Document 6429703

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Document 6429703

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 2004, p. 1441–1453
0066-4804/04/$08.00⫹0 DOI: 10.1128/AAC.48.5.1441–1453.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.
Vol. 48, No. 5
MINIREVIEW
Issues in Pharmacokinetics and Pharmacodynamics of Anti-Infective
Agents: Distribution in Tissue
Markus Müller,1,2 Amparo dela Peña,1 and Hartmut Derendorf1*
Health Science Center, Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida,1
and Vienna General Hospital, Division of Clinical Pharmacokinetics, Department of Clinical Pharmacology,
School of Medicine, Vienna University, Vienna, Austria2
Most drugs, with few notable exceptions, such as heparin,
exert their effects not within the plasma compartment but in
defined target tissues into which drugs must be distributed
from the central compartment. Unfortunately, a complete and
lasting equilibration between blood and tissue cannot always
be taken for granted. This fact is also taken into account in
local-regional strategies for drug applications, e.g., intra-arterial or intrathecal chemotherapy or intra-articular injections,
which aim at delivering drugs to otherwise virtually inaccessible target sites.
Although it has been commonly believed that most antibiotics nearly achieve equilibrium in tissues and plasma (5, 6,
11), recent studies have indicated that the antibiotic distribution process is characterized by high intertissue and intersubject variabilities (Fig. 1) and that target site drug levels may
substantially differ from corresponding plasma drug levels (15,
16, 22, 55, 57, 63, 65, 78, 80, 81, 83, 108, 109, 116, 188).
Suboptimal target site concentrations may have important clinical implications, as they may explain therapeutic failures (22,
80, 129), in particular, for bacteria for which in vitro MICs are
high (22, 80); in addition, it is conceivable that subinhibitory
concentrations in tissues may also trigger bacterial resistance
(76, 87, 117, 120). Therefore, it is also recommended in standard reference texts on current medical treatment (78) that
one consider impaired target site distribution, particularly
when there are discrepancies between clinical response and
susceptibility testing (78). Data on tissue penetration of drugs
therefore could provide important clinical information, especially since several studies have shown that the concentration
profile at the target site is an important determinant of clinical
outcome and is more predictive in this respect than the concentration in plasma (109, 129).
Impaired tissue penetration of antibiotics is best recognized
for central nervous system (CNS) infections (84, 121). The
barrier mechanism in the CNS and other organs, such as the
eye, is the presence of active transport pumps that lead to
target site concentrations which, even at equilibrium, are lower
FOUR COMMON MISCONCEPTIONS ABOUT TISSUE
DRUG DISTRIBUTION
* Corresponding author. Mailing address: Department of Pharmaceutics, College of Pharmacy, University of Florida, P.O. Box 100494,
Gainesville, FL 32610-0494. Phone: (352) 846-2726. Fax: (352) 3924447. E-mail: [email protected]fl.edu.
For many years, research on pharmacokinetics (PK) was
limited for practical reasons to concentration measurements
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than those in plasma (5). This mechanism, which has been well
described both in vitro and in vivo, likely also is the reason for
therapeutic failures in CNS and eye infections (5).
However, besides CNS infections, many other situations in
which impaired drug penetration and blood-tissue inequilibrium can be observed have been reported. In particular, antibiotic failures have been attributed to impaired target site
penetration in cases of soft tissue infections (134), osteomyelitis and orthopedic surgery (45, 98, 127), peridontitis and odontogenic infections (1), endocarditis (94), septic embolism (14,
142), foreign body- and catheter-related infections (142), gastric ulcer (67), hematomas (142), epidermal infections (101),
abscesses (142), granuloma-inducing infections and tuberculosis (51, 186), prostatitis (46), eye infections (21), ear infections
(69), tonsillitis (136), sinusitis (50), liver infections (139), urinary tract infections (116, 142), pelvic inflammatory disease
(122), solid malignancies (79, 129), respiratory tract infections
(126, 131), heart-lung bypass surgery (22), and septic shock
(80).
