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Infect Dis Clin N Am 17 (2003) 599–613
Antimicrobial tissue concentrations
Ping Liu, PhD, Hartmut Derendorf, PhD*
Department of Pharmaceutics, College of Pharmacy, University of Florida,
1600 SW Archer Road, PO Box 100494, Gainesville, FL 32610, USA
In the past, pharmacokinetic (PK) and pharmacodynamic (PD)
assessment of antimicrobial agents was based mostly on measuring plasma
or serum concentrations. More attention has been given to the respective
tissue concentrations, however, because most infections occur at tissue sites.
Moreover, most bacterial pathogens are extracellular, and it has been
realized that only unbound antibiotic concentrations at the infected sites are
responsible for antibacterial activity. Insuﬃciently high free tissue concentrations of antibiotics may provide an explanation for some of the clinical
failures in which the antibiotics showed desired plasma PK proﬁles and in
vitro sensitive susceptibility to targeted pathogens.
So far, the optimal dosing regimens for antimicrobial agents are still
poorly deﬁned because the treatment of bacterial infections is frequently
based on clinical experience rather than a rational scientiﬁc approach. The
clinical outcome of anti-infection treatment, however, is determined by both
PK and PD properties of an antibiotic. A PK-PD link allows one to relate
the PK properties and their antibacterial activity of the antimicrobial
agents. Currently, the most common PK-PD approaches for anti-infective
agents rely on plasma concentration as the PK input value and in vitro
minimum inhibitory concentration (MIC) as the PD input value, and several
PK-PD indices have been used extensively for making dosing decisions [1].
For instance, the time above MIC is proposed for b-lactams, AUC24-MIC is
proposed for quinolones, and Cmax-MIC is proposed for aminoglycosides.
The use of both total plasma concentrations and in vitro MIC values,
however, is not ideal. Relating the PKs of antimicrobial plasma concentrations to its MIC values seriously compromises the PK-PD link. This
article focuses mainly on the application of antimicrobial free tissue
concentrations as PK target for anti-infective therapy.
* Corresponding author.
E-mail address: hartmut@cop.uﬂ.edu (H. Derendorf).
0891-5520/03/$ - see front matter Ó 2003 Elsevier Inc. All rights reserved.
doi:10.1016/S0891-5520(03)00060-6
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P. Liu, H. Derendorf / Infect Dis Clin N Am 17 (2003) 599–613
Plasma concentrations versus tissue concentrations
Previously, because of the limited sampling techniques, plasma concentrations were monitored routinely and used as a surrogate marker for
pharmacologic eﬀect in most PK studies and clinical practice. With several
recent breakthroughs in tissue sampling techniques, more tissue data are
available and it is possible to obtain a clear picture of drug tissue
distribution. Still, several issues, such as cost and convenience of the
techniques, limited their applications. This is the major reason that plasma
concentration measurement is still dominant in PK studies.
Because most infections do not occur in plasma but rather in tissue sites
(extracellular ﬂuid), the ability of antibiotics to reach the target sites is a key
determinant of clinical outcome. It is very important to realize that only free
(unbound) antibiotic concentrations in the interstitial ﬂuid at the target site
are responsible for the antibacterial activity. Free antimicrobial tissue
concentrations are more relevant than plasma concentrations in predicting therapeutic eﬃcacy. Tissues are not homogenous compartments. The
distribution of drug molecules in plasma and tissue depends on their
physicochemical properties (Fig. 1). In plasma, some drug molecules bind to
plasma proteins or blood cells, or diﬀuse into the blood cells, and some also
remain unbound in plasma and can move freely in the body. A similar
scenario also occurs in the tissue. Some drug molecules bind to tissue
proteins or tissue cells, and some stay unbound in tissue ﬂuid. The
distribution of free drug in plasma and tissues reaches equilibrium.
Theoretically, at steady state, free drug levels in plasma and tissues should
be equal assuming that tissue distribution of drug molecules only depends
on passive diﬀusion. Based on these assumptions, the total plasma
Fig. 1. Schematic diagram of drug distribution in plasma and tissues.
P. Liu, H. Derendorf / Infect Dis Clin N Am 17 (2003) 599–613
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concentrations and plasma protein binding values can be used to predict the
free tissue concentrations. This statement does not always hold true because
many studies have shown the discrepancy between free drug levels in plasma
versus tissue [2–5].
