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Moxifloxacin Pharmacokinetics and Pleural Fluid Penetration in

Patients with Pleural Effusion


Kalliopi Chatzika,a Katerina Manika,a Paschalina Kontou,b Georgia Pitsiou,c Despina Papakosta,c Konstantinos Zarogoulidis,a
Ioannis Kioumisa
Respiratory Infections Unit, Pulmonary Department, Aristotle University of Thessaloniki, G. Papanikolaou Hospital, Thessaloniki, Greecea; AIntensive Care Unit, G.
Papanikolaou Hospital, Thessaloniki, Greeceb; Pulmonary Department, Aristotle University of Thessaloniki, G. Papanikolaou Hospital, Thessaloniki, Greecec

The aim of this study was to evaluate the pharmacokinetics and penetration of moxifloxacin (MXF) in patients with various
types of pleural effusion. Twelve patients with empyema/parapneumonic effusion (PPE) and 12 patients with malignant pleural
effusion were enrolled in the study. A single-dose pharmacokinetic study was performed after intravenous administration of 400
mg MXF. Serial plasma (PL) and pleural fluid (PF) samples were collected during a 24-h time interval after drug administration.
The MXF concentration in PL and PF was determined by high-performance liquid chromatography, and main pharmacokinetic
parameters were estimated. Penetration of MXF in PF was determined by the ratio of the area under the concentration-time
curve from time zero to 24 h (AUC24) in PF (AUC24PF) to the AUC24 in PL. No statistically significant differences in the pharmacokinetics in PL were observed between the two groups, despite the large interindividual variability in the volume of distribution, clearance, and elimination half-life. The maximum concentration in PF (CmaxPF) in patients with empyema/PPE was
2.23 1.31 mg/liter, and it was detected 7.50 2.39 h after the initiation of the infusion. In patients with malignant effusion,
CmaxPF was 2.96 1.45 mg/liter, but it was observed significantly earlier, at 3.58 1.38 h (P < 0.001). Both groups revealed
similar values of AUC24PF (31.83 23.52 versus 32.81 12.66 mg h/liter). Penetration of MXF into PF was similarly good in
both patient groups (1.11 0.74 versus 1.17 0.39). Despite similar plasma pharmacokinetics, patients with empyema/parapneumonic effusion showed a significant delay in achievement of PF maximum MXF levels compared to those with malignant
effusion. However, in both groups, the degree of MXF PF penetration and the on-site drug exposure, expressed by AUC24PF, did
not differ according to the type of pleural effusion.

he development of a pleural effusion is a common complication of pneumonia, occurring in up to 57% of cases. The majority of these effusions are clear, sterile exudates that frequently
resolve with antimicrobial treatment and do not require drainage.
In some cases, this initial effusion may progress to a complicated
parapneumonic effusion (PPE), which is characterized by fibrin
deposition and fluid infection. These effusions cannot resolve
without drainage and usually require placement of a chest tube.
Persistent pleural infection may result in the accumulation of pus
in the pleural space, which is called empyema (1).
All patients with parapneumonic effusion or empyema should
initially be treated with intravenous antibiotics. The initial selection of the agent and dose is usually based on whether the patient
has community-acquired pneumonia (CAP) or hospital-acquired
pneumonia (HAP) and depends on the severity of the patients
clinical condition (2). Respiratory fluoroquinolones, such as
moxifloxacin (MXF) or levofloxacin, are recommended as initial
empirical antibiotic therapy both for hospitalized patients with
severe and nonsevere CAP (3) and for those with HAP or ventilator-associated pneumonia without known risk factors for multidrug-resistant pathogens and early onset (4).
MXF is widely used in the treatment of community-acquired
pneumonia and pleural effusion due to its broad antimicrobial
activity against Gram-positive and Gram-negative bacteria, including anaerobes (1). Although there are several studies (59)
about ciprofloxacin (CIP) penetration in human pleural fluid
(PF), data on MXF are scarce and are based on experimental pleural empyema in rabbits (10, 11). On the basis of these data, MXF
penetrates well into infected rabbit pleural fluid. However, limitations, such as the different route and time of MXF administra-

