4
Pharmacokinetics and
Pharmacodynamics of
Antimicrobial Therapy
Drugs are in use for the treatment of various
diseases since many centuries, however,
chemotherapy as a science began within the
first decade of 20th century with under-
standing of the principles of selective toxicity,
the precise chemical relationships between
a microbe and drug, the event of drug
resistance, and the role of combined therapy.
The goal of antimicrobial chemotherapy is
to generate an amount of antibiotic high
enough to kill or inhibit the pathogen at the
site of infection, without producing significant
toxic effect in the patient. It is important to
keep in mind that the response to the therapy
in vivo may not always reflect the result of
testing the sensitivity of the patient’s pathogen
in vitro. Thus, therapy for a pathogen found
sensitive to a drug in vitro may fail, because
the drug is not adequately absorbed by the
patient, or unable to penetrate in a good
concentration at the site of infection, or is
inactivated by a concomitant drug resistant
bacterium.
An understanding of the pharmacokinetic
(PK) and pharmacodynamic (PD) principles
that determine response to antimicrobial
therapy can provide the clinician with better-
informed dosing regimens while minimizing
toxicity to patients.
Pharmacokinetics (PK) is the quantitative
study of drug movement in, through and out
of the body. It is governed by the four essential
processes of absorption, distribution, meta-
bolism, and excretion. These parameters are
31
Madhu Sharma
usually measured by studying the achievable
drug levels in blood and other body fluids in
healthy volunteers. Antibiotic PK is usually
taken in terms of what the body does to the
drug.
Pharmacodynamics (PD) is associated with
describing what the drugs do, and how they
do. Thus, it refers to the way in which
antibiotics interact with their target organisms
to exert their effects. Ideally, the effect of an
antimicrobial agent is to eradicate the
infecting organism with no adverse effects to
the patient.
The PD effect is the result of the exposure
of the bacteria to the unbound drug fraction
at the site of infection. This implies that the
total serum concentration does not reflect the
active fraction of the drug. We cannot measure
the drug concentration at the site of infection
but assay of the concentration of an antibiotic
in blood, serum or other body fluids of a
patient under treatment can be done before
and after the administration of a dose that are
expected to give the minimum and maximum
concentrations achieved and the results
obtained helps clinician to regulate the dosage
schedule so that drug concentration will
mainly be at a non-toxic but effective level,
i.e. will either inhibit or kill the organism.
Drug concentration within the blood has been
correlated to in vivo eradication.
It is also worthwhile to know the protein
binding capacity of an antibiotic as only free
 32 Infectious Diseases in Critical Care
or unbound drug is capable of exerting
antimicrobial effects. Hence, unbound (free)
drug concentration should be considered
when implementing and adjusting dosing
regimens.
ANTIMICROBIAL SUSCEPTIBILITY TESTING
Susceptibility testing is usually performed by
a disk diffusion or dilution (minimum
inhibitory concentration—(MIC) method.
MIC is done by mixing a standard concen-
tration of the organism that the patient has
grown with increasing concentrations of the
antibiotic in a broth solution. It is done in test
tubes or in microdilution/microtiter plates.
The mixture is incubated for 24 hours at 37°C,
and then tubes or plates are examined with
the naked eye for turbidity, indicating growth
of the organism.
The MIC is the lowest concentration of
an antibiotic that completely inhibits the
growth of a microorganism in vitro. For each
organism-antibiotic pair there is a particular
cut-off of MIC at which the organism is
considered susceptible. This particular MIC is
termed the breakpoint. PK/PD is also crucial
in the process used to determine breakpoints.
Breakpoints are needed to label an isolate as
“susceptible”, “intermediate”, “susceptible-
dose-dependent”, “non-susceptible”, or
“resistant”. If the organism is reported as
“sensitive”, the MIC is <1/2 or 1/4 the
concentration of antibiotic likely to be found
within the infected tissues of a patient given
the standard dosing schedule, i.e. the infection
is treatable. Resistance implies that the
infection is not treatable with the antibiotic
because its MIC exceeds achievable safe tissue
or urine levels. If a drug has the lowest MIC
for a microbe, it does not mean it is the most
effective option for treatment, different
antibiotics achieve different concentrations in
the body at different sites.
The MIC may be extended to measure the
minimum bactericidal concentration (MBC) of
the antibiotic by putting subcultures of
samples obtained from clear tubes or wells (in
the case of microdilution testing) on a solid
culture medium without antibacterial agent
and is further incubated for 18–24 hrs. MBC
is the lowest concentration of an antibacterial
agent that either totally prevents growth or
shows a ≥99.9% reduction in the initial
inoculum [i.e. a 3-log10 reduction in colony-
forming units (cfu)/mL] on subculture.
BACTERIOSTATIC AND BACTERICIDAL
At the MIC, the antibiotic is inhibiting growth,
but it may or may not actually be killing the
organism. Antibiotics that inhibit growth of
the organism without killing it are termed
bacteriostatic. If antibiotics are removed,
the organisms can begin growing again.
Bacteriostatic drugs though are successful in
treating most infections by inhibiting their
growth and allowing host immune system to
takeover and kill the pathogens. Whereas,
bactericidal drugs directly kill the organism
without the assistance of host immune system.
It is generally recommended that severely ill
and immunosuppressed patients with serious
bacterial infections should be treated with
bactericidal antibiotics. Apart from being
bacteriostatic or bactericidal, antimicrobial
agents also differ in how they manifest their
effects over time.
Potency and Efficacy
Drug potency refers to the quantity of drug
needed to produce a certain response. Relative
potency is commonly more meaningful than
absolute potency, and is mostly defined by
comparing the concentration of two agonists
at which they elicit half maximal response.
