Objectives

• Discuss the current challenges associated with antimicrobial dosing in critically ill patients.
• Review the antimicrobial selection process in patients with severe infections.
• Examine ways to optimize antimicrobial delivery to better achieve pharmacodynamic targets.
• Discuss the purpose and values of using antimicrobial continuous infusions in critically ill patients.
• Provide a summary of the research currently being done in veterinary medicine to demonstrate the value of antimicrobial continuous infusions.

Overview

• An increasing incidence of multidrug-resistant infections has been noted in both human and veterinary intensive care unit patient populations.
• Stresses the importance of appropriate and effective antimicrobial treatment protocols.
• Ideal dosing schedules, appropriate selection of antimicrobial spectrum, and timely antimicrobial administration are the primary actionable items in the optimization of antimicrobial therapy.
• There is a sparse pipeline of new antimicrobials available for use, emphasizing the need to develop more effective dosing schedules for the antimicrobials currently available in order to reduce the development of antimicrobial resistance, especially in the critically ill population.

Antimicrobial Challenges in Critically Ill Patients

• Critically ill patients exhibit a vast array of pathophysiologic changes that can complicate antimicrobial dosing.
• Most antimicrobial dosing schedules have been derived from trials with non-critically ill patients and it is important to take this into consideration when developing treatment plans for critically ill patients.
• The two primary factors in critically ill patients that can affect the pharmacokinetics (PK), and therefore the pharmacodynamics (PD) of the antimicrobials used are changes in the volume of distribution and systemic clearance of the administered drugs.

Volume of Distribution

• Volume of distribution is defined as the volume (i.e., amount of tissue) that is needed to contain the total amount of administered drug at the same concentration as the blood.
• Volume of distribution is calculated by dividing the amount of drug in the body by the plasma concentration.
• Systemic inflammation is a common sequela of critical illness and is the primary factor that leads to increases in the volume of distribution of administered drugs.
• Specifically, increases in the volume of distribution can be caused by endothelial damage, increased capillary permeability, maldistribution of blood flow, and hypoalbuminemia.
• All of the above consequences lead to lower concentrations of antimicrobial getting delivered to the target site of infection.

Drug Clearance

• Clearance is defined as the rate at which a drug is removed from the body.
• Clearance is calculated by determining the rate of drug clearance and dividing this by the plasma concentration of the drug.
• Drug elimination half-life (T_½) is directly related to the volume of distribution (Vd) and drug clearance (CL): T_½=(0.693 x Vd)/CL
• Increases in CL will therefore result in a reduced T_½, assuming Vd remains unchanged.
• Critically ill patients frequently have an increased cardiac output, resulting in increased renal blood flow.
• This may lead to augmented renal clearance (ARC) of drugs from the circulation, therefore lowering the serum concentration more rapidly.
• ARC has been demonstrated in approximately half of critically ill human patients requiring antimicrobial therapy.
• Patients with ARC show greater treatment failure rates.

Beta-Lactam Antimicrobials

• Beta-lactam antimicrobials are commonly used for the treatment of life-threatening infections in critically ill patients with severe sepsis.
• Beta-lactam antimicrobials include penicillins, cephalosporins, monobactams, and carbapenems.
• Generally, well tolerated and have broad spectrums of activity.
• Beta-lactams are time-dependent antimicrobials, reaching an initial peak serum concentration once administered, which then gradually decrease over time.

Antimicrobial Breakpoints

• Antimicrobial breakpoint is a chosen antimicrobial concentration which defines whether a bacterial pathogen is susceptible or resistant to that antimicrobial.
• Antimicrobial susceptibility breakpoints are developed by groups such as the Clinical and Laboratory Standards Institute (CLSI).
• Reference laboratories use these breakpoints when reporting culture susceptibility data.
• The 2020 CLSI veterinary performance standards do not contain a breakpoint for ampicillin-sulbactam, but in humans the breakpoint is 8 µg/mL.
• Studies to define the pharmacokinetic profile of ampicillin-sulbactam in veterinary patients are needed to allow for the development of antimicrobial optimization strategies, which would likely entail new breakpoint development by bodies like CLSI.

Meeting PD Targets with Time-Dependent Antimicrobials

• Bacterial killing properties of time-dependent antimicrobials are contingent on the amount of time that the antimicrobial serum concentration is greater than the minimum inhibitory concentration (MIC) of the infecting pathogen.
• Once the antimicrobial concentration falls below the MIC, bacterial multiplication has been shown to resume immediately and there is an increased risk for drug resistance to develop.
• Maintaining a time (T) of the free fraction of the antimicrobial (f) above the MIC (fT>MIC) of 100% has been associated with a significantly greater clinical cure and bacteriologic eradication in patients with severe infections.
• It has been shown that the MIC needed to kill 90% of gram-negative isolates was 4–8 times higher in critically ill patients.
• With conventional bolus dosing regimens of beta-lactam antimicrobials it may be challenging, and in some cases impossible, to meet these PK targets, resulting in periods of time where the antimicrobial concentration falls below the MIC of the infecting pathogen.

Utilizing Antimicrobial Continuous Infusions

• Continuous infusions (CI) of beta-lactam antimicrobials have been shown to achieve significantly greater fT>MIC in humans than when delivered as intermittent infusions (II).
• An antimicrobial CI is initiated with a standard bolus dose of the time-dependent antimicrobial, which achieves the peak serum concentration. A CI is then started by taking the total daily dose of that antimicrobial and administering it continuously over 24 hours.
  Example:
• Time-dependent antimicrobial: Ampicillin-sulbactam
• Standard dose in septic patients: 50 mg/kg IV q 8 h
• Initial bolus dose: 50 mg/kg IV
• Continuous infusion rate: 6.25 mg/kg/h (equivalent of 150 mg/kg/day)
• For any MIC, CI has a higher likelihood of attaining PK/PD cut-off values than with II, making it a safer choice when starting empirical therapy.
• In humans with severe sepsis, the use of time-dependent antimicrobials as a CI was associated with decreased hospital mortality.

Use of Antimicrobial CI in Current Practice

• A 2012 study showed that approximately 11% of human hospitals within the United States use CI of antimicrobials, with the majority of these institutions being medical schools, pharmacy schools, nursing schools, and allied health professions.
• In veterinary medicine, few studies have focused on the use of antimicrobial CI.
• A recent study in canine septic shock reported the use of a CI for 22% of dogs receiving time-dependent antimicrobials.

What Is Ethos Discovery Currently Doing?

• Previously conducted a pilot study in a small cohort of septic dogs to evaluate the PK of ampicillin-sulbactam when delivered as a CI or as an II.
• Well tolerated with no reported adverse events.
• For a MIC of 16 µg/mL, the fT>MIC was significantly greater in the CI group than the II group (mean 67.06% vs. 36.29%, respectively, p=0.04).
• Currently planning a second study in a larger group of septic dogs to further evaluate the PK of ampicillin-sulbactam CI and to also evaluate its effect on clinical outcome.

Summary

• Critically ill patients commonly experience pathophysiological changes that can complicate the obtainment of antimicrobial pharmacodynamic targets.
• The use of antimicrobial continuous infusions is a promising method to better meet treatment goals than when delivered as intermittent infusions.
• Beta-lactam and other time-dependent antimicrobials are the ideal drugs to use in continuous infusions.
• More research is still needed to fully support a wider adoption of antimicrobial CI in veterinary medicine.

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