Documente Academic
Documente Profesional
Documente Cultură
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-
p. 13151319
aac.asm.org
1315
Chatzika et al.
M M M M F
M M M 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.
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
1316 aac.asm.org
CmaxPL (mg/liter)
CtroughPL (mg/liter)
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
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
0.288
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.
aac.asm.org 1317
Chatzika et al.
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)
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)
1318
aac.asm.org
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.
REFERENCES
1. Light RW. 2007. Parapneumonic effusions and empyema, p 179 207. In
Light RW (ed), Pleural diseases, 5th ed. Lippincott Williams & Wilkins,
Philadelphia, PA.
2. Chapman SJ, Davies RJO. 2004. The management of pleural space infections. Respirology 9:4 11. http://dx.doi.org/10.1111/j.1440-1843.2003
.00535.x.
3. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD,
Dean NC, Dowell SF, File TM, Jr, Musher DM, Niederman MS, Torres
A, Whitney CG. 2007. Infectious Diseases Society of America/American
Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin. Infect. Dis. 44(Suppl 2):2772.
http://dx.doi.org/10.1086/511159.
4. American Thoracic Society Documents. 2005. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and
healthcare-associated pneumonia. Am. J. Respir. Crit. Care Med. 171:
388 416. http://dx.doi.org/10.1164/rccm.200405-644ST.
5. Padberg WM, Jager E, Buhr J, Zimmermann T. 2000. Ciprofloxacin
levels in pleural fluid and serum during systemic administration after
pneumonectomy. Zentralbl. Chir. 125:450 453. (In German.)
6. Joseph J, Vaughan LM, Basran GS. 1994. Penetration of intravenous and
23.
24.
25.
26.
27.
oral ciprofloxacin into sterile and empyemic human pleural fluid. Ann.
Pharmacother. 28:313315.
Umut S, Demir T, Akkan G, Keskiner N, Yilmaz V, Yildirim N,
Sipahioglu B, Hasan A, Barlas A, Szer K, et al. 1993. Penetration of
ciprofloxacin into pleural fluid. J. Chemother. 5:110 112.
Morgenroth A, Pfeuffer HP, Seelmann R, Schweisfurth H. 1991. Pleural
penetration of ciprofloxacin in patients with empyema thoracis. Chest
100:406 409. http://dx.doi.org/10.1378/chest.100.2.406.
Jacobs F, Marchal M, de Francquen P, Kains JP, Gangji D, Thys JP. 1990.
Penetration of ciprofloxacin into human pleural fluid. Antimicrob. Agents
Chemother. 34:934 936. http://dx.doi.org/10.1128/AAC.34.5.934.
Strahilevitz J, Lev A, Levi I, Fridman E, Rubinstein E. 2003. Experimental pneumococcal pleural empyema model: the effect of moxifloxacin.
J. Antimicrob. Chemother. 51:665 669. http://dx.doi.org/10.1093/jac
/dkg094.
Liapakis , Kottakis , Tzatzarakis , Tsatsakis , Pitiakoudis
MS, Ypsilantis P, Light RW, Simopoulos CE, Bouros DE. 2004. Penetration of newer quinolones in the empyema fluid. Eur. Respir. J. 24:466
470. http://dx.doi.org/10.1183/09031936.04.00007804.
Hamm H, Light RW. 1997. Parapneumonic effusion and empyema. Eur. Respir.
J. 10:11501156. http://dx.doi.org/10.1183/09031936.97.10051150.
Light RW, MacGregor MI, Luchsinger PC, Ball WC. 1972. Pleural
effusions: the diagnostic separation of transudates and exudates. Ann.
Intern. Med. 77:507513. http://dx.doi.org/10.7326/0003-4819-77-4-507.
Cockcroft DW, Gault MH. 1976. Prediction of creatinine clearance from serum
creatinine. Nephron 16:3141. http://dx.doi.org/10.1159/000180580.
Liang H, Kays MB, Sowinski KM. 2002. Separation of levofloxacin,
gatifloxacin, moxifloxacin, trovafloxacin and cinoxacin by HPLC: application to levofloxacin determination in human plasma. J. Chromatogr. B
772:53 63. http://dx.doi.org/10.1016/S1570-0232(02)00046-6.
Song JH. 2003. Introduction: the goals of antimicrobial therapy. Int. J.
Infect. Dis. 7(Suppl 1):S1S4. http://dx.doi.org/10.1016/S1201-9712(03)
90064-6.
Bergogne-Brzin E. 1995. Predicting the efficacy of antimicrobial agents
in respiratory infections: is tissue concentration a valid measure? J. Antimicrob. Chemother. 35:363371. http://dx.doi.org/10.1093/jac/35.3.363.
Taryle DA, Good JT, Jr, Morgan EJ, III, Reller LB, Sahn SA. 1981.
Antibiotic concentration in human parapneumonic effusions. J. Antimicrob. Chemother. 7:171177. http://dx.doi.org/10.1093/jac/7.2.171.
Teixeira LR, Sasse SA, Villarino MA, Nguyen T, Mulligan ME, Light
RW. 2000. Antibiotic levels in empyemic pleural fluid. Chest 117:1734
1739. http://dx.doi.org/10.1378/chest.117.6.1734.
Valcke Y, Pauwels R, van der Straeten M. 1990. Pharmacokinetics of
antibiotics in the lungs. Eur. Respir. J. 3:715722.
Antony VB, Mohammed KA. 1999. Pathophysiology of pleural space
infections. Semin. Respir. Infect. 14:9 17.
Ashchi M, Golish J, Eng P, ODonovan P. 1998. Transudative malignant
pleural effusions: prevalence and mechanisms. South. Med. J. 91:2326.
http://dx.doi.org/10.1097/00007611-199801000-00004.
Light RW, Vargas FS. 1997. Pleural sclerosis for the treatment of pneumothorax and pleural effusion. Lung 175:213223. http://dx.doi.org/10
.1007/PL00007568.
Hooper DC, Strahilevitz J. 2010. Quinolones, p 487510. In Mandell GL,
Bennett JE, Dolin R (ed), Mandell, Douglas, and Bennetts principles and
practice of infectious diseases, 7th ed, vol 1. Churchill Livingstone, Philadelphia, PA.
Dalhoff A, Schubert S, Ullmann U. 2005. Effect of pH on the in vitro
activity of and propensity for emergence of resistance to fluoroquinolones, macrolides, and a ketolides. Infection 33(Suppl 2):36 43. http://dx
.doi.org/10.1007/s15010-005-8206-y.
Herrlinger C, Klotz U. 2001. Drug metabolism and drug interactions in
the elderly. Best Pract. Res. Clin. Gastroenterol. 15:897918. http://dx.doi
.org/10.1053/bega.2001.0249.
Lai Y, Varma M, Feng B, Stephens JC, Kimoto E, El-Kattan A, Ichikawa
K, Kikkawa H, Ono C, Suzuki A, Suzuki M, Yamamoto Y, Tremaine L.
2012. Impact of drug transporter pharmacogenomics on pharmacokinetic
and pharmacodynamic variability considerations for drug development. Expert Opin. Drug Metab. Toxicol. 8:723743. http://dx.doi.org/10
.1517/17425255.2012.678048.
aac.asm.org 1319