Outline how the pathophysiological changes in septic shock affect the pharmacokinetics and pharmacodynamics of commonly used antimicrobials.

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College Answer

The major changes in pharmacokinetic parameters of critically ill patients include alterations in volume of distribution (Vd) and clearance (Cl). Subsequently, these alterations affect the concentrations of antimicrobials in the body and the extent to which they are cleared.

The Vd is the volume in which the total amount of drug would have to be evenly distributed in to equal the same concentration as in the plasma. The toxins produced by various bacteria often lead to endothelial damage and result in increased capillary permeability. This leads to the phenomenon of “third spacing” where fluid shifts into the interstitial space from the intravascular space. These fluid shifts will increase the Vd of hydrophilic antimicrobials. Generally speaking, hydrophilic antimicrobials have a low Vd and therefore are greatly affected by these fluid shifts. Since lipophilic antimicrobials have a larger Vd, they typically distribute further into tissues and are less affected by these fluid shifts.

Patients in the ICU often have hypotension as a result of septic shock, which requires the administration of fluid boluses. Additionally, heart failure and renal failure lead to more oedematous states where patients can retain large amounts of fluid. These situations also lead to increases in Vd of hydrophilic drugs.

Changes in protein binding can also have a substantial effect on the Vd, especially for drugs that are highly protein bound. Only unbound or free drug is microbiologically active. Hypoalbuminemia in critically ill patients can result in decreased binding of drugs and subsequently higher free concentrations of drugs. While free drug will distribute into tissues, critically ill patients often have greater amounts of fluid in the interstitial space causing the antimicrobial concentrations in the tissues to remain low.

The administration of large volumes of fluid and use of vasopressors leads to a hypermetabolic state in which cardiac output and glomerular filtration rate are increased. The term often used to describe this enhanced elimination is augmented renal clearance. These physiological changes affect the clearance of drugs and can lead to sub-therapeutic levels of antimicrobials that are typically cleared by the kidneys. In contrast, decreased organ perfusion in the presence of end organ damage can lead to kidney and/or liver failure in which concentrations of these antimicrobials would be increased. Inadequate clearance or metabolism of these drugs would lead to accumulation and potential toxicity. Typically, equations such as Cockroft-Gault are used to estimate renal function; however, these are often not good predictors of renal function in critically ill patients due to the acute and rapid changes such patients often experience. Since many antimicrobials are dosed based on renal function it is even more challenging to ensure adequate doses are being administered. The most accurate way to calculate renal function is the use of 8- or 12-hour creatinine collections. In situations where renal replacement therapy is utilized, careful consideration of timing and supplemental dosing post-dialysis would be needed depending on the antimicrobial agent

Discussion

The college model answer to this question is a excessive block of prose, which cannot be expected from the trainees under any sort of exam conditions. Instead, a more streamlined point-form answer is suggested. In essence, the college ask about septic shock, but then go on to discuss pharmacological changes which are common to all critically ill patients.

These are as follows:

Pharmacokinetic changes:

  • Factors which decrease the antibiotic peak concentration:
    • Suboptimal gut absorption.
    • Increased volume of distribution (patients are typically fluid-overloaded)
    • Poor penetration to the site of action (poor tissue perfusion and generalised oedema)
  • Factors which increase the antibiotic peak concentration
    • Increased free fraction (decreased protein binding due to low albumin)
    • Diminished clearance (renal and hepatic failure)
  • Factors which increase the antibiotic half-life
    • Diminished clearance (renal and hepatic failure)
  • Factors which decrease the antibiotic half-life
    • Renal replacement therapy (enhances clearance)
    • Increased hepatic clearance (hyperdynamic circulation)
    • Increased glomerular filtration rate (hyperdynamic circulation)
    • Increased rate of drug metabolism due to a "hypermetabolic state" induced by trauma,  burns and exogenous catecholamine infusions

Pharmacodynamic changes:

  • Increased nephrotoxicity from aminoglycosides, if the renal function is already impaired
  • Increased cardiotoxicity from bleomycin and vancomycin
  • Increased risk of QT prolongation and arrhythmia with fluoroquinolones in the context of cardiac ischaemia, profound hypothermia, or extreme electrolyte derangement
  • Increased bone marrow toxicity from linezolid, cotrimoxazole, gancyclovir, chloramphenicol, beta-lactams of all sorts...
  • With a disrupted blood-brain barrier, an increased risk of seizures from high-dose beta-lactams, due to enhanced penetration.  
  • Worsening shock due to dapsone-induced methaemoglobinaemia and thus diminished oxygen-carrying capacity.

As such, this model answer to a question about sepsis would have also answered Question 1 from the first paper of 2000, which asks about pharmacological changes in critical illness in a broader sense. There are a few pharmacological peculiarities which dveelop exclusively (or almost exclusively) in the context of sepsis, and these are sumarised below using the excellent article by De Paepe et al (2002)

Change to pharmacology which are unique to sepsis and septic shock

  • Increased volume of distribution due to sepsis-associated "capillary leak" results in a decreased effective concentration of antimicrobials.
  • Decreased bioavailability of basic drugs: because α-1-acid glycoprotein is an acute phase reactant
  • Increased penetration of formerly impenetrable tissues due to their inflamed state, as in the enhanced penetration of β-lactams into the CNS which is associated with meningitis
  • Impaired hepatic metabolism due to inhibition of CYP-450 enzymes by  endotoxin-mediated release of nitric oxide

References

References

Craig, William A. "Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men." Clinical infectious diseases (1998): 1-10.

Ulldemolins, Marta, et al. "Antibiotic dosing in multiple organ dysfunction syndrome." CHEST Journal 139.5 (2011): 1210-1220.

Trotman, Robin L., et al. "Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy." Clinical infectious diseases 41.8 (2005): 1159-1166.

Drusano, George L. "Antimicrobial pharmacodynamics: critical interactions of'bug and drug'." Nature Reviews Microbiology 2.4 (2004): 289-300.

De Paepe, Peter, Frans M. Belpaire, and Walter A. Buylaert. "Pharmacokinetic and pharmacodynamic considerations when treating patients with sepsis and septic shock." Clinical pharmacokinetics 41.14 (2002): 1135-1151.

Piafsky, Kenneth M., et al. "Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of plasma α1 acid glycoprotein." New England Journal of Medicine 299.26 (1978): 1435-1439.

Muller, Claudia M., et al. "Nitric oxide mediates hepatic cytochrome P450 dysfunction induced by endotoxin." The Journal of the American Society of Anesthesiologists 84.6 (1996): 1435-1442.