ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 2010, p. 1275–1282 Vol. 54, No.

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0066-4804/10/$12.00 doi:10.1128/AAC.00936-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetic Comparison and Pharmacodynamic

Breakpoints of Ceftazidime in Cystic Fibrosis Patients and
Healthy Volunteers䌤
J. B. Bulitta,1† C. B. Landersdorfer,1† S. J. Hüttner,1 G. L. Drusano,2
M. Kinzig,1 U. Holzgrabe,3 U. Stephan,1,4‡ and F. Sörgel1,5*
IBMP Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany1; Ordway Research Institute, Albany,
New York2; Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany3; Department of Pediatrics,
University of Duisburg-Essen, Essen, Germany4; and Department of Pharmacology, University of Duisburg-Essen, Essen, Germany5
Received 7 July 2009/Returned for modification 29 September 2009/Accepted 29 December 2009

Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there
has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis
(CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and
PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF
patients (total body weight [WT] [average ⴞ standard deviation] ⴝ 42.9 ⴞ 18.4 kg) and seven healthy
volunteers (WT ⴝ 66.2 ⴞ 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance
liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and
NPAG were used for parametric and nonparametric population PK modeling. We considered linear and
allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based
on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of >65%, which
represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of
distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy
volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability
by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling
by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (>90%) probabilities
of target attainment (PTAs) for MICs of <1 mg/liter in CF patients and <3 mg/liter in healthy volunteers.
Alternative modes of administration achieved robust PTAs up to markedly higher MICs of <8 to 12 mg/liter
in CF patients for 5-h infusions of 2 g/70 kg WT q8h and <12 mg/liter for continuous infusion of 6 g/70 kg WT
daily.

Respiratory tract infections are the primary reason for fre- pared the pharmacodynamic (PD) profiles of CF patients and

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quent hospitalization of patients with cystic fibrosis (CF) and
the main cause of mortality (4, 60). About 4 of 5 adults with CF
(age: 26 to 30 years) are infected by Pseudomonas aeruginosa
(24). Ceftazidime is still one of the most active antibiotics
against P. aeruginosa isolates from CF patients and has activity
against species belonging to the Burkholderia cepacia complex
(45, 46, 64). Infections by B. cepacia are of particular interest
to CF patients, since B. cepacia can cause a rapid deterioration
of lung function (29, 71). Efficacious anti-infective therapy
against both B. cepacia and P. aeruginosa is critical, in partic-
ular as eradication of P. aeruginosa in the lungs of CF patients
is possible only in the early stage of infection (19, 34).
Two groups compared the pharmacokinetics (PK) in CF
patients and healthy volunteers within the same study (33, 44).
CF patients had higher clearances (liters/h/kg) and shorter
terminal half-lives for ceftazidime. Mouton et al. (53) com-
* Corresponding author. Mailing address: IBMP Institute for Bio-
medical and Pharmaceutical Research, Paul-Ehrlich-Str. 19, D-90562
Nürnberg-Heroldsberg, Germany. Phone: 49-911-518290. Fax: 49-911-
5182920. E-mail: ibmp@osn.de.
† Present address: Ordway Research Institute, Albany, NY 12208.
‡ Deceased.
䌤
Published ahead of print on 11 January 2010.
healthy volunteers based on data from two different studies
and found that CF patients required higher doses than healthy
volunteers to achieve the same PD target.
For beta-lactams, the duration of non-protein-bound plasma
concentration above the MIC (fT⬎MIC) is the PK-PD index
that best predicts the drug-related responses (2, 22, 25). An
fT⬎MIC of 65% has been identified as the target for near-
maximal bacterial killing, and an fT⬎MIC target of 40% best
predicts bacteriostasis at 24 h for cephalosporins in mouse
infection models (22, 25). Based on these target values the
probability of target attainment (PTA) can be predicted via
Monte Carlo simulation (MCS). The effect of an altered body
composition on PK requires dose adjustment in certain patient
populations (21, 31, 49, 55, 71). Therefore, it may be important
to use a descriptor that accounts for body size and body com-
position for dose selection and optimization of the PTA. A lack
of adipose tissue in CF patients may require dose adjustments
(16, 48, 62, 71).
