Standard Vs Adjusted Dosing of Piperacillin/Tazobactam in Acute Renal Failure and Septic Shock

Study Overview
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Brief Summary
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The objective of this study is to determine the feasibility of conducting a large scale randomized controlled trial comparing standard and renally adjusted dosage of antibiotics in the septic shock patients with acute renal dysfunction. We will use Piperacillin as the prototype antibiotic in our study.

Detailed Description
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Septic shock is a significant cause of morbidity and mortality. Early Goal Directed therapy, fluid resuscitation, use of vasopressors and/or inotropes, and appropriate empiric antibiotic administration remain the cornerstone of therapy in the treatment of septic shock. Despite aggressive interventions, the death rate from septic shock in North America remains as high as 50 percent. Septic shock is defined as severe sepsis with hypotension not reversed by adequate fluid resuscitation. This state of distributive shock often results in hypo-perfusion of all major organ systems, including the kidneys, and is a common cause of multi-organ failure. Acute renal failure in the setting of septic shock often leads clinicians to adjust dosing of empiric antibiotics according to the apparent renal function. Renally adjusted antibiotic dosing in septic shock may be insufficient for several reasons. First, renal failure secondary to hypoperfusion often reverses following fluid resuscitation and vasopressor use, leading to subsequent under dosing. Second, a hypoperfusion state theoretically results in a reduction in the amount of antibiotic delivered to the site of infection. Lastly, for drugs with large volumes of distribution or prolonged half lives, large initial doses are required to quickly to achieve therapeutic concentrations. To date, no studies have attempted to answer this important question by comparing standard doses to renally adjusted doses of empiric antibiotics in patients with both septic shock and renal dysfunction during the initial resuscitative period. Currently there is no uniform practice among clinicians with respect to antibiotic dosing, which reflects the paucity of evidence in this area. Some clinicians currently use full dosing of antibiotics in the setting of septic shock with acute renal failure while others adjust the dose based on renal function. Well designed, prospective, randomized controlled trials are urgently needed to clarify the role of antibiotic adjustment during the resuscitative period of septic shock. The objective of this study is to determine the feasibility of conducting a large scale randomized controlled trial comparing standard and renally adjusted dosage of antibiotics in the septic shock patients with acute renal dysfunction. We will use Tazocin as the prototype antibiotic in our study.

Official Title
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A Comparison of Standard Vs Renal Dosing of Piperacillin/Tazobactam in Acute Renal Failure and Septic Shock

Conditions
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Septic Shock, Acute Renal Failure

Intervention / Treatment
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* Drug: Piperacillin/Tazobactam
* Drug: Piperacillin/Tazobactam


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with septic shock according to the Surviving Sepsis Campaign Age > 19 Most recent eGFR<40 mls/min Exclusion Criteria: Pregnant Known chronic renal failure patients who are dialysis dependant Administration of systemic antibiotics > 1 dose Not expected to survive 28 days due to an underlying medical illness Allergy to Piperacillin/Tazobactam or any components of formulation within

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dose Adjusted<br>This arm will receive their broad spectrum antibiotic as an adjusted dose based on their renal function as measured when sepsis is diagnosed and antimicrobials are initiated | Drug: Piperacillin/Tazobactam<br>* eGFR 20-40 mls/min: Piperacillin/Tazobactam 3.375g IV q6h x 24 hours eGFR < 20 mls/min: Piperacillin/Tazobactam 2.25g IV q6h x 24 hours<br>* Other names: Tazocin;|
| Experimental: Unadjusted Dose<br>This arm will receive their broad spectrum antibiotic as an unadjusted dose regardless of their renal function | Drug: Piperacillin/Tazobactam<br>* Piperacillin/Tazobactam 4.5g IV q 6h x 24 hours<br>* Other names: Tazocin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine rate of patient accrual (ability to identify and enrol patients in a timely fashion) and protocol adherence for this pilot randomized controlled trial. |  | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ICU and hospital mortality. ICU and hospital length of stay. Duration of mechanical ventilation. |  | 1 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Septic shock, Acute Renal Failure, Antimicrobial, Drug Dosing, Feasibility Study