JAC Advance Access originally published online on February 24, 2005
Journal of Antimicrobial Chemotherapy 2005 55(4):511-517; doi:10.1093/jac/dki059
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Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin) against extracellular and intracellular infection by Listeria monocytogenes and Staphylococcus aureus in J774 macrophages
Unité de pharmacologie cellulaire et moléculaire, Université catholique de Louvain, Brussels, Belgium
* Corresponding author. Tel: +32-2-764-73-78; Fax: +32-2-764-73-73; Email: vanbambeke{at}facm.ucl.ac.be
Received 16 September 2004; returned 23 October 2004; revised 27 December 2004; accepted 14 January 2005
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Abstract |
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Objectives: Quinolones accumulate in eukaryotic cells and show activity against a large array of intracellular organisms, but systematic studies aimed at examining their pharmacodynamic profile against intracellular bacteria are scarce. The present work aims at comparing intracellular-to-extracellular activities in this context.
Methods: We assessed the activities of ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin against the extracellular (broth) and intracellular (infected J774 macrophages) forms of Listeria monocytogenes (cytosolic infection) and Staphylococcus aureus (phagolysosomal infection) using a range of clinically meaningful extracellular concentrations (0.06–4 mg/L).
Results: All four quinolones displayed concentration-dependent bactericidal activity against extracellular and intracellular L. monocytogenes and S. aureus for extracellular concentrations in the range 1–4-fold their MIC. Compared at equipotent extracellular concentrations, intracellular activities against L. monocytogenes were roughly equal to those that were extracellular, but were 50–100 times lower against S. aureus. Because quinolones accumulate in cells (ciprofloxacin, 
3 times; levofloxacin, 5 times; garenoxacin, 10 times, moxifloxacin, 13 times), these data show that, intracellularly, quinolones are 5–10 times less potent against L. monocytogenes (P=0.065 [ANCOVA]), and at least 100 times less potent (P < 0.0001) against S. aureus. Because of their lower MICs and higher accumulation levels, garenoxacin and moxifloxacin were, however, more active than ciprofloxacin and levofloxacin when compared at similar extracellular concentrations.
Conclusions: Quinolone activity is reduced intracellulary. This suggests that either only a fraction of cell-associated quinolones exert an antibacterial effect, or that intracellular activity is defeated by the local environment, or that intracellular bacteria only poorly respond to the action of quinolones.
Keywords: cellular pharmacodynamics , cellular pharmacokinetics , bactericidal activity , accumulation
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Introduction |
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Effective treatment of intracellular infections remains a challenge in spite of the availability of several classes of antibiotics capable of entering and accumulating in eukaryotic cells. In this context, quinolones are considered as potentially ideal drugs since they combine a number of desirable properties, such as a high bactericidal potency,1,2 a fair accumulation in phagocytes3 and an excellent diffusibility throughout subcellular compartments.4 Accordingly, quinolones have been found to be effective in several types of intracellular infections disregarding the subcellular localization of the organisms, such as those caused by Listeria monocytogenes (cytosol),5–8 Legionella pneumophila (phagosomes)4,9 or Staphylococcus aureus (phagolysosomes).10–13 Systematic comparisons of extracellular and intracellular activities, however, are rarely reported. Nevertheless, recent studies with intracellular L. monocytogenes and THP-1 macrophages have shown that cell-associated ciprofloxacin and moxifloxacin are considerably less active against intracellular L. monocytogenes than could be anticipated on the basis of their cellular accumulation.8 This has triggered us to enlarge the scope of our studies (i) by examining another Gram-positive organism, namely S. aureus, (ii) by expanding the study to two additional quinolones based on their wide clinical usage (levofloxacin) and potential interest for specific activity against Gram-positive organisms (garenoxacin). We examine here the relationship between cell accumulation and intracellular activity of these four quinolones in cells exposed to clinically meaningful drug concentrations.
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Materials and methods |
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Bacterial strains and measurement of extracellular activity of antibiotics
We used a haemolysin-producing strain (EGD serotype 1/2a) for L. monocytogenes (obtained from P. Berche, Laboratoire de Microbiologie, Faculté de Médecine, Necker, Paris, France), and a methicillin-susceptible strain of S. aureus (ATCC 25923) obtained from the American Tissue Cell Collection (Manassas, VA, USA). MICs and MBCs were determined in tryptic soy broth (L. monocytogenes) or Mueller–Hinton broth (S. aureus) as in our previous publications.8,13 MICs for S. aureus were also determined in the same medium adjusted to pH 5. For killing-curve experiments, bacteria in logarithmic growth were resuspended at a density of 106 cfu/mL in broth. The number of viable bacteria was determined after incubation at 37 °C with antibiotics for suitable periods of time (up to 24 h) by plate assay with appropriately diluted samples.
