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ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 2004, p.

369–377
0066-4804/04/$08.00⫹0 DOI: 10.1128/AAC.48.2.369–377.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Vol. 48, No. 2

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 drug⬘s 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.

MODELS BASED ON STATIC MICs
The most common approach to antibiotic dosing is to adjust
the doses to obtain antibiotic plasma concentrations that are
above the MIC for the respective pathogen throughout the
dosing interval. The MIC is the lowest concentration that completely inhibits visible growth of the organism as detected by
the unaided eye after a 18- to 24-h incubation period with a
standard inoculum of approximately 105 CFU/ml (87).
In these approaches, the pharmacokinetic parameter is usually the serum concentration of the anti-infective agent, and
the pharmacodynamic parameter is almost exclusively the MIC
(104, 71, 105). The minimal bactericidal concentration (MBC),
which is the lowest concentration of the antibiotic that causes
complete destruction of the pathogen, has also been used for
the same purpose (1, 4, 30, 51, 95, 108).
Figure 1 shows the most frequently used parameters, which
are time above the MIC (t ⬎ MIC), ratio of peak concentration
and MIC (Cmax/MIC), and ratio of 24-h area under the curve
and MIC (AUC/MIC).
Another parameter similar to AUC/MIC is the area under
the inhibitory curve (AUIC), which can be calculated from the
area under the curve for the time period over 24 h where the
serum concentration exceeds the MIC (AUCt ⬎ MIC/MIC
over 24 h) (106, 25). However, AUC/MIC is much easier to
calculate than AUIC which does not offer any significant advantage. Moreover, if the drug concentration remains above
the MIC at all times, AUIC and AUC/MIC are identical.
Using the MIC approach, antibiotics are frequently divided
into two major groups: those that exhibit time-dependent (concentration-independent) killing and minimally to moderately
persistent effects and those that exhibit concentration-dependent killing and prolonged persistent effects (19).
For antibiotics that belong to the first group (beta-lactam
antibiotics, vancomycin, macrolides), their effect depends on
the length of time that the drug is in contact with the bacteria.
Their effect will increase with increasing concentrations until a
finite point (the maximum kill rate) is reached. After that
point, increasing concentrations will not produce a corresponding increase in the effect; therefore, high peak concentration will not help. Maximum killing has been seen to occur
at concentrations approximately four to five times the MIC
(88). The parameter that has been most used to assess the
efficacy of time-dependent antibiotics is the time that the antibiotic plasma concentration exceeds the MIC for a particular

* 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.
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FIG. 1. Currently used pharmacokinetic-pharmacodynamic parameters.

microorganism, or time above MIC (t ⬎ MIC) (33, 24, 115,
112).
The second group of antibiotics, which include the aminoglycosides and fluoroquinolones, exhibit a different killing pattern. In their case, the bacterial rate of killing is seen to increase with increasing concentrations of the antibiotic. The
goal in this case is to maximize the drug concentration. The
parameters that are most currently used are those which reflect
an increase in drug concentration, i.e., Cmax/MIC (the ratio
between the peak concentration and the MIC) and AUC ⬎
MIC. The area under the inhibitory curve (AUIC) is also
popular and it can be easily calculated as the ratio of 24-h AUC
(for time points with respective concentrations above the MIC)
and the MIC (24, 115, 70, 83).
Time above MIC
This index measures the time during which antibiotic concentrations in plasma are above the MIC for a particular
pathogen and it has been used to assess the bactericidal activity
of ␤-lactam antibiotics (72, 52).
Craig has reviewed the data from the literature that use
mortality as an endpoint and in which animals infected with
Streptococcus pneumoniae were treated with penicillins or
cephalosporins (20). A relationship was found between the
duration of time that the serum level is above MIC and the
efficacy, which was between 90 to 100% when serum levels
were above the MIC for approximately half of the dosing
interval (23).

pathogen responsible for the infection (99). Many studies have
used it as a good predictor of clinical outcome for drugs showing concentration-dependent bactericidal effects, particularly
for aminoglycosides (24, 99, 60, 78, 84, 10, 11, 56).
Parameters That Use AUC
The AUC24 h/MIC ratio relates the total AUC at steady state
to the MIC, and has been found to correlate best with the
efficacy of fluoroquinolones (106, 70, 56, 21). The term AUIC
was introduced by Flaherty et al. for the area under the serum
inhibitory concentration of clindamycin. It was calculated as
the AUC of the reciprocal values of the serum inhibitory titer
(SIT) versus time, similarly to that previously described for
evaluating the area under the bactericidal curve (43, 44).
Later, Schentag et al. pointed out the equivalence between
the area under the bactericidal curve and AUIC for several
antibiotic classes, and proposed a method to calculate AUIC as
the AUC for the period of time the concentrations are above
the MIC divided by the MIC (106). However, today AUC24
h/MIC ratios are preferred since they are easier to calculate
and are independent of the fact if concentrations exceed the
MIC or not. However, the same AUC24 h/MIC, which implies
equal potency, can be obtained with different dosage regimens
that resulted in very different times above MIC. Particularly in
the case of beta-lactams, the use of a constant AUC24 h/MIC
can produce regimens that have significant time below the
MIC and may result in negative therapeutic effects (25).
DISADVANTAGES OF STATIC MIC APPROACH

