Journal of Antimicrobial Chemotherapy (2006) 58, 994–999
doi:10.1093/jac/dkl353
Advance Access publication 6 September 2006
Penetration of moxifloxacin into the human pancreas
following a single intravenous or oral dose
Rainer Wacke1*, Sven Förster2, Ulrich Adam3, Ralf G. Mundkowski1, Ernst Klar2,
Ulrich T. Hopt3 and Bernd Drewelow1
1
Institute of Clinical Pharmacology, Centre of Pharmacology and Toxicology, University of Rostock,
Rostock, Germany; 2Department of Surgery, University of Rostock, Rostock, Germany;
3
Department of Surgery, University of Freiburg, Freiburg, Germany
Received 9 May 2006; returned 17 June 2006; revised 7 July 2006; accepted 3 August 2006
Objectives: Failure to prevent secondary infectious complications in acute necrotizing pancreatitis
(ANP) is attributable in part to the limited penetration of antimicrobial drugs. As newer quinolones are
particularly attractive owing to their antimicrobial activity, for the first time we studied the penetration of
moxifloxacin into pancreatic tissue in patients.
Patients and methods: In this prospective, non-comparative clinical trial, 60 patients undergoing elective
pancreas resection received a single oral or intravenous (iv) dose of 400 mg moxifloxacin for
perioperative antimicrobial prophylaxis. The concentration of moxifloxacin was measured in samples
taken from blood and from pancreatic tissue at the beginning and at the end of resection.
Results: Mean moxifloxacin concentrations in pancreatic tissue following iv or oral administration were
3.1 – 0.9 and 2.7 – 1.4 mg/kg at 3–3.7 h post-dose (first sampling) and 3.6 – 1.5 and 3.1 – 1.8 mg/kg at
4.3–5.3 h post-dose (second sampling), respectively. Corresponding mean plasma concentrations of
moxifloxacin were 1.8 – 0.5 and 1.2 – 0.6 mg/L (first sampling) and 1.5 – 0.4 and 1.0 – 0.5 mg/L (second
sampling), respectively. From first to second sampling, the mean tissue-to-plasma ratios varied from
1.8 – 0.6 to 2.6 – 1.2 (iv) and from 2.4 – 0.8 to 3.1 – 1.2 (oral). Pancreatic tissue concentrations of
moxifloxacin exceeded the MIC90 for the relevant pathogens covered by moxifloxacin for at least 5 h after
dosing.
Conclusions: Moxifloxacin has been demonstrated to penetrate efficiently into human pancreatic tissue
following iv or oral administration. From a pharmacological perspective, moxifloxacin appears to be
promising for prophylaxis and treatment of local pancreas infections. Whether it is beneficial in the
prevention and therapy of infectious complications in patients with ANP should be investigated in a
controlled clinical trial.
Keywords: pancreatitis, pharmacokinetics, fluoroquinolones
Introduction
In patients suffering from acute necrotizing pancreatitis (ANP),
prophylaxis with antibiotics is still a matter of debate, not only
because of the risk of development of resistance but also because
of conflicting results from clinical studies. National and
international guidelines for the management of acute pancreatitis
and even a recent Cochrane review recommend antimicrobial
prophylaxis in patients at risk for secondary infection.1–5 In many
unblinded trials and meta-analyses prophylactic antibiotics have
indeed been shown to result in a reduction of the infection rate
and mortality or an improved clinical course.6,7 The only doubleblind and also the largest randomized clinical trial, the so-called
ASAP study, failed to show a reduction of infection and hospital
mortality by antibiotic prophylaxis in patients with severe acute
pancreatitis.8
Possible reasons for failure to reduce pancreatic infection are
the timing, as prophylactic treatment has to start early in the
course of disease to be effective,9–11 and also a limited penetration
of antimicrobial drugs. A sufficient penetration into pancreas
tissue is necessary to influence the local infection and is explicitly
demanded in most guidelines as a prerequisite for antimicrobials
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*Corresponding author. Tel: +49-381-4-94-57-77; Fax: +49-381-4-94-57-82; E-mail: [email protected]
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994
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Moxifloxacin penetration into human pancreas
used in ANP patients.12 The pancreas is a specialized site with
regard to drug penetration. Some antibiotics such as aminoglycosides do not penetrate well into this compartment.13 The number
of drugs whose penetration into pancreatic tissue has been studied
is limited.