Due to the hydrophilic properties of ceftazidime, we believed
that fat-free mass (FFM) may better describe body size than total
body weight (WT), as FFM but not WT accounts for body com-
position. In addition to explaining the differences in average PK
parameters between lean, “normal,” and obese patients, a useful
body size descriptor should reduce the unexplained between-

1275
1276 BULITTA ET AL.
TABLE 1. Demographic data
Median 关range兴 for:
Parameter CF patients Healthy volunteers
(n ⫽ 8c) (n ⫽ 7d)
Height (cm) 164 关105–176兴 175 关164–191兴
Age (yr) 20 关10–45兴 22 关19–33兴
Total body wt (kg) 37.9 关14.2–73.5兴 67 关56–71兴
Fat-free massa (kg) 35.9 关13.9–57.7兴 54.0 关46.4–60.5兴
Lean body massb (kg) 34.7 关13.3–58.6兴 54.5 关46.7–60.5兴
Body mass index (kg m⫺2) 15.0 关12.5–23.7兴 21.7 关19.5–23.7兴
a
Calculated by the formula of Janmahasatian et al. (39).
b
Calculated by the formula of Cheymol and James (21, 38).
c (39), and (v) allometric scaling by FFM. We assessed the ability of each body size
Four males and four females.
d
Four males and three females.
subject variability (BSV) in PK parameters. Such a body size
descriptor can be used to select dosage regimens that achieve
target concentrations and target effects more precisely.
Our first objective was to compare the population PK of
ceftazidime between CF patients and healthy volunteers within
the same study. Second, we assessed whether the difference in
average PK parameters and the BSV in clearance and volume
of distribution are better described by FFM than by WT. Our
third objective was to predict the PK-PD MIC breakpoints for
various ceftazidime dosage regimens in CF patients. We ap-
plied the latest parametric and nonparametric population PK
methodology and evaluated linear and allometric body size
models comparing the PK in CF patients and healthy volun-
teers in order to greatly extend a descriptive noncompartmen-
tal analysis of our study reported previously (65–67).
(The population PK modeling work has in part been pre-
sented as part of a meta-analysis [14, 15] and in part as a poster
[37].)
MATERIALS AND METHODS
Subjects. A total of 15 Caucasian volunteers (8 CF patients and 7 healthy
volunteers) participated in the study after they had given their written informed
consent. For the two CF patients 10 and 15 years old, written informed consent
was obtained from their legal representative. General clinical procedures were as
described previously (16). The study was performed in 1983; the study protocol
had been approved by the local ethics committee, and the study was conducted
by following the revised version of the Declaration of Helsinki.
Study design and drug administration. The study was a single-dose, single-
center, open, parallel group trial. Subjects received 2 g ceftazidime as a 5-min
intravenous infusion. As some CF patients were notably smaller or required a
higher dose for clinical reasons as judged by the physician, one CF patient
received 1.5 g, one CF patient received 1 g, and one CF patient received 3 g
instead of 2 g ceftazidime. All infusions were administered with Perfusors
(Braun, Melsungen, Germany). These instruments were checked on a daily basis
by weighing defined volumes delivered by the Perfusors.
Blood sampling. All blood samples were drawn from a forearm vein via an
intravenous catheter contralateral to the one used for drug administration. Blood
samples were drawn immediately before the start of the infusion (0 min), at the
end of the infusion (5 min), and at 5, 10, 15, 20, 30, 45, 60, and 90 min and 2, 2.5,
3, 3.5, 4, 5, 6, 8, 10, and 12 h after the end of infusion. Conditions of sample
handling and storage were the same as described previously (16).
Drug analysis. Ceftazidime concentrations in plasma were determined by a
reversed-phase high-performance liquid chromatography (HPLC) assay with an
internal standard. An amount of 100 ␮l of NaH2PO4 buffer was added to 100 ␮l
of each sample. Acetonitrile (400 ␮l) was used to deproteinize each sample.
