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Clinical Therapeutics/Volume 30, Number 12, 2008

Pharmacokinetic/Pharmacodynamic Modeling to Predict In


Vivo Effectiveness of Various Dosing Regimens of
Piperacillin/Tazobactam and Piperacillin Monotherapy
Against Gram-Negative Pulmonary Isolates from Patients
Managed in Intensive Care Units in 2002
Christopher R. Frei, PharmD, MSc; and David S. Burgess, PharmD

Center for the Advancement of Research and Education in Infectious Diseases, The University of Texas at
Austin College of Pharmacy and Pharmacotherapy Research and Education Center, Austin, Texas; and the
University of Texas Health Science Center at San Antonio, San Antonio, Texas
ABSTRACT
Objective: This study compared the pharmacokineticl
pharmacodynamic (PK/PD) properties of piperacillinl
tazobactam (PTZ) combination treatment with those
of piperacillin (PIP) monotherapy against clinical gramnegative pulmonary isolates from US patients treated in
intensive care units.
Methods: Computer modeling was used to integrate
national in vitro microbiologic data from 2002 with
pharmacokinetic data from published studies in healthy
volunteers. PTZ (3.375 g q4h, 3.375 g q6h, 4.5 g q6h,
and 4.5 g q8h) and PIP (3 g q4h, 3 g q6h, 4 g q6h, and
4 g q8h) were modeled using Monte Carlo simulations.
The cumulative fraction of response (CFR) was determined for percentage of time that the free serum concentration remained above the MIC of ::::30% (bacteriostatic) and ::::50% (bactericidal). Because simulated
comparisons with an artificially derived sample size were
used, statistical methods were not applied.
Results: Overall, 2584 gram-negative pulmonary
isolates were evaluated, including Enterobacteriaceae
(n = 1430), Pseudomonas aeruginosa (n = 799),
Acinetobacter baumannii (n = 179), and "other" (n =
176). The percents susceptible with PTZ and PIP were
as follows: Enterobacteriaceae, 86% and 66%, respectively; P aeruginosa_. 89% and 84%; and A baumannii_.
47% and 34%. CFR rates with PTZ were numerically
higher than those with PIP against Enterobacteriaceae
(ranges, 86%-89% and 66%-73%, respectively) and
A bazt1nannii (47%-53% and 33%-42%), but not
against P aeruginosa (79%-84% and 75%-81 %).
Conclusion: Results from PKlPD models with Monte
Carlo simulation suggested that susceptibility differences
among these selected gram-negative isolates collected in
December 2008

2002 may be of sufficient magnitude to result in notable PK/PD differences between PTZ and PIP. (Clin The]:
2008;30:2335-2341) 2008 Excerpta Medica Inc.
Key words: Monte Carlo simulation, piperacillinl
tazobactam, aerobic gram-negative bacteria, pulmonary disease, infectious disease.

INTRODUCTION
The primary resistance mechanism of gram-negative
bacteria against ~-lactam antibiotics is the production
of ~-lactamase enzymes. 1 These enzymes cleave the
~-lactam ring, thereby rendering ~-lactam antibiotics
(eg, piperacillin [PIP]) ineffective. ~-Lactamase inhibitors (eg, tazobactam) counteract the ~-lactamase enzyme and protect the ~-lactam antibiotic from degradation. In studies, combinations of a ~-lactam plus a
~-lactamase inhibitor (eg, piperacillin/tazobactam [PTZ])
have been found to be more active compared with
monotherapy with ~-lactam antibiotics against bacteria that produce ~-lactamase.2
Over the past decade, the pharmaceutical industry
has begun to monitor antibiotic resistance, including
that which results from increased production of
~-lactamase. These programs provide valuable information regarding bacterial epidemiology and emerging resistance. One such surveillance program is the
Intensive Care Unit Surveillance System (ISS), developed by Merck & Co, Inc. (Rahway, New Jersey). 3,4
Accepted for publicatIOn October 31,2008
dOl:1 0_1 016!J-cIinthera_2008_12_009
0149-2918/$32_00

