1 Department of General Surgery, University of Heidelberg, Im Neuenheimer Feld 110, D-69120 Heidelberg; 2 Institute of Hygiene, University of Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg; 3 Pharmacy Department, University of Heidelberg, Im Neuenheimer Feld 670, D-69120 Heidelberg, Germany
Received 13 November 2003; returned 16 January 2004; revised 31 January 2004; accepted 6 February 2004
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Abstract |
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Patients and methods: Twenty-eight patients undergoing GI-tract surgery received 400 mg of moxifloxacin twice pre-operatively [eight patients orally (po) and 20 patients intravenously (iv)], of whom 22 completed the study. Mucosal tissues (three stomach, three small bowel and 16 colon) and serum samples were collected and moxifloxacin concentrations were measured by HPLC.
Results: The highest tissue concentrations were detected in the mucosa of the stomach (10.9 ± 5.1 mg/kg), followed by colon mucosa (7.8 ± 7.1 mg/kg after iv; 6.6 ± 3.6 mg/kg after po) and small bowel mucosa (5.4 ± 0.5 mg/kg). The tissue-to-serum ratio of moxifloxacin was 2.0 ± 1.6 in the small bowel mucosa, 5.8 ± 3.4 and 6.8 ± 3.9 in the colon mucosa after po and iv administration, respectively, and 9.7 ± 5.7 in the stomach mucosa.
Conclusion: Moxifloxacin penetrates into and accumulates in the mucosa of the stomach, small bowel and colon. The clinical applicability of moxifloxacin administration for bacterial GI-tract infections should be investigated in controlled trials.
Keywords: methoxyquinolone, bacterial infection, tissue concentrations
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Introduction |
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Since moxifloxacin has good antimicrobial activity against both anaerobic and aerobic bacteria, the aim of the study was to investigate the penetration and accumulation of the drug in different tissues of the alimentary tract.
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Materials and methods |
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Exclusion criteria, other than the general exclusion criteria in accordance with the manufacturers instructions, were (i) administration of moxifloxacin within 7 days before surgery, (ii) known allergy to fluoroquinolones, (iii) history of or present inflammatory bowel disease, and (iv) presence of sigma diverticulitis.
The protocol was approved by the Ethics Committee of the University of Heidelberg, and written informed consent was obtained from all patients.
Analytical method
Moxifloxacin concentration was determined by HPLC with fluorometric detection, as described by Stass & Dalhhoff.3 Briefly, serum samples spiked with the internal standard levofloxacin (Aventis Pharmaceuticals, Germany) were prepared by protein precipitation using a precipitation reagent consisting of acetonitrile and orthophosphoric acid 0.1 M (9:1 v/v). Tissue samples were homogenized with an Ultra Turrax disperser and then deproteinized with the precipitation reagent. After centrifugation (10°C, 7826g, 10 min), 20 µL of supernatant was injected into the analytical column (Purospher RP-18e column, 5 µm, 250 x 4 mm). The mobile phase consisted of an aqueous solution of 0.01 M tetrabutyl ammonium sulphate and 0.05 M sodium dihydrogen phosphate (a, pH 3.0) and acetonitrile. Moxifloxacin and the internal standard were eluted using a gradient elution method as described previously in detail.3 The analysis was performed at 50°C. The fluorescence detector (Perkin-Elmer, Germany) was set at excitation and emission wavelengths of 296 and 504 nm, respectively. The standard curve with five concentrations of moxifloxacin (serum/tissue) was linear over the usable concentration range of 0.054 mg/L. Calibration standards for tissues were prepared as described previously.4 The analytical method provided good validation data for accuracy and precision (QC samples). The inter-day coefficients of variation (0.1, 1.0, 4.0 mg/L) were <5%. The limit of quantification was determined as 0.05 mg/L. A cross-validation to external controls (Bayer AG, Germany) was carried out successfully.
Statistics
Data are expressed as mean ± standard deviation (S.D.), unless indicated otherwise. All statistical analysis was performed using SPSS for Windows, release 10 (SPSS Inc., Chicago, IL, USA). For comparison of drug concentrations for different forms of administration and at different sampling sites, the MannWhitney U test was used.
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Results |
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Serum concentrations were obtained after intravenous administration in 14 patients and gave mean moxifloxacin concentrations of 0.92 ± 0.98 mg/L at 17.5 h (1055 ± 194 min) after the first administration and 1.58 ± 1.08 mg/L at 5.5 h (327 ± 155 min) after the second dose. The concentrations in the po subgroup were slightly lower, being 0.69 ± 0.49 mg/L at 17 h (1040 ± 395 min) after the first dose and 1.27 ± 0.77 mg/L at 4 h (250 ± 66 min) after the second dose. However, these differences in concentration were not statistically significant.
The highest tissue concentration was seen in the stomach mucosa (10.9 ± 5.1 mg/kg), followed by the colon mucosa (7.8 ± 7.1 mg/kg after iv administration, 6.6 ± 3.6 mg/kg after po administration) and the small bowel mucosa (5.4 ± 0.5 mg/kg) (Figure 1). The tissue-to-serum ratio of moxifloxacin was 2.0 ± 1.6 in the small bowel mucosa, 5.8 ± 3.4 and 6.8 ± 3.9 in the colon mucosa after po and iv administration, respectively, and 9.7 ± 5.7 in the stomach mucosa (Figure 1). In the control patients neither blood nor tissue analysis revealed detectable levels of moxifloxacin, confirming our analytical settings.
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Discussion |
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The highest tissue concentrations of moxifloxacin were found in the mucosa of the stomach (10.9 ± 5.1 mg/kg); these were up to 9.7 times higher than the serum concentrations, indicating accumulation of the drug in these tissues. The lowest mucosal tissue concentrations were observed in the small bowel (5.4 ± 0.5 mg/kg), which nonetheless exceeded the MIC90 for most anaerobic bacteria (2 mg/L).6
Serum concentrations of moxifloxacin determined 17 h after the first drug administration were within the range of those found by Stass & Kubitza,7 whereas moxifloxacin serum concentrations measured
5 h after the second administration were somewhat lower than expected, most likely due to serum dilution effects, i.e. iv fluid application and blood loss during surgery.
Our observation of high tissue concentrations in the alimentary tract might open a new perspective for the potential use of moxifloxacin in bacterial infections of the alimentary tract. Since a recent clinical study showed that a moxifloxacin-based triple therapy resulted in 90% eradication of Helicobacter pylori8,9 and high moxifloxacin tissue concentrations were found in the stomach, this drug could be considered as a candidate in the eradication schema for H. pylori.
Although the comparison of moxifloxacin tissue concentrations does not provide evidence that a high and effective concentration is also present at the site of infection or site of contamination, we nonetheless hypothesize that effective drug levels might be present in the extracellular luminal environment in the lower GI tract. This is also supported by data from Edlund et al.,1 who demonstrated high moxifloxacin levels in the faeces, well above the MIC for many groups of microorganisms in the normal microflora.
The potential role of moxifloxacin for the treatment of bacterial infections of the alimentary tract such as sigma diverticulitis and bacterial gastroenteritis is promising and should therefore be further investigated in controlled clinical trials.
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Acknowledgements |
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Footnotes |
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References |
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