After centrifugation, 1,000 ␮l of dichloromethane was added for extraction of the
organic phase. From the remaining aqueous phase, 20 ␮l was injected into the
HPLC system. After sample preparation, the prepared samples were stored in an
ice-water bath until injection. We assured the stability of ceftazidime during all
ANTIMICROB. AGENTS CHEMOTHER.
sample handling, storage, and drug analysis procedures for the applied condi-
tions. A LiChrosphere RP 18-5 ␮ (50- by 4-mm) column with a water-acetonitrile
mixture at pH 5.0 was used. Ceftazidime was detected at a wavelength of 275 nm.
Calibration was performed by linear regression. The ceftazidime assay was linear
between 0.6 and 200 mg/liter. The assay was validated, and its performance
(including bias and precision) was deemed acceptable.
Population PK analysis. (i) Structural model. We tested one-, two-, and
three-compartment models with linear disposition and evaluated competing
models using their predictive performance assessed via visual predictive checks
(VPCs), the objective function, and standard diagnostic plots as described pre-
viously (16, 18).
(ii) Body size model. The following body size descriptors and body size models
were considered: (i) no body size model, (ii) linear scaling by WT, (iii) allometric
scaling by WT (3, 35, 80), (iv) linear scaling by a new equation estimating FFM
model to describe the differences in average PK parameters between both subject
groups and to reduce the unexplained (random) BSV. The exponents for the
effect of body size on clearance were fixed to 1.0 for linear scaling and to 0.75 for
allometric scaling as described previously (16). Exponents were fixed to 1.0 for
volumes of distribution for linear and allometric body size models.
(iii) Differences between subject groups. We used scale factors for clearance
(FCYFCL) and volume of distribution at steady state (FCYFVSS) to describe the
difference in average PK parameters after accounting for the effect of body size
as described previously (16).
(iv) Between-subject variability and observation model. An exponential model
was used to describe the BSV of PK parameters, and a combined additive and
proportional error model was used to describe the residual unidentified variabil-
ity as reported previously (16, 18). We used the first-order conditional estimation
with the interaction option (FOCE⫹I) in NONMEM V release 1.1 (10), the
importance sampling Monte-Carlo parametric expectation maximization method
(pmethod ⫽ 8) in S-ADAPT (version 1.56) (9), and the nonparametric adaptive
grid (NPAG) algorithm of the USC*PACK (version 12.00) (43) for population
PK modeling as described previously (16, 18). WinNonlin Professional (version
4.0.1; Pharsight Corp., Mountain View, CA) was used for noncompartmental
analysis and statistics.
Monte Carlo simulation. PK-PD targets of 65% fT⬎MIC for near-maximal
bactericidal activity and of 40% fT⬎MIC for bacteriostasis at 24 h were applied
based on data from animal infection models (22, 25). We studied a range of
MICs from 0.125 to 128 mg/liter. As the reported protein binding of ceftazidime
ranges between 2 and 19% (32, 44, 52, 54), we assumed an average protein
binding of 11%.
We compared the following five dosage regimens, all at a daily dose of 6 g
ceftazidime per 70 kg WT: (i) short-term (30-min) infusion every 8 h (q8h), (ii)
30-min infusion q6h, (iii) prolonged (5-h) infusion q8h, (iv) prolonged (4-h)
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infusion q6h, and (v) continuous infusion. Concentrations of each dosage regi-
men were simulated at steady state in the absence of residual error. We simu-
lated 11,200 CF patients and 9,800 healthy volunteers with the same demo-
graphic data as the subjects in our study. All estimated covariance terms were
included in the VPC and MCS. The PTA was calculated as the fraction of
subjects who attained the PK-PD target at each MIC. The highest MIC with a
PTA of at least 90% was defined as PK-PD MIC breakpoint.