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

VOL. 48, 2004

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

MINIREVIEW

371

profile, be it either in plasma or at the infection site. The
resulting kill curves can be subsequently analyzed with appropriate pharmacokinetic-pharmacodynamic models. Finally
these pharmacokinetic-pharmacodynamic models then aid to
optimize dosage regimens based on a rational, scientific approach. The advantage of these in vitro models is that they
allow direct comparison of the effects of various concentration
profiles and provide for a much more detailed assessment of
the pharmacokinetic-pharmacodynamic relationship than the
simple use of MICs.
Kill curves can and have been used to study anti-infective
effects both in animal and in vitro models, with the advantage
of providing more detailed information about the time course
of antibacterial effect.
Various types of in vitro models have been devised. the main
classes are those with constant antibiotic concentrations, which
study the effects of a constant concentration of drug against
bacteria as a function of time; and those with variable antibiotic concentrations, in which the antibiotic concentrations fluctuate by dilution or diffusion.
Models with Constant Antibiotic Concentration
These models study the number of bacteria exposed to a
constant antibiotic concentration. Early studies by Garrett et
al. investigated the effect of constant concentrations of bacteriostatic and bactericidal drugs against bacteria as a function of
time (48, 82, 49).
Curves in the presence (kill curves) and absence (growth
curves) of antibiotic were compared. After an initial lag time,
bacteria typically show a phase of logarithmic growth (log
phase) that can be described by: equation 1
N ⫽ N0 e⫺k0t

(1)

where N is the number of bacteria at any given time point, N0
is the number of bacteria in the initial inoculum, and k0 is the
first-order growth rate constant. N and N0 are usually expressed in CFU per milliliter. Exposure to an antibiotic while
the bacteria are in log phase will produce a change in k0,
resulting in a different growth rate constant (kapp).
The mathematical relationship between antibiotic concentration and kapp for bacteriostatic drugs was studied, and the
interactions found were classified into four classes by Garrett
(47). The classes were defined as follows. Class I interactions
are defined by a linear relationship between kapp and concentration that can be expressed by: equation 2
kapp ⫽ k0 ⫺ kIC

(2)

where kI is a second-order inhibitory rate constant specific for
the drug, C is the drug concentration, and k0 and kapp have
been defined before.
Class II interactions, where the kapp decreases with increasing concentrations to approach zero asymptotically, are represented by the equation: equation 3
kapp ⫽ k0 ⫺

KA 䡠 C
1 ⫹ KB 䡠 C

(3)

where KA is an equilibration constant between the medium and
the receptor sites at steady state, KB is the affinity constant

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between drug and receptor, and C, k0 and kapp have been
defined before.
Class III interactions exhibit class I behavior at low concentrations, which turns into class II behavior at high concentrations. Class IV interactions show S-shaped plots of kapp versus
concentration that may be due to binding of the drug to nutrients at low concentrations.
The main difference between bacteriostatic and bactericidal
drugs is that for the latter the kapp may take negative values, as
the bacteria are now being killed. There is a linear relationship
between kapp and C that can be expressed mathematically by:
equation 4
kapp ⫽ k0 ⫺ ki 䡠 共C ⫺ Ci兲

(4)

