A Phase 4 interventional study of anti-pseudomonal cephalosporin and anti-pseudomonal penicillin in Sepsis, AKI and Neurotoxicity, sponsored by Vanderbilt University Medical Center. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2023-12-22.
Sponsored by Vanderbilt University Medical Center · Phase 4, Interventional, and Treatment
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.
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.
137 studies on the registry are indexed under Neurotoxicity Syndromes; 16 are open to participants now.
This study's enrollment of 2,634 is above the median of 92 across 92 interventional studies indexed under Neurotoxicity Syndromes.
Browse Neurotoxicity Syndromes studies →Vanderbilt University Medical Center is the lead sponsor of 824 studies on the registry; 164 are open to participants now.
Of its 122 completed or terminated interventional studies of FDA-regulated products, 91 (75%) have results posted.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
Participants in the anti-pseudomonal cephalosporin arm will receive at least one dose of an anti-pseudomonal cephalosporin.
Drug: anti-pseudomonal cephalosporin
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 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.
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.
Acute Kidney Injury (AKI) Ordinal Scale
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 1. = Stage 1 AKI (Creatinine increase by 1.5-1.9 times baseline OR increase by \>= 0.3 mg/dL) 2. = Stage 2 AKI (Creatinine increase by 2.0-2.9 times baseline) 3. = Stage 3 AKI (Creatinine increase by \>= 3.0 times baseline OR increase to \>= 4.0 mg/dL OR New RRT) 4. = Death
Time frame: 14 days post-enrollment
Major Adverse Kidney Events Within 14 Days (MAKE14)
Composite outcome of death within 14 days, new renal replacement therapy within 14 days, or stage 2 or higher AKI at day 14
Time frame: 14 days post-enrollment
Delirium and Coma-Free Days to Day 14
The number of days alive and free of coma and delirium in the 14 days after enrollment
Time frame: 14 days post-enrollment
Post-Emergency Department Disposition
Patient disposition (ex. floor unit or intensive care unit) at day 14 post-enrollment from the emergency department.
Time frame: 14 days post-enrollment
| Milestone | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin |
|---|---|---|
| Started | 1277 | 1357 |
| Completed | 1214 | 1297 |
| Not completed | 63 | 60 |
| Withdrew: Participants experiencing incarceration or involuntary detainment. | 3 | 1 |
| Withdrew: Did not receive appropriate drug in 7 days post-enrollment. | 60 | 59 |
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 1. = Stage 1 AKI (Creatinine increase by 1.5-1.9 times baseline OR increase by \>= 0.3 mg/dL) 2. = Stage 2 AKI (Creatinine increase by 2.0-2.9 times baseline) 3. = Stage 3 AKI (Creatinine increase by \>= 3.0 times baseline OR increase to \>= 4.0 mg/dL OR New RRT) 4. = Death
| Participants | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin |
|---|---|---|
| 0 = Survived without AKI | 910 | 952 |
| 1 = Survived with Stage 1 AKI | 86 | 100 |
| 2 = Survived with Stage 2 AKI | 41 | 70 |
| 3 = Survived with Stage 3 AKI | 85 | 97 |
| 4 = Died | 92 | 78 |
Composite outcome of death within 14 days, new renal replacement therapy within 14 days, or stage 2 or higher AKI at day 14
| Participants | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin |
|---|---|---|
| Major Adverse Kidney Events Within 14 Days (MAKE14) | 124 | 114 |
The number of days alive and free of coma and delirium in the 14 days after enrollment
| days | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin |
|---|---|---|
| Delirium and Coma-Free Days to Day 14 | 14 (14 to 14) | 14 (14 to 14) |
Patient disposition (ex. floor unit or intensive care unit) at day 14 post-enrollment from the emergency department.
| participants | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin |
|---|---|---|
| Home | 26 | 23 |
| Ward | 1016 | 1117 |
| ICU | 93 | 103 |
Collected over 28 days.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Anti-pseudomonal Cephalosporin | 104/1,214 (8.6%) | 0/1,214 (0%) | 0/1,214 (0%) |
| Anti-pseudomonal Penicillin | 106/1,297 (8.2%) | 0/1,297 (0%) | 1/1,297 (0.1%) |
| Event | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin |
|---|---|---|
| Blood product related allergyImmune system disorders | 0/1214 | 1/1297 |
| Age, Continuous(years) | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin | Total |
|---|---|---|---|
| Median | 57 (42 to 68) | 59 (44 to 69) | 58 (43 to 69) |
| Sex: Female, Male(Participants) | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin | Total |
|---|---|---|---|
| Female | 523 | 548 | 1071 |
| Male | 691 | 748 | 1439 |
| Race/Ethnicity, Customized(Participants) | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin | Total |
|---|---|---|---|
| Race and Ethnicity — White, non-Hispanic | 913 | 950 | 1863 |
| Race and Ethnicity — Black, non-Hispanic | 190 | 209 | 399 |
| Race and Ethnicity — Hispanic | 59 | 73 | 132 |
| Race and Ethnicity — Other | 24 | 32 | 56 |
| Region of Enrollment(participants) | Anti-pseudomonal Cephalosporin | Anti-pseudomonal Penicillin | Total |
|---|---|---|---|
| United States | 1214 | 1297 | 2511 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — Individual participant data that underlie the results reported will be made available (including data dictionaries) after de-identification.
Supporting information: Study protocol, Sap, Analytic code
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