This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Müller, M. Articles by Eichler, H. G. Search for Related Content PubMed PubMed Citation Articles by Müller, M. Articles by Eichler, H. G.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, August 1999, p. 2056-2058, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Penetration of Ciprofloxacin into the Interstitial Space of Inflamed Foot Lesions in Non-Insulin-Dependent Diabetes Mellitus Patients

Departments of Clinical Pharmacology,¹ Internal Medicine I, Division of Infectious Diseases and Chemotherapy,² Medical and Chemical Laboratory Diagnosis,³ and Internal Medicine II, Division of Angiology,⁴ University of Vienna Medical School, Vienna, Austria

Received 20 November 1998/Returned for modification 17 April 1999/Accepted 25 May 1999

	ABSTRACT

Top Abstract Text References

Interstitial ciprofloxacin concentrations were measured by microdialysis in inflamed foot lesions of non-insulin-dependent diabetes mellitus patients following intravenous administration of 0.2 g of ciprofloxacin. Interstitial ciprofloxacin concentrations were significantly lower than corresponding serum concentrations. There was no significant difference in the penetration of ciprofloxacin into inflamed and unaffected tissue (area under the concentration-time curve_infection/area under the concentration-time curve_{unaffected tissue} = 0.99 ± 0.15 [mean ± standard error], n = 6). Thus, inflammation appears to have little or no effect on the penetration of ciprofloxacin into tissue.

	TEXT

Top Abstract Text References

Bacterial foot infections are frequent and serious complications in patients with diabetes mellitus (19) and account for more in-hospital days than any other complication of diabetes mellitus (8). The importance of diabetic foot infections is further underlined by the fact that the necessity of amputations is often determined by the extent of inflammation (12). Thus, immediate antimicrobial chemotherapy is of crucial importance in patients with inflamed diabetic foot ulcers. In some cases, however, empiric therapy fails to be effective, despite documented in vitro susceptibility of the causative pathogen (6).

One of the antibiotic agents that is most frequently employed for diabetic foot infections is ciprofloxacin (19), with total tissue concentrations exceeding corresponding serum concentrations (5, 13). Measurement of tissue concentrations in tissue homogenates (3, 5, 7) or from skin blisters (18, 24), however, may be misleading, since the unbound, interstitial drug concentration which exerts antibacterial activity (11, 15, 20) may be substantially lower than the total tissue concentration (2, 17). Subinhibitory effect site concentrations may, thus, provide an explanation for those cases in which ciprofloxacin failed to eradicate the relevant pathogen, despite documented in vitro susceptibility (6). Moreover, an impaired target site penetration may gain particular importance if the infecting pathogens are located in poorly accessible peripheral sites or if drug penetration is hampered by interstitial diffusion barriers which may develop during inflammatory processes (20, 21).

In the present study, we aimed at measuring ciprofloxacin concentrations in infected diabetic foot ulcers by microdialysis (14, 16, 17), an innovative clinical technique, which allows for the exclusive measurement of unbound drug concentrations in the interstitial space, the relevant target compartment for antimicrobial chemotherapy (20).

The study was approved by the local ethics committee. All patients were given a detailed description of the study, and their written consent was obtained. The study population included six patients (one female, five males) with non-insulin-dependent diabetes mellitus, aged 72 ± 6 years (mean ± standard error [SE]) (weight, 70 ± 4 kg; height, 166 ± 3 cm), who presented with a diabetic foot infection severe enough to require hospital admission and parenteral antibiotic therapy.

To measure interstitial ciprofloxacin concentrations, we employed microdialysis as described previously (2, 17). Two microdialysis probes (CMA 10; CMA, Stockholm, Sweden) were inserted, one into the inflamed lesion close to the border of the primary necrosis and a reference probe into unaffected subcutaneous adipose tissue of the ipsilateral extremity, as described previously (16, 17). Following an in-vivo calibration period (17, 22), ciprofloxacin (Ciproxin; Bayer, Leverkusen, Germany) was administered as a single intravenous (i.v.) dose of 200 mg over 20 min. Ciprofloxacin concentrations in the samples were analyzed by a published high-perfusion liquid chromatography method (10).