RESULTS
Demographics and noncompartmental analysis. Our CF pa-
tients had a normal renal function and were smaller and leaner
than our healthy volunteers (Table 1). Peak concentrations
in CF patients were approximately twice as high as those in
healthy volunteers (Table 2). We did not scale the noncom-
partmental PK parameters (Table 2) by any body size descrip-
tor. Total clearance was 19% lower, volume of distribution at
steady state was 36% smaller, and terminal half-life was 24%
shorter in CF patients than in healthy volunteers.
Population PK analysis. The visual predictive check (Fig. 1)
indicated highly sufficient predictive performance for the linear
three-compartment model, which was slightly better than that
for the linear two-compartment model. A one-compartment
model had insufficient predictive performance and yielded
poor curve fits. As the objective function in NONMEM was
VOL. 54, 2010 CEFTAZIDIME POPULATION PK AND CF PATIENT BREAKPOINTS 1277

TABLE 2. Unscaled PK parameters from noncompartmental analysis volunteers after adjusting for body size using the respective
Median 关minimum–maximum兴 for:
body size model. The scale factors from NONMEM (Table 4)
Parameter were well comparable to results from S-ADAPT (data not
CF patients Healthy volunteers
shown).
Total clearance (liters/h) 5.37 关3.35–12.8兴 6.59 关4.87–9.50兴 Without accounting for body size, clearance and volume of
Volume of distribution 9.14 关2.77–19.9兴 14.3 关10.8–17.1兴 distribution were 14 to 15% lower in CF patients (Table 4).
at steady state (liters)
The linear body size models yielded 45% or 30% higher clear-
Peak concn (mg/liter) 445 关151–1200兴a 210 关148–397兴
Terminal half-life (h) 1.48 关0.49–1.78兴 1.94 关1.28–2.78兴 ances in CF patients. The allometric body size models ex-
Mean residence time (h) 1.54 关0.62–2.35兴 2.10 关1.71–2.87兴 plained the differences between CF patients and healthy vol-
a
Normalized to a dose of 2 g ceftazidime, since three CF patients received a
unteers better than linear models. The allometric model based
slightly higher or slightly lower dose. on FFM yielded a 17% higher clearance in CF patients (Table
4). Allometric body size models also reduced the unexplained
BSV in clearance and volume of distribution more than the
worse by 46 for the two-compartment model than for the linear body size models. Allometric scaling by FFM reduced
three-compartment model, the latter model was selected as the the unexplained BSV by 32% for total clearance and by ap-
final model. This choice was consistent with results from S- proximately 18 to 26% for volume of distribution for the
ADAPT and NPAG. peripheral compartments (Table 5). As the allometric body size
The estimates for the final population PK model with model based on FFM explained most of the differences in
allometric scaling by FFM were well comparable between clearance and volume of distribution between both subject
NONMEM, S-ADAPT, and NPAG (Table 3) despite the differ- groups, we did not seek to include other potentially confound-
ent estimation algorithms applied. Estimates for volume of the ing variables in the covariate model.
deep peripheral compartment were larger in NPAG, since Monte Carlo simulation. CF patients had lower PTAs than
there were 3 subjects in each group who had large volumes for healthy volunteers, which resulted in 1.5- to 3-times-lower
this compartment. Allometric scaling by FFM explained the PK-PD MIC breakpoints for the studied dosage regimens (Fig.
differences in average PK parameters better than the other 2). Continuous infusion of 6 g/70 kg WT per day had a PK-PD
body size models, since it yielded disease-specific scale factors breakpoint of 12 mg/liter in CF patients and 16 mg/liter in
(FCYFCL and FCYFVSS in Table 4) closest to 1.0. A scale healthy volunteers for both targets. For the near-maximal kill
factor of 1.0 means that the average clearance or volume of target (fT⬎MIC ⱖ 65%), PK-PD MIC breakpoints were 8 to 12
distribution is the same in both patient groups, if the patient mg/liter in CF patients and 16 mg/liter in healthy volunteers for
groups are matched in body size. These scale factors represent both prolonged-infusion regimens. For the near-maximal kill
the ratios of group estimates between CF patients and healthy target, CF patients had breakpoints of 2 mg/liter for short-term

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FIG. 1. Visual predictive check based on 8,000 CF patients and 7,000 healthy volunteers simulated from the three-compartment model based
on FFM (see Table 3; based on results from NONMEM). The plots show the observed data, the 80% prediction intervals (10 to 90% percentile),
and the interquartile ranges (25 to 75% percentile). Ideally, 50% of the observed data points should fall inside the interquartile range and 80%
of the observed data should fall inside the 80% prediction interval.