Cell infection and measurement of intracellular activity
All experiments were conducted with J774 macrophages, a continuous reticulosarcoma cell line of murine origin,14 following exactly the procedures described earlier.13,15 In brief, infection was achieved by incubating macrophages with bacteria for 1 h [5 cfu/cell for L. monocytogenes and 0.5 cfu/cell for S. aureus (human serum-opsonized)]. Extracellular bacteria were eliminated by washing in PBS (for S. aureus, a first washing was made by bathing the cells for 1 h in a medium supplemented by 50 mg/L gentamicin). For experiments in which infected cells were maintained in culture 24 h post-phagocytosis, gentamicin was added at its MIC (1 mg/L for L. monocytogenes and 0.5 mg/L for S. aureus) during the whole incubation period to prevent the extracellular growth of released bacteria, and the ensuing fast acidification of the medium and subsequent loss of cell viability.13
Cellular accumulation of quinolones
Infected and uninfected cells were collected and analysed following the general procedure described earlier.16
In brief, cell sheets were washed three times with ice-cold PBS and collected by scraping in 0.1 M glycine-NaOH pH 3 buffer for fluorimetric determinations, or in distilled water for radiochemical assays. Cell-associated ciprofloxacin, moxifloxacin and levofloxacin were assayed by fluorimetry (
exc=275, 298 and 298 nm; em=450, 504 and 500 nm respectively), as previously described.8
Garenoxacin was assayed by scintillation counting using 14C-labelled drug. These methods have been fully validated with respect to specificity and reproducibility, and linearity under our conditions of assay. All drug contents in cell samples were expressed by reference to the cell protein (assayed by the Folin-ciocalteu/biuret method),17
and the apparent cellular-to-extracellular concentration ratio calculated using a conversion factor of 3.08 µL of cellular volume per mg cell protein, as determined for J774 macrophages by the sucrose/urea partition method.16
Data analyses
Curve-fitting and statistical analyses [one way analysis of variance (ANOVA), analysis of covariance (ANCOVA) and Tukey's Honestly Significant Difference (HSD) tests (for differences between groups with a confidence interval of 95%)] were made using Prism version 4.02 and InStat version 3.00 (GraphPad Software, San Diego, CA, USA), or XLSTAT version 6.0 (Addinsoft SARL, Paris, France).
Materials
Ciprofloxacin (potency, 85.0%) and moxifloxacin (potency, 91%) were obtained as laboratory samples for microbiological evaluation from Bayer AG (Leverkusen, Germany), and garenoxacin (purity 99.8%) from Bristol Myers Squibb, New Brunswick, CT, USA. Levofloxacin and gentamicin were procured as Tavanic and Geomycin, the registered commercial products available for intravenous administration in Belgium. 14C-labelled garenoxacin (0.8 MBq/mg; 98.3% of radiochemical purity) was obtained from the Bristol Myers Squibb Research Institute, Princeton, NJ, USA. Cell culture media and fetal calf serum (FCS) were purchased from Gibco Biocult (Paisley, Scotland, UK). Human serum for opsonization of S. aureus was obtained from healthy volunteers as pooled samples stored as aliquots at –80 °C until use. Unless stated otherwise, all other reagents were of analytic grade and purchased form E. Merck AG (Darmstadt, Germany) or from Sigma-Aldrich (St Louis, MO, USA).
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Results |
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Determination of MIC and MBC
Table 1 shows the MIC and MBC values of the four quinolones under investigation against the two bacterial strains used in this study. Bearing in mind the results obtained at pH 7, the four drugs were less active against L. monocytogenes than S. aureus, and levofloxacin or ciprofloxacin were in all cases less active than moxifloxacin and garenoxacin. All MICs, however, were still lower than the maximal serum concentrations observed in healthy volunteers (Cmax, see Table 1). On investigating the extracellular activities of quinolones, we observed that the MIC/MBC ratios were between 2 and 8, demonstrating the bactericidal activity of these drugs. MICs and MBCs measured at acid pH against S. aureus (to mimic the conditions prevailing in lysosomes)18 were 2 (ciprofloxacin) to 33 (garenoxacin) times higher than at pH 7 but still lower than Cmax.
