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Antimicrobial Agents and Chemotherapy, May 1999, p. 1307-1309, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Distribution and Antimicrobial Activity of
Ciprofloxacin in Human Soft Tissues
Martin
Brunner,1
Ursula
Hollenstein,2
Simon
Delacher,1
Dorothea
Jäger,1
Rainer
Schmid,3
Edith
Lackner,1
Apostoulos
Georgopoulos,2
Hans Georg
Eichler,1 and
Markus
Müller1,*
Department of Clinical
Pharmacology,1 Department of Internal
Medicine I, Division of Infectious Diseases and
Chemotherapy,2 and Department of
Clinical and Laboratory Investigation,3
University of Vienna Medical School, Vienna, Austria
Received 11 August 1998/Returned for modification 3 January
1999/Accepted 3 March 1999
 |
ABSTRACT |
Interstitial ciprofloxacin concentrations in soft tissues were
measured by microdialysis following intravenous administration of 200 mg to each of eight healthy volunteers. Interstitial ciprofloxacin concentrations were significantly lower than corresponding total serum
drug concentrations; the interstitium-to-serum concentration ratios
ranged from 0.55 to 0.73. An in vitro simulation based on interstitial
pharmacokinetics showed a substantially lower antimicrobial activity
than did the simulation based on serum pharmacokinetics. Thus,
ciprofloxacin concentrations at the site of effect may be subinhibitory
although effective concentrations are attained in serum.
| |
TEXT |
Antibiotic dosing is usually
tailored to obtain serum drug concentrations that exceed the minimum
concentration required to inhibit bacterial growth (i.e., MIC) for the
infecting microorganism. However, as the majority of infections are
located in peripheral tissues, it is considered more appropriate to
study the process of drug penetration of the target site, rather than
merely assessing serum pharmacokinetics (7).
One antibiotic frequently employed in peripheral compartment infections
is ciprofloxacin. The rationale for administering ciprofloxacin to
individuals with these conditions relies on biopsy studies describing a
favorable tissue penetration of ciprofloxacin (1, 13).
Measurement of total tissue drug concentrations, however, may be
misleading since only the free, interstitial drug concentration exerts
antibacterial activity in most cases (12, 14). Unbound-drug
concentrations may be substantially lower than total tissue drug
concentrations and may even be severalfold below corresponding
concentrations in serum (15). In light of these
considerations, subinhibitory concentrations of ciprofloxacin in the
sites of effect may provide an explanation for those cases in which
ciprofloxacin failed to eradicate the relevant pathogen despite
documented in vitro susceptibility (9).
The present study therefore was undertaken to measure unbound
ciprofloxacin concentrations in the interstitial space of skeletal muscle and subcutaneous adipose tissue by means of microdialysis in
healthy volunteers (15).
The study was approved by the local ethics committee. All volunteers
were given a detailed description of the study, and their written
consent was obtained. The study was performed in accordance with the
Declaration of Helsinki and the Good Clinical Practice Guideline of the
European Commission. Eight healthy, drug-free, male volunteers of
normal weight (mean ± standard error [SE], 76 ± 4 kg) and
ranging from 28 to 37 years old were enrolled in the study.
For the measurement of free interstitial ciprofloxacin concentrations
we employed in vivo microdialysis as described previously (15-17). Two microdialysis probes (both CMA 10; CMA,
Stockholm, Sweden) were inserted, one into the musculus vastus medialis
and one into the subcutaneous adipose layer of the thigh, and perfused with Ringer's solution at a flow rate of 1.5 µl/min. After a 30-min baseline sampling period, in vivo probe calibration was performed as
described previously by a retrodialysis procedure (21) with a perfusion medium containing 30 µg of ciprofloxacin/ml for 30 min
(15, 16). Following a 30-min washout period, ciprofloxacin (Ciproxin; Bayer, Leverkusen, Germany) was administered as a single intravenous dose of 200 mg over 10 min.
The unbound ciprofloxacin fraction in serum was obtained by employing
Ultrafree-MC Centrifugal Filter Units with a molecular mass cutoff of
10 kDa (Millipore Corporation). One hundred fifty microliters of serum
was placed into the Ultrafree-MC Centrifugal Filter Units and
centrifuged at 14,000 × g and 37°C for 20 min. Ciprofloxacin concentrations in microdialysates and serum were analyzed
by a published high-performance liquid chromatography method
(11). In order to generate a pharmacodynamic model which allows for the description of the antibacterial activity of
ciprofloxacin in serum and the interstitial-space fluid, the in vivo
time-concentration profile of ciprofloxacin was simulated in vitro. For
that purpose, Mueller-Hinton broth which was kept in a water bath at
37°C was inoculated with select bacteria at an approximate
concentration of 108 CFU/ml. Subsequently, the
time-ciprofloxacin concentration profiles obtained in vivo were
simulated in vitro by changing ciprofloxacin concentrations in broth as
described previously (4, 18). After vortexing of the culture
tube, 40-µl samples were withdrawn at select time points and serially
diluted with 0.9% sodium chloride. Twenty-microliter samples obtained
at each dilution step were then plated onto agar plates and incubated
at 37°C for 18 to 26 h. Subsequently, the colonies were counted
and back-extrapolated to the original volume.