1278 BULITTA ET AL. ANTIMICROB. AGENTS CHEMOTHER.

TABLE 3. Estimates from the population PK model based on allometric scaling by fat-free mass
Estimate (CV 关%兴 for between-subject variabilityc) by:

NONMEM S-ADAPT NPAGf

Parametera
Healthy CF Healthy CF Healthy
CF patients
volunteers patients volunteers patients volunteers

CL (liters h⫺1) 7.82b (28) 6.68 (28) 7.70 (30) 6.61 (30) 7.51 6.30
Vssd (liters) 12.8 12.7 12.5 13.6 24.0g 17.9g
V1 (liters) 5.73 (45)e 5.67 (45) 5.43 (40) 6.56 (40) 4.36 6.34
V2 (liters) 3.92 (25) 3.88 (25) 4.34 (43) 4.01 (43) 4.94 3.24
V3 (liters) 3.16 (29) 3.13 (29) 2.75 (33) 3.02 (33) 14.7g 8.35g
CLicshallow (liters h⫺1) 27.9 27.9 19.2 (68) 19.2 (68) 24.3 24.3
CLicdeep (liters h⫺1) 2.57 2.57 1.05 (60) 1.05 (60) 2.24 2.24
CVC 0.122 0.122 0.119 0.119 0.149 0.149
SDC (mg/liter) 0.059 0.059 0.057 0.057 0.078 0.078
a
CL, total clearance; Vss, volume of distribution at steady state; V1, volume of distribution for the central compartment; V2, volume of distribution for the shallow
peripheral compartment; V3, volume of distribution for the deep peripheral compartment; CLicshallow, intercompartmental clearance between the central and the
shallow peripheral compartment; CLicdeep, intercompartmental clearance between the central and the deep peripheral compartment; CVC, proportional residual error
component for the plasma concentrations; SDC, additive residual error component for the plasma concentrations. The duration of zero order input was fixed to 5 min
and not estimated.
b
All clearance and volume estimates are group estimates of the respective PK parameter for subjects of standard size (fat-free mass: 53 kg).
c
Apparent coefficients of variation describing the between-subject variability. As sample size was small, one joint variance was estimated for CF patients and healthy
volunteers for each parameter.
d
Derived from the group means of V1, V2, and V3, not an estimated parameter.
e
Coefficients of correlation for the random variability between pairs of random effects are as follows: r(V1,V2) ⫽ ⫺0.67, r(V1,V3) ⫽ 0.56, r(V2,V3) ⫽ ⫺0.59.
f
Estimates reported for NPAG are geometric means of the support points for each subject group.
g
The nonparametric estimation algorithm in NPAG yielded large volumes of the deep peripheral compartment (between 20 and 50 liters) for three CF patients and
three healthy volunteers. Therefore, the geometric means for V3 in NPAG are larger than those in NONMEM and S-ADAPT.

infusion q6h and of 1 mg/liter for short-term infusion q8h at a
daily dose of 6 g/70 kg WT. Healthy volunteers had breakpoints of
4 mg/liter for short-term infusion q6h and of 3 mg/liter for short-
term infusion q8h at a daily dose of 6 g/70 kg WT.
For the bacteriostasis target (fT⬎MIC ⱖ 40%), the PK-PD
MIC breakpoints were 16 mg/liter in CF patients and 24 mg/
liter in healthy volunteers for both prolonged-infusion regi-
mens. For this target, CF patients had breakpoints of 6 mg/liter
for short-term infusion q6h and of 4 mg/liter for short-term
infusion q8h at a daily dose of 6 g/70 kg WT. Healthy volun-
this pathogen in CF patients. Ceftazidime is still the cephalo-
sporin with the best activity against P. aeruginosa (45) and is a
valuable treatment option in antipseudomonal therapy in CF
patients (6, 12, 61, 69).
