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Antimicrobial Agents and Chemotherapy, January 1999, p. 12-15, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Uptake and Intracellular Activity of Moxifloxacin
in Human Neutrophils and Tissue-Cultured Epithelial Cells
Alvaro
Pascual,*
Isabel
García,
Sofía
Ballesta, and
Evelio J.
Perea
Department of Microbiology, School of
Medicine, University of Seville, Seville, Spain
Received 25 February 1998/Returned for modification 23 August
1998/Accepted 19 October 1998
 |
ABSTRACT |
The penetration by moxifloxacin of human neutrophils
(polymorphonuclear leukocytes [PMN]) and tissue-cultured epithelial
cells (McCoy cells) was evaluated by a fluorometric assay. At
extracellular concentrations of 5 mg/liter, the
cellular-to-extracellular concentration ratios (C/E) of moxifloxacin in
PMN and McCoy cells were 10.9 ± 1.0 and 8.7 ± 1.0, respectively (20 min; 37°C). The uptake of moxifloxacin by PMN was
rapid, reversible, nonsaturable (at extracellular concentrations
ranging from 1 to 50 µg/ml), and not affected by cell viability. The
uptake of moxifloxacin was affected by external pH and the
environmental temperature. The incubation of PMN in the presence of
sodium fluoride, sodium cyanide, and carbonyl cyanide
m-chlorophenylhydrazone significantly decreased the C/E of
this agent. Neither PMN stimulation nor phagocytosis of opsonized Staphylococcus aureus significantly affected the uptake of
moxifloxacin by human PMN. This agent, at concentrations of 0.5, 1, and
5 mg/liter, induced a significant reduction in the survival of
intracellular S. aureus in human PMN. In summary,
moxifloxacin reaches much higher intracellular concentrations within
phagocytic and nonphagocytic cells than extracellular ones, remaining
active inside the neutrophils.
| |
INTRODUCTION |
Fluoroquinolones are able to
concentrate intracellularly in human phagocytic cells, fibroblasts, and
epithelial and endothelial cells (10). Moreover, these
agents are not affected by the intracellular environment and remain
active against different facultative and obligate intracellular
pathogens, such as Staphylococcus aureus (1, 12),
Legionella spp. (17), Mycobacterium
spp. (9), and Chlamydia spp. (7).
Moxifloxacin (BAY 12-8039) is a new 8-methoxyquinolone with a bicyclic
amine substituent at the 7 position and with a broad spectrum of
activity against both gram-negative and gram-positive bacteria
(2). Moxifloxacin has been found to be 2 to 16 times more
active than ciprofloxacin and ofloxacin against staphylococci, streptococci, enterococci, anaerobes, and Chlamydia spp.
(3, 6, 18).
The purpose of this study was to evaluate the uptake of moxifloxacin by
human polymorphonuclear leukocytes (PMN) and tissue-cultured epithelial
cells. The mechanism involved in the penetration by this agent of human
PMN and its intracellular activity compared with those of ofloxacin and
ciprofloxacin were also evaluated.
| |
MATERIALS AND METHODS |
Isolation of PMN.
PMN were recovered from heparinized venous
blood of healthy donors by using dextran sedimentation and a
Ficoll-Hypaque gradient and purified by previously described methods
(16). PMN preparations were 97% pure. Final cell
suspensions were adjusted to 5 × 106 PMN per ml in
Hanks balanced salt solution (HBSS) containing 1% gelatin. PMN were
95% viable as determined by trypan blue exclusion.
Tissue culture cells.
McCoy cells (Flow Laboratories,
Irvine, United Kingdom) were grown in minimal essential medium (Flow)
supplemented with 1 mM HEPES (Flow) and containing 10% fetal calf
serum (Flow) without antibiotics. For each experiment, the cells were
detached from tissue culture bottles with trypsin-EDTA (Flow), washed
once with minimal essential medium containing fetal calf serum (10%),
and suspended in HBSS at a concentration of 5 × 106
per ml.
Moxifloxacin uptake by cells.
A previously described
fluorometric assay was used to measure quinolone uptake by human PMN
and epithelial cells (11). Moxifloxacin was kindly supplied
by Bayer AG, Leverkusen, Germany. In these experiments, PMN or tissue
cells were incubated in HBSS containing different concentrations of
antimicrobial agent (1 to 50 mg/liter). After different incubation
times at 37°C, cells were separated from the extracellular solution
by centrifugation through a water-impermeable silicone-oil barrier
(density, 1,029 g/cm3) in a microcentrifuge tube. The
entire cell pellet, obtained by cutting off the portion of the
microcentrifuge tube containing the pellet, was placed in 2 ml of 0.1 M
glycine-HCl buffer (pH 3.0) and agitated vigorously in a vortex shaker.