Besides imipenem, the fluoroquinolones ciprofloxacin and
ofloxacin are among the antibiotics most often recommended
for ANP and have shown the highest penetration rates (tissue/
plasma ratio) in animals14 as well as in patients.12,15 However,
considering the relative shift from predominantly Gram-negative
bacteria towards a higher proportion of infections due to Grampositive organisms noted in recent years,16,17 newer thirdgeneration fluoroquinolones with enhanced Gram-positive activity
and more convenient dosing intervals like moxifloxacin would be
an attractive option. Besides its activity against a broad-spectrum
of Gram-negative and of Gram-positive bacteria, moxifloxacin has
anti-anaerobic activity as an additional benefit18 and exhibits an
excellent tissue penetration especially into rat pancreas.19,20 But as
of yet, no human data were available. We therefore evaluated
moxifloxacin penetration into pancreatic tissue following administration of a single dose of 400 mg moxifloxacin in patients
undergoing pancreas surgery.
Patients and methods
Study population
The study population of this prospective, two-centre, noncomparative Phase I study consisted of 60 patients who planned to
undergo elective pancreas resection for pancreas carcinoma or
chronic pancreatitis. Patients below 18 years of age, with hypersensitivity against quinolones, pregnancy, severe liver dysfunction
(Child Pugh class C), heart failure with reduced left ventricular
ejection fraction, arrhythmia requiring medical treatment or chronic
renal insufficiency, among others, were excluded from the study.
The study was approved by the responsible Ethics Committee of
the Ärztekammer Mecklenburg-Vorpommern (II HV 09/2001) and
performed according to the principles of the Declaration of Helsinki.
Written informed consent was obtained from all patients.
Safety
Besides measuring moxifloxacin concentrations in tissue and plasma
as the primary parameter of this study, safety was assessed as a
secondary variable. All patients were monitored for adverse events
from the preoperative phase until day 7 post-surgery.
Analytical methods
Sample preparation and HPLC analysis using ofloxacin as internal
standard were performed by methods that have been cross-validated
with the Bayer HealthCare Reference Laboratory (Wuppertal,
Germany) according to industry standards. This method was also
fully validated for the determination of levofloxacin by interchanging
of analyte (S-enantiomer of ofloxacin) and internal standard
(moxifloxacin).21
Procedures and sampling
Before induction of anaesthesia all patients received a single dose of
400 mg moxifloxacin for perioperative antibiotic prophylaxis, given
either intravenously (20 patients) or orally (40 patients). In order to
investigate time effect on pharmacokinetic parameters surgeons had
to take pancreatic tissue samples at the beginning of the operation
after proven resectability (first sample) and at the end of pancreas
resection (second sample). Samples from peripheral venous blood
were withdrawn simultaneously and kept at +4 C until centrifugation
(12 min, 1500 g) for no longer than 1 h. Tissue samples were snapfrozen in liquid nitrogen immediately after removal. Plasma and
tissue samples were frozen and stored at –80 C until analysis for no
longer than 6 weeks. No significant loss of analyte was observed
during sample preparation and storage. Tissue samples were
homogenized in an ice bath using 0.9% NaCl (1:1, w/v) and an
Ultraturrax T25 (IKA-Werke, Staufen, Germany) for 1 min.
HPLC assay
Homogenized tissue samples were diluted with an equal volume of
water to bring concentrations into the range of calibrators. One
hundred microlitres of serum or 40 mL of homogenate was spiked
with 20 mL each of aqueous ofloxacin (final concentration: 200 ng/
mL) as internal standard and, in the case of the calibrators,
appropriate concentrations (100–2000 ng/mL) of moxifloxacin.
Then, 20 mL of 25% trifluoroacetic acid (purity >99.5%) was
added, and the mixture was vortexed and centrifuged at 6000 g for
4 min. Eighty microlitres of the supernatant was added to 21 mL of
5.0 M aqueous ammonium acetate, and 20 mL of the mixture was
subjected to HPLC/fluorescence analysis. The chromatographic
system consisted of a guarded YMC Pro C18 column (particle size:
5 mm, pore diameter: 120 Å, 150 mm length, 2 mm inner diameter)
maintained at 20 C, and a gradient mobile phase comprising
methanol/1.0 M ammonium acetate/H2O (10:5:85 v/v/v for component A and 40:5:55 for component B), pumped at a rate of 250 mL/
min, with 22% initial B changed to stages of 25% and 32% after 1 and
2 min, respectively. Fluorescence detection was performed at an
excitation wavelength of 296 nm and an emission wavelength of 504
nm. The retention times were 4.5 and 12.5 min for ofloxacin
and moxifloxacin, respectively. The assay was validated intra- and
inter-daily according to standard procedures. The lower limits of
quantification were set to 30 ng/mL for plasma and 150 ng/mL for
pancreatic tissue homogenates with coefficients of variation and
relative errors of <5% and <+1%, and 29% and +9%, respectively.