MCS can identify dosage regimens that achieve a high PTA
for treatment of a specific patient population (26). To better
understand the potentially altered PK in CF patients compared
to healthy volunteers, differences in body size and body com-
position should be considered for an MCS. We assessed the
effect of these factors on the PK of ceftazidime within the same

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teers had breakpoints of 12 mg/liter for short-term infusion study. While this assures that the clinical and bioanalytical
q6h and of 8 mg/liter for short-term infusion q8h at a daily dose procedures are standardized, one limitation of our study is that
of 6 g/70 kg WT. the demographic characteristics of CF patients and healthy
volunteers were not matched. The resulting larger range in
DISCUSSION body composition in our study is likely to support a distinction
between different body size models. Another potential limita-
The life expectancy and quality of life of CF patients have
improved impressively during the last 70 years. Optimal treat-
ment of infections by P. aeruginosa (28) is crucially important, TABLE 5. Between-subject variability (variances) for
as it is almost impossible to eradicate chronic lung infections by different body size modelsa
Relative between-subject variance (%) for:
Body size model
CL V1 V2 V3
TABLE 4. Ratiosa of group estimates for clearance and volume of
b b b
distribution for different body size models (based on WT (linear scaling) 100 100 100 100b
results from NONMEM) WT (allometric scaling) 75c 97 96 89
FFM (linear scaling) 85c 105 78 95
Body size model FCYFCL FCYFVSS
FFM (allometric scaling) 68c 104 74 82
No body size model 0.861 0.853 a
Shown are relative between-subject variances for the respective PK param-
WT (linear scaling) 1.45 1.13 eter and body size models (see Table 3 for parameter explanations) based on
WT (allometric scaling) 1.27 1.13 results from NONMEM.
b
FFM (linear scaling) 1.30 1.01 The between-subject variance for linear scaling by WT was used as the
FFM (allometric scaling) 1.17 1.01 reference.
c
The lower this number, the more variability was explained by the respective
a
FCYFCL, ratio of group estimates for total clearance in CF patients divided body size model. These values indicate that the between-subject variability (vari-
by total clearance in healthy volunteers; FCYFVSS, ratio of group estimates for ance) for total clearance was reduced by 25% for allometric scaling by WT, by
volume of distribution at steady state in CF patients divided by volume of 15% for linear scaling by FFM, and by 32% for allometric scaling by FFM, all
distribution at steady state in healthy volunteers. compared to linear scaling by WT.
VOL. 54, 2010 CEFTAZIDIME POPULATION PK AND CF PATIENT BREAKPOINTS
FIG. 2. Probability of target attainment for different dosage regimens of 6 g ceftazidime per 70 kg WT daily at steady state (based on results
from NONMEM).
tion of our study from 1983 is that our results for relatively lean
CF patients may not be directly applicable to therapy of CF
patients with normal body composition nowadays. However,
our results may be very valuable for CF patients in economi-
cally challenged countries and potentially for other patient
groups with lean body composition. A population PK analysis
with lean CF patients seems important to put PK studies of
(relatively) lean CF patients from the 1970s and 1980s in per-
spective with more recent studies of CF patients of normal
body size and body composition that are matched to healthy
volunteers, as in the aztreonam study by Vinks et al. (77).
Our final population PK model (Table 3) had highly suffi-
cient predictive performance (Fig. 1) for CF patients, whereas
predictions for healthy volunteers were slightly too variable.
This results in slightly more-conservative predictions for the
PTA in healthy volunteers. One limitation of our MCS is that
1279
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it was based only on 15 subjects for whom we had frequent
plasma samples. However, our results for the PK parameters of
ceftazidime in healthy volunteers were in good agreement with
those from other authors (5, 27, 40, 52, 57, 70, 78). We are
aware of only two studies on the PK of ceftazidime in CF
patients which included a healthy volunteer control group.