Having only higher potency does not mean
clinical superiority, it is only if the drug’s
potency for therapeutic effect is better than
the potency of adverse effects. Drug efficacy
means the maximal response that may be
produced by the drug. The MIC could be a
good indicator of the potency of an antibiotic,
it indicates nothing about the time course of
 Pharmacokinetics and Pharmacodynamics of Antimicrobial Therapy
antimicrobial activity. When determining the
potency of an antibiotic against a bacterium,
factors like protein binding capacity, drug
concentration at the site of infection, adequacy
of host defenses and also the amount of
exposure of a pathogen to the antimicrobial
needed for its eradication are important
considerations. Therefore, to know the
relevance of drug dose to efficacy, we should
integrate PK-PD characteristics.
PK-PD PARAMETERS
PK parameters quantify the serum level time
course of an antibiotic (Fig. 4.1). The three
pharmacokinetic parameters that are most
vital for evaluating antibiotic efficacy are:
i. Peak serum level (Cmax),
ii. Trough level (Cmin), and
iii. Area under the serum concentration time
curve (AUC).
While these parameters quantify the serum
level time course, they do not describe the
bactericidal effect of an antibiotic. By
integrating the PK parameters with the MIC
three PK/PD parameters are obtained which
quantify the activity of an antibiotic:
• The peak/MIC ratio—it is the C max
divided by the MIC.
• The T>MIC—time above MIC is the
percentage of a dosage interval during
which the serum level exceeds the MIC
Fig. 4.1: Pharmacokinetic parameters
33
Fig. 4.2: Pharmacokinetic parameters in relation
to MIC
• The 24h-AUC/MIC ratio—it is deter-
mined by dividing the 24-hour-AUC
(AUC0–24) by the MIC (Fig. 4.2).
An agent’s bactericidal pattern of activity
is not entirely predictive of the PK-PD
measure most closely related to effcacy. The
presence and duration of postantibiotic effect
(PAE) is additionally important. It is the
delayed regrowth of bacteria after exposure
to antibiotic and is seen with most antibiotics
except for most beta-lactams against Gram-
negative bacteria. The carbapenems do have
PAE with Gram-negative bacteria.
Antibiotics can be divided on the basis of
pattern of antimicrobial activity:
i. Time-dependent bactericidal effect:
This group of antimicrobials require that
the drug concentrations be above the
MIC for a particular percentage of the
dosing interval to effectively kill the
organism. With time-dependent killing,
PAE are minimal. Increasing the free
drug concentration of the drugs above
the standard dose after achieving the
target of time above MIC has no extra
benefit in clearance of that pathogen. The
time needed above the MIC varies, based
on the type of pathogen, infection site
and drug. Examples are beta-lactams,
macrolides and clindamycin (Table 4.1).
 34 Infectious Diseases in Critical Care
TABLE 4.1: Antibacterial activity and PK-PD measure of antibiotics
Drugs Antibacterial Plasma protein
activity binding
Aminoglycosides Concentration Low
dependent
Beta-lactams Time dependent Low–moderate
Vancomycin Time dependent Moderate
Fluoroquinolones Concentration Low–moderate
dependent
ii. Concentration-dependent bactericidal
effect: These antimicrobials achieve
increasing bactericidal effect with
increased serum levels of the drug.
Prolonged PAE is often seen even when
the concentration is below MICs. These
drugs are dosed to attain maximum safe
concentrations at the infection site for
optimal bactericidal activity. Examples
are aminoglycosides, quinolones, keto-
lides and vancomycin. The important PD
parameters which correlate with the
clinical and bacteriologic efficacy of these
drugs are the 24 hour AUC:MIC ratio
and/or peak drug concentration to MIC
ratio (Table 4.1).
PK-PD RELATIONSHIP
Antibiotic dosing is best performed with an
understanding of pharmacokinetics and
pharmacodynamics. The MIC of a drug for an
organism is compared to the achievable
unbound drug concentrations at a site of
infection, usually in blood. To identify the PK/
PD parameter and magnitude of that
parameter that best correlates with efficacy,
animal or in vitro models of infection are used.
Usually, the “susceptible” breakpoint is fixed
at the highest MIC where the PK/PD target
for efficacy is achieved in approximately 90%
of the patient population using standard
dosing. For determining breakpoints,
population pharmacokinetics and Monte
Solubility PK-PD Clearance
measure
Hydrophilic AUC0-24: MIC, Renal
Cmax: MIC
Hydrophilic T>MIC Renal
Hydrophilic AUC0-24: MIC Renal
Lipophilic Peak: MIC Renal
Carlo simulations are utilized together with
the PK/PD targets. Monte Carlo simulation
is a statistical tool and is used to incorporate
the potential variability expected in the patient
population for an antibiotic and generate data
for PK-PD target attainment for efficacy at
different MICs which helps in formulating
antibiotic dosing regimens. It uses a computer
software used to perform virtual clinical trials.
In general, the goal is to attain a minimum of
90% target attainment.
Altered PK parameters among intensive
care unit seriously ill patients, e.g. decreased
renal function, hyperdynamic state, and use
of vasoactive drugs, have direct implications
on the antimicrobial serum concentrations.
Moreover, with increasing antimicrobial
resistance, the efficacy of standard dosing
regimens may be reduced and hence
integration of PK-PD becomes even more
important because these parameters may be
used to redesign dosing regimens which
counteract or can help prevent resistance.
BIBLIOGRAPHY
1. Patricia JS, Linda M. Understanding pharma-
cokinetics (PK) and pharmacodynamics (PD).
Published in AST news update 2018; vol 3: (1):
1-8.
2. Tripathi KD. General Pharmacology Principles
in Textbook of Essentials of Medical Pharma-
cology, Jaypee Brothers Medical Publishers (Pvt)
Ltd. reprint 2014, 1–82.