The diﬀerence between total plasma concentrations and free tissue
concentrations can be signiﬁcant in many situations, such as the drug with
high or nonlinear plasma protein binding. Tissue penetration and tissue
metabolism also aﬀect the PK proﬁles of the antibiotics in the tissues. Total
plasma concentration is not an ideal PK input value for rational dosing of
antibiotics, and free antibiotic concentrations at the infection site should be
considered.
Protein binding
Because protein binding plays an important role in drug distribution,
many analytic techniques have been developed to determine the plasma
protein binding of the compounds. There are several conventional methods
including equilibrium dialysis, ultraﬁltration, and ultracentrifugation, and
chromatographic methods [6]. Equilibrium dialysis is the classic method,
which is based on establishing equilibrium between a protein compartment
and a buﬀer compartment that are separated by a dialysis membrane.
Ultraﬁltration produces a separation of the free drug from bound drug
by using a pressure gradient that forces the small molecules through
a semipermeable membrane. Ultraﬁltration has been used widely to measure
plasma protein binding of compounds in clinical laboratories because of its
several advantages (eg, fast, simple, commercially available kits; lack of
dilution eﬀects and volume shifts; and so forth). The major concern of this
method is the stability of the binding equilibrium during the separation
process. Ultracentrifugation can avoid problems associated with membrane
eﬀects and can separate free drug from unbound drug in a natural
environment. Possible ﬂoating lipoproteins in the supernatant are the
major concern. Chromatographic methods (eg, aﬃnity chromatography,
size-exclusion chromatography, capillary electrophoresis, and ﬂuorescence
spectroscopy) could oﬀer more precise and reproducible binding data
compared with conventional methods. Cost, inconvenience, and timeconsuming properties keep chromatographic methods from becoming the
routine method.
There is a misconception that drugs in the same class with similar total
plasma PK proﬁles have similar therapeutic eﬀect. Only the unbound drug
molecules are able to distribute throughout the body and only free drug
concentrations at the target site are responsible for pharmacologic eﬀect.
Conclusions or judgments based on total plasma PK proﬁles could be
misleading in many cases. It is understood that only the unbound drug
molecules are able to distribute freely throughout the body. In many cases,
free plasma levels are equal to free tissue levels after fast equilibrium, where
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the protein binding values can be used to link total plasma levels with free
tissue levels.
A skin blister study of amoxicillin and ﬂucloxacillin showed that total
plasma concentrations of these two drugs were similar, whereas the
simultaneously measured unbound concentrations in blister ﬂuid showed
signiﬁcant diﬀerence because of diﬀerent protein binding values [7]. When
data from this study were ﬁtted with a two-compartment PK model, free
concentrations of both antibiotics in skin blisters were in agreement with the
respective calculated free concentrations in the peripheral compartment,
based on total plasma concentrations and protein binding values (Fig. 2) [8].
Fig. 2. Antibiotic concentrations in plasma (d) and blister ﬂuid () after intravenous
administration of 1-g dose (mean SD). The dashed lines are the free tissue concentrations
predicted from a two-compartment pharmacokinetic model. (A) Amoxicillin. (B) Flucloxacillin.
(From Derendorf H. Pharmacokinetic evaluation of beta-lactam antibiotics. J Antimicrob
Chemother 1989;24:407–13; with permission.)
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603
In this case, it is possible to perform indirect modeling of free tissue
concentrations from total plasma concentrations. This indirect modeling of
tissue concentrations from plasma concentrations relies on the assumptions
that free plasma levels are equal to free tissue levels at equilibrium and that
tissue distribution is fast. It cannot be applied unconditionally, however,
because of the discrepancy between free concentrations in tissues versus
plasma.