Leeder et al. (44) found a total clearance of 8.5 ⫾ 1.0 liters/
h/1.73 m2 and Hedman et al. (33) found 7.6 ⫾ 0.7 liters/h/1.73
m2 in CF patients. Although some authors report (47, 56, 72)
higher clearances of 0.23 to 0.36 liters/h/kg (equivalent to 16 to
25 liters/h/70 kg WT) for ceftazidime in CF patients, most
studies (41, 50, 53, 58, 75, 76) of juvenile to adult CF patients
find an average total clearance of 8 to 11 liters/h for CF pa-
tients of standard body size (i.e., 70 kg WT or 1.73 m2 body
surface area) and a coefficient of variation (CV) of 9 to 26%
for the BSV of total clearance. Our geometric mean of 7.82
1280 BULITTA ET AL.
liters/h (CV, 28.3%; from NONMEM) for total clearance in
CF patients with 53 kg FFM (Table 3) was in good agreement
with the clearances for CF patients in the literature.
The reported average volume of distribution ranges between
0.237 and 0.46 liters/kg WT (equivalent to 16.6 and 32 liters/70
kg WT), with coefficients of variation between 14 and 53% in
CF patients (41, 44, 47, 50, 53, 56, 58, 76). Our geometric mean
of 12.8 liters (from NONMEM) for CF patients with 53 kg
FFM and coefficients of variation between 25 and 45% for the
individual volumes (Table 3) was at the lower end of the
arithmetic means reported in the literature. The nonparamet-
ric estimation algorithm in NPAG yielded larger volumes of
distribution at steady state (Table 3), which were well compa-
rable with literature estimates. Our results on terminal half-life
(Table 2) were in good agreement with the shorter terminal
half-life of 1.5 ⫾ 0.2 h in CF patients compared to 1.76 ⫾ 0.2 h
in healthy volunteers reported by Leeder et al. (44). The re-
ported average half-lives in juvenile to adult CF patients range
between 1 and 2 h (41, 47, 50, 56, 58, 68, 72, 76).
As our CF patients were smaller and leaner than our healthy
volunteers (Table 1), we evaluated various body size models to
describe differences in average PK parameters using popula-
tion PK modeling. The differences in average PK parameters
were better explained by FFM than by WT (Table 4), most
likely since FFM accounts for body composition whereas WT
does not. Lean body mass calculated by the Cheymol and
James formula (21, 38) yielded results very similar to those of
FFM (results not shown). In agreement with theoretical con-
siderations (79) and other studies (3), allometric scaling ex-
plained the difference in average clearance between both pa-
tient groups better than linear scaling of clearance (Table 4).
Furthermore, allometric scaling by FFM reduced the unex-
plained BSV of clearance and of both peripheral volumes of
distribution most (Table 5). This allows one to design dosage
regimens based on FFM that achieve target concentrations and
target effects more precisely.
These results are in agreement with studies on the PK of
beta-lactams in CF patients and healthy volunteers (16, 17, 62,
71, 77) and are comparable to results from Leeder et al. (44)
on ceftazidime. Leeder et al. found a 42% increased total
clearance (142 ⫾ 17 ml/min/1.73 m2 in CF patients versus
101 ⫾ 10 ml/min/1.73 m2 in healthy volunteers) and Hedman
et al. (33) found a 25% increased renal clearance (125 ⫾ 20
ml/min/1.73 m2 in CF patients and 100 ⫾ 9 ml/min/1.73 m2 in
healthy volunteers) for ceftazidime. Hedman et al. explained
this increased renal clearance primarily by an increased glo-
merular filtration rate in CF patients determined via inulin
clearance. This might have been in part caused by an altered
glomerulotubular balance due to a primary tubular transport
defect (7, 11) or by a 16% higher resting energy expenditure in
CF patients (73) due to a higher energy need secondary to
chronic lung infection. A potential limitation of our model is
that it did not account for renal function.
