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369377
0066-4804/04/$08.000 DOI: 10.1128/AAC.48.2.369377.2004
Copyright 2004, American Society for Microbiology. All Rights Reserved.
MINIREVIEW
Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective
Agents: Kill Curves versus MIC
Markus Mueller,1,2 Amparo de la Pen
a,1 and Hartmut Derendorf1*
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida,1 and Department
of Clinical Pharmacology, Vienna University Medical School, Vienna, Austria2
The success of antimicrobial therapy is determined by complex interactions between an administered drug, a host, and an
infecting agent. In a clinical situation, the complexity of these
interactions is usually reflected by a high variability in the
dose-response relationship. Therefore, to minimize the doseresponse variability, key characteristics of the drug, the infecting agent and the host have to be taken into account for
selecting an appropriate antibiotic and an appropriate dose.
Failure to do so may result in either therapeutic failure or
emergence of resistant strains.
To date, dose and drug selection is mostly based on a static
in vitro parameter, the MIC and on the drugs serum concentration as a pharmacokinetic parameter. In practice, however,
a pharmacodynamic effect in vivo is rather the result of a
dynamic exposure of the infective agent to the unbound antibiotic drug fraction at the relevant effect site. Thus, static
conditions in an in vitro setting hardly reflect a dynamic situation in a target organ under in vivo conditions. Furthermore,
serum concentrations do not reflect the unbound concentrations at the target site.
In recent years substantial efforts were devoted to systematically elucidate the dynamic relationship between pharmacokinetic and pharmacodynamic variables. The main concept of
this pharmacokinetic-pharmacodynamic approach is to use the
concentration-effect relationship of the drug of interest in dosage adjustment and product development in a logical way and
minimize trial-and-error approaches (29, 80). This approach
can potentially result in substantial savings of time and expenses and may help to avoid unnecessary and, hence, unethical clinical studies (97). Thus, dosages and dosing intervals of
antimicrobial agents should be designed with reference to dynamic pharmacokinetic and pharmacodynamic parameters.
Accordingly, several efficacy indices or surrogate markers that
take into account both pharmacokinetic and pharmacodynamic information have been defined and used by different
authors to describe the antibacterial activity of various classes
of antimicrobial agents (100, 106, 59).
Currently there are two main trends for antibiotic pharmacokinetic-pharmacodynamic models; those based on the MIC
and those based on a kill-curve approach, both of which will be
described in detail in the following.
* Corresponding author. Mailing address: Department of Pharmaceutics, College of Pharmacy, University of Florida, PO Box 100494,
Gainesville, FL 32610. Phone: (352) 846-2726. Fax: (352) 392-4447.
E-mail: hartmut@cop.ufl.edu.
369
370
MINIREVIEW
Cmax/MIC Ratio
This parameter is the relationship between the Cmax reached
in the patient at steady state and the MIC established for the
The MIC is a well-established laboratory parameter routinely determined in microbiology. It is currently by far the
most commonly used pharmacodynamic parameter for the
evaluation of efficacy of anti-infective agents. Once the desirable pharmacokinetic-pharmacodynamic parameters are determined, the drug concentrations are compared to the MIC to
make dosing decisions.
However, although these parameters are useful predictors of
the potency of the drug-microorganism interaction, this approach has both pharmacokinetic and pharmacodynamic disadvantages.
From the pharmacokinetic point of view, all of these models
compare the MIC to measurements obtained from the concentration-time curve measured in plasma. Thus, two important
factors are overlooked: protein binding and tissue distribution.
After absorption most drugs are bound to plasma proteins.
They can also leave the plasma and enter the tissues, where,
again, they can be nonspecifically bound to either tissue proteins or structures (28). Protein binding is relevant because
only the drug that is unbound from the plasma proteins will be
available to exert a pharmacological effect. Tissue distribution
also needs to be taken into account, given that most of the
infections occur not in plasma, but in the interstitial space of
the tissues.
From the pharmacodynamic point of view, the MIC approach provides only limited information on the kinetics of the
drug action. For instance, the MIC does not provide information on the rate of bactericidal activity and whether increasing
antimicrobial concentrations can enhance this rate. Since the
MIC determination depends on the number of bacteria at a
single time point, many different combinations of growth and
kill rates can result in the same MIC. These different kill
kinetics may be therapeutically relevant. Similarly, the MIC
approach does not provide any information about the persistent activity of the antimicrobial agent that remains following
exposure to the drug (56). These shortcomings are frequently
compensated for by modifications of the MIC interpretation
such as postantibiotic effects or sub-MIC effects.
An additional and important shortcoming is that MICs are
conventionally measured for constant antibiotic concentrations
and therefore represent threshold concentrations. This implies
the existence of an all-or-nothing concentration-effect relationship. All concentrations below the MIC are treated equally and
similarly no quantitative distinction is made for all concentrations above MIC. This is a very crude way of using antimicrobial information. Clearly, concentrations just below the MIC
show some anti-infective activity and are different from those
that are close to zero. Similarly, concentrations just above the
MIC do not show the maximum effect that is only achieved
with higher concentrations.