Issues in tissue distribution
It is commonly believed that the unbound antibiotic concentrations in
plasma and tissue ﬂuids are equal at equilibrium assuming that the driving
force of distribution is passive diﬀusion only [9]. Time to equilibrium may
range from minutes to days, however, depending on the ratio of surface
area of the capillary to volume of the tissue ﬂuid compartment and the
physicochemical properties of the compound [9]. It has been realized that
tissue distribution is also aﬀected by anatomic barriers, such as the bloodbrain barrier in the central nervous system, the eye, and the prostate gland
[10]. The active transport system also plays an important role in tissue
distribution; a typical example is P-glycoproteins in the central nervous
system. Besides, anesthesia may aﬀect tissue distribution because it is
possible that the interaction between the anesthetic and the drug aﬀect the
disposition of the drug in the body. Also, it is possible that the physiologic
function of the elimination organs (eg, liver, and kidney) decreases under the
anesthesia condition.
Many studies have shown impaired tissue penetration of antibiotics at
diﬀerent infection sites, such as epidermal infections [11], ear infections [12],
tonsillitis [13], liver infections [14], urinary tract infections [15,16], and
respiratory infections [2–5]. These phenomena cannot be explained by
barrier mechanisms. One speculation is that structural resistance of the
capillary wall is based on alterations in local blood ﬂow, capillary density,
capillary permeability, interstitial diﬀusion coeﬃcients, and transcapillary
osmotic pressure gradients [17–19]. It is also possible that active transporter
plays a role. Some studies have shown impaired tissue penetration of
antibiotics at normal tissue sites, such as soft tissue and lung [20,21]. Direct
measurement of free tissue levels is necessary.
Techniques for free tissue concentration measurement
In the last few decades, several techniques (eg, skin blisters, saliva,
imaging techniques, and microdialysis) were used to monitor free drug
concentrations in extracellular ﬂuids in animal and human studies [22,23].
Traditionally, total tissue homogenate from biopsy was used to determine
the tissue concentrations and the results from this approach oﬀered
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misleading information because a tissue homogenate represents a mixture of
total and free drug in the tissue. Currently, in vivo imaging techniques and
microdialysis make it possible to monitor directly the real-time course of
free drug levels in the extracellular ﬂuids in animals and humans.
Skin blister and saliva techniques
Skin blister and saliva techniques are traditional techniques that provide
approximate information about free tissue concentrations. These two
techniques are relatively simple in terms of requirement of technical skills
and cost. Skin blister and saliva samples have been used as surrogate
markers for free antibiotic tissue levels [24–28]. The skin blister technique
has been used in many PK studies, although it has several major disadvantages. For instance, the blisters are manipulated by suction with
pressure, which only mimics the extracellular ﬂuid to a certain extent.
Results showed that the sampling ﬂuid is not completely free of proteins.
Many factors (eg, the site of the blisters, the time and the pressure of the
suction used) aﬀect the composition of the blister ﬂuid. The risk of inducing
inﬂammation is high. Saliva sampling is a noninvasive method, but is
suitable only for a few compounds. In most cases, results obtained from this
technique are not reliable because there is a signiﬁcant diﬀerence in the
composition of saliva versus extracellular ﬂuids in the tissue. Because saliva
usually has a more acidic pH than blood, it usually shows high
concentration of basic compounds and low concentration of acidic
compounds.
Microdialysis
Previously, microdialysis has been used extensively in the neurosciences
to monitor neurotransmitter release, and now is applied for various tissue
PK studies. Microdialysis is a reliable sampling technique, which is able
directly and continuously to monitor the free drug levels in diﬀerent tissues
and organs in both animals and humans [20,29–34]. Many endogenous
compounds and a large variety of exogenous compounds have been studied.
Valuable information about tissue distribution of many antibiotics is
available [20,34].
The basic principle of microdialysis is to mimic the function of blood
capillary by perfusing a thin dialysis probe implanted into the tissue with
physiologic solution at a very low ﬂow rate. The semipermeable probe tip
excludes the large molecules from sampling and the dialysate (outlet of the
solution) reﬂects the composition of the interstitial ﬂuid over time. Based on
the analytical technique, either average free tissue concentrations during
ﬁxed interval are measured or on-line analysis is performed.