Studies on the distribution of active transporters and studies
with P-glycoprotein knockout mice have indicated that active
transporters may play a broader role in drug disposition, affecting tissue drug distribution in non-CNS organs substantially as well (143). Nevertheless, in most of the above-mentioned situations, the barrier mechanism more likely is related
to pH partitioning of acidic or alkaline drugs, which may occur
in inflammatory lesions and in the prostate gland (5). Another
mechanism is the presence of functional or structural resistance of the capillary wall based on alterations in local blood
flow, capillary density, capillary permeability, interstitial diffusion coefficients, and transcapillary oncotic and osmotic pressure gradients (36, 90, 102, 132). In contrast to pH partitioning
and active barrier mechanisms, mean tissue drug concentrations will eventually equal those in plasma if the capillary wall
constitutes the sole, passive barrier to drug diffusion. However,
since the rate of diffusion is low, this event could take a long
time, and tissue drug concentrations will be subinhibitory, at
least at the beginning of therapy.
IMPAIRED TISSUE DRUG DISTRIBUTION IN ANTIINFECTIVE THERAPY
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ANTIMICROB. AGENTS CHEMOTHER.
derived from matrices which were easy to obtain, such as blood
and total tissue specimens. These approaches, however, caused
considerable confusion, as their interpretation was flawed by
four misconceptions.
(i) Indirect modeling of tissue drug levels from plasma drug
concentration curves implied a seldom-communicated consensus on the fact that compartment models have no actual
anatomical correlate and merely represent virtual values in
hypothetical spaces. However, the body is a multimillion-compartment model, and studies of capillary physiology (36, 90,
102, 132) and PK have shown that rate constants for analyte
transfer from plasma to tissues are heterogeneous and tissue
specific (48, 113) (Fig. 1). Although methods for the prediction
of volume of distribution based on experimentally determined
physicochemical parameters can predict the average volume of
distribution at steady state within or very close to twofold the
actual value (92), it must be kept in mind that drug-based or
plasma-based models refer to the process of penetration into
hypothetical compartments as “tissue penetration.” This concept is misleading, as it does not take into account the uniqueness of separate organ systems and disease processes. Thus,
although plasma-based modeling may provide useful information in many cases, it must be kept in mind that it assumes
rapid, unrestricted, and homogeneous diffusion processes in
hypothetical spaces—assumptions that do not always hold true.
(ii) A second misconception was the reasoning that tissue is
a uniform matrix. Although tissue antibiotic concentrations
may be readily measured from total tissue biopsy specimens,
total antibiotic concentration measurements from biopsy specimens may be misleading for several reasons. Most importantly, it must be considered that the actual target space for
anti-infective agents, with few exceptions, such as infections
with rickettsiae or chlamydiae, is the interstitial space fluid
(ISF) (133). If only overall tissue drug concentrations are measured, then the effective site concentrations of drugs that equilibrate exclusively with the extracellular space, such as ␤-lactams, may be underestimated (108). This situation, in turn, will
lead to an overestimation of the effective site concentrations of
intracellularly accumulating drugs, such as quinolones or macrolides (108). Thus, the admixture of various compartmental
fluids will lead to a hybrid tissue drug concentration which is
difficult to interpret.
A closely related misconception was the introduction of “tissue-partition coefficients” (3, 20, 125). This concept, which is
gleaned from the chemical concept of in vitro Nernst partition
coefficients for drugs between a lipid phase and a water phase,
assumes the presence of a tissue/blood partition coefficient
under equilibrium conditions. For this purpose, the partitioning of a given compound between homogenized tissue and
plasma is experimentally determined, and the value is used for
further calculations. This concept, which was mainly used for
physiologically based PK models (20), however, is substantially
flawed, as the basic assumption that tissue is a homogeneous
phase comparable to a liquid phase is incorrect. Since the
physiological structure of tissue compartments is destroyed
during the procedure, the compound of interest interacts with
FIG. 1. Tissue drug distribution is nonhomogeneous and tissue specific. Representative PET images of human subjects following the administration of 18F-trovafloxacin are shown. The area of maximum tissue trovafloxacin concentration on each image is represented as 100% on the
color scale. Reprinted from reference 57 with permission.