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Extracellular and intracellular activities of quinolones
The activity of the four quinolones was then examined against extracellular and intracellular forms of L. monocytogenes and S. aureus. In the first series of experiments (Figure 1), all drugs were compared at a fixed post-phagocytosis time point (5 h for L. monocytogenes, 24 h for S. aureus; these times were selected based on previous observations showing that intracellular L. monocytogenes grows after a lag period of about 1 h only, whereas this lag period extends for up to 8 h for S. aureus)8,13 and at the same extracellular concentration (4 mg/L). We observed that the growth of L. monocytogenes was similar in broth and in infected macrophages, whereas that of S. aureus was significantly lower intracellularly as compared with broth. On examining the extracellular activities of quinolones, we see that these were only slightly bactericidal towards L. monocytogenes (achieving an inoculum reduction from about 1.2 log for ciprofloxacin, 1.5 log for levofloxacin and garenoxacin, and about 2 log for moxifloxacin (these differences were statistically significant). In contrast, they were highly bactericidal against S. aureus, achieving an inoculum reduction of about 4 log for ciprofloxacin and levofloxacin, and of 4.5 log for moxifloxacin and garenoxacin (these differences were statistically significant). However, when considering activities against intracellular bacteria, a global analysis of the results showed that these were always significantly lower than what was seen against extracellular bacteria, the difference being, however, smaller for L. monocytogenes (especially for moxifloxacin) than for S. aureus. Comparison between drugs showed a ranking (with statistically significant differences) of ciprofloxacin < levofloxacin < garenoxacin < moxifloxacin for L. monocytogenes, and of ciprofloxacin = levofloxacin < moxifloxacin = garenoxacin for S. aureus.
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In the next series of experiments, we examined the influence of varying the concentrations of the quinolones. We concentrated on garenoxacin, for which no previous data were available, and used levofloxacin as a comparator (the results of similar studies with ciprofloxacin and moxifloxacin have been reported previously8,13,15 ). Figure 2 shows the change in bacterial counts observed in broth (left panels) and in cells (right panels) at 5 h for L. monocytogenes and at 24 h for S. aureus when exposed to drug concentrations up to 4 mg/L. On examining L. monocytogenes first (upper panels), we see that activity was concentration-dependent both extracellularly and intracellularly over the whole range investigated. Garenoxacin was significantly more effective than levofloxacin, reflecting their differences of MIC. In sharp contrast, activity against S. aureus developed in a narrow concentration range (0–0.25 mg/L), after which no or only little gain was noticeable whether in broth or in cells. Interestingly, the ratio of intracellular to extracellular activities remained almost constant at all concentrations above 0.25 mg/L. The difference between garenoxacin and levofloxacin was not statistically significant when examined globally (ANCOVA), although the plateau of activity in broth was obtained at a two-fold lower concentration for garenoxacin compared with levofloxacin, reflecting their differences of MIC.
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In the last series of experiments, we examined the time-dependency of the killing activities of the quinolones towards L. monocytogenes and S. aureus, again concentrating on garenoxacin and using levofloxacin as comparator. Figure 3 shows that there was no significant difference in extracellular and intracellular growth of L. monocytogenes in controls, as previously reported.19 In contrast, S. aureus grew significantly more slowly intracellularly, with a definite lag period of at least 5 h, as also observed previously.13 The Figure also shows that the activity of the two quinolones was time-dependent with, however, a slower rate for intracellular as compared with extracellular bacteria.
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Accumulation of quinolones in uninfected and infected cells
Table 2 compares the apparent cellular accumulations of the four quinolones in both uninfected and infected cells, under the conditions used for the experiments described in Figure 1. Marked differences were observed among drugs, with the following ranking: ciprofloxacin < levofloxacin < garenoxacin <moxifloxacin. Differences between data obtained at 5 and 24 h in uninfected cells were either not significant (ciprofloxacin, moxifloxacin) or small (levofloxacin, garenoxacin), indicating that an apparent steady state had been reached or was close to being obtained. Differences between uninfected and infected cells were also not significant (ciprofloxacin, garenoxacin) or small (levofloxacin, moxifloxacin).
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Discussion |
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It has been known for a long time that quinolones accumulate in eukaryotic cells,4,10,12,16 and this property has, generally speaking, been considered an important asset as far as activity against intracellular organisms is concerned.8,13,20,21 Surprisingly, however, few studies have directly compared the extracellular and intracellular activities of quinolones in models where (i) the influence of time and concentration can be fully assessed; (ii) the results can be directly correlated with levels of cellular accumulation. Together with recent studies by our group,8,13,15 the experiments reported here are part of a systematic approach in this direction.
Two main conclusions emerge from the present data. First, whereas quinolones appear to be concentration-dependent drugs for L. monocytogenes (whether extra- or intracellularly), this seems not to be the case for S. aureus. However, closer examination of the data suggests that concentration-dependency is observed for both organisms but may be limited to a range of concentrations that span from the MIC up to a maximum of 4 times the MIC. Future studies will need to explore these limits in more detail, perhaps by using strains of S. aureus with higher MICs.
