pharmacokinetics

Changes in sepsis / critical illness

Δ in absorption

effect on GI tract

↓ intestinal peristalsis
mucosal impairment
altered drug metabolism
Enteric drug absorption and availability are difficult to predict, mainly due to
fluctuations in gastric pH,
loss of enteric architecture,
↓ enzymatic activity
delay in gastric emptying extends the time needed to achieve maximum concentrations of the antibiotic

Vd

↑Vd → ↓Cmax & total drug concentration over time
→ risks of underdosing / subtherapeutic conc.
→ may need ↑ loading dose

As the Vd of antibiotics is often increased, higher loading doses are needed for hydrophilic antimicrobials (e.g., β-lactams, vancomycin, aminoglycosides, and colistin) to achieve similar and adequate therapeutic concentrations

↑Vd ∵ Δcompartment volume

↑ vascular permeability
- ↑ interstitial space compartment vol
administration of fluids
presence of pleural effusion / ascites / surgical drains
→ Hydrophilic drugs more susceptible
ß lactam
aminoglycosides
vancomycin

↑Vd ∵ Hypoalbuminaemia

↓Albumin → ↑ fraction of unbound drug → ↑Vd
drug w/ high plasma protein binding more susceptible

ceftriaxone
cefazolin
ertapenem
echinocandins
teicoplanin

Δ drug clearance

clearance = determinant of maintenance dose

↓ organ perfusion → organ dysfunction

↓ hepatic blood flow ↓ drug metabolism
- esp drugs w/ ↑hepatic metabolism + high extraction ratio

Augmented renal clearance

In clinical practice, a measured urinary creatinine clearance (CrCl) value of ≥130 mL⋅min-1⋅1.73 m-2 is most commonly used as the cut-off value for defining ARC

hyperdynamic haemodynamic states ↑ organ blood flow
- a/w conditions e.g.
  - SIRS
  - trauma
  - burns
  - pregnancy
renal function reserve
- ability to ↑GFR
  - nephron recruitment
  - ↑ renal blood flow
  - → ↑ hyperfiltration
brain-kidney crosstalk in neuro patients
- ? ∵ autonomic dysfunction affecting organ perfusion
Risk factors
- young age
- sepsis
- trauma / burns
- surgery / neurosurgery
- febrile neutropenia
  affecting hydrophilic drugs primarily cleared via kidney

usually develops early
duration of ARC varied widely, with a median and maximum time frame of 5 days and more than 1 month

The Cockroft-Gault, Chronic Kidney Disease Epidemiology Collaboration, and Modification of Diet in Renal disease equations have been shown to underestimate renal function in critically ill patients. It is therefore essential to evaluate the measured CrCl on a daily basis to better identify ARC in patients receiving hydrophilic antibiotics (e.g., β-lactams, vancomycin, or aminoglycosides)

RRT

changes to the PK depend on

specific characteristics of the extracorporeal circuit
- membrane permeability,
- intensity of therapy,
physicochemical properties of the drug
- molecular size,
- degree of ionization,
- extent of protein binding,
- hydro- or lipophilicity
residual renal function

Δ in tissue perfusion

In the presence of sepsis, the microcirculatory blood flow may be significantly impaired due to endothelial dysfunction and the presence of microthrombi, which decrease tissue perfusion. These alterations may lead to suboptimal antibiotic exposure at the site of infection and thereby to potential therapeutic failure, emergence of resistance, and higher morbidity.

Suboptimal tissue concentrations may even be found in patients with adequate plasma concentrations, as the antibiotic concentrations in plasma do not accurately reflect those in infected tissue

The main factors found to correlate with tissue penetration include oxygen saturation, serum lactate levels, and the dose per time unit of norepinephrine

Δ from extracorporeal therapies

ECMO circuit can

sequester drugs,
alter apparent Vd,
- drug sequestration
- haemodilution from priming solution
  - ↓ impact on drugs w/ ↑ apparent Vd
    - e.g. quinolones
  - ↑ impact w/ ↓ Vd
    - ß lactam
    - aminoglycosides
affect drug CL
- usually ↓ CL
  - ∵ ↓ renal / hepatic perfusion
- many patients on ECMO also on RRT → ↑ complexity
  degree of drug sequestration depends on
physicochemical properties
- lipophilicity
- protein binding
circuit factors
- membrane surface area,
- type of tubing,
- oxygenator used,
- priming solution

PK/PD approaches for antimicrobials

PK/PD targets can be expressed as

Cmax/MIC,
%T > MIC,
area under the curve (AUC)/MIC
depending on whether the antibiotic exhibits
dose-,
time-,
AUC-dependent killing

In critically ill patients, 100% of time where the free concentration is above the MIC (100% fT > MIC) is often suggested as a therapeutic target for β-lactams

the use of a higher target ratio is based on the considerations of tissue diffusion and technical uncertainties pertaining to MIC and β-lactam concentration measurements. However, only observational studies have demonstrated higher PK/PD targets to offer improved microbiological and clinical remission without any notable impact on mortality

Actual MICs are considered to define the therapeutic range in documented infections. The turnaround time remains the main issue with the use of MICs

The epidemiological cut-off (ECOFF) value, based on local ecology and the “worst-case scenario MIC” is the most common alternative used in this context. The “worst-case scenario MIC” refers to the highest MIC of susceptible pathogens that can be covered by the considered antibiotic. However, such approaches underestimate the probability of target attainment compared to actual MICs

intermittent bolus vs continuous infusion

BLING III

Inhaled Abx

for treatment: evidence not established
INAHLE & VAPORISE trials

? for preventing VAP: inhaled amikacin

Concept of model-informed precision dosing

nomograms
therapeutic drug monitoring

delay in response time
results difficult to interpret
?useful to minimise toxicity / excessive dosing
does not guide loading dose

References

725 — Clinically Relevant Pharmacokinetic Knowledge on Antibiotic Dosing

Understanding Antimicrobial Pharmacokinetics in Critically Ill Patients to Optimize Antimicrobial Therapy A Narrative Review

Pharmacokinetics in Sepsis