VOL. 48, 2004
MINIREVIEW
1443
various intracellular and extracellular components in an unphysiological way, and it becomes impossible to discriminate
the in vivo ratio of the bound drug to the active drug.
Although approaches based on total tissue data are of limited value for the interpretation of drug efficacy, total tissue
data may correlate with drug toxicity, e.g., nephrotoxicity of
aminoglycosides.
(iii) A third misconception was the notion that the entire
drug fraction present in various tissue spaces exerts pharmacologic activity. In fact, it has been shown that only the unbound drug fraction in the ISF has the ability to exert antiinfective efficacy, both in vitro and in vivo (31, 32, 33, 34, 86, 99,
184). Clinical examples for the relevance of protein binding
were given in an article by Wise (184); these included therapeutic failures with fusidic acid or ceftriaxone in gonorrhoea
and the close relationship between the failure of cefoperazone
in serious illness and the degree of protein binding. Besides the
fact that only the free fraction exerts activity, it is also only the
free fraction which has the ability to be distributed to the target
site. This information was experimentally shown by various
investigators, who found that differences in penetration were
directly related to the free drug concentrations in serum (4, 13,
110) (Fig. 2). Although this concept has been described best
for antibacterial agents, it seems reasonable to assume that
similar concepts hold true for liposomal and nonliposomal
antifungal formulations.
It follows from these three considerations that an appropriate definition of tissue drug concentrations should imply in
most cases the meaning of unbound interstitial drug concentrations and that a method which is to be considered the “gold
standard” for the measurement of tissue drug concentrations
should allow for the direct measurement of unbound antibiotic
concentrations in the ISF of a given organ.
(iv) Another frequently encountered misconception included the beliefs that, with the exception of the blood-brain
barrier (BBB), restricted penetration into tissues is physiologically impossible and that diffusion-driven transport will inevitably lead to fast and complete equilibration of solutes (5, 6,
11). Besides data supporting an important role of active transporters in various non-CNS tissues (143), studies of capillary
physiology based on the fiber matrix theory, which implies the
existence of 5-nm capillary pores (36, 90), have revealed several findings which could be extrapolated to tissue antibiotic
distribution. Histological sections have revealed that closed
capillaries are not an exquisite feature of the brain but are also
present in other organs, such as skeletal muscle or lungs (90).
Thus, the barrier properties of capillaries represent a continuum. This conclusion is also supported by studies which
showed that the capillary permeability of, e.g., sucrose, which
has a molecular weight (MW) of 342, varies from 270 ⫻ 10⫺6
cm/s in mesenteric capillaries to 6 ⫻ 10⫺6 to 9 ⫻ 10⫺6 cm/s in
muscle capillaries and 0.1 ⫻ 10⫺6 cm/s in CNS capillaries (36,
90, 102, 132). Interestingly, capillary permeabilities for glucose
(MW, 180) and oxygen (MW, 32) are approximately 2 and
10,000 to 20,000 times, respectively, higher than that for sucrose in continuous capillaries (90). Permeability quickly decreases for compounds with higher MWs, e.g., cyanocobalamin
(MW, 1,355), for which skeletal muscle capillaries show restricted diffusion (36, 90, 102, 132). Thus, it is likely that molecules such as vancomycin (MW, 1,449) follow similar patterns.
Apart from MW, it is seldom considered that for most capillaries, only 0.1% of the capillary surface is available for the
transfer of hydrophilic solutes, whereas this value is 100% for
lipophilic solutes, e.g., anesthetics (90). Additional factors,
such as Frank-Starling mechanisms (90) and Gibbs-Donnan
equilibria (90) with interstitial glycosaminoglycans and paracrine mediators, such as bradykinin, or systemic factors, such as
exercise, affect solute transfer from the plasma to the ISF.