where k0 is the growth rate constant in absence of drug, ki is the
kill rate constant, C is the drug concentration, and Ci is the
minimum drug concentration that will produce an effect (50).
Using a different mathematical approach, the growth curves
for bacteria exposed to different antibiotic concentrations were
described taking into account the effect lag time after initial
drug exposure. Curves of growth in the presence of the antibiotic were expressed as quadratic functions of time, with initial growth rates and rates of change of growth as concentration dependent variables. Assuming k0 is a constant, kill rates
would only depend on drug concentration (75, 76, 77, 114).
A disadvantage of these approaches is that they do not
reflect the in vivo situation where drug concentrations fluctuate. Therefore, although they are good mathematical descriptors of antibacterial behavior, they have limited ability of predicting or correlating with clinical outcomes.
Models with changing antibiotic concentrations, on the
other hand, try to simulate in vivo concentration-time profiles
using human pharmacokinetic parameters in order to assess
the antibacterial effect. Changing concentrations can be produced either by dilution or diffusion.
Models with Variable Antibiotic Concentrations
Dilution models. A kinetic model that operated by pumping
sterile broth into a flask (containing bacteria in log growth
phase and antibiotic) at a constant rate resulted in antibiotic
dilution (101, 102). The main limitation of this model was that
the volume in the flask increased throughout the experiment,
diluting also the inoculum and posing practical problems for
large dilutions. A one compartment open model that used a
system consisting of two flasks interconnected by a peristaltic
pump to simulate first-order kinetics was developed by Grasso
et al. (53). Sterile broth was pumped from the diluent reservoir
flask to the flask containing the bacterial culture and the antibiotic. The volume in the culture flask could be regulated,
resulting in exponentially decreasing antibiotic concentrations
that simulated the human serum t1/2 of the antibiotic. An
adjustment in the model enabled it to also simulate first-order
absorption kinetics (53). Further modifications of this model
enable to continuously monitor bacterial level by including a
photometer to read turbidity levels, and to control the system
using a computer (7, 6, 8, 69).
The main concern with these models is that the bacterial
inoculum is diluted together with the antibiotic. This effect is
particularly important when the dilution rate is higher than the

bacterial growth rate, and the resulting increased bacterial
clearance needs to be accounted for. Some equations to correct this effect for exponentially changing cultures have been
proposed (117, 64). Lo
¨wdin et al. employed a 0.45-␮m filter
membrane in the culture flask to prevent bacterial outflow. By
placing a stirrer above the filter, they avoided blockage of the
membrane and ensured that the culture was homogeneously
mixed. The culture flask had two arms, one of which was used
to take samples through a silicon diaphragm. Medium was
drawn from the culture vessel by a pump at a constant rate,
causing a vacuum in the flask that in turn caused fresh sterile
medium to be sucked into the flask through the other arm. The
antibiotic was added through the first arm and followed firstorder elimination kinetics (73). The original model contained
the stirrer with a magnet covered in Teflon, however, bacteria
were suspected to adhere to this surface. The Teflon-covered
stirrer was substituted by a new stirrer in which the magnet was
encased in glass (74).
A modification of this model allows to study the effects of
antibiotics on intracellular pathogens (58). Instead of the culture flask, a glass chamber with a metal rack fitting Falcon cell
culture inserts was used and connected to a pump. Cells cultures are grown in the inserts, infected and then transferred to
the glass chamber, which contains medium with antibiotic.
Half-lives of the antibiotics are simulated using a pump as
described above, and samples are taken at appropriate time
points. A magnet is placed in the bottom of the glass chamber
to achieve an even concentration through the medium. After
the experiments, cells are lysed and intracellular bacteria
counted by plating (58).
Recently a simple one-compartment in vitro model was developed to study the pharmacodynamic effect of concentrations of piperacillin against E. coli, following administration of
constant or fluctuating concentrations (90). The free interstitial concentrations of the drug reached in humans after different doses and dosing regimens were simulated. To simulate
drug elimination in a stepwise fashion, broth solution containing antibiotic was withdrawn from the model at fixed time
intervals and replaced with drug-free broth. The bacterial inoculum was not changed because the broth was both withdrawn and added through a filter. The number of cells was
determined by colony count after overnight incubation. This
model was also used in a separate study for the determination
of the effect of different dosing regimens of piperacillin alone
and in combination with tazobactam on Escherichia coli (26).
Diffusion models. In diffusion models, the antibiotic concentrations are changed by applying concentration gradients. An
in vitro model in which the compartments were separated by a
hollow-fiber dialyser was used to simulate two-compartment
kinetics. Drug dilution was achieved by pumping sterile broth
from one compartment to the other. However, the model was
reportedly too complex and impractical. Its use was recommended only when a very short drug t1/2 needed to be simulated or very flexible kinetics required (96). A different twocompartment model using a regenerated cellulose dialyser was
developed by Ko
¨nig et al. (66, 67). Dilution was accomplished
by antibiotic diffusion from the culture compartment to the
second compartment along a concentration gradient.
A model by Murakawa et al. uses bidirectional flow between
the central and peripheral compartments to achieve a biexpo-