All data are presented as means ± SE. Data were analyzed by using model-independent equations with a commercially available computer program (Kinetica; Micropharm International, Champs sur Marne, France). An a priori sample size calculation was performed according to the equation published by Stolley and Strom (23), based on a priori assumptions of  = 0.05 and  = 0.20 and an intraindividual coefficient of variation of 10% for interstitial concentration measurements (14, 16). Thus, a study with six patients had the statistical power to detect a 16% intraindividual difference in area under the concentration-time curves (AUCs). For correlations or comparisons between pharmacokinetic parameters of different compartments, Spearman rank-order correlations (rs) or Mann-Whitney U tests, respectively, were employed, as pharmacokinetic parameters were nonnormally distributed. P < 0.05 was considered the level of significance.

The time versus concentration profiles for ciprofloxacin in serum and in the interstitial space fluid of diabetic ulcer lesions and an unaffected reference tissue, i.e., subcutaneous adipose tissue, are shown in Fig. 1. Pharmacokinetic parameters are given in Table 1. Half-life at  phase for the serum compartment was 309 ± 121 min. There was a significant correlation between AUC_lesion and AUC_serum (rs = 0.94, P = 0.005), with a mean AUC_lesion/AUC_serum ratio of 0.78 ± 0.08 (range, 0.56 to 1.09). The mean AUC_reference/AUC_serum ratio was 0.82 ± 0.08 (range, 0.51 to 0.95; rs = 0.83, P = 0.041), and the mean AUC_lesion/AUC_reference ratio was 0.99 ± 0.15 (range, 0.61 to 1.69; rs = 0.94; P = 0.005). There was no significant difference between AUC_lesion and AUC_reference.

View larger version (18K): [in this window] [in a new window]   FIG. 1.   Time versus ciprofloxacin concentration profiles for serum and interstitial space fluid of inflamed diabetic foot ulcers and unaffected subcutaneous adipose tissue following administration of ciprofloxacin to patients with non-insulin-dependent diabetes mellitus (single i.v. dose of 200 mg over 20 min; n = 6). Results are presented as means ± SE. Time of administration, 0 to 20 min.

View this table: [in this window] [in a new window]   TABLE 1.   Pharmacokinetic parameters for serum and interstitial space fluid of inflamed diabetic foot lesions and unaffected subcutaneous adipose tissue following administration of ciprofloxacin to patients with non-insulin-dependent diabetes mellitusa

Our main objective in the present study was to assess the effect of severe tissue inflammation on the penetration of drug into tissue. The rationale for this study was derived from various reports describing poor clinical outcome in up to 30% of patients suffering from soft-tissue infections (1), which were treated with ciprofloxacin, a drug of choice in polymicrobial soft-tissue infections (19). Some of these cases could be attributed to the persistence of nonsusceptible pathogens or the development of resistance (6, 13). However, in the remainder of cases, ciprofloxacin failed to be effective, despite documented in vitro susceptibility of the causative pathogen. One plausible explanation for these therapeutic failures may be an impaired penetration of ciprofloxacin to the infected target site.

In our experiments, interstitial ciprofloxacin concentrations were significantly lower than corresponding serum concentrations. This result is in line with previous reports on ciprofloxacin (2) and other antimicrobial agents (16, 17) showing that total serum concentrations and serum-derived pharmakokinetic surrogate parameters (9) may not necessarily reflect target site concentrations. The main finding of the present study, however, was that interstitial ciprofloxacin concentrations at the site of inflammation did not differ significantly from concentrations attained at an unaffected site. This does not support the hypothesis that the process of drug distribution may be significantly impaired by the development of diffusion barriers in inflamed tissue (20, 21). Our findings are in contrast to previous reports, mostly on whole-tissue biopsies, showing that ciprofloxacin may preferentially distribute via phagocytes to inflamed sites (4, 7), thereby reaching concentrations at the target site which are severalfold higher than those in the serum (13).