These mechanisms are well established but are seldom recognized for antibiotics; in addition, due to a lack of methodology,
FIG. 2. Protein binding is an important determinant of tissue penetration. Mean drug concentration-time profiles were plotted for cefodizime,
a drug with a protein-bound fraction of 74 to 89% (A), and cefpirome, a drug with a protein-bound fraction of 10% (B), in plasma (closed squares;
total concentration) and in the ISF of skeletal muscle tissue (open squares, unbound concentration) after a single intravenous bolus administration
of 2 g to healthy volunteers. The dotted lines for tissue data indicate the predicted tissue drug levels based on plasma PK parameters and protein
binding values of 74 and 89% for cefpirome and of 10% for cefodizime. The data are presented as means and standard deviations. The data are
from reference 110.
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FIG. 3. Tissue drug distribution may be substantially altered by disease state. Mean unbound drug concentration-time profiles were plotted for
piperacillin in serum and in the ISF of skeletal muscle tissue of healthy volunteers (left panel) and intensive care patients on a heart-lung machine
following heart operations (right panel) after a single intravenous bolus administration of 4 g. The data are presented as means and standard errors.
The data are from reference 22.
METHODS FOR STUDIES OF TARGET SITE DRUG
DISTRIBUTION IN ANTIMICROBIAL CHEMOTHERAPY
PK studies are an integral and often decisive component of
anti-infective drug development and also are needed to provide data on tissue drug distribution. Clinical tissue drug distribution studies are also encouraged by regulatory agencies,
such as the Food and Drug Administration (FDA) in the
United States and the European Medicines Evaluation Agency
(EMEA) in Europe (58, 159). According to current guidance
documents for industry (58, 159), these agencies require measurements of the distribution of antibiotics to unaffected and
infected target sites and require the unbound drug concentration at the site of action to be related to the in vitro susceptibility of the infecting microorganism (159). For these purposes,
several experimental methods have been developed and are
discussed below.
Traditional techniques. (i) Indirect methods. For many
years, direct assessment of tissue drug concentrations was
beyond technical reach. Therefore, several mathematical algorithms were used to obtain indirect information about peripheral compartments from plasma-derived data. These algorithms were based on compartment (20, 43) or physiological (3,
20, 125) concepts. As discussed above, however, indirect modeling of tissue drug levels from plasma drug concentration
curves relies on several assumptions that, in most situations, do
not hold true.
(ii) Direct methods. Due to the inherent limitations of indirect approaches, several experimental tools were developed to
determine antibiotic concentrations in various surrogates for
the ISF. These approaches comprised the use of in vitro models, fibrin clots, tissue chambers, skin chambers, wound exudates, surface fluids, implanted fibrin clots, and peripheral
lymph. These methods were reviewed by several groups of
investigators (5, 6, 10, 11, 12, 130, 144, 183, 185); Wise (185)
concluded that they “only yield limited information on tissue
penetration as they often have no pathophysiologic counterpart in humans.”
Given the conceptual problems with these techniques, which
were mostly limited to one-point measurements in a few clinical settings, skin blister sampling (SBS) became the most frequently applied approach for obtaining the information requested by regulatory agencies. Therefore, there are many
available data on the penetration of various antibiotics into
cantharis- or suction-induced skin blister fluid (9, 17, 19, 23, 30,
60, 71, 111, 137, 138, 146; K. M. Williams, S. Cooper, K. Parisis,
M. Handel, and R. O. Day, Clin. Pharmacol. Ther. 69:P61,
2001). These studies were justified by the notion that “skin
blister fluid levels are closer to the biophase than blood” (138).
Although closer to the biophase than blood, SBS is only a
conceptual extrapolation of plasma-based modeling procedures, resulting in a better-defined “second compartment.”