Müller’s group has conducted many microdialysis studies to monitor
the pharmacokinetics of several antibiotics, such as ciproﬂoxacin [35],
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moxiﬂoxacin [36], ﬂeroxacin [37], phenoxymethylpenicillin [37], dirithromycin [37], cefodizime [38], cefpirome [38], and piperacillin [39] in soft tissues of
healthy volunteers. Also, the eﬀects of surgery, intensive care procedures,
and septicemia on peripheral distribution of piperacillin in patients [39,40]
and the eﬀect of inﬂammation on antibiotic penetration into foot lesions in
diabetics [41] and dermatologic patients [37] were investigated. For instance,
microdialysis study of phenoxymethylpenicillin in patients with cellulitis
showed that there was no signiﬁcant diﬀerence in the time course of free
tissue levels in infected and noninfected dermis. Other groups have also
studied the tissue PK proﬁles of diﬀerent antibiotics in humans using
microdialysis, such as gentamicin [42] and penciclovir (antiviral agent) [43].
The antibiotic drug penetration into the interstitial space ﬂuid of human
brain also was investigated [44]. The results of these studies further
demonstrated that antimicrobial concentrations at the eﬀected site may be
subinhibitory, although eﬀective concentrations are attained in plasma.
In the authors’ group, microdialysis studies of several antibiotics (eg,
piperacillin [45], ceftriaxone [46], piperacillin-tazobactam combinations [47],
cefaclor [21,48], cefpodoxime, and ceﬁxime [49]) in animals and humans
have been performed. When piperacillin and ceftriaxone were compared,
results showed that the diﬀerence between free muscle concentrations of
ceftriaxone and its total plasma concentrations was much more signiﬁcant
than that of piperacillin (Fig. 3) [45,46]. These ﬁndings are consistent with
their protein binding values (ceftriaxone: up to 98%; piperacillin: 40% to
50%). In both studies, a two-compartment PK model could ﬁt the data well,
and comparisons between calculated free concentrations in the peripheral
compartment and measured free tissue concentrations revealed excellent
agreement. This study also showed that rat is a suitable animal model for
tissue penetration study of antibiotics.
Orally available cephalosporins have been studied. A modiﬁed release
formulation of cefaclor was evaluated for its therapeutic eﬃcacy [21]. The
PK proﬁles of 500 mg and 750 mg single doses of cefaclor in this
formulation in plasma and muscle were evaluated in 12 healthy male
subjects using microdialysis (Fig. 4). It showed that the oral absorption of
cefaclor could be sustained, but only up to 3 hours because of the presence
of an absorption window. Free muscle concentrations of cefaclor were
suﬃcient for therapeutic levels, but lower than respective total and free
plasma concentrations. The discrepancy between the free drug levels in
plasma and soft tissue is probably caused by an active transport mechanism
or metabolism of cefaclor at the tissue sites. The kinetic proﬁles of cefaclor
in the muscle conﬁrmed that this sustained-release formulation could have
suﬃcient clinical eﬃcacy for anti-infective treatment.
In another study, cefpodoxime and ceﬁxime with diﬀerent protein
binding values (about 25% and 65% for cefpodoxime and ceﬁxime,
respectively) have similar plasma kinetic proﬁles after oral administration.
Using microdialysis, a direct comparison of the kinetic proﬁles of these two
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Fig. 3. Plasma concentrations (n) and free, unbound concentrations in muscle (d) after intravenous administration of 120 mg/kg of piperacillin (left) and
50 mg/kg of ceftriaxone (right) in male Wistar rats (N = 6). The lines are the ﬁtted curves based on a two-compartment pharmacokinetic model. Values are
mean SD (Data from references 45 and 46.)
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Fig. 4. Concentrations of cefaclor in plasma (n) and free, unbound concentrations in muscle () after given 500 mg of modiﬁed-release tablets (left) and 750
mg of modiﬁed-release tablets (right) in 12 healthy male volunteers. The lines are the ﬁtted curves based on a two-compartment pharmacokinetic model.
Values are mean SD (From de la Peña A, Brunner M, Eichler HG, Rehak E, Gross J, Thyroﬀ-Friesinger U, et al. Comparative target site pharmacokinetics
of immediate- and modiﬁed-release formulations of cefaclor in humans. J Clin Pharmacol 2002;42:403–11; with permission.)