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MINIREVIEW

nential decline in concentrations. Bacteria and drug are placed
initially in the central compartment, broth is pumped into the
central compartment and bacteria are diluted out of the central compartment and the system, therefore necessitating
mathematical adjustment for bacterial dilution (86). A model
that integrates bidirectional flow with the use of a membrane
to prevent bacterial dilution has been used by Palmer et al.
(93).
A more complex model to simulate two-compartment pharmacokinetic was introduced by Blaser et al. (12). Serially
placed bacterial compartments, representing extravascular infection sites, interface with a central compartment through
artificial capillaries. Broth containing antibiotic is constantly
pumped from the central compartment through the tubing.
The porous capillary walls allow for bidirectional passage of
antibiotics (⬍10 kDa) but are impermeable to bacteria. Sterile
drug-free broth is continuously pumped to the central compartment from a diluent reservoir, thus displacing drug-containing broth from the system. An additional “absorption”
compartment may be added between the diluent reservoir and
the central compartment to simulate first-order absorption
(10). The model can be used for simulation of both continuous
and intermittent drug administration (13). Simultaneous first
order elimination kinetics of two drugs with different half-lives
were simulated to study antibacterial effects of drug combinations (120, 119, 14).
Models that mimic effect site pharmacokinetics. Several in
vitro models were developed that simulate in vivo conditions in
specific infection sites or conditions, such as an bladder (54,
103), bacterial cystitis (55), otitis medium (113, 35), endocarditis (79), chronic pneumonia (68), tuberculosis (9), infected
fibrin clots (94), and implant-related infections (27, 15). However, such attempts to more closely mimic an in vivo situation
and to predict clinical response were hampered by the inability
to measure pharmacokinetics (pharmacokinetic) at the site of
infection. Measuring target site pharmacokinetics has recently
become possible by microdialysis, a technique which allows for
the on-line measurement of unbound drug concentrations in
the interstitial space. Since microdialysis monitors free antibiotic concentrations in the fluid which directly surrounds the
infective agents, the antimicrobial effect linked to the time
versus drug concentration profile obtained by microdialysis
may easily be simulated in an in vitro setting on bacterial
cultures. This dynamic simulation may, thus, provide a rational
approach to describing and predicting pharmacodynamics at
the relevant targt site.
KILL CURVE DATA ANALYSIS
Although experimental kill curves enable a dynamic interpretation of drug-bacteria interactions, the strength of this
approach is not fully exploited until the data are analyzed by
means of mathematical models. Based on experimental data
derived from kill curve experiments these models then serve as
a basis to simulate different dosing scenarios. Several mathematical models have been proposed for this purpose, which
may be divided into concentration-based, AUC-based, and
dose-based approaches.

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 䡠 C
⫽ k0 ⫺
dt
EC50 ⫹ C

䡠 N

(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 䡠 C
⫽ k0 ⫺
N
EC50 ⫹ C

䡠 dt

(6)

which can be integrated on both sides: equation 7

Nt

N0

1
䡠 dN ⫽
N

冕冉
t

0

k0 ⫺

kmax 䡠 C
EC50 ⫹ C

䡠 dt

(7)

where t is the incubation time necessary for measurement of
the MIC, Nt is the number of bacteria at the end of the
incubation period, and N0 is the initial bacterial inoculum.
Solving and rearranging equation 7 yields: equation 8
kmax 䡠 C
lnNt ⫺ lnN0
⫽ k0 ⫺
EC50 ⫹ C
t

(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
䡠 EC50 ⫽ MIC
kmax ⫺ d

(9)

Since this equation is true for any given concentration, it is
also true for the MIC. The MIC was previously defined as the
lowest concentration that completely inhibits visible growth of
the organism as detected by the unaided eye after an 18- to

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24-h incubation period (t) with a standard initial inoculum (N0)
of approximately 105 CFU (87). Turbidity (visible growth) occurs at about 107 CFU/ml (Nt) (89).
AUC- and Dose-Based Analysis
Firsov et al. used a two-compartment in vitro dynamic model
with antibiotic and bacterial dilution to study the effect of
antibiotics and suggested two integral parameters to characterize antimicrobial effect duration (TE) and intensity (IE). The
first parameter, TE is defined by the time from the moment of
antibiotic administration to the moment when the bacterial
count reaches its initial level again, and IE is the area between
the microbial growth curves in the presence and absence of an
antibiotic (36). These parameters were compared to 10 other
indicators of bacterial killing and regrowth kinetics in terms of
the respective AUC-response relationships as applied to the
action of ciprofloxacin against E. coli. Comparisons were made
on the basis of four criteria: relevance to be related to the
AUC, sensitivity to the AUC, robustness and predictive ability
in terms of IE. The authors conclude only IE and TE met all
four criteria and propose IE as a more universal measure of the
antimicrobial effect (37). Using the same model, commonly
used predictors of antimicrobial effect (AUC/MIC, AUC ⬎
MIC, and t ⬎ MIC) were examined for pharmacokinetically
different quinolones, trovafloxacin, and ciprofloxacin. Linear
correlations were established between IE and log AUC/MIC,
log AUC ⬎ MIC, and log t ⬎ MIC, the first two being specific
for each drug and dosing regimen, allowing quantitative comparison of the effects (38, 39, 40, 41, 42).
A sigmoid dose-response model was used by Craig et al. to
characterize the in vivo antimicrobial activity in an animal
model: equation 10
E⫽

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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