Incubation for 2 h at room temperature was sufficient to release
the intracellular antimicrobial agent fully (11). Samples
were centrifuged for 5 min at 5,600 × g, and the
amount of antimicrobial agent was determined by fluorescence emission
of supernatants with an F 2000 fluorescence spectrophotometer (Hitachi,
Tokyo, Japan). The fluorescence excitation and emission maxima in 0.1 M
glycine-HCl (pH 3.0) were 295 and 498 nm, respectively. Controls
without antimicrobial agents were always used to determine the
background fluorescence.
Intracellular water space was measured by using tritiated water and the
extracellular marker [14C]polyethylene glycol (1.4 mCi/g;
New England Nuclear Corp., Boston, Mass.). Cells were incubated with
these radiolabeled compounds for 2 min at 37°C, separated from
extracellular fluid by velocity gradient centrifugation as described
above, and counted in a liquid scintillation counter. Total water
content of the cell pellet was corrected for trapped extracellular
water, i.e., polyethylene glycol space, to obtain the intracellular
water space. From the values obtained by this procedure,
cell-associated antimicrobial agent concentrations were calculated and
expressed as ratios of the cellular concentration to extracellular
concentration (C/E ratios) (8).
The efflux of reversibility of the binding of PMN or tissue
cell-associated moxifloxacin was also studied. Cells were incubated
for
20 min at 37°C with moxifloxacin (extracellular concentration,
5 mg/liter), collected by centrifugation, and rapidly suspended
in
quinolone-free medium. Cell-associated moxifloxacin was quantitated
at
various intervals (1, 5, 10, 20, and 30 min) after removal
of the
extracellular antimicrobial agent. All assays were performed
in
duplicate with PMN from five
donors.
Characterization of moxifloxacin uptake.
Further studies to
elucidate the mechanism of moxifloxacin uptake by PMN were performed as
described previously (11). The importance of cell viability
was studied by using PMN killed by exposure to 10% formalin for 30 min. These cells were washed and then suspended in fresh medium.
Moreover, the influences of environmental temperature, pH, and
metabolic inhibitors were evaluated. The influence of temperature was
examined by comparing antimicrobial uptake at 4 and 37°C. The pH
profiles of moxifloxacin uptake in media preadjusted to different
external pHs (pH 5, 6, 7, and 8) by the addition of 10 N HCl or 10 N
NaOH were measured. An inhibitor of glycolysis (sodium fluoride,
1.5 × 10
3 M) (Sigma Chemical Co., St. Louis, Mo.),
an inhibitor of mitochondrial oxidative metabolism (sodium cyanide,
1.5 × 103 M) (Sigma), a blocker of the proton
gradient (carbonyl cyanide m-chlorophenylhydrazone [CCCP];
1.5 × 105 M) (Sigma), and an uncoupler of oxidative
phosphorylation (2,4-dinitrophenol; 1 × 104 M)
(Sigma) were used as metabolic inhibitors. PMN in HBSS with and without
metabolic inhibitors were incubated for 30 min at 37°C. Moxifloxacin
(final concentration, 5 mg/liter) was then added, and the uptake was
measured as described above.
In a series of experiments, moxifloxacin (extracellular concentration,
5 mg/liter) uptake by human PMN was measured after
the stimulation of
cells with 200 nM phorbol myristate acetate
(PMA; Sigma) and after the
phagocytosis of
S. aureus ATCC 25923
opsonized in 5% pooled
human serum (15 min, 37°C) at a 10/1 ratio
of bacteria to PMN. PMA or
opsonized bacteria were added to PMN
suspensions at the same time as
the antimicrobial agent, and the
uptake was measured as described
above. Controls were always used
to evaluate the effects of inhibitors
and substrates on the fluorescence
of moxifloxacin in cell-free
systems. All assays were performed
in duplicate with PMN from five
different
donors.
Organisms and susceptibility testing.
S. aureus ATCC
25923 was used for the killing assays. Susceptibility studies were
determined by dilution assay. The MICs and minimum bactericidal
concentrations of ciprofloxacin (Bayer AG), ofloxacin (Hoechst AG), and
moxifloxacin for this strain were 0.25, 0.25, and 0.06 mg/liter, respectively.