March 2014 Volume 58 Number 3

tion, the difference in visceral pleura thickness between human


and rabbit, and the turpentine-induced empyema, render the extrapolation of these results to human patients uncertain. To the
best of our knowledge, despite its widespread use during the last
15 years, there are no studies investigating MXF penetration either
in human empyema or in effusions due to other etiologies.
The aim of the present study was to determine the pharmacokinetics (PK) of MXF in plasma (PL) and human pleural fluid and
to evaluate under actual clinical conditions its penetration into
human exudative pleural fluid effusions of different etiologies,
namely, empyemic/parapneumonic and malignant effusions.
MATERIALS AND METHODS
Study design. The study was designed as a prospective, open-label study
and took place in the Pulmonary Department of the G. Papanikolaou
Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece, from
October 2012 to June 2013. The research was conducted in accordance
with the Declaration of Helsinki as well as national and institutional standards. The study protocol was approved by the institutional review board
of G. Papanikolaou Hospital (reference no. 12/25-10-2012), and written
informed consent was obtained from all study participants.
Patient population. Patients were eligible for enrollment in the study
if they were admitted to the Pulmonary Department for empyema/para-

Received 23 October 2013 Accepted 14 November 2013


Published ahead of print 9 December 2013
Address correspondence to Ioannis Kioumis, ikioum@yahoo.gr.
Copyright 2014, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.02291-13

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Chatzika et al.

TABLE 1 Demographic data and clinical characteristicsa


Patients with empyema/PPE (n 12)
Characteristic

M M M M F

M M M F

Patients with malignant pleural effusion (n 12)


M M M Mean SD F

Age (yr)
51 80 22 74 40 33 69 49 48 64 79 65 56.2 18.6
Wt (kg)
85 82 92 86 50 50 65 81 83 94 74 82 77.0 14.7
Length of hospital 30 9 13 37 50 20 37 10 8 31 15 52 26.0 15.8
stay (days)
a

M M M F

M M M M M F

M Mean SD

61 76 92 56 72 81 82 68 60 61 85 57 70.9 12.2
87 79 81 82 89 79 82 82 86 92 74 78 82.6 5.1
19 7 13 32 11 14 7 9 17 7 12 22 14.2 7.4

M, male; F, female.

pneumonic effusion or exudative malignant pleural effusion and had in


place a chest tube for continuous drainage. The documentation of the
pleural effusions etiology was based on clinical manifestations, imaging
studies, and pleural fluid biochemical analysis, microbiology, and cytology (12). Differentiation of transudates from exudates was performed
according to the criteria of Light et al. (13).
A complete medical history and laboratory test results, including complete blood cell counts, erythrocyte sedimentation rate, serum glucose and
electrolyte levels, liver function test results, total protein and albumin
concentrations, serum creatinine levels, and results of urine analyses, were
recorded prior to the commencement of the protocol. Pleural fluid specimens were examined for glucose, pH, lactate dehydrogenase (LDH) and
protein levels, and total white blood cell count and differential. Samples of
pleural fluid underwent Grams staining, microbiology, and cytology
studies upon clinical indication. Exclusion criteria were as follows: a history of allergy to fluoroquinolones, a prolonged Q-T interval, renal insufficiency (defined as a creatinine clearance [CLCR] of 30 ml/min or less, as
calculated by the Cockcroft-Gault equation [14]), hepatic impairment
(defined as a Child-Pugh score of B or C), a history of convulsions, and
concomitant therapy with cytostatic agents.
MXF was prescribed empirically to the patients suffering from empyema or parapneumonic pleural effusion by their treating physician. MXF
was given intravenously to these patients at a dosage of 400 mg every 24 h
by infusion over 1 h via a peripheral venous line, and the study was conducted on the first day of treatment. Patients with malignant pleural effusion were administered a single intravenous dose of 400 mg MXF only for
study purposes.
Specimen collection. Blood samples were obtained via a separate peripheral venous catheter just prior to the MXF administration (time zero)
and at the following time points postdosing: 1 h (at the end of the infusion), 2 h, 3 h, 4 h, 6 h, 9 h, 12 h, and 24 h. Pleural fluid samples were
obtained through a chest tube at the same time points. Plasma was separated from whole blood by centrifugation. All plasma and pleural fluid
samples were stored at 20C until analysis.
Moxifloxacin HPLC assay. MXF (Bayer AG, Leverkusen, Germany)
concentrations in plasma and pleural fluid were determined using highperformance liquid chromatography (HPLC) with fluorescence detection
according to the method previously described by Liang et al., with modifications (15).
Analytical separation was performed via a Nucleosil 100C18, 250- by
4.6-mm, 5-m column (M-Z Analysentechnic, Mainz, Germany) protected by a guard column (20 by 4.6 mm; 5 m) of the same composition.
The detector was set at an excitation wavelength of 293 nm and at an

