:

210591

First Posted:

Oct 26, 2021

Last Update Posted:

Aug 10, 2022

Last Verified:

Aug 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Additional relevant MeSH terms:

Neurotoxicity Syndromes

Penicillins

Cephalosporins

Study Results

No Results Posted as of Aug 10, 2022