Skin blister fluid, however, is hardly representative of ISF in
other organs, such as the brain. SBS usually also provides no
information on the unbound drug fraction and is prone to
artifacts due to differences in blister size, surface area/volume
ratio, and diffusion capacity across the blister basis (17) and
due to the inflammation which accompanies the induction of
skin blisters (30; Williams et al., Clin. Pharmacol. Ther. 69:
P61). Furthermore, a direct comparison with newer technologies revealed that SBS has many methodological disadvantages
(19, 23, 30, 60).
The large amount of information on the distribution of antibiotics into skin blisters led to incorrect interpretations because many investigators referred to the event of skin blister
penetration as “tissue penetration,” a wording that has con-
only scant data are available from experiments designed to
study the effect of capillary permeability on the transcapillary
transfer of antibiotics. The limited available data, however,
indicate that blood-tissue equilibrium is tissue specific and may
be incomplete, at least for prolonged periods of time (Fig. 1
and 3).
VOL. 48, 2004
1445
related fields, notably, neuropharmacology (56). Typically,
PET studies are based on compound labeling with 11C, 13N,
13
O, or 18F (56). Several published studies have shown the
general applicability of PET in the field of antibiotic evaluation, albeit it involves the burden of high costs (55, 56, 57, 188).
Erythromycin was the first antibiotic studied by PET, in 1982
(188). In that study, the time course of 11C-labeled erythromycin accumulation in inflamed lung tissue of patients with pneumonia was described (188). Unfortunately, radiolabeling of
antibiotics is not a simple undertaking, and most antibiotics do
not lend themselves to appropriate labeling conditions (56).
Another compound that was studied is fluconazole, because it
is an ideal candidate for 18F labeling and undergoes only minimal metabolism in vivo (56), a property which implies that the
signal is representative of the intact drug concentration. A
class of compounds that follows similar patterns for PET studies are the fluorinated quinolones, and studies were performed
with trovafloxacin (57) (Fig. 1), lomefloxacin (158), and
fleroxacin (83). Although these measurements would be useful
for many other drugs, the requirement of devising new synthetic procedures is a major limitation.
Like the application of PET and SPECT, the application of
MRS for studies of anti-infective agents has been gleaned from
anticancer drug research. However, it is surprising that there
are only a few studies on antibiotics in the literature. As shown
by Jynge et al. (83), magnetic resonance imaging has proven to
be particularly feasible for fluorinated antibiotics, since 19F is
one of the lead isotopes for nuclear magnetic resonance spectroscopy. It was shown that fleroxacin could be detected in 19F
magnetic resonance spectra from both liver and calf muscle at
6-h imaging intervals during a 24-h period (83). That study
documented for the first time the potential use of 19F MRS to
observe noninvasively the time-related changes for a fluorinecontaining drug.
Altogether, the imaging techniques provided for the first
time a means to quantify the between- or within-subject variability associated with the distribution process in vivo in humans. In particular, they provided evidence that distribution
contributes more to total variability in the dose-effect relationship than the combination of factors determining the plasma
drug concentration profile (48, 56, 113). PET and MRS were
also shown to support the definition of optimal dosing schedules in phase I and II studies and the design of phase III studies
(56). Important limitations of these techniques are that (i) only
drugs that lend themselves to radiolabeling or the induction of
an appropriate magnetic response may be studied; (ii) the
signal is not necessarily a measure of the intact drug concentration; and (iii) these techniques do not provide information
about specific tissue compartments, such as the ISF. Agencies
such as the FDA are therefore very cautious in using results
from imaging studies for regulatory purposes (106). At present,
the use of these techniques is also limited to large research
centers with good funding opportunities.
(ii) MD. One of the most promising tools for the measurement of tissue drug distribution is in vivo microdialysis (MD)
(52, 54, 115, 172). MD was initially designed to measure concentrations of various neurotransmitters in the rat brain and
was gradually adopted for other research areas, including preclinical PK (52). The increasing use of MD for human PK
studies as well (68, 100, 115, 141) was catalyzed by the avail-
tributed to some of the above misconceptions and should probably be avoided.