emission wavelength of 500 nm. The mobile phase consisted of 10 mM


sodium dodecyl sulfate, 25 mM citric acid, 10 mM tetrabutylammonium
hydrogen sulfate with 43% (vol/vol) acetonitrile at pH 3.5 adjusted with
NaOH (1 N). CIP (Elpen Pharmaceuticals, Athens, Greece) was used as
the internal standard. The isocratic flow rate was 1 ml/min, the column
temperature was set at 37C, the total run time was 7 min, and the retention times of CIP and MXF were 4.4 and 6.1 min, respectively.
Coefficients of determination (r) (2) for MXF and CIP over the standard curve concentrations of 0.05 to 10 mg/liter for plasma and pleural
fluid were 0.999 for the entire study. Intraday and interday coefficients of
variation were 5%. The rates of recovery of MXF and CIP in plasma and
pleural fluid were greater than 100% and 99%, respectively.
Sample preparation and extraction procedure. Fifty microliters of an
internal standard solution of 20 mg/liter and 500 l of acetonitrile were
added to 250 l of plasma or pleural fluid, and the mixture was then
vortexed for 30 s and centrifuged at 3,600 rpm for 10 min (Zentrifugen
Micro 20; Hettich, Germany). The clear supernatant was then injected
into the column via an autosampler and a 20-l loop.
Pharmacokinetic analysis. PL and PF MXF concentrations were plotted against time, and the pharmacokinetic parameters were estimated by
compartmental analysis using the WinNonlin software program (version
3.0; Pharsight Corporation, Mountain View, CA). A two-compartment
model with first-order elimination and no lag time was used, and the
goodness of fit of the model was determined by using the Akaike and
Schwartz criteria, as well as the correlation between the observed and
the calculated concentrations. The peak (maximum) concentration in
plasma (CmaxPL) and the trough (minimum) concentration in plasma
(CtroughPL) were observed at 24 h postdosing. The peak (maximum)
concentration in pleural fluid (CmaxPF) and the time to reach CmaxPF
(TmaxPF) were obtained observationally from individual concentrationtime data. All concentrations in both matrices were total drug concentrations. The area under the concentration-time curve from time zero to 24
h (AUC24) was determined by the trapezoidal rule. The penetration ratio
for each patient was obtained by dividing the AUC24 for pleural fluid
(AUC24PF) by the AUC24 for plasma (AUC24PL). Calculation of the volume of distribution (V), total body clearance (CL), and elimination halflife (t1/2) was performed by a compartmental method, as described above.
Statistical analysis. All data are expressed as means standard deviations unless otherwise noted. Biostatistical analysis was performed using
SPSS for Windows, release 17.0.1 (standard version; SPSS Inc.). The normality of the distribution was assessed by the Shapiro-Wilk test. Pharmacokinetic parameters between empyemic/parapneumonic and malignant
effusions were compared by an independent samples t test if the data were

TABLE 2 PF characteristicsa
Patient group

pH

LDH concn
(IU/liter)

Protein concn
(g/dl)

Glucose concn
(mg/dl)

WBC count
(no. of cells/mm3)

Differential

Empyema/PPE
Malignant effusion

6.9 0.3
7.3 0.1

2,665.6 4,544.1
546.2 418.8

4.3 0.9
4.3 1.0

70.7 68.4
110.0 34.3

4,944.4 4,514.4
946.6 735.6

Neutrophil predominance
Lymphocyte predominance

0.004

0.135

0.878

0.108

0.029

Data represent means standard deviations.