Intracellular activity of antimicrobial agents.
To evaluate
the intracellular activity of antimicrobial agents, a previously
described method was used (15). Briefly, 0.1 ml of bacterial
suspension preopsonized in 5% pooled human serum (5 × 107 CFU/ml) and 0.1 ml of PMN (5 × 106
per ml) were combined in a series of polypropylene biovials (Beckman) and the vials were incubated in a shaker (50 rpm) for 60 min at 37°C.
After incubation, the mixtures were washed three times with 2.5 ml of
ice-cold phosphate-buffered saline (pH 7.2) by using differential
centrifugation (160 × g; 5 min at 4°C) to remove the
extracellular bacteria. The cells were then suspended in 0.2 ml of RPMI
medium (Sigma). At this time (designated time zero) different
concentrations of the different fluoroquinolones (0.125 to 5 mg/liter)
were added, and the vials were reincubated in a shaker (50 rpm) at
37°C. The vials were removed at time zero (control without
antimicrobial agents) and after 3 h of incubation (control without
antimicrobial agents and samples with antimicrobial agents). Cells were
lysed in distilled water, and samples were diluted and pour plated in
agar. Colonies were counted after 24 h of incubation at 37°C.
The data were expressed as percentages of staphylococci surviving,
compared with the levels in the controls (without antimicrobial agents)
at 3 h. In addition to determining bacterial survival, morphologic
studies were also routinely performed at time zero and after 3 h
of incubation to evaluate the disposition of bacteria (cell associated
or extracellular). Samples (50 µl) were removed from biovials and
were deposited on glass slides. After being stained with Wright stain,
the samples were examined by light microscopy. All assays were
performed in duplicate with PMN from five different donors.
Statistical analysis of data.
Data were expressed as
means ± standard deviations. Differences among groups were
compared by analysis of variance, used to assess statistical
significance at a P value of 
0.05.
| |
RESULTS |
Uptake of moxifloxacin by PMN and tissue-cultured epithelial
cells.
Figure 1 shows the kinetics
of uptake of moxifloxacin by both human PMN and tissue-cultured
epithelial cells. Moxifloxacin uptake by these cells was rapid and
high. With extracellular concentrations of 5 mg/liter, the C/E ratios
were higher than 6 after 1 min of incubation. The kinetics of efflux of
moxifloxacin in both types of cells are also shown in Fig. 1. The
reversibility of binding of moxifloxacin was rapid, with 75 and 88% of
the cell-associated drug being lost by 5 min in PMN and McCoy cells,
respectively.
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FIG. 1.
Moxifloxacin uptake by both human PMN and McCoy cells
and efflux of cell-associated moxifloxacin after the removal of
the extracellular drug (n = 5). The extracellular
concentration was 5 mg/liter.
|
|
The effect of extracellular concentrations of moxifloxacin on uptake by
PMN is presented in Fig.
2.
Cell-associated moxifloxacin
was not saturable at concentrations
ranging from 1 to 50 mg/liter.
Similar results were observed when McCoy
cells were used.
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FIG. 2.
Effect of extracellular concentrations on the
intracellular penetration of moxifloxacin in human PMN (n = 5).
|
|
The effects of environmental temperature, cell viability, and pH on the
uptake of moxifloxacin by human PMN are shown in Table
1. The intracellular penetration of
moxifloxacin was significantly
impaired at 4°C but was not affected
by cell viability. The C/E
values also decreased at pH 5, 6, and 8.
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|
TABLE 1.
Effect of environmental temperature, cell viability, and
external pH on the uptake of moxifloxacin by human PMN
|
|
The effects of different metabolic inhibitors on moxifloxacin uptake by
human PMN are shown in Table
2. Among the
inhibitors
evaluated, sodium fluoride, sodium cyanide, and CCCP
significantly
impaired the intracellular penetration of this quinolone.
The
stimulation of PMN by a membrane activator (PMA) and the
phagocytosis
of opsonized
S. aureus did not affect the
intracellular penetration
by moxifloxacin of PMN (Table
2).
Intracellular activity of moxifloxacin against S. aureus.
The intracellular activity of moxifloxacin against
S. aureus ATCC 25923 compared with those of ciprofloxacin
and ofloxacin was evaluated by a 3-h assay (Fig.