2008 Excerpta Medica Inc All nghts reserved_

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Clinical Therapeutics

The study of pharmacokinetic and pharmacodynamic (PK/PD) properties involves the integration of
pharmacokinetic properties and microbiologic activity
and is an important consideration when evaluating
antimicrobial alternatives. 5-7 The PK/PD profile of each
antimicrobial can be classified as one of the following:
Cma)MIC, AUC/MIC, or the percentage of time that
the free serum concentration remains above the MIC
(f% T>Mld 8- 1O For aminoglycosides, the literature suggests that Cma)MIC is the best predictor of clinical
outcome, whereas for fluoroquinolones, the literature
supports free AUC/MIC as the best predictor of clinical outcome. 8- 1O For ~-lactams, the literature supports
T>MIC as the best predictor of clinical outcome. 8- 1O PK/
PD profiles can be compared based on the mean serum
concentration and a single MIC value, usually MIC go .
However, this approach does not take into account the
variability of the pharmacokinetics or the distribution
of MICs; hence, this single-point PK/PD analysis can
indicate what is possible but not what is probable. ll
Monte Carlo simulation is a method that integrates the
pharmacokinetic and microbiologic data to determine
the probability of achieving a specific parameter.
Given our understanding of PK/PD principles, it
follows that the enhanced in vitro activity of PTZ is
relevant only if the following are true: (1) ~-lactamase
producing bacteria are prevalent, and (2) the presence
of ~-lactamase results in susceptibility changes of sufficient magnitude to compromise the PK/PD properties of PIP. The present study used PK/PD modeling to
predict the potential PK/PD benefits of PTZ compared
with PIP for the treatment gram-negative pulmonary
infections in the intensive care unit (ICU).

MATERIALS AND METHODS


Institutional review board approval was not required
because this analysis used a computer simulation that
did not include any identifiable patient information.
Microbiologic data were extracted from the 2002 ISS
database for gram-negative bacteria. Only isolates
obtained from pulmonary cultures were included in
this analysis. Bacteria were subdivided into 3 groups:
Enterobacteriaceae, Pseudomonas aeruginosa, and
Acinetobacter baumannii. MIC distributions were
determined for each group. MIC 50 , MIC gO ' and percent susceptible were calculated according to standards
of the Clinical and Laboratory Standards Institute. 12
The PK/PD properties of multiple antibiotic regimens of PTZ- (3.375 g q4h, 3.375 g q6h, 4.5 g q6h,
and 4.5 g q8h) and PIP (3 g q4h, 3 g q6h, 4 g q6h, and
4 g q8h) were assessed. Pharmacokinetic parameters
(volume of distribution at steady state [VsJ and secondphase t 1/2 [tll2~]) were obtained from a peer-reviewed
study in healthy volunteers, as listed in Table 1. 13 Protein binding was obtained from the PTZ prescribing
information,14 which indicates that the plasma protein binding is 30% for both piperacillin and tazobactam independently and in combination. Furthermore,
binding of the tazobactam metabolite is negligible:
because only the unbound fraction (Eu) of drug has
microbiologic activity, the fu was derived by subtracting the protein binding from 100%.
A 10,000-patient Monte Carlo simulation (Crystal
Ball, Decisioneering, Inc., Denver, Colorado) was con*Trademark: Zosyn' (Wyeth Pharmaceuticals, Inc., Philadelphia, Pennsylvania).

Table I. Published pharmacokinetic (PK) properties of piperacillin/tazobactam (PTZ) and piperacillin (PIP)
monotherapy in healthy volunteers. 13 * Data are mean (sD).
PTZ
PK Parameter

PIP

3.375 g q4h, q6h t

4.5 g q6h, q8h t

3 g q4h, q6h t

4 g q6h, q8h t

11.2(2.1)
0.76 (0.11)

10.5 (1.4)
0.75 (0.10)

11.2(2.1)
0.76 (0.11)

10.5 (1.4)
0.75 (0.10)

Vss ~ volume of distribution at steady state; tl,'2~ ~ second-phase t 1,'l"


*Proteln bmdmg was obtained from a PTZ PK study that reported that the protem bmdmg was 30% for both plperacillm
and tazobactam. 14
tValues were Identical across dosmg frequencies.