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cephalosporins in soft tissue given the same oral dose was conducted in six
healthy male volunteers [49]. The ability to penetrate the tissue is a key
determinant for clinical eﬃcacy. Cefpodoxime with low protein binding of
25% had more than twice higher peak concentration in the muscle than
ceﬁxime (2.1 mg/L versus 0.9 mg/L) (Fig. 5). The average tissue penetration
(AUCtissue,free /AUCplasma,total) of cefpodoxime (70%) was much higher than
that of ceﬁxime (29%). These results were consistent with their protein
binding values, which indicate that the higher the protein binding, the lower
the tissue penetration. The authors’ results suggest that cefpodoxime
produces higher tissue levels than ceﬁxime with the same dosing regimen for
the treatment of uncomplicated soft tissue infections. Also, as with other
antibiotic studies in humans, the free tissue levels of these two cephalosporins were lower than the respective total plasma levels. These ﬁndings
conﬁrmed that using total plasma concentrations overestimates the target
site concentrations and likely their clinical eﬃcacy. This might explain the
therapeutic failure of some antibiotics, which have high in vitro antibacterial
activity (expressed as low MIC values). The subinhibitory levels at the target
site are one of the major reasons for many therapeutic failures of antiinfective treatment, and resistance development.
Imaging techniques
Several imaging techniques based on radiopharmaceuticals or nuclear
magnetic drug eﬀects have been developed for the study of drug distribution
in humans, such as planar c-scintigraphy, single photon emission CT,
positron emission tomography, and MR spectroscopy [50–55]. Imaging
techniques are only applicable for a small group of compounds with special
functional groups. The most signiﬁcant advantage of microdialysis is that it
can be applied to monitor a large variety of compounds in all kinds of
tissues with relatively low cost. Compared with microdialysis, imaging
techniques are very expensive and labor-intensive, which is not suitable for
clinical routine settings.
Issues in minimum inhibitory concentration measurements
The MIC is deﬁned as the lowest antibiotic concentration allowing no
visible bacterial growth after 20-hour incubation, and determined by
macrodilution method using twofold dilutions. Obviously, antibacterial
activity of an antibiotic is a dynamic process, whereas MIC is only a threshold
value, a one-point measurement with poor precision. Although MIC is
a good predictor of potency for antibiotics, it oﬀers little information about
the time course of the antibacterial activity of an antibiotic. The in vitro MIC
values are determined in the presence of free antibiotic concentrations and
the protein binding of the antibiotic is frequently not taken into account.
Nath et al [56] studied the eﬀect of plasma protein binding on antibacterial
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Fig. 5. Plasma concentrations (m) and free, unbound concentrations in muscle (n) after 400-mg oral dose of cefpodoxime (left) and ceﬁxime (right) in six
healthy male volunteers. The dashed lines are the calculated free plasma concentrations based on average protein binding values (cefpodoxime, 25%; ceﬁxime,
65%). Values are mean SD (From Liu P, Muller M, Grant M, Webb AI, Obermann B, Derendorf H. Interstitial tissue concentrations of cefpodoxime.
J Antimicrob Chemother 2002;50:19–22; with permission.)
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activities of two antibiotics: ceftriaxone (protein binding: 90% to 95%) and
cefotaxime (protein binding: 45% to 50%). Results conﬁrmed that the free
plasma concentration of an antibiotic has better correlation with its
antibacterial activity. Using total plasma concentration to compare with
MIC values overcomes the true subinhibitory levels at the infection site so
that it causes treatment failure. Also, subinhibitory concentration at the
infection site is one of major reasons for the emergence of resistance.
Food and Drug Administration guidance in 1997 stated that PD studies
should include relating the concentrations at the site of action to the in vitro
susceptibility of the target microorganism [57]. To evaluate the antibacterial
activity in this way, the free drug concentrations at the target tissue are
appropriate PK input values for rational dosing of antibiotics.
Summary
The clinical outcome of anti-infective treatment is determined by both
PK and PD properties of the antibiotic. Only the free tissue concentrations
of antibiotics at the target site, which are usually lower than the total plasma
concentrations, are responsible for therapeutic eﬀect. The free antibiotic
concentrations at the site of action are a more appropriate PK input value
for PK-PD analysis. The unbound tissue concentrations can be measured
directly by microdialysis. Using plasma concentrations overestimates the
target site concentrations and its clinical eﬃcacy. The optimal dosing
regimens of antibiotics have an impact on patients’ outcome and cost of
therapy, and reduce the emergence of resistance.