Precisions and accuracies of other controls in the medium and upper
range of the calibration range were better than –15%. Recoveries
ranged between 80% and 85% based on spiking solution.
Statistics
All data were analysed descriptively. Calculations were performed
using the SPSS software release 11.0 (SPSS GmbH, Munich,
Germany). Results are presented as means – SD. As data were
distributed normally (Kolmogorov–Smirnov test), means of moxifloxacin concentrations were compared using an unpaired t-test
(Student’s test). Findings were considered statistically significant if
the P value was <0.05.
Results
Of the 60 patients enrolled in the study, 47 were male and 13 were
female. Mean age was 55.9 – 13.3 years (range: 25–80) and mean
body weight was 72.8 – 12.0 kg. Underlying disease was chronic
pancreatitis in 28 cases and pancreatic carcinoma in 32 cases. For
demographic data of the subgroups with oral or intravenous (iv)
administration of moxifloxacin, see Table 1.
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Wacke et al.
Table 1. Demographic and medical data
Subgroup
administered
MXF
400 mg iv
Subgroup
administered
MXF
400 mg oral
20
18/2
40
29/11
51.5 – 13.7
25–74
58.1 – 12.5
39–80
72.7 – 10.3
55–90
9
11
72.9 – 12.8
53–115
23
17
Mean MXF concentration (mg/L plasma; mg/kg tissue)
Number of patients enrolled
Male/female
Age (years)
mean
range
Body weight (kg)
mean
range
Diagnosis of pancreas carcinoma
Diagnosis of chronic pancreatitis
MXF plasma and tissue concentrations after intravenous administration
6
Plasma
Pancreatic tissue
5
4
3
2
1
0
3.0 h
4.3 h
Mean time after intravenous administration
MXF, moxifloxacin.
From the 60 patients enrolled, 13 patients could not be
evaluated. In five of them the pancreas was shown to be nonresectable intraoperatively, whereas in three other patients no or
too little pancreatic tissue was harvested owing to a complicated
course of surgery. In the remaining five cases there were protocol
violations, mainly due to failures in sampling.
As shown in other studies, the resectability rate for cancer of
head of the pancreas is 75–80%. This was also true for this
study.
Moxifloxacin was well tolerated; no serious drug reactions
were observed. None of the patients had to be excluded because of
adverse events.
iv subgroup
In the iv subgroup, samples were collected at a mean time of
3.0 – 0.6 h (first) and 4.3 – 1.3 h (second) after iv administration
of moxifloxacin. Owing to the reasons mentioned above, at the
first and the second time-point moxifloxacin tissue concentrations
were available from 5 (25%) and 16 (80%) patients, respectively,
and plasma concentrations from 8 (40%) and 18 (90%) patients.
Following iv administration of moxifloxacin, mean concentrations were 1.8 – 0.5 mg/L in plasma and 3.1 – 0.9 mg/kg in tissue
at the first sampling time and 1.5 – 0.4 mg/L (plasma) and
3.6 – 1.5 mg/kg (tissue) at the second sampling at the end of
pancreas resection (Figure 1). The corresponding penetration rates
were 1.8 – 0.6 and 2.6 – 1.2 (Figure 2).
Oral subgroup
In two patients of the oral subgroup moxifloxacin was
administered through a feeding tube; the other patients received
moxifloxacin in tablet form. Mean times for first and second
sampling were 3.7 – 0.9 h and 5.3 – 1.5 h after oral administration
of moxifloxacin, respectively. Tissue concentrations were available from 18 (45%) patients at the first and 30 (75%) patients at
the second time-point. Plasma concentrations could be obtained
from 21 (53%) and 32 (80%) patients, respectively.