Thus, although these techniques were an attempt to overcome the limitations of plasma-based modeling procedures by
gaining direct access to tissues, the interpretation of the data
was hampered by the inability to discriminate free drug concentrations in ISF. Also, it was typically not possible to record
the entire tissue drug concentration-time profile, since most
sampling procedures allowed for only one sampling point at a
given site.
Novel clinical techniques. (i) Imaging techniques. As a conceptual extension of autoradiography (7, 145, 173), several
novel imaging methods that lend themselves to the study of
drug distribution in humans were developed (26, 53, 55, 56, 57,
61, 64, 74, 77, 83, 88, 128, 147, 150, 156, 158, 182, 187). These
comprised radiopharmaceutical techniques, such as two-dimensional planar gamma scintigraphy (PGS) (88, 174), and
three-dimensional techniques, such as single photon emission
computed tomography (SPECT) (26, 61, 77, 182), positron
emission tomography (PET) (56, 57, 128, 188) (Fig. 1), and
magnetic resonance spectroscopy (MRS) (83, 129, 187), which
does not require radioactive labeling. Although these techniques mainly were introduced to clinical medicine for various
diagnostic purposes (150) and for the study of tissue metabolism and blood flow (128), they also opened a unique opportunity for PK research. They enabled for the first time noninvasive measurement of the path of a drug from the plasma
compartment to anatomically defined regions (Fig. 1) and visualization of the entire pattern of distribution in given organs.
(a) Two-dimensional techniques. PGS was the first available
technique and has been used frequently for various PK studies.
Typically the test formulation is labeled with the gamma-emitting nucleotide 99mTc, and the label density is studied over
defined regions of interest. The greatest disadvantage of PGS
is that it can generate only two-dimensional pictures and therefore does not allow different overlying tissues to be distinguished. PGS has been used extensively to study the patterns of
disposition of aerosols in the lungs, including studies on antibiotics such as 99m Tc-labeled tobramycin (88, 174).
(b) Three-dimensional techniques. The shortcomings of
PGS were overcome by the introduction of SPECT, which
allowed for three-dimensional imaging. The primary focus of
SPECT was not the field of anti-infective drug evaluation but
cancer research, and it is also used for staging, for diagnostic
purposes (such as fever of unknown origin or otitis externa),
and for local blood flow measurements (26, 182). In vivo
SPECT studies enabled quantitative measurements of the tissue PK of 57Co- or 111In-labeled bleomycin and 195mPt-cisplatin in humans (61, 77) and indicated that there is marked
variability in drug delivery to given tissues. In the field of
antibiotic evaluation, SPECT was used to evaluate the penetration of 99mTc-labeled ciprofloxacin into inflammatory lesions (156). Although there are only a few reported studies of
SPECT in antibiotic PK research, the general applicability
seems obvious, as it is already possible to use quantitative
SPECT to predict drug responses and to tailor individual chemotherapy in oncology (61, 77).
Historically, the first technique that enabled three-dimensional radiopharmacokinetic studies was PET, and its application for studies of anti-infective agents has been gleaned from
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flomoxef (135); fusidic acid (8); aminoglycosides (49); and rifampin (103, 104). These studies have been carried out with
samples of brain tissue (103, 159, 162, 164, 166, 167), blood
(159, 162, 164, 166, 167), lung tissue (49), soft tissues (85), bile
(161, 171), middle ear (Sawchuk et al., Abstr. 2nd Int. Symp.
Microdialysis Drug Res. Dev., abstr. 7), and eye (175) from
various experimental animals. In addition, MD has been used
to study the tissue drug distributions of nucleoside antiviral
agents (75), notably, alovudine (153), penciclovir (19), zalcitabine (18), BEA005 (18), zidovudine (47, 152, 154, 179, 180,
181), 3-fluoro-3-deoxythymidine (91), and stavudine (193), and
of the antifungal agent fluconazole (191, 192).
In the field of neuropharmacology, MD is frequently used as
a screening tool for neurological drug development because it
enables the selection of drug candidates which can cross the
BBB (D. Welty, Abstr. 2nd Int. Symp. Microdialysis Drug Res.