References
[1] Craig WA. Pharmacodynamics of antimicrobials: general concepts and applications. In:
Nightingale CH, Murakawa T, Ambrose PG, editors. Antimicrobial pharmacodynamics in
theory and clinical practice. New York: Marcel Decker; 2002. p. 1–23.
[2] Nordbring F. Tissue penetration of antibiotics. Introduction. Focus on some problems
involved in the treatment of infectious diseases. Scand J Infect Dis Suppl 1978;14:21–2.
[3] Fischman AJ, Babich JW, Bonab AA, Alpert NM, Vincent J, Callahan RJ, et al.
Pharmacokinetics of [18F]trovaﬂoxacin in healthy human subjects studied with positron
emission tomography. Antimicrob Agents Chemother 1998;42(8):2048–54.
[4] Jain RK. The next frontier of molecular medicine: delivery of therapeutics. Nat Med
1998;4:655–7.
[5] Heikkinen T, Laine K, Neuvonen PJ, Ekblad U. The transplacental transfer of the
macrolide antibiotics erythromycin, roxithromycin and azithromycin. Br J Obstet
Gynaecol 2000;107:770–5.
[6] Oravcova J, Bohs B, Lindner W. Drug-protein binding sites: new trends in analytical and
experimental methodology. J Chromatogr B Biomed Appl 1996;677:1–28.
[7] Wise R, Gillett AP, Cadge B, Durham SR, Baker S. The inﬂuence of protein binding upon
tissue ﬂuid levels of six beta-lactam antibiotics. J Infect Dis 1980;142:77–82.
[8] Derendorf H. Pharmacokinetic evaluation of beta-lactam antibiotics. J Antimicrob
Chemother 1989;24:407–13.
P. Liu, H. Derendorf / Infect Dis Clin N Am 17 (2003) 599–613
611
[9] Barza M, Cuchural G. General principles of antibiotic tissue penetration. J Antimicrob
Chemother 1985;15(suppl A):59–75.
[10] Barza M. Anatomical barriers for antimicrobial agents. Eur J Clin Microbiol Infect Dis
1993;12(suppl 1):S31–5.
[11] Mertin D, Lippold BC. In-vitro permeability of the human nail and of a keratin membrane
from bovine hooves: penetration of chloramphenicol from lipophilic vehicles and a nail
lacquer. J Pharm Pharmacol 1997;49:241–5.
[12] Harrison CJ, Belhorn TH. Antibiotic treatment failures in acute otitis media. Pediatr Ann
1991;20:600–1603–8.
[13] Savolainen S, Mannisto PT, Gordin A, Antikainen R, Haataja H, Tuominen RK, et al.
Tonsillar penetration of erythromycin and its 2’-acetyl ester in patients with chronic
tonsillitis. J Antimicrob Chemother 1988;21(suppl D):73–84.
[14] Schentag JJ, Heller AS, Hardy BG, Wels PB. Antibiotic penetration in liver infection: a case
of tobramycin failure responsive to moxalactam. Am J Gastroenterol 1983;78:641–4.
[15] Naber KG. Renal lymph concentrations of antibiotics. Scand J Infect Dis Suppl
1978;14:164–5.
[16] Schierholz JM, Beuth J, Pulverer G. ‘‘Diﬃcult to treat infections’’ pharmacokinetic and
pharmacodynamic factors–a review. Acta Microbiol Immunol Hung 2000;47:1–8.
[17] Renkin EM. Multiple pathways of capillary permeability. Circ Res 1977;41:735–43.
[18] Michel CC. Filtration coeﬃcients and osmotic reﬂexion coeﬃcients of the walls of single
frog mesenteric capillaries. J Physiol 1980;309:341–55.
[19] Curry FE. Determinants of capillary permeability: a review of mechanisms based on single
capillary studies in the frog. Circ Res 1986;59:367–80.
[20] de la Peña A, Liu P, Derendorf H. Microdialysis in peripheral tissues. Adv Drug Deliv Rev
2000;45:189–216.
[21] de la Peña A, Brunner M, Eichler HG, Rehak E, Gross J, Thyroﬀ-Friesinger U, et al.
