Pharmacokinetic and pharmacodynamic considerations in antimicrobial therapy for sepsis

ABSTRACT

Introduction: Antimicrobial dose optimization for the treatment of sepsis remains challenging because of dynamic pharmacokinetic alterations and physiological/pathological responses of the host. Subtherapeutic plasma levels of antimicrobials are commonly observed in patients with sepsis, which potentially leads to both treatment failure and emergence of antimicrobial resistance. The knowledge of antimicrobial pharmacokinetics and pharmacodynamics is helpful in order to tailor antimicrobial dosing strategies.

Areas covered: This narrative review summarizes pharmacokinetic alterations of antimicrobial agents and provides useful information on antimicrobial dose optimization. Literature was searched using PubMed database, focusing on pharmacokinetics and pharmacodynamics of antibacterial and antifungal agents in sepsis.

Expert opinion: In patients with sepsis, increased volume of distribution and variable changes in renal clearance are the two major factors for antimicrobial pharmacokinetic alterations. Traditional ‘one-dose-fits-all’ dosing strategy is not suitable for patients with sepsis and hence individualized antimicrobial dosing adjustment is preferable. In general, the initial dose of hydrophilic antimicrobials such as ß-lactams, aminoglycosides, and vancomycin should be given at a high dose regardless of renal function. Improved methods of drug administration (e.g. extended/continuous infusion of β-lactams) help to increase the chance of pharmacodynamic target attainment. The use of therapeutic drug monitoring should be considered where available.

KEYWORDS:

• Anti-Bacterial Agents
• antifungal Agents
• anti-Infective Agents
• drug Monitoring
• pharmacology
• pharmacokinetics
• renal Elimination
• sepsis

Article highlights

• Antimicrobial therapy for the treatment of sepsis requires not only an appropriate choice of agents but also appropriate dosing strategy.

• Dose optimization of antimicrobials in the treatment of sepsis requires an understanding of physicochemical properties and PD parameters of antimicrobials, antimicrobial PK alterations which occur in patients with sepsis, and MICs of pathogenic organisms.

• Antimicrobial agents are classified into hydrophilic or lipophilic agents according to physicochemical properties.

• Significant increase in the volume of distribution of hydrophilic antimicrobials in patients with sepsis occurs secondary to capillary leak, a large volume of resuscitation fluid, hypoalbuminemia, fluid retention in body cavities, and extra-corporeal circuits.

• Renal clearance of hydrophilic antimicrobials is significantly altered in patients with sepsis. Both increased (ARC) or decreased renal clearance (acute kidney injury) of those agents often occurs.

• Lipophilic antimicrobials may experience decreased clearance in patients with liver failure and increased volume of distribution in patients on ECMO.

• Hydrophilic antimicrobials, which experience increased volume of distribution, generally require a loading dose in patients with sepsis regardless of renal function.

• Extended/continuous infusion of β-lactams should be considered for the treatment of sepsis especially in difficult-to-treat infections (e.g. high MIC pathogens, immunocompromised patients, and uncontrolled source of infection).

• Therapeutic drug monitoring for β-lactams has been increasingly introduced in order to optimize antimicrobial therapy in ICU.

This box summarizes the key points contained in the article.

Declaration of interest

J Lipman has received payments from Merck and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.