Dev., abstr. 6, 2000). In addition, MD offers the opportunity to
quantify the brain penetration properties of various drugs. For
anti-infective agents, several studies found significant differences in levels in blood versus brain, e.g., for cephalosporins
(162, 163, 164, 165, 166) and rifampin (103), with penetration
ratios ranging from 0.3% for rifampin to approximately 4% for
cefuroxime. In contrast, significant distribution in the brain was
shown for fluconazole, with a dose-independent brain/tissue
ratio of 0.6 (191). Another study evaluated the ability of ceftriaxone to cross the BBB and analyzed the effects of dexamethasone on the permeative properties of ceftriaxone through
quantification of ceftriaxone in dexamethasone-treated animals with meningitis (124).
Given the important clinical aspects of the distribution of
antiviral agents in the brain, e.g., in AIDS patients, several
studies addressed the abilities of various antiviral agents to
cross the BBB and to attain pharmacologically active concentrations in the brain ISF. For zidovudine, the brain/plasma
ratio was 0.09, whereas the liquor/plasma ratio was 0.18 (189,
190). From these data, it was calculated that the efflux from
brain to blood was approximately fivefold higher than the influx from blood to brain. Probenecid was able to decrease the
clearance of zidovudine from the brain ISF, thereby prolonging the elimination half-life in brain and increasing the area
under the curve (AUC) for the brain by five to sixfold, whereas
the AUC for plasma was increased by twofold. These data
provide evidence that zidovudine is actively transported out of
the brain and that target site exposure could be substantially
increased by the coadministration of probenecid. Restricted
diffusion across the BBB was also described and quantified for
several other antiviral agents (18, 91, 153, 155). Fluconazole
was shown to rapidly reach a distribution equilibrium between
brain extracellular fluid and plasma, and the distribution to the
brain was shown to be substantial and not dependent on the
dose over a twofold range (192).
Similar to the problem of BBB penetration, it was shown for
the eye (176) that the penetration of ceftazidime into the
vitreous after intramuscular injection was ⬃50% higher in inflamed than in noninflamed eyes, suggesting interference with
the blood-retina barrier (177). The problem of transport across
the blood-retina barrier is particularly important for the treatment of cytomegalovirus retinitis. It was shown that MD could
also be used to administer ganciclovir to the rabbit vitreous
within the therapeutic range, offering a route of drug delivery
ability of commercially available MD probes and by the refinement of chemical analytical procedures (96, 97), which today,
at least theoretically, allow for online measurements of concentrations in the ISF. In contrast to the imaging techniques,
MD can be used readily and routinely for clinical and preclinical studies in almost any research center.
The principles of MD have been decribed in detail elsewhere (52, 54, 115, 172). Briefly, MD is based on the diffusion
of drugs across a semipermeable membrane at the tip of an
MD probe implanted into the ISF of the tissue of interest. The
probe is constantly perfused with a physiological solution (perfusate) at a low flow rate, 1 to 10 ␮l/min. Once the probe is
implanted into the tissue, substances present in the ISF are
filtered by diffusion out of the extracellular fluid into the probe,
resulting in their presence in the perfusion medium (dialysate).
Samples are collected and analyzed. To obtain concentrations
in the ISF from concentrations in the dialysate, MD probes
need to be calibrated. Although several techniques can be used
for that purpose, the most suitable technique for human PK
studies is an approach proposed by Ståhle et al. (151), the
retrodialysis or delivery method. The principle of this method
relies on the fact that the diffusion process is quantitatively
equal in both directions through the semipermeable membrane. Therefore, the study drugs are added to the perfusion
medium and the rate of disappearance through the membrane
equals in vivo recovery. The in vivo percent recovery is calculated as follows: 100 ⫺ [(100 ⫻ (analyte concentration in the
dialysate/analyte concentration in the perfusate)]. When
proper in vivo calibration procedures were used, intraindividual variation coefficients for drug concentration measurements obtained by MD were shown to range between 10 and
20% for different analytes (2, 107, 149, 192).