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Volume 30 Number 12

C.R. Frei and D.S. Burgess

ducted for each regimen-bacteria combination. Pharmacokinetic and microbiologic data were integrated
according to a I-compartment IV bolus model. IS Vss
and tl/2~ were varied according to logarithm-normal
distributions, which were constructed using the published mean (SD) values. Protein binding was varied
according to a uniform distribution (30% [SD 10%]).
In contrast, the actual MIC values from the microbiologic data were used to construct discrete distributions. The cumulative fraction of response (CFR) was
determined for f% T >MIC values of ::::30% (bacteriostatic) and ::::50% (bactericidal).l0
Because this study involved simulated patients, the
relationships described herein should be viewed as
qualitative as opposed to quantitative. With simulations such as these, the sample size is artificially chosen; in this case, we chose 10,000 simulations by
convention. Because the size of the P value is largely
dependent on the chosen sample size in simulated
comparisons, we believed it would not have been valid
to apply statistical methods to these simulated comparisons. We also point to similar studies that have
not applied statistics to these simulations. 16,17
RESULTS
Overall, the 2002 ISS database included susceptibility
data from 2584 gram-negative pulmonary isolates
(Enterobacteriaceae, 1430; P aeruginosa_. 799; A balt11lannii. 179; and "other," 176). Table II depicts the in
vitro activity of PTZ and PIP against these clinical
isolates. Against Enterobacteriaceae, the MIC so and
MIC gO were similar with PTZ (4/4 and 64/4 rg/mL,
respectively) and PIP (4 and 128 rg/mL); however,
the percent susceptible was 20% higher with PTZ
than PIP (86% vs 66%). For P aeruginosa, values
were similar between PTZ and PIP in terms of MIC so
(4/4 vs 4 rg/mL), MIC gO (128/4 vs 128 rg/mL), and
percent susceptible (89% vs 84%). In contrast, for
A bazt1nannii, PTZ had a lower MIC so than PIP (32/4 vs
128 flg/mL) and a higher percent susceptible than PIP
(47% vs 34%), whereas the MIC gO was similar between the 2 antibiotics (128/4 vs 128 rg/mL).
Table III and the figure show the PK/PD results for
both the bacteriostatic (f% T >MIC ::::30%) and bactericidal (f% T >MIC ::::50%) targets. For the bacteriostatic
target, CFR rates were higher with PTZ than PIP
against Enterobacteriaceae (ranges, 86%-89% and
66%-73 %, respectively) and A balt11lannii (47%-53 %
and 33 %-42 %) but similar against P aeruginosa
December 2008

(79%-84% and 75%-81 %). Notably, rates of CFR


against A balt11lannii were 0:;53 % with both PTZ and
PIP. Results for the bactericidal target were similar.
Another important observation was greater variability in CFR rates for the bactericidal target than for
the bacteriostatic target. For the bacteriostatic target,
the CFR varied by <10% regardless of the chosen
PTZ regimen. The same was true among the PIP regimens. However, the variation was more pronounced
with both PTZ and PIP for the bactericidal PK/PD
target. In fact, the CFR at the bactericidal target varied by up to the following percentages with PTZ and
PIP, respectively: Enterobacteriaceae, 21 % and 28%;
P aeruginosa. 36% and 36%; and A balt11lannii. 22 %
and 24%.
DISCUSSION
Clinical trials are the only studies that can provide
information regarding the efficacy and tolerability of
therapeutic alternatives; however, in the absence of
head-to-head clinical trials, health care providers can
optimize antibiotic therapy through the careful application of PK/PD principles. PK/PD studies can address
specific populations (eg, ICU patients with gramnegative pulmonary infections) and can direct the
provider to the optimal dosing regimen. Additionally,
because PK/PD models with Monte Carlo simulation
incorporate the MIC distributions, they consider epidemiologic data together with drug-exposure data. 11
Based on the results from the present comparisons
of the in vitro activities of PTZ and PIP in the present
study, it can be deduced that many gram-negative
pulmonary isolates in US ICUs produced ~-lactamase
in 2002, and that ~-lactamase production appears to
be more problematic among Enterobacteriaceae and
A balt11lannii than among P aeruginosa; therefore,
PTZ may offer some advantage over PIP against these
2 subgroups.
The regimens listed in Table III were organized
from most to least intensive. The small variations in
CFR rates for the bacteriostatic PK/PD target suggest
that less intensive regimens may be suitable in some
patients; however, the variations in CFR rates observed for the bactericidal PK/PD target suggest that
certain PTZ and PIP regimens may be preferred for
immunocompromised patients (eg, transplant recipients, patients with HIV/AIDS, patients undergoing
splenectomy). Ultimately, the results from the present
study suggest that when bactericidal activity is de-

