Pk and pd for antibiotic in icu

1. Critical Care Medicine
Apollo Hospitals
Chennai
Ramesh Venkataraman, AB (Int. Med) AB (CCM), FACP, FCCP, FCCM
Consultant, Critical Care Medicine,
 Department of Critical Care Medicine, Apollo Hospitals 
Apollo Hospitals
Pharmacokinetic and Pharmacodynamic
Principles of Antibiotic therapy

2.  Department of Critical Care Medicine, Apollo Hospitals 
What is PK/PD?
PK PD

3.  Department of Critical Care Medicine, Apollo Hospitals 
Relevant PK/PD parameters
Volume of distribution (Vd)
Clearance
Half-life(t1/2)
Dictated by Clearance and Vd
Peak drug concentration (Cmax)
Minimal drug concentration (Cmin)
Area under the concentration time curve (AUC)

4.  Department of Critical Care Medicine, Apollo Hospitals 
Volume of distribution (Vd)
Apparent volume of fluid that contains the total
drug dose administered at the same
concentration as in the plasma
Drug to plasma concentration
Dictates loading dose
Hydrophilic vs. Lipophilic drugs
Protein binding
Varghese J et al. Crit Care Clin 27 (2011) 19–34
High dose
for meningitis

5.  Department of Critical Care Medicine, Apollo Hospitals 
Clearance of drug
Volume of blood cleared of drug per unit time
Irreversible elimination of a drug from the body by
excretion and/or metabolism
Dictates maintenance doses
Altered by
Protein binding
Cardiac output
End-organ dysfunction
Type of RRT
ECMO
Plasma exchange
High protein binding and low Vd

6.  Department of Critical Care Medicine, Apollo Hospitals 
Bioavailablity unpredictable
Roberts JA, et al. Crit Care Med. 2009;37: 840 -851

7.  Department of Critical Care Medicine, Apollo Hospitals 
Abscesses
Abscesses – pH acidic
De-activation by binding with DNA
Slow growth of bacteria – hinders β - lactam
Special infections
Pancreatitis – carbapenems maximal penetration
Pneumonia – Linezolid > Vancomycin
Daptomycin inactivated by surfactant
Urosepsis – Tigecycline very minimal concentrations
Bacteremia – Tigecycline poor blood levels
Some Clinical Examples

8.  Department of Critical Care Medicine, Apollo Hospitals 
What is PK/PD?
PK PD

9.  Department of Critical Care Medicine, Apollo Hospitals 
PD - Minimal Inhibitory Concentration (MIC)
Minimum concentration of an antibiotic that inhibits visible
growth in a broth culture
Describes the relationship between antimicrobial drug and
physiologic activity
Provides a quantitative measure of drug activity against the
bacterial pathogen
Has limitations
Static measure
Only measures growth inhibition
Quantifies ONLY net growth over the observation period
Does not account for the postantibiotic effects of antibiotics
Lodise T, et al. Crit Care Clin 27 (2011) 1–18

10.  Department of Critical Care Medicine, Apollo Hospitals 
Optimal Antibiotic Delivery
MIC
Time (hours)
Cmax/MIC
Cmin
T > MIC
Concentration Dependent –
Aminoglycosides
Time dependemt –
Β lactams
AUC/MIC - Fluroquinolones

11.  Department of Critical Care Medicine, Apollo Hospitals 
PD Characteristics
Concentration dependent drugs
High Cmax/MIC
AUC to MIC - area under the inhibition curve (AUIC)
AUIC > 125 for gram negatives, but > 30 for pneumococcus
High dose, less frequent administration
Aminoglycosides
Post-antibiiotic effect (PAE) – AG and quinolones for
gram negatives
Time-dependent drugs
High T>MIC – 40 - 50%
Rate of killing saturated once Cmax/MIC > 4
Frequent dosing or continuous infusions
Beta-lactams
Drug stability ACCP Board review book 2010

12.  Department of Critical Care Medicine, Apollo Hospitals 
Antibiotics Induce Resistance
Mutant Prevention Concentration - MPC
Resistant Strain
Abx kills susceptible strain
Sensitive strain
Resistant Mutant

13.  Department of Critical Care Medicine, Apollo Hospitals 
Clinical Summary
Varghese J et al. Crit Care Clin 27 (2011) 19–34

14.  Department of Critical Care Medicine, Apollo Hospitals 
Clinical Summary
Varghese J et al. Crit Care Clin 27 (2011) 19–34

15.  Department of Critical Care Medicine, Apollo Hospitals 
Conclusion
PK/PD factors determine the efficacy of antibiotics in
critically ill patients
Interactions are complex and bioavailability unpredictable
Drug levels when available may improve efficacy
Invitro MIC does not mirror invivo efficacy
Understanding of the key PK/PD principles key to
optimal delivery of antibiotics
Main clinical considerations
Volume of distribution
Clearance
Concentration vs. time-dependent killing

16.  Department of Critical Care Medicine, Apollo Hospitals 