Data are presented as means ± SEs. Interstitial concentrations
were calculated from dialysate concentrations as described previously
(15, 16). Individual data sets were fitted by a commercially available computer program (Topfit 2.0; Gustav
Fischer, Stuttgart, Germany) according to a two-compartment model
for serum values and according to a one-compartment model for tissues
as described previously (16). The ratios for the areas
under the concentration-time curves (AUCs)
AUCmuscle/AUCfree serum and
AUCsubcutaneous/AUCfree serum were
calculated as a measure of drug penetration into the peripheral compartments.
The time-concentration profiles for total ciprofloxacin concentrations
in serum and in the interstitial-space fluid of skeletal muscle and
subcutaneous adipose tissue are shown in Fig.
1. The maximum concentrations were
1.36 ± 0.09, 0.73 ± 0.80, and 0.86 ± 0.20 µg/ml,
and the AUC values were 155.7 ± 9.9, 110.5 ± 16.7, and
85.1 ± 15.2 µg · min · ml
1,
respectively. The half-life at 
phase was 98 ± 1 min for
ciprofloxacin in serum, and the times to maximum concentration of the
drug in skeletal muscle and in subcutaneous adipose tissue
were 19 ± 3 and 17 ± 5 min, respectively. The
mean AUCmuscle/ AUCfree serum ratio
was 1.23 ± 0.24, and the mean
AUCsubcutaneous/AUCfree serum ratio was
0.89 ± 0.16. Time-kill curves for the in vitro simulation model
are depicted in Fig. 2.
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FIG. 1.
Time-concentration profiles for drug concentrations in
total serum and interstitial space fluids of skeletal muscle and
subcutaneous adipose tissue following administration of ciprofloxacin
to healthy volunteers (single intravenous dose of 200 mg administered
over 10 min; n = 8). Results are presented as
means ± SEs. 0 to 10 min, time of administration.
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FIG. 2.
Mean time-kill curves for the in vitro simulation model,
in which the in vivo time course of ciprofloxacin concentration,
obtained by measuring antibiotic concentrations in serum and the
interstitial space fluid in the experiments shown in Fig. 1, was
simulated in vitro for Proteus mirabilis, Klebsiella
pneumoniae, Pseudomonas aeruginosa, and
Staphylococcus aureus. Solid symbols indicate time-kill data
for serum drug concentrations; open symbols indicate time-kill data for
interstitial subcutaneous concentrations; the dotted lines (small solid
symbols) are the growth control curves.
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|
The main finding of our study was that interstitial ciprofloxacin
concentrations were significantly lower than corresponding total serum
drug concentrations: the interstitial fluid/serum concentration ratios
reached only about 0.7. Given that ciprofloxacin has a protein binding
efficiency of approximately 30% (6), our results are in
very good agreement with the notion that only the unbound fraction of
the drug exerts antimicrobial activity and may penetrate into the
interstitial space (12). This is further corroborated by our
finding that the AUCtissue/AUCfree serum ratios
were about 1 (range, 0.89 to 1.23). Our finding of substantially lower
concentrations at the sites of effect than in serum, however, is in
contrast to previous reports describing tissue/serum ciprofloxacin concentration ratios of up to 7 (5). How could this
discrepancy be explained? The overestimation of concentrations measured
from biopsy specimens is necessarily the result of an admixture of different compartmentalized drug fractions by tissue homogenization. For ciprofloxacin, a drug which is characterized by intracellular accumulation (2), concentrations in tissue homogenates
reflect mean concentrations in the intra- and extracellular
compartments but provide no information on those in the interstitium
(20), since binding to tissue proteins is not accounted for.
Total tissue measurements may thus overestimate the concentrations of
antibiotics, like ciprofloxacin, that accumulate in the intracellular
spaces at the site of effect and may underestimate concentrations at these sites of drugs, like beta-lactams, that equilibrate exclusively with the extracellular space (19). Our in vitro simulation
experiments (Fig. 2) further showed that applying serum
pharmacokinetics overestimated not only the antibiotic concentration
but also the antibiotic activity at the target site. For instance, the
simulation based on serum pharmacokinetics indicated a complete
eradication for Proteus mirabilis, whereas that employing
interstitial pharmacokinetic data indicated failure to eradicate the
strain in vitro.
In conclusion, our study supports the concept that ciprofloxacin
concentrations at the sites of effect may be subinhibitory although
effective concentrations are attained in sera. These findings for
healthy volunteers may warrant further studies on ciprofloxacin
penetration in conditions like soft tissue infections, as the degrees
of target site penetration could differ considerably in these situations.
| |
ACKNOWLEDGMENTS |
This work was supported by a grant (Nr. P12659-MED) from the FWF,
the Austrian Science Fund (Fonds zur Förderung der
Wissenschaftlichen Forschung).
| |
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, May 1999, p. 1307-1309, Vol. 43, No. 5
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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