2337

Clinical Therapeutics

Table II. Frequency distribution of MICs of piperacillin/tazobactam (PTZ) and piperacillin (PIP) monotherapy
for gram-negative pulmonary isolates from the 2002 Intensive Care Unit Surveillance System database.
Enterobacteriaceae
(n = 1430)

Pseudomonas aeruginosa
(n = 799)

Acinetobacter baumannii
(n = 179)

MIC, I-lg/mL

PTZ

PIP

PTZ

PIP

PTZ

PIP

:C:;4

0.77*

0.50*

0.57*

0.51 *

0.32

0.07

0.84

0.60

0.72

0.67

0.42

0.21

16

0.86

0.66

0.80

0.77

0.47

0.34

32

0.89

0.73

0.84

0.81

0.50*

0.42

64

0.93t

0.78

0.89

0.84

0.69

0.45

:::128

1.00

1.00t

1.00t

1.00t

1.00t

1.00*t

%5*

86

66

89

84

47

34

%S ~ percent susceptible.
*MIC so '
t MIC 9o '
f Percent susceptible at the current susceptibility breakpoints of the Clinical and Laboratory Standards Institute for PTZ
and PIP: Enterobacteriaceae (~16/4 and ~16 IJg/mL), P aerugtnosa (~64/4 and ~64 IJg/mL), and A baumanntt (~16/4 and
~16IJg/mL).12

Table III. Pulmonary pharmacokinetic/pharmacodynamic data of piperacillin/tazobactam (PTZ) and piperacillin (PIP) monotherapy against gram-negative pulmonary isolates from patients hospitalized in the intensive care unit.* Values are %.
PTZ

PIP
4.5 g

3.375 g
Bacteria/ Rate

3g

4g

q4h

q6h

q6h

q8h

q4h

q6h

q6h

q8h

Enterobacteriaceae
Bacteriostatic
Bactericidal

89
85

87
68

88
83

86
54

73
65

67
47

71
60

66
37

Pseudomonas aeruginosa
Bacteriostatic
Bactericidal

84
78

80
56

84
72

79
42

81
74

76
51

80
68

75
38

Acinetobacter baumannii
Bacteriostatic
Bactericidal

53
46

48
33

50
42

47
24

42
32

35
13

40
24

33
8

*The cumulative fraction of response was determined for percentage of time that the free serum concentration remained
above the MIC of:::30% (bacteriostatic) and :::50% (bacteriCidal).

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Volume 30 Number 12

C.R. Frei and D.S. Burgess

PTZ 3375 g q4h

.PTZ3 375 gq6h


-D- PIP 3 g q6h
-+- PTZ 4 5 g q8h
-0- PIP 4 g q8h

-0- PIP 3 g q4h


-6- PTZ 4 5 g q6h
-!::r PIP 4 g q6h

100
90
80

g
ci
LL

70
60
50

40
30
20

10

a~----,--------,-----,-----,----,---~,------~=::;;~~~~~
10
20
30
40
50
60
70
80
90
100
a
B
100
90
80

70

g
ci
LL

60
50

40
30
20

10
o--.L-,---------r------r---r--------r----;-------,r---~==~""""~~"""""=Q

10

20

30

40

50

60

70

80

90

100

100
90
80

70

60

ci

50

LL

40
30
20

10

a~-_____,_------r--___,_-_,__-~~~~~~~~::::::::s
10
20
30
40
50
60
70
80
90
100
a

Figure. Pharmacokinetic/pharmacodynamic data of piperacillin/tazobactam (PTZ) and piperacillin (PIP)


monotherapy against gram-negative pulmonary isolates. (A) Enterobacteriaceae (n = 1430);
(B) Pseudomonas aeruginosa (n = 799); (C) Acinetobacter baumannii (n = 179). CFR = cumulative fraction of
response; f%T>MIC = percentage oftime that the free serum concentration remained above the MIC.