1316 aac.asm.org

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Moxioxacin PK and Pleural Fluid Penetration

CmaxPL (mg/liter)
CtroughPL (mg/liter)

TABLE 3 Pharmacokinetic parameters of moxifloxacin in PLa

Patient group
TmaxPL (h)

Empyema/PPE
4.64 0.68 (3.575.56) 0.37 0.13 (0.200.63) 1.00 0
Malignant effusion 4.28 0.69 (3.125.97) 0.39 0.07 (0.250.52) 1.00 0

0.647

AUC24PL (mg h/liter)


t1/2 (h)

0.303

CL (liters/h)

0.615

V (liters)

0.599

28.39 5.47 (22.1138.08) 13.98 10.49 (3.8436.20) 12.17 3.96 (6.8219.10) 165.12 62.77 (82.66310.95)
28.06 4.37 (20.3235.38) 10.71 2.48 (7.9615.28) 12.14 2.27 (9.8716.78) 155.22 24.99 (106.77187.68)

0.627

March 2014 Volume 58 Number 3

0.288

Twenty-four patients (19 males and 5 females) were included in


the study. Twelve of these patients were admitted to the hospital
due to complicated parapneumonic effusion (PPE) or empyema
(group A), and the rest suffered from malignant pleural effusion
(group B). Their demographics and pleural fluid characteristics
are shown in Tables 1 and 2, respectively.
The pharmacokinetic parameters of MXF in plasma for both
patient groups are summarized in Table 3. The mean peak concentrations in plasma were 4.64 0.68 mg/liter for group A and
4.28 0.69 mg/liter for group B, respectively, and were achieved
by the end of drug infusion. The observed mean concentrations in
plasma at 24 h (CtroughPL) were 0.37 0.13 mg/liter for group A
and 0.39 0.07 mg/liter for group B. A large variability in the
pharmacokinetic data was observed for both groups, especially in
V, which ranged from 82.66 to 310.95 liters, although their mean
values were similar (165.12 liters for group A versus 155.22 liters
for group B). Similarly, CL ranged from 6.82 to 19.10 liters/h, and
t1/2 was as short as 3.84 h and as long as 36.20 h. In both groups, a
similar AUC24PL was observed (28.39 5.47 mg h/liter for group
A versus 28.06 4.37 mg h/liter for group B).
Regarding the pleural fluid, the mean CmaxPF in patients with
empyema/PPE was 2.23 1.31 mg/liter, and it was detected
7.50 2.39 h after the initiation of the infusion. In patients with
malignant effusion, the mean CmaxPF was 2.96 1.45 mg/liter,
and it was observed significantly earlier at 3.58 1.38 h after the
start of the infusion (P 0.001). Both groups revealed a similar
mean AUC24PF (31.83 23.52 mg h/liter for group A versus
32.81 12.66 mg h/liter for group B), but patients with empyema/PPE showed a remarkable interindividual variability
(AUC24PF range, 51 to 96.11 mg h/liter). The penetration of MXF
into pleural fluid was similarly good in patients from both groups
(1.11 0.74 for group A versus 1.17 0.39 for group B). The
mean CtroughPF was found to be 0.99 0.84 for group A and
0.73 0.46 mg/liter for group B, with empyemic patients showing
a slightly higher but not statistically significanttrough concentration of moxifloxacin at the end of the 24-h interval. The
equilibration of the MXF concentration between plasma and
pleural fluid occurred at 5 h in patients with empyema/parapneumonic effusion, whereas it occurred at 3 h in those with malignant
effusion. The pharmacokinetic parameters of MXF in pleural fluid
for both patients groups are summarized in Table 4, while Fig. 1A
and B represent the concentration-time curves of MXF in the
plasma and pleural fluid of the two groups.
In order to overcome the age difference between the two
groups, we assessed the PF pharmacokinetic data in two subgroups of the 10 older patients with empyema/PPE (mean age,
61.9 years) and compared them to the data for the eight younger
patients with malignant effusion (mean age, 63.8 years). TmaxPF
and CmaxPF maintained the same difference between the two
groups (for TmaxPF, 7.50 versus 3.87 h for groups A and B, respectively; for CmaxPF, 3.13 versus 2.81 mg/liter for groups A and B,
respectively), while AUC24PF and AUC24PF/AUC24PL remained
equal (for AUC24PF, 31.49 mg h/liter for group A versus 33.07
mg h/liter for group B; for AUC24PF/AUC24PL, 1.12 for group A
versus 1.15 for group B).