Thus, static MIC approaches do by no means reflect the in
vivo scenario, where bacteria are not being exposed to constant
but constantly changing antibiotic concentrations.
DYNAMIC IN VITRO MODELS BASED ON
KILL CURVES
A different approach to assess the anti-infective efficacy of
antibiotics is to use pharmacokinetic-pharmacodynamic models based on time-kill curves. Time-kill curves can follow microbial killing and growth as a function of both time and
antibiotic concentration. Antibiotic concentration can either
be held constant or changed to mimic an in vivo concentration
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371
(1)
(2)
KA C
1 KB C
(3)
372
MINIREVIEW
(4)
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373
Concentration-Based Analysis
Zhi et al. published the mathematical solutions for. linear
nonsaturable and nonlinear saturable possible pharmacodynamic interactions between -lactam antibiotics and microorganisms (118). The equations, developed from a model originally proposed by Jusko et al. (63) were derived for different
dosage regimens, such as single and multiple intravenous bolus
and constant infusion at steady state. The authors applied the
model to the activity of piperacillin against Pseudomonas
aeruginosa in neutropenic mice and concluded that the saturable nonlinear model appeared to be appropriate.
A similar approach for concentration based pharmacokinetic-pharmacodynamic analysis is based on an Emax model.
The concept of the mathematical method is briefly shown below (89). For a beta-lactam antibiotic, the rate of change in
bacteria versus time (dN/dt) can be described by the following
expression: equation 5
dN
kmax C
k0
dt
EC50 C
(5)
where N is the number of bacteria in CFU/ml, k0 is the bacterial growth rate constant in the absence of drug, kmax is the
maximum bacterial kill rate, C is the drug concentration, and
EC50 is the drug concentration necessary to achieve half of the
maximum effect.
If the bacteria are not in the logarithmic growth phase at
Zt
time zero, an exponential correction factor (1 e ) may be
necessary to compensate for this delay.
This model has been very useful to describe the effects of a
number of beta lactam antibiotics (26, 89, 90). It could also be
shown that the Emax model used for kill-curve fitting can be
related to MICs.
Rearranging of equation 5 yields: equation 6
dN
kmax C
k0
N
EC50 C
dt
(6)
Nt
N0
1
dN
N
k0
kmax C
EC50 C
dt
(7)
(8)
where the right-hand term is a constant defined as d. Substituting the right-hand term with d and rearranging gives: equation 9
C
d
EC50 MIC
kmax d
(9)
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MINIREVIEW
EmaxDn
n
P50
Dn
(10)
where E is the observed effect at 24 h (measured as the reduction in log10 CFU/thigh or lung compared to untreated controls), D is the cumulative 24-h dose of amikacin, Emax is the
maximum antimicrobial effect attributable to the drug, P50 is
the 24-h dose producing 50% of Emax, and n is the slope of the
dose-response relationship. Emax was calculated from the
change in log10 CFU/thigh or lung over the 24 h of treatment,
at the highest dose studied for each organism. P50 and n were
calculated separately for each dosing interval using nonlinear
regression.
A general shortcoming of AUC- and dose-based analyses is
related to the fact that the parameters AUC and dose merely
reflect single integrated parameters and do not reflect the
dynamic profile of the drug concentration in vivo.
CONCLUSION: KILL CURVES VERSUS MIC
Traditionally dose and drug selection in antimicrobial therapy is based on a single static in vitro parameter, the MIC. In
practice, however, an in vivo antimicrobial effect is rather the
result of a dynamic exposure of the infective agent to the
unbound antibiotic drug fraction at the relevant effect site. In
light of this consideration, dynamic pharmacokinetic-pharmacodynamic approaches were developed to systematically eluci-
date the dynamic relationship between bacteria and anti-infectives. The concept of this pharmacokinetic-pharmacodynamic
approach is to use the full concentration-profile versus effect
rather than the MIC.
Few comparisons of the two approaches in the literature
have been performed (18). It seems that the goal has been to
minimize the available information and limit the pharmacodynamic input to the MIC. However, kill curve approaches and
subsequent pharmacokinetic-pharmacodynamic analysis may
provide more meaningful information about the interaction
between bacteria and anti-infectives because these approaches
describe this interaction in a more dimensional way by a dynamic integration of concentration and time and, hence, use
the complete available information. In contrast, MIC measurements only provide a still photo of the effect of an antibiotic at
a single concentration value. This value is regarded as an all
or nothing threshold value, which would imply the antibiotic
activity would be turned on or off above or below the MIC
limit, respectively. However, this scenario does by no means
reflect an in vivo setting where antibiotics actually also exert
effects at very low concentrations.
It may therefore be concluded that a dynamic pharmacokinetic-pharmacodynamic approach based on kill curves is a
more rational approach to describe drug-bacteria interactions
than the classical MIC approach.
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