1 Institute of Hygiene, University of Heidelberg, Im Neuenheimer Feld 324, D-69120 Heidelberg; 2 Pharmacy Department, University of Heidelberg, Im Neuenheimer Feld 670, D-69120 Heidelberg; 3 Department of Surgery, Krankenhaus Salem, Zeppelinstrasse 1113, D-69121 Heidelberg, Germany
Received 25 June 2002; returned 12 September 2002; revised 16 October 2002; accepted 23 October 2002
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Abstract |
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Patients and methods: Patients with gall-bladder surgery were given levofloxacin 500 mg as a single dose either intravenously (iv) or orally pre-operatively, at the treating physicians decision. Gall-bladder tissue and serum samples were collected, and drug concentrations were determined by HPLC with fluorescence detection. Additionally, all tissue samples underwent routine microbiological diagnostics. MICs for aerobic isolates were determined using the Etest.
Results: A total of 61 patients (48 female, 13 male) were included. The medians of the levofloxacin concentrations in serum were 11.37 mg/L (iv) and 9.65 mg/L (oral), and in gall-bladder tissue they were 15.61 mg/kg (iv) and 17.93 mg/kg (oral). Eleven pathogens were isolated from gall-bladder samples. Post-operative wound infection was observed in two of the 61 patients.
Conclusion: Our data suggest that levofloxacin may be considered for peri-operative prophylaxis in biliary tract surgery.
Keywords: quinolones, pharmacokinetics, pharmacodynamics, cholecystitis, wound infection
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Introduction |
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Levofloxacin is an agent that has good activity in vitro against Gram-positive, Gram-negative and atypical bacteria.3 The drug shows very low protein binding, excellent oral bioavailability and has a large volume of distribution.3 Although drug elimination is primarily renal, drug levels in the biliary fluid are high.4 Levofloxacin might therefore be an ideal candidate for peri-operative prophylaxis in gall-bladder surgery.
The aim of our study was to investigate the penetration of levofloxacin into gall-bladder tissue. This was achieved by determination of tissue and serum concentrations following a single oral or intravenous (iv) administration of levofloxacin 500 mg prior to cholecystectomy.
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Materials and methods |
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A single dose of levofloxacin 500 mg was administered at the treating physicians decision, either iv 3060 min (n = 54) or orally (n = 7) 25 h prior to surgery. The patients received no other antimicrobial prophylaxis peri-operatively, and no other oral medications that interact with levofloxacin. There was no significant difference in the duration of surgery between either group. The time of drug administration was documented, as was the time of tissue and blood sampling.
Blood samples were collected when the tissues were removed. Serum was separated by centrifugation (2772g, 10 min), tissue specimens were wiped gently with dry gauze. Tissue and serum were stored at 25°C until analysis.
Levofloxacin was determined by HPLC with fluorimetric detection.4 Briefly, serum samples spiked with the internal standard ciprofloxacin were prepared, by protein precipitation, with perchloric and phosphoric acid, and methanol. Whenever possible, fatty and connective tissue was separated from gall-bladder tissue. Tissue samples were de-proteinized and homogenized with an Ultra Turrax Disperser (IKA-Werke, Staufen, Germany). After centrifugation (10°C, 7826g, 10 min), 20 µL of supernatant was injected onto the analytical column (Waters Symmetry column C18). The mobile phase consisted of water, methanol, triethylamine and ortho-phosphoric acid (750:250:4:2.5, by vol.). Analysis was performed at room temperature, at a flow rate of 1.5 mL/min. The fluorescence detector (Perkin Elmer, Überlingen, Germany) was set at excitation and emission wavelengths of 295 and 490 nm. The limit of quantification was determined as 0.01 mg/L, the limit of detection was 0.001 mg/L.
All gall-bladder samples were transferred to the microbiological laboratory, cultured aerobically, and MICs of levofloxacin were determined using the Etest (VIVA, Hürth, Germany).
Statistical analysis was carried out using the JMP statistical software package (SAS Institute Inc., NC, USA). All data were log-transformed before statistical analysis. Students t-test (unpaired, two-tailed) was used to determine any significant differences in concentration. Values of P 0.05 were considered significant.
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Results |
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The mean tissue-to-serum ratio of levofloxacin after iv administration was 1.62 ± 1.42, and 1.7 ± 1.12 in the oral group. The tissue concentrations of levofloxacin exceeded the serum levels in 72% (iv) and 71% (oral) of the patients.
Microorganisms were isolated from eight gall-bladder samples in the iv group (n = 54), comprising eight Gram-positive cocci and three Gram-negative bacilli. With the exception of one Enterococcus faecium and one Enterococcus faecalis with MICs of >32 mg/L, all isolates had MICs of 0.5 mg/L (Table 2). None of the samples in the oral group showed bacterial growth. Two of the 61 patients (3.3%) developed a post-operative incisional surgical wound infection. Both had negative bacteriological gall-bladder cultures. No other relationship to either aetiology or levofloxacin concentrations could be found.
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Discussion |
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As it is difficult to determine the AUC of levofloxacin in human tissue, owing to ethical and practical considerations, we took paired plasma and tissue samples and calculated the ratio between them. Our study confirmed the excellent penetration of levofloxacin into the various tissues investigated. Inflammation appeared to have no significant effect on the penetration of levofloxacin into acutely inflamed tissue, which is in accordance with other findings.8 There are small studies, described by Fish & Chow,3 which also determined gall-bladder tissue concentrations. However, as they administered only 100 mg orally they found far lower levels than we did. In comparison with literature data with ofloxacin (400 mg), the relatively high tissue and serum concentrations found in our study could have been caused by the short infusion and sampling time.9 Reasons for the high inter-patient variability of the concentrations could be: the range of infusion duration, time to sampling or underlying disease. However, there was no significant difference in concentration between the iv and the oral group in our study. Our data are not surprising since several studies have demonstrated that drug absorption of levofloxacin after oral administration is almost 100%, resulting in serum levels similar to those after iv dosing. The longer interval between oral intake and tissue sampling reflects the good tissue penetration of levofloxacin. As most physicians still believe that iv administration of levofloxacin yields higher tissue concentrations than the much cheaper alternative, they are reluctant to use the latter.
Regarding pharmacokinetic and pharmacodynamic parameters, it has been demonstrated that the breakpoint for increased probability of successful antimicrobial efficacy is a peak/MIC ratio >10.10 As we were not able to determine the peak, we used the ratio concentration/MIC. For the cultured microorganisms, except the two resistant pathogens, the ratio of 10 was easily reached during sampling. The post-operative wound infection rate was in the range, or lower, of that described in the literature, indicating that the peri-operative prophylaxis was successful.1
Cholecystectomy usually lasts between 20 and 120 min, therefore antibiotics with a serum half-life exceeding this time are suitable for prophylaxis. Since the half-life of levofloxacin is 7 h, this drug is an ideal candidate, even for long operations. Disadvantages include possible patient non-compliance, and facultative drug interactions. The major advantages of oral prophylaxis are lower costs and ease of administration, especially with regard to ambulant surgeries.
In conclusion, we have shown that levofloxacin reached high concentrations, both in serum and gall-bladder tissue, following either oral or iv administration. For antibiotic prophylaxis in biliary tract surgery, these results indicated that both parenteral and oral administration of levofloxacin can be given prior to surgery.
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Acknowledgements |
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Footnotes |
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References |
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