RESULTS

a
Data represent means standard deviations (ranges). CmaxPL, peak (maximum) concentration in PL; CtroughPL, concentration in PL at the end of 24 h; TmaxPL, time when the CmaxPL was achieved; AUC24PL, area under the
concentration-time curve from time zero to 24 h; t1/2, elimination half-life; CL, total body clearance; V, volume of distribution.

normally distributed and by the Mann-Whitney test if the data were nonnormally distributed.

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Chatzika et al.

TABLE 4 Main pharmacokinetic parameters of moxifloxacin in PFa


Patient group

CmaxPF
(mg/liter)

CtroughPF
(mg/liter)

AUC24PF
(mg h/liter)

AUCPF/AUCPL

TmaxPF (h)

Empyema/PPE
Malignant effusion

2.23 1.31
2.96 1.45

0.99 0.84
0.73 0.46

31.83 23.52
32.81 12.66

1.11 0.74
1.17 0.39

7.50 2.39
3.58 1.38

0.288

0.365

0.899

0.81

0.001

Data represent means standard deviations. CmaxPF, peak (maximum) concentration in PF; CtroughPF, concentration in PF at the end of 24 h; AUC24PF, area under the
concentration-time curve from time zero to 24 h; TmaxPF, time when the CmaxPF was achieved.
a

DISCUSSION

Concentration (mg/L)

Antibiotic penetration into the site of infection is critical in order


to achieve a favorable clinical outcome. The success of an antimicrobial agent in the treatment of pleural space infection depends
on the achievement of sufficient drug concentrations in the pleura
and, more specifically, in pleural fluid (16, 17). For the first time in
the literature, results from the present study indicate that MXF
penetrates sufficiently into pleural fluid in patients with empyema
and those with malignant effusion, though penetration is significantly slower in the empyemic patients.
In general, it is believed that antibiotic levels in pleural fluid are
similar to those in serum, but most studies in humans involved
patients with diseases other than empyema (18). Teixeira et al.
have suggested that pleural fluid antibiotic levels are lower than
serum antibiotic levels in patients with empyema, due to the decreased permeability of the thickened pleura and the more acidic
local environment (19). On the contrary, under circumstances of
acute infection, which involves inflammation, vasodilation,
edema, and increased membrane permeability, the penetration of
antimicrobial agents may be increased (20).
Therefore, it is important to evaluate the penetration of anti-

Plasma

Pleural Fluid

3
2
1
0
-1 0

12

15

18

21

24

Time (hours)

Concentration (mg/L)

6
5
4
Plasma

Pleural Fluid

2
1
0
-1

12

15

18

21

24

Time (hours)

FIG 1 Mean SD moxifloxacin concentration-time curves in plasma and


pleural fluid in patients with empyema/parapneumonic effusion (A) and malignant effusion (B).