Mean concentrations of moxifloxacin after oral administration
were 1.2 – 0.6 mg/L in plasma and 2.7 – 1.4 mg/kg in pancreatic
Figure 1. Plasma (mg/L) and pancreatic tissue (mg/kg) concentrations
following a single 400 mg intravenous dose of moxifloxacin (MXF). Values
presented as means – SD.
tissue at the first sampling time and 1.0 – 0.5 mg/L (plasma) and
3.1 – 1.8 mg/kg (tissue) at the second sampling (Figure 3). The
resulting tissue/plasma ratios were 2.4 – 0.8 and 3.1 – 1.2,
respectively (Figure 2).
The difference between mean moxifloxacin plasma concentrations following iv versus oral administration was significant at
both first and second sampling time-point. Corresponding
moxifloxacin tissue concentrations did not differ significantly.
In patients with pancreatic disease the moxifloxacin concentrations found in pancreatic tissue after either iv or oral administration of a single dose of 400 mg moxifloxacin exceeded the MIC90
for the pathogens12 most commonly found in infected necroses of
patients with severe acute pancreatitis, i.e. Escherichia coli
(0.008–0.06 mg/L),22,23 methicillin-susceptible Staphylococcus
aureus (0.06–0.12 mg/L),22–26 Staphylococcus epidermidis
(0.12–0.25 mg/L),22,23 Klebsiella spp. (0.13 mg/L),23 Enterococcus faecalis (0.25–0.5 mg/L),23,26 Bacteroides fragilis
(0.5–1.0 mg/L)18,23,26 and Enterobacter spp. (0.06 mg/L),22–24
for at least 5 h after dosing.
Discussion
In the present study, the penetration ability of moxifloxacin in
human pancreatic tissue was evaluated for the first time. These
results show that moxifloxacin readily penetrates into human
pancreas and achieves high tissue concentrations following a
single oral or iv dose. At both sampling times, moxifloxacin
concentrations in pancreatic tissue were noticeably higher than
the corresponding plasma concentrations. The resulting tissue/
plasma ratios varied between 1.8 and 3.1.
While moxifloxacin plasma concentrations exhibited the
expected decrease from first (3.0–3.7 h) to second (4.3–5.3 h)
sampling time, in pancreatic tissue moxifloxacin concentrations
increased from first to second sampling in both the oral subgroup
and the iv subgroup. This contrasts with the penetration kinetics in
rats, where we observed a sharp and steady decrease of
moxifloxacin concentrations in healthy and inflamed pancreatic
tissue within 10–240 min after drug administration.20 This
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Moxifloxacin penetration into human pancreas
Moxifloxacin penetration rates in human pancreatic tissue
Mean MXF tissue/plasma concentration ratio
5
4
3
2
1
Intravenous administration
Oral administration
0
3.0 h
4.3 h
3.7 h
5.3 h
Mean time after MXF administration
Figure 2. Penetration rates of moxifloxacin (MXF) into human pancreatic tissue following a single 400 mg iv or oral dose. All values presented as means – SD.
Mean MXF concentration (mg/L plasma; mg/kg tissue)
MXF plasma and tissue concentrations after oral administration
5
Plasma
Pancreatic tissue
4
3
2
1
0
3.7 h
5.3 h
Mean time after oral administration
Figure 3. Plasma (mg/L) and pancreatic tissue (mg/kg) concentrations
following a single 400 mg oral dose of moxifloxacin (MXF). Values
presented as means – SD.
difference could be explained mainly by the more rapid
moxifloxacin metabolism and excretion in rats in comparison
with man.27 Furthermore, possible differences between the acute
model in the rat versus the chronic disease in the study patients
have to be taken into account. Apart from that, our results are in
line with prior findings of a good penetration of moxifloxacin into
the pancreas of rats.19,20 The pancreatic tissue/plasma ratio of
moxifloxacin now found in patients is in the same range as in
healthy rats (2) or in rats with experimental ANP (2–3).20
The pancreatic tissue/plasma ratio of moxifloxacin (1.8–3.1)
observed in the present study is one of the highest reported for
bactericidal antibiotics in patients. With the exception of
metronidazole and fluoroquinolones, the pancreatic penetration
rates of all other classes of antibiotic drugs are <1.12,28 For
quinolones penetration rates into the human pancreatic tissue lie
in a broad range following single as well as multiple doses.