December 2008

2339

Clinical Therapeutics

sired, health care providers should select the more intensive PTZ and PIP regimens for ICU patients with
gram-negative bacterial infections.
This study had some potential limitations regarding the microbiological data, pharmacokinetic data,
and the design of the PK/PD models. The 2002 ISS
database is a rich source of microbiological data that
focuses on ICU patients. It is unique because it allows
subgroup analyses by culture site 18 ; however, the database was not developed for PK/PD modeling, so in
vitro activity was evaluated only over a narrow range
of MICs from 4 to 128 rg/mL. As a result, more than
half of the MICs of PTZ and PIP against Enterobacteriaceae and P aeruginosa were assigned a MIC of
4 rg/mL when the actual MIC was at or below the
limit of detection (ie, 4 rg/mL). Lower MICs would
have caused the CFR rates to be higher. In contrast,
for A balt11lannii, 31 % of isolates for PTZ and 55%
of isolates for PIP were at or above the highest limit
of detection (ie, 128 rg/mL). Higher MICs would
have resulted in lower CFRs for each of these antibiotics against A balt11lannii. Another limitation about the
microbiological data is that they were collected in
2002, and their clinical relevance to the current year
is unknown.
Pharmacokinetic data were derived from healthy
volunteers and may not accurately represent the values observed among critically ill patients. Because
most ~-lactams are renally eliminated, compromised
renal function may result in elevated drug concentrations and improved CFR rates. In addition, the pharmacokinetic parameters were measured in serum, but
the results were extrapolated to patients with pulmonary infections. Pulmonary pharmacokinetics would
be preferable, but to our knowledge, they are not
available in a format that can be used for PK/PD modeling. Finally, pharmacokinetic data studies are typically quite small (<10 patients) and the one that was
used for the pharmacokinetics in this study was no
exception; therefore, it is important to realize that although the microbiological data in this study were
derived from >2500 MICs, the pharmacokinetic data
were derived from only a handful of patients, as is the
case for most PK/PD simulation studies. 19-21
The PK/PD relationships were based on animal
studies, and most have not been confirmed in human
studies. 8- 1O This study used a I-compartment PK/PD
model that did not account for the % T >MIC contributed by the time of infusion. Recent investigations
2340

have suggested that the infusion time can be prolonged to enhance the % T >MIC' 22-24 The PK/PD impact
would be minimal for short infusions (:c:;30 minutes),
but prolonged infusions would enhance the ability of a
~-lactam to achieve its PK/PD targets. In defense of the
methods used in this study, any PK/PD benefit achieved
by prolonged infusions should be similar for PIP and
PTZ. Finally, the focus of this PK/PD model was efficacy, and simulations regarding tolerability were not
attempted. Therefore, although more intensive dosing
regimens might improve PK/PD, it is uncertain whether
this improvement would be outweighed by an increased risk for adverse events.
CONCLUSIONS
Based on the results from the present comparisons
of the in vitro activities of PTZ and PIP in the present
study, it can be deduced that many gram-negative
pulmonary isolates collected from US ICUs in 2002
produced ~-lactamase. ~-Lactamase production appeared to be more common among Enterobacteriaceae
and A balt11lannii than among P aeruginosa_. thereby
resulting in improved in vitro susceptibilities for PTZ
than for PIP against Enterobacteriaceae and A balt11lannii. Furthermore, PK/PD models with Monte
Carlo simulation suggested that the reductions in susceptibility for PIP as compared with PTZ may be of
sufficient magnitude to result in notable differences in
the PK/PD profiles of these antibiotics.
ACKNOWLEDGM ENTS
This research was sponsored by Wyeth Pharmaceuticals.
Dr. Burgess has received educational grants, honoraria,
and research grants from Wyeth and serves as a consultant for Wyeth. The sponsor did not have any role in the
design, conduct, analysis, or publication of this study.
The authors thank Brittany Makos and Christine
Oramasionwu, PharmD, for their technical assistance
with this manuscript.
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December 2008

Address correspondence to: Christopher R. Frei, PharmD, MSc, The


University of Texas Health Science Center at San Antonio, Clinical
Pharmacy Programs-MSC 6220, 7703 Floyd Curl Drive, San Antonio,
TX 78229-3900. E-mail: freic@uthscsa.edu
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