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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
Markus
Müller,1,*
Martin
Brunner,1
Ursula
Hollenstein,2
Christian
Joukhadar,1
Rainer
Schmid,3
Erich
Minar,4
Herbert
Ehringer,4 and
Hans
Georg
Eichler1
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 |
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 curveinfection/area under the concentration-time
curveunaffected 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.
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TEXT |
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 AUClesion and AUCserum (rs = 0.94, P = 0.005), with a mean AUClesion/AUCserum ratio of 0.78 ± 0.08 (range, 0.56 to 1.09). The mean
AUCreference/AUCserum ratio was 0.82 ± 0.08 (range, 0.51 to 0.95; rs = 0.83, P = 0.041), and the mean
AUClesion/AUCreference ratio was 0.99 ± 0.15 (range, 0.61 to 1.69; rs = 0.94; P = 0.005). There was no significant difference between
AUClesion and AUCreference.
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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.
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View this table:
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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
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|
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.
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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.
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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.
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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.
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