Our MCS used an allometric body size model based on FFM
and predicted lower PTAs for CF patients than for healthy
volunteers (Fig. 2). The PK-PD MIC breakpoint was 1 mg/liter
in CF patients and 3 mg/liter in healthy volunteers for short-
term infusion of 2 g/70 kg WT q8h for the near-maximal kill
target. The proposed allometric body size model provides an
explanation why our CF patients, who were smaller than our
ANTIMICROB. AGENTS CHEMOTHER.
healthy volunteers, had shorter drug half-lives (Table 2) and
required higher beta-lactam doses to achieve similar PK-PD
MIC breakpoints, in particular for short-term infusions. This
prediction matches with the higher clinically recommended
doses (in mg/kg of total body weight) of beta-lactams for pe-
diatric CF patients than for adult CF patients (30). Mouton et
al. (53) found a PTA of ⱖ90% for MICs of ⱕ4 mg/liter in CF
patients and for MICs of ⱕ8 mg/liter in healthy volunteers for
a fixed dose of 2 g q8h and the target fT⬎MIC of ⱖ60%. When
we used this target and a fixed dose of 2 g q8h as a 30-min
infusion, we obtained a comparable breakpoint of 3 mg/liter in
CF patients. Daily doses of up to 12 g ceftazidime split into 3
or 4 intermittent doses have been recommended for CF pa-
tients (24), whereas other authors recommend lower daily
doses of 6 g in adult CF patients (30). To increase the PK-PD
MIC breakpoints and clinical outcome, continuous infusion of
ceftazidime has been proposed and studied in CF patients (8,
13, 23, 36, 42, 59, 74–76).
Our MCS assessed the benefit of continuous and prolonged
infusion in comparison to short-term infusions, all at a daily
dose of 6 g/70 kg WT. Both prolonged infusion regimens
achieved PK-PD MIC breakpoints of 8 to 12 mg/liter in CF
patients, which were approximately 10 times higher than the
breakpoint for short-term infusions q8h at the same daily dose.
Giving the same daily dose as a short-term infusion q6h instead
of q8h achieved only a PK-PD MIC breakpoint of 2 mg/liter in
CF patients. This prediction is in excellent agreement with the
better outcome for CF patients with resistant or intermediate
isolates when they received continuous ceftazidime infusion
compared to when they received short-term infusion (both
coadministered with tobramycin) (36, 63) and with results from
in vitro PD models (1, 20, 51).
In conclusion, we found a 19% lower unscaled total clear-
ance and a 36% lower volume of distribution at steady state in
CF patients than in healthy volunteers, because our CF pa-
tients were smaller and leaner. Allometric scaling by FFM
Downloaded from https://journals.asm.org/journal/aac on 10 August 2021 by 196.191.48.216.
explained the differences in average PK parameters better than
linear scaling by WT, probably because WT does not account
for body composition. Additionally, allometric scaling by FFM
reduced the unexplained BSV by 32% for clearance and by 18
to 26% for volume of the peripheral compartments relative to
linear scaling by WT. Dosage regimens based on FFM can
therefore achieve target concentrations more precisely. The
PK-PD MIC breakpoint for near-maximal bactericidal activity
was 1 mg/liter in CF patients for short-term infusions of 2 g/70
kg WT q8h. As alternative modes of administration, prolonged
(5-h) infusion of 2 g/70 kg WT q8h or continuous infusion of 6
g/70 kg WT/day achieved a PK-PD MIC breakpoint of 8 to 12
mg/liter in CF patients. More large clinical trials are warranted
to compare the time course of clinical responses to prolonged
or continuous infusion with short-term infusion of beta-lac-
tams in CF patients and to compare clinical responses for dose
selection via an allometric body size model based on FFM with
standard dosing of CF patients as mg/kg WT.
ACKNOWLEDGMENTS
This work is dedicated to Klaus-Jürgen Hess at the Gymnasium
Scheinfeld, Germany, who inspired this work by his continuous support
of one of us (J.B.B.).
There are no conflicts of interest for any of the authors.
VOL. 54, 2010 CEFTAZIDIME POPULATION PK AND CF PATIENT BREAKPOINTS
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