Second, and surprisingly, our data show that the intracellular activity of quinolones against both L. monocytogenes and S. aureus is only a fraction of what could be anticipated if their apparent accumulation in cells is taken into account. Thus, whereas all quinolones used in the present study show higher concentrations in cells compared with medium, all are also characterized by somewhat weaker activity against intracellular L. monocytogenes and drastically reduced activity against intracellular S. aureus in comparison with broth. To substantiate this conclusion further, we used all data generated in this study—pooling them with a series of data obtained previously with the same models—13,15 to compare activities in broth and in cells after normalization of concentrations for differences in MIC (Figure 4). Thus, the activity of quinolones against intracellular L. monocytogenes was lower (five- to 20-fold depending on the concentration) than against the extracellular forms, but the global difference was at the limit of statistical significance (P=0.065 by ANCOVA). For S. aureus, the difference is at least 100-fold and was highly significant. Several factors could account for such a loss of activity. For instance, we know that intracellular L. monocytogenes is surrounded by a thick layer of actin that confers motility to the bacteria,22,23 but could also partially protect it from antibiotics. For S. aureus, the slow intracellular growth of this organism may make it poorly sensitive to quinolones, as suggested from studies in broth with slowly growing bacteria.24–26 (This could result from the decreased expression of quinolone targets as recently found for topoisomerase IV).27 Part of the drastic reduction in activity against intracellular S. aureus could also be due to the acidic environment of phagolysosomes, which is unfavourable to their activity (see Table 1). Moreover, we have to consider that we do not know with certainty where the drugs are located intracellularly. Whereas in fractionation studies the bulk of cell-associated ciprofloxacin is recovered in the cytosol,15 we cannot exclude a binding to proteins28 or lipids,29 or simply the formation of complexes with ions.30 These various, non-mutually exclusive hypotheses are now open to experimental evaluation.
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The present data may have important implications for the correct assessment of existing and newly developed quinolones. First, they stress the importance of comparing extracellular and intracellular activities of antibiotics in a systematic fashion and using appropriate models, so as to refrain from simplistic conclusions such as those equating cell accumulation and activity (or denying a relationship between them). In this context, the selection of ‘best candidates’, within a given drug class, must be based on both MIC and cellular accumulation considerations. This is exemplified here by the behaviour of garenoxacin and moxifloxacin, which always showed larger intracellular activity in comparison with levofloxacin and ciprofloxacin. Finally, it is essential to perform experimental confirmation studies at clinically meaningful concentrations, since doing otherwise may lead to erroneous conclusions as far as the potential clinical applications are concerned.
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Footnotes |
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Present address. Department of Clinical Microbiology, University Hospital ‘Lozano Blesa’, Zaragoza, Spain. 
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Acknowledgements |
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We thank M. C. Cambier for expert technical assistance. C. S. was the recipient of a postdoctoral fellowship from the Belgian Fonds National de la Recherche Scientifique Médicale (fellowship no. 3.4549.00) and F. V. B. is Chercheur Qualifié of the Belgian Fonds National de la Recherche Scientifique. This work was supported by the Belgian Fonds National de la Recherche Scientifique Médicale (grants nos 3.4549.00 and 3.4542.02) and by a Grant-in-aid from the Bristol Myers Squibb Research Institute.
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H. A. Nguyen, J. Grellet, V. Dubois, M.-C. Saux, and C. Quentin Factors compromising the activity of moxifloxacin against intracellular Staphylococcus aureus J. Antimicrob. Chemother., April 1, 2007; 59(4): 755 - 758. [Abstract] [Full Text] [PDF]
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J. Le Carrou, M. Laurentie, M. Kobisch, and A. V. Gautier-Bouchardon Persistence of Mycoplasma hyopneumoniae in Experimentally Infected Pigs after Marbofloxacin Treatment and Detection of Mutations in the parC Gene. Antimicrob. Agents Chemother., June 1, 2006; 50(6): 1959 - 1966. [Abstract] [Full Text] [PDF]
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H. A. Nguyen, J. Grellet, D. Paillard, V. Dubois, C. Quentin, and M.-C. Saux Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte model J. Antimicrob. Chemother., May 1, 2006; 57(5): 883 - 890. [Abstract] [Full Text] [PDF]
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M. Barcia-Macay, C. Seral, M.-P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics against Staphylococcus aureus in a Model of THP-1 Macrophages Antimicrob. Agents Chemother., March 1, 2006; 50(3): 841 - 851. [Abstract] [Full Text] [PDF]
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