3). At extracellular concentrations of
0.5, 1, and 5 mg/liter, moxifloxacin showed significant intracellular activity against that microorganism compared to a control without antimicrobial agents. This activity was similar to that observed for
ciprofloxacin and ofloxacin.
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FIG. 3.
Intracellular activity of moxifloxacin against S. aureus in human PMN in a 3-h assay (n = 5). Data
are expressed as percentages of intracellular surviving staphylococci
compared to controls without antimicrobial agents (100%). *,
P 0.05 compared with control without antimicrobial
agent. CPX, ciprofloxacin; OFX, ofloxacin; MFX, moxifloxacin.
|
|
| |
DISCUSSION |
The intracellular penetration by moxifloxacin of human PMN and
tissue-cultured epithelial cells was evaluated. At therapeutic extracellular concentrations, moxifloxacin reached intracellular concentrations in PMN 9 or more times higher than extracellular ones.
The C/E ratio of this quinolone was slightly higher than those observed
previously for ciprofloxacin, ofloxacin, sparfloxacin, and other
quinolones (4, 5, 12, 13).
Moxifloxacin also reached high intracellular concentrations in
tissue-cultured epithelial cells. These values are higher than those
observed for ofloxacin, levofloxacin, and lomefloxacin and similar to
those observed for trovafloxacin and sparfloxacin (4, 12-14). The greater uptake of trovafloxacin and sparfloxacin by these cells may be related to the higher hydrophobicity of these molecules, which allows them to cross the cytoplasmic membranes more
easily. This phenomenon, however, would not explain the high accumulation of moxifloxacin, whose hydrophobicity is similar to that
ofloxacin. Since moxifloxacin showed high intrinsic activity against
Chlamydia spp. and since these microorganisms can multiply within epithelial cells, these results could reinforce the potential use of this agent against chlamydial infections (18).
The penetration by moxifloxacin of human PMN was rapid, nonsaturable,
and reversible. In contrast to the case with most quinolones, the
uptake of moxifloxacin by PMN was significantly decreased at acidic pHs
(3, 4, 10, 13). This may be related to the fact that this
quinolone displays a bicyclic amine and a metoxy substituent at the 7 and 8 positions, respectively. The uptake of moxifloxacin was affected
by environmental temperature and some metabolic inhibitors, as has been
described for ofloxacin and BAY Y 3118 (5, 11). The uptake
of other quinolones, such as sparfloxacin and trovafloxacin, was not
affected by any of these parameters (4, 14). The mechanisms
whereby quinolones accumulate in cells are not yet known, and no simple
model can be presented in view of the findings presented above.
Although most data point towards a passive mechanism, some are typical of an active one. Sparfloxacin and trovafloxacin seem to use a passive
mechanism, probably related to their high hydrophobicities, which allow
easier penetration of cell membranes. Other less hydrophobic quinolones, such as ofloxacin, BAY Y 3118, and moxifloxacin, seem partially to require an active process. As has been described previously for other quinolones (4, 14), neither the
phagocytosis of S. aureus nor the stimulation of the cell
membrane affected the intracellular accumulation of moxifloxacin in PMN.
Moxifloxacin showed high intracellular activity against S. aureus, similar to that of ciprofloxacin and ofloxacin. This
activity was dose dependent and probably related to intrinsic activity against the strain used, its ability to concentrate within phagocytes, and the fact that it is not affected by the intracellular environment. Although the intrinsic activity of moxifloxacin was superior to that of
ciprofloxacin and ofloxacin, its intracellular activity was only
slightly higher than theirs. This discrepancy could be related to
different degrees of quinolone activity in the intracellular compartment or to limitations in the method of detecting differences of
activity in compounds offering very high intracellular activity.
In summary, moxifloxacin penetrates phagocytic and nonphagocytic
cells, reaching intracellular concentrations several times higher than
extracellular ones, while it remains active intracellularly in human
PMN. The high intracellular activity of this agent and its broad
spectrum of activity, in addition to the properties observed in this
study, enhance the potential uses of moxifloxacin.
| |
ACKNOWLEDGMENTS |
We thank Patricia Hidalgo and Janet Dawson for preparation of the manuscript.
This study was partially supported by Bayer AG.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Dept. of
Microbiology, School of Medicine, University of Seville, Apdo 914, Seville 41080, Spain. Phone: 34.5.4557448. Fax: 34.5.4377413. E-mail: atomas{at}cica.es.
| |
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Antimicrobial Agents and Chemotherapy, January 1999, p. 12-15, Vol. 43, No. 1
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