Comparative target site pharmacokinetics of immediate- and modiﬁed-release formulations
of cefaclor in humans. J Clin Pharmacol 2002;42:403–11.
[22] Wise R. Protein binding of beta-lactams II: the eﬀects on activity and pharmacology
particularly tissue penetration. Studies in man. J Antimicrob Chemother 1983;12:
105–18.
[23] Benfeldt E, Serup J, Menne T. Microdialysis vs. suction blister technique for in vivo
sampling of pharmacokinetics in the human dermis. Acta Derm Venereol 1999;79:338–42.
[24] Simon C, Malerczyk V, Klaus M. Absorption of bacampicillin and ampicillin and
penetration into body ﬂuids (skin blister ﬂuid, saliva, tears) in healthy volunteers. Scand J
Infect Dis Suppl 1978;14:228–32.
[25] Hoﬀstedt B, Walder M, Forsgren A. Comparison of skin blisters and implanted cotton
threads for the evaluation of antibiotic tissue concentrations. Eur J Clin Microbiol
1982;1:33–7.
[26] Blaser J, Rieder HL, Luthy R. Interface-area-to-volume ratio of interstitial ﬂuid in humans
determined by pharmacokinetic analysis of netilmicin in small and large skin blisters.
Antimicrob Agents Chemother 1991;35:837–9.
[27] Freeman CD, Nightingale CH, Nicolau DP, Belliveau PP, Banevicius MA, Quintiliani R.
Intracellular and extracellular penetration of azithromycin into inﬂammatory and
noninﬂammatory blister ﬂuid. Antimicrob Agents Chemother 1994;38:2449–51.
[28] Brunner M, Schmiedberger A, Schmid R, Jager D, Piegler E, Eichler HG, et al. Direct
assessment of peripheral pharmacokinetics in humans: comparison between cantharides
blister ﬂuid sampling, in vivo microdialysis and saliva sampling. Br J Clin Pharmacol
1998;46:425–31.
[29] Rittenhouse KD, Pollack GM. Microdialysis and drug delivery to the eye. Adv Drug Deliv
Rev 2000;45:229–41.
[30] Verbeeck RK. Blood microdialysis in pharmacokinetic and drug metabolism studies.
Adv Drug Deliv Rev 2000;45:217–28.
612
P. Liu, H. Derendorf / Infect Dis Clin N Am 17 (2003) 599–613
[31] Chu J, Gallo JM. Application of microdialysis to characterize drug disposition in tumors.
Adv Drug Deliv Rev 2000;45:243–53.
[32] Hammarlund-Udenaes M. The use of microdialysis in CNS drug delivery studies:
pharmacokinetic perspectives and results with analgesics and antiepileptics. Adv Drug
Deliv Rev 2000;45:283–94.
[33] Sawchuk RJ, Elmquist WF. Microdialysis in the study of drug transporters in the CNS.
Adv Drug Deliv Rev 2000;45:295–307.
[34] Müller M. Microdialysis in clinical drug delivery studies. Adv Drug Deliv Rev
2000;45:255–69.
[35] Brunner M, Hollenstein U, Delacher S, Jager D, Schmid R, Lackner E, et al. Distribution
and antimicrobial activity of ciproﬂoxacin in human soft tissues. Antimicrob Agents
Chemother 1999;43:1307–9.
[36] Müller M, Stass H, Brunner M, Moller JG, Lackner E, Eichler HG. Penetration of
moxiﬂoxacin into peripheral compartments in humans. Antimicrob Agents Chemother
1999;43:2345–9.
[37] Müller M, Haag O, Burgdorﬀ T, Georgopoulos A, Weninger W, Jansen B, et al.
Characterization of peripheral-compartment kinetics of antibiotics by in vivo microdialysis
in humans. Antimicrob Agents Chemother 1996;40:2703–9.
[38] Müller M, Rohde B, Kovar A, Georgopoulos A, Eichler HG, Derendorf H. Relationship
between serum and free interstitial concentrations of cefodizime and cefpirome in muscle
and subcutaneous adipose tissue of healthy volunteers measured by microdialysis. J Clin
Pharmacol 1997;37:1108–13.
[39] Brunner M, Pernerstorfer T, Mayer BX, Eichler HG, Muller M. Surgery and intensive care
procedures aﬀect the target site distribution of piperacillin. Crit Care Med 2000;28:1754–9.