1318

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biotics into the pleural space, and careful consideration should be


given to the underlying pathophysiology and the different mechanisms of fluid formation. In empyema, during the exudative
stage, pleural fluid accumulates in the pleural space secondary to
inflammation and the increased permeability of the visceral
pleura. As the infection progresses, the bacterial invasion of the
pleural space, the deposition of fibrin on pleural membranes, and
the formation of septations lead to a thick, nonelastic pleural peel
(21). Regarding malignant effusions, which are predominantly
exudates (22), the main mechanisms of fluid production include
impaired drainage of the pleural space due to obstruction of blood
vessels and lymphatics of the lung and pleura and increased formation of pleural fluid (23).
Hence, it could be assumed that the penetration of antimicrobial agents into pleural effusions of a different etiology could vary
according to the underlying pathophysiology. Indeed, in a rabbit
model of empyema, penetration of antibiotics varied significantly
(19). On the other hand, a previous study concluded that there is
very little difference between chemically diverse antimicrobial
agents in their degree of pleural penetration (18). Notably, none of
these studies included fluoroquinolones, a class of antimicrobials
able to achieve a large volume of distribution and extensive tissue
penetration (24). There are indications that the antimicrobial activity of compounds like MXF, which is devoid of a piperazinyl
ring at position 7, is not affected by acidic conditions (25). Therefore, it could be expected that newer fluoroquinolones, and specifically MXF, would be an attractive treatment option for infected
or contaminated pleural effusions. The present data are in favor of
this hypothesis.
Our results show that the interindividual variability of MXFs
pharmacokinetic parameters is considerable. This could be explained by the fact that all subjects were seriously ill, and therefore,
pharmacokinetic parameters were subjected to a number of modifying factors, such as cardiac performance, the adequacy of tissue
perfusion, coadministration of drugs, and competition for the
same metabolic pathways (26). Moreover, it is known that the
genetic variability of the metabolic pathways represents a major
modifying factor (27). It is evident that the coexistence of more
than one modifying factor in a given patient makes determination
of the individual contribution practically impossible. Nevertheless, MXF revealed similar pharmacokinetic characteristics (e.g.,
Cmax, Ctrough, AUC24, and AUC24PF/AUC24PL) in both groups of
patients, confirming its excellent ability to penetrate into tissue
compartments independently of the degree of inflammation or
pH reduction.
The main finding in our study is the statistically significant
prolongation of TmaxPF in the group of patients with empyema/
parapneumonic effusion and the slightly lower CmaxPF. Correspondingly, the same group of patients tended to achieve higher

Antimicrobial Agents and Chemotherapy

Moxioxacin PK and Pleural Fluid Penetration

trough moxifloxacin levels in pleural fluid, although the difference did not reach statistical significance. It could be assumed that
fibrin deposition on pleural surfaces, along with a degree of thickening, raises a barrier to prompt penetration into the pleural
space. Notwithstanding, MXF was able to achieve AUCs in pleural
fluid equal to or higher than those obtained in plasma in both
groups of patients, indicating that microbial exposure to the
drugs antimicrobial action is not compromised by tissue factors
or the degree of the inflammatory process. However, patients with
empyema/PPE showed a remarkable variation in AUC24PF, indicating that in some patients, therapeutic drug monitoring and
treatment individualization may be needed.
The main limitation of the present study was the age difference
between the two groups. Although the possibility that this difference may interfere with MXF penetration into PF cannot be excluded, we do not believe that this is the case, for two reasons.
First, both groups had similar plasma pharmacokinetic profiles,
despite the age difference. Second, patients of similar ages from
both groups maintained the same PF pharmacokinetic characteristics as the original groups. Therefore, it is reasonable to assume
that the delay in TmaxPF in the case of empyema/parapneumonic
effusion does not result from age-dependent differences in the
MXF tissue distribution.
The results of the present study support the wide empirical use
of MXF in the treatment of parapneumonic effusion and empyema, providing evidence for the first time under actual clinical
conditions that MXF sufficiently penetrates into the pleural space
and exhibits a favorable pharmacokinetic profile regardless of
pleural fluid origin. The delay in the achievement of the maximum
pleural fluid MXF concentration observed in patients with PPE/
empyema may trigger further studies on the penetration of different antibiotics into the pleural space.

7.
8.
9.
10.

11.

12.
13.
14.
15.

16.
17.
18.
19.

ACKNOWLEDGMENTS
We thank the staff of the Pulmonary Department of G. Papanikolaou
Hospital for their assistance.
No funding was received for this study.
We have no competing interests to declare.

20.
21.
22.

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