Although our small sample size precludes a detailed analysis, it is noteworthy that an unfavorable outcome, i.e., the requirement of a surgical intervention, was observed in our study in two of three cases (data not shown) in which an isolate was cultured that was not susceptible to ciprofloxacin. Thus, it may be speculated that, at least under the present conditions, biological properties of the relevant bacterial isolate may contribute more to overall clinical outcome than an altered penetration of the antibiotic agent to the target site.

In conclusion, the results of the present study demonstrate that inflammation has little or no effect on target site concentrations of ciprofloxacin which are in the range of free serum concentrations.

	ACKNOWLEDGMENTS

This work was supported by a grant (no. P 12659-MED) from the FWF, the Austrian Science Fund (Fonds zur Förderung der Wissenschaftlichen Forschung).

We are grateful to Edith Lackner and Ines Hertling for their contributions.

	FOOTNOTES

^* Corresponding author. Mailing address: Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna Medical School, Allgemeines Krankenhaus, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: 43-1-40400-2981. Fax: 43-1-40400-2998. E-mail: markus.mueller{at}univie.ac.at.

	REFERENCES

Top Abstract Text References

1.	Arcieri, G., R. August, N. Becker, C. Doyle, E. Griffith, G. Gruenwaldt, A. Heyd, and B. O'Brien. 1986. Clinical experience with ciprofloxacin in the USA. Eur. J. Clin. Microbiol. 5:220-225[Medline].
2.	Brunner, M., U. Hollenstein, S. Delacher, D. Jäger, R. Schmid, E. Lackner, A. Georgopoulos, H. G. Eichler, and M. Müller. 1999. Distribution and antimicrobial activity of ciprofloxacin in human soft tissues. Antimicrob. Agents Chemother. 43:1307-1309[Abstract/Free Full Text].
3.	Burgmann, H., A. Georgopoulos, W. Graninger, R. Koppensteiner, T. Maca, E. Minar, B. Schneider, A. Stümpflen, and H. Ehringer. 1996. Tissue concentration of clindamycin and gentamicin near ischaemic ulcers with transvenous injection in Bier's arterial arrest. Lancet 348:781-783[Medline].
4.	Capecchi, P. L., P. Blardi, A. De Lalla, L. Ceccatelli, L. Volpi, F. L. Pasini, and T. Di Perri. 1995. Pharmacokinetics and pharmacodynamics of neutrophil-associated ciprofloxacin in humans. Clin. Pharmacol. Ther. 57:446-454[Medline].
5.	Dan, M., K. Torossian, D. Weissberg, and R. Kitzes. 1993. The penetration of ciprofloxacin into bronchial mucosa, lung parenchyma, and pleural tissue after intravenous administration. Eur. J. Clin. Pharmacol. 44:101-102[Medline].
6.	Fass, R. J. 1986. Treatment of skin and soft tissue infections with oral ciprofloxacin. J. Antimicrob. Chemother. 18(Suppl. D):153-157[Abstract/Free Full Text].
7.	Fong, I. W., W. H. Ledbetter, A. C. Vandenbroucke, M. Simbul, and V. Rahm. 1986. Ciprofloxacin concentrations in bone and muscle after oral dosing. Antimicrob. Agents Chemother. 29:405-408[Abstract/Free Full Text].
8.	Gibons, G. W., and G. M. Eliopoulous. 1984. Infection of the diabetic foot, p. 97-102. In G. P. Kozak, D. Campbell, and C. S. Hoar (ed.), Management of diabetic foot problems. W. B. Saunders, New York, N.Y.