Penetration rates of 0.6–1.0 have been reported for ciprofloxacin,12,15,29,30 0.5–3.3 for ofloxacin12,31 and necrotic tissue/
plasma ratios of 0.9–5.1 for pefloxacin.28,32 The high variability
can in part be explained by varying sampling. For pefloxacin that
has a similar half-life as moxifloxacin, no significant accumulation was observed following multiple-dose administration.32
Considering the relative shift of the bacterial spectrum in ANP
patients to more Gram-positive pathogens,16,17 moxifloxacin is of
particular interest as it retains most of the Gram-negative activity
of older fluoroquinolones like ciprofloxacin but exhibits a higher
Gram-positive activity. Even after a single dose of 400 mg,
moxifloxacin tissue concentrations in human pancreas were above
the MICs for the most common Gram-negative and Gram-positive
pathogens.
Since we could not measure moxifloxacin concentrations over
the total 24 h post-dosing, we did not calculate the pharmacodynamic index AUC/MIC that is currently used to predict the
clinical efficacy of fluoroquinolones.
In comparison with ciprofloxacin, moxifloxacin has weaker
in vitro activity against Pseudomonas aeruginosa. Whether this
fact is clinically relevant for the prevention of secondary infection
of the necrotic pancreas in severe acute pancreatitis has to be
evaluated in clinical trials.
The combination with an additional anti-anaerobic drug like
metronidazole, as recommended with the use of ciprofloxacin and
ofloxacin,1,4 might become unnecessary with moxifloxacin
because of its anti-anaerobic activity.
In this study, moxifloxacin mean plasma concentrations,
especially after oral administration, were somewhat lower than
those reported from healthy subjects at corresponding sample
times.33,34 An explanation for this difference could be a
diminished or delayed intestinal absorption before and during
surgery due to these patients’ condition, or due to a gastroparesis in
the third of patients in the oral subgroup who had diabetes mellitus
as underlying disease.
997
Wacke et al.
With a total number of 47 patients evaluated, the present study
includes the largest ever sample of patients evaluated for pancreas
tissue pharmacokinetics of a single antimicrobial. Even in the
study by Büchler et al.12 including 89 patients the largest sample
per single drug was 15.
A limitation of this study is that the patients enrolled did suffer
from pancreas cancer or chronic pancreatitis but not from ANP
though that is the actual target population for antibiotic treatment
and prophylaxis. In contrast to earlier trials pharmacokinetic
studies in patients with acute pancreatitis are no longer feasible as
this condition is rarely operated on nowadays and the intervention
is restricted to a strict necrosectomy sparing any viable tissue.
However, animal studies indicate sufficient penetration of
fluoroquinolones into inflamed pancreas. In a rat-model of ANP
Spicak et al.13 have shown that the penetration of b-lactam
antibiotics and ofloxacin into pancreatic tissue is not influenced
by necrotic inflammation at an early stage of disease. In our oliveoil pancreatitis model we found a 50% higher moxifloxacin
concentration in inflamed pancreas than in healthy pancreas
tissue.20 From their studies with pefloxacin Bassi et al.28
concluded that antibiotics capable of penetrating into the pancreas
under physiological conditions maintain this ability in the
course of acute disease with a necrotic component.
Conclusions
Simultaneous measurement of pancreatic tissue and plasma
concentrations have demonstrated that moxifloxacin readily
penetrates into human pancreatic tissue following iv or oral
administration. The resulting tissue concentrations exceed the
corresponding plasma concentrations as well as the MICs for the
relevant pathogens present in pancreatitis.
Moxifloxacin fulfils the pharmacological requirements to be
beneficial for prophylaxis and treatment of local pancreas
infections. A controlled clinical trial is warranted for its
evaluation in the prevention and therapy of infective complications in patients suffering from ANP.
Acknowledgements
We express our thanks for excellent technical assistance provided
by Katrin Krösche. We thank Klaus A. Schmidt, Aachen, for his
assistance in the preparation of the manuscript. Presented in part
at the Fifteenth European Congress of Clinical Microbiology and
Infectious Diseases (ECCMID), Copenhagen, Denmark, 2005
(Abstract P1104). Financial support: this study was supported in
part by an unrestricted grant by Bayer Vital GmbH, Leverkusen,
Germany.
Transparency declarations
R. W.: none to declare; S. F.: none to declare; U. A. has received
research grants from Bayer Vital GmbH; R. G. M.: none to
declare; E. K.: none to declare; U. T. H. has received research
grants from Bayer Vital GmbH; B. D. has served as a consultant
to and has received research grants from Bayer Vital GmbH.
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