[40] Joukhadar C, Frossard M, Mayer BX, Brunner M, Klein N, Siostrzonek P, et al. Impaired
target site penetration of beta-lactams may account for therapeutic failure in patients with
septic shock. Crit Care Med 2001;29:385–91.
[41] Müller M, Brunner M, Hollenstein U, Joukhadar C, Schmid R, Minar E, et al. Penetration
of ciproﬂoxacin into the interstitial space of inﬂamed foot lesions in non-insulin-dependent
diabetes mellitus patients. Antimicrob Agents Chemother 1999;43:2056–8.
[42] Lorentzen H, Kallehave F, Kolmos HJ, Knigge U, Bulow J, Gottrup F. Gentamicin
concentrations in human subcutaneous tissue. Antimicrob Agents Chemother 1996;
40:1785–9.
[43] Borg N, Gotharson E, Benfeldt E, Groth L, Stahle L. Distribution to the skin of
penciclovir after oral famciclovir administration in healthy volunteers: comparison of the
suction blister technique and cutaneous microdialysis. Acta Derm Venereol 1999;79:274–7.
[44] Mindermann T, Zimmerli W, Gratzl O. Rifampin concentrations in various compartments
of the human brain: a novel method for determining drug levels in the cerebral extracellular
space. Antimicrob Agents Chemother 1998;42:2626–9.
[45] Nolting A, Dalla Costa T, Vistelle R, Rand KH, Derendorf H. Determination of free
extracellular concentrations of piperacillin by microdialysis. J Pharm Sci 1996;85:369–72.
[46] Kovar A, Dalla Costa T, Derendorf H. Comparison of plasma and free tissue levels of
ceftriaxone in rats by microdialysis. J Pharm Sci 1996;86:52–6.
[47] Dalla Costa T, Nolting A, Kovar A, Derendorf H. Determination of free interstitial
concentrations of piperacillin-tazobactam combinations by microdialysis. J Antimicrob
Chemother 1998;42:769–78.
[48] de la Peña A, Dalla Costa T, Talton JD, Rehak E, Gross J, Thyroﬀ-Friesinger U, et al.
Penetration of cefaclor into the interstitial space ﬂuid of skeletal muscle and lung tissue in
rats. Pharm Res 2001;18:1310–4.
[49] Liu P, Muller M, Grant M, Webb AI, Obermann B, Derendorf H. Interstitial tissue
concentrations of cefpodoxime. J Antimicrob Chemother 2002;50:19–22.
[50] Wiebe LI, Stypinski D. Pharmacokinetics of SPECT radiopharmaceuticals for imaging
hypoxic tissues. Q J Nucl Med 1996;40:270–84.
P. Liu, H. Derendorf / Infect Dis Clin N Am 17 (2003) 599–613
613
[51] Fischman AJ, Alpert NM, Babich JW, Rubin RH. The role of positron emission
tomography in pharmacokinetic analysis. Drug Metab Rev 1997;29:923–56.
[52] Gibson RE, Burns HD, Hamill TG, Eng WS, Francis BE, Ryan C. Non-invasive
radiotracer imaging as a tool for drug development. Curr Pharm Des 2000;6:973–89.
[53] Spencer SS, Theodore WH, Berkovic SF. Clinical applications: MRI, SPECT, and PET.
Magn Reson Imaging 1995;13:1119–24.
[54] Bujenovic LS, Perry JR, McCartney WH. Comparison of planar, SPECT, and 3-D
synthetic reprojection images: a case study. Clin Nucl Med 1995;20:302–5.
[55] Phelps ME. PET: the merging of biology and imaging into molecular imaging. J Nucl Med
2000;41:661–81.
[56] Nath SK, Foster GA, Mandell LA, Rotstein C. Antimicrobial activity of ceftriaxone versus
cefotaxime: negative eﬀect of serum albumin binding of ceftriaxone. J Antimicrob
Chemother 1994;33:1239–43.
[57] FDA-CDER. Guidance for industry: evaluating clinical studies of antimicrobials in the
division of anti-infective drug products, Food and Drug Administration. Available at:
www.fda.gov/cder. 1997.