9.	Hyatt, J. M., P. S. McKinnon, J. S. Zimmer, and J. J. Schentag. 1995. The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome. Clin. Pharmacokinet. 28:143-160[Medline].
10.	Krol, G. J., G. W. Beck, and T. Bentham. 1995. HPLC analysis of ciprofloxacin and ciprofloxacin metabolites in body fluids. J. Pharm. Biomed. Anal. 14:181-190[Medline].
11.	Kunin, C. M., W. A. Craig, M. Kornguth, and R. Monson. 1973. Influence of binding on the pharmacologic activity of antibiotics. Ann. N. Y. Acad. Sci. 26:214-224.
12.	Lassen, N. A. 1973. General discussion on occlusive arterial disease in diabetes mellitus. Scand. J. Clin. Lab. Investig. 128(Suppl.):235-237.
13.	Licitra, C. M., R. G. Brooks, and B. E. Sieger. 1987. Clinical efficacy and levels of ciprofloxacin in tissue in patients with soft tissue infection. Antimicrob. Agents Chemother. 31:805-807[Abstract/Free Full Text].
14.	Lönnroth, P., P. A. Jansson, and U. Smith. 1987. A microdialysis method allowing characterization of intercellular water space in humans. Am. J. Physiol. (Endocrinol. Metab.) 16:E228-E231.
15.	Merrikin, D. J., J. Briant, and G. N. Rolinson. 1983. Effect of protein binding on antibiotic activity in vivo. J. Antimicrob. Chemother. 11:233-238[Abstract/Free Full Text].
16.	Müller, M., R. Schmid, A. Georgopoulos, A. Buxbaum, C. Wasicek, and H. G. Eichler. 1995. Application of microdialysis to clinical pharmacokinetics in humans. Clin. Pharmacol. Ther. 57:371-380[Medline].
17.	Müller, M., O. Haag, T. Burgdorff, A. Georgopoulos, W. Weninger, B. Jansen, G. Stanek, E. Agneter, H. Pehamberger, and H. G. Eichler. 1996. Characterization of peripheral compartment kinetics of antibiotics by in vivo microdialysis in humans. Antimicrob. Agents Chemother. 40:2703-2709[Abstract].
18.	Müller, M., M. Brunner, R. Schmid, E. M. Putz, A. Schmiedberger, I. Wallner, and H. G. Eichler. 1998. Comparison of three different experimental methods for the assessment of peripheral compartment pharmacokinetics in humans. Life Sci. 62:PL227-PL234[Medline].
19.	Peterson, L. R., L. M. Lissack, K. Canter, C. E. Fasching, C. Clabots, and D. N. Gerding. 1989. Therapy of lower extremity infections with ciprofloxacin in patients with diabetes mellitus, peripheral vascular disease, or both. Am. J. Med. 86:801-808[Medline].
20.	Ryan, D. M., O. Cars, and B. Hoffstedt. 1986. The use of antibiotic serum levels to predict concentrations in tissues. Scand. J. Infect. Dis. 18:381-388[Medline].
21.	Seabrook, G. R., C. E. Edmiston, D. D. Schmitt, C. Krepel, D. F. Bandyk, and J. B. Towne. 1991. Comparison of serum and tissue antibiotic levels in diabetes-related foot infections. Surgery 110:671-676[Medline].
22.	Stahle, L., P. Arner, and U. Ungerstedt. 1991. Drug distribution studies with microdialysis. III. Extracellular concentration of caffeine in adipose tissue in man. Life Sci. 49:1853-1858[Medline].
23.	Stolley, P. D., and B. L. Strom. 1986. Sample size calculations for clinical pharmacology studies. Clin. Pharmacol. Ther. 39:489-490[Medline].
24.	Wise, R., and I. A. Donovan. 1987. Tissue penetration and metabolism of ciprofloxacin. Am. J. Med. 82:103-107[Medline].

This article has been cited by other articles:

• Lipsky, B. A., Giordano, P., Choudhri, S., Song, J. (2007). Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin-tazobactam/amoxicillin-clavulanate. J Antimicrob Chemother 60: 370-376 [Abstract] [Full Text]  
• Skhirtladze, K., Hutschala, D., Fleck, T., Thalhammer, F., Ehrlich, M., Vukovich, T., Muller, M., Tschernko, E. M. (2006). Impaired Target Site Penetration of Vancomycin in Diabetic Patients following Cardiac Surgery.. Antimicrob. Agents Chemother. 50: 1372-1375 [Abstract] [Full Text]  
• Langer, O., Karch, R., Muller, U., Dobrozemsky, G., Abrahim, A., Zeitlinger, M., Lackner, E., Joukhadar, C., Dudczak, R., Kletter, K., Muller, M., Brunner, M. (2005). Combined PET and Microdialysis for In Vivo Assessment of Intracellular Drug Pharmacokinetics in Humans. JNM 46: 1835-1841 [Abstract] [Full Text]  
• Joukhadar, C., Dehghanyar, P., Traunmuller, F., Sauermann, R., Mayer-Helm, B., Georgopoulos, A., Muller, M. (2005). Increase of Microcirculatory Blood Flow Enhances Penetration of Ciprofloxacin into Soft Tissue. Antimicrob. Agents Chemother. 49: 4149-4153 [Abstract] [Full Text]  
• Legat, F. J., Krause, R., Zenahlik, P., Hoffmann, C., Scholz, S., Salmhofer, W., Tscherpel, J., Tscherpel, T., Kerl, H., Dittrich, P. (2005). Penetration of Piperacillin and Tazobactam into Inflamed Soft Tissue of Patients with Diabetic Foot Infection. Antimicrob. Agents Chemother. 49: 4368-4371 [Abstract] [Full Text]  
• Zeitlinger, M. A., Erovic, B. M., Sauermann, R., Georgopoulos, A., Muller, M., Joukhadar, C. (2005). Plasma concentrations might lead to overestimation of target site activity of piperacillin in patients with sepsis. J Antimicrob Chemother 56: 703-708 [Abstract] [Full Text]  
• Lipsky, B. A., Berendt, A. R., Deery, H. G., Embil, J. M., Joseph, W. S., Karchmer, A. W., LeFrock, J. L., Lew, D. P., Mader, J. T., Norden, C., Tan, J. S. (2005). Diagnosis and Treatment of Diabetic Foot Infections. J. Am. Podiatr. Med. Assoc. 95: 183-210 [Full Text]  
• Brunner, M., Langer, O., Dobrozemsky, G., Muller, U., Zeitlinger, M., Mitterhauser, M., Wadsak, W., Dudczak, R., Kletter, K., Muller, M. (2004). [18F]Ciprofloxacin, a New Positron Emission Tomography Tracer for Noninvasive Assessment of the Tissue Distribution and Pharmacokinetics of Ciprofloxacin in Humans. Antimicrob. Agents Chemother. 48: 3850-3857 [Abstract] [Full Text]  
• Muller, M., dela Pena, A., Derendorf, H. (2004). Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective Agents: Distribution in Tissue. Antimicrob. Agents Chemother. 48: 1441-1453 [Full Text]  
• Swoboda, S., Oberdorfer, K., Klee, F., Hoppe-Tichy, T., von Baum, H., Geiss, H. K. (2003). Tissue and serum concentrations of levofloxacin 500 mg administered intravenously or orally for antibiotic prophylaxis in biliary surgery. J Antimicrob Chemother 51: 459-462 [Abstract] [Full Text]  
• Brunner, M., Stass, H., Moller, J.-G., Schrolnberger, C., Erovic, B., Hollenstein, U., Zeitlinger, M., Eichler, H. G., Muller, M. (2002). Target Site Concentrations of Ciprofloxacin after Single Intravenous and Oral Doses. Antimicrob. Agents Chemother. 46: 3724-3730 [Abstract] [Full Text]  
• Delacher, S., Derendorf, H., Hollenstein, U., Brunner, M., Joukhadar, C., Hofmann, S., Georgopoulos, A., Eichler, H. G., Muller, M. (2000). A combined in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate target site pharmacodynamics of antibiotics in humans. J Antimicrob Chemother 46: 733-739 [Abstract] [Full Text]  
• Frossard, M., Joukhadar, C., Erovic, B. M., Dittrich, P., Mrass, P. E., Van Houte, M., Burgmann, H., Georgopoulos, A., Müller, M. (2000). Distribution and Antimicrobial Activity of Fosfomycin in the Interstitial Fluid of Human Soft Tissues. Antimicrob. Agents Chemother. 44: 2728-2732 [Abstract] [Full Text]  

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Müller, M. Articles by Eichler, H. G. Search for Related Content PubMed PubMed Citation Articles by Müller, M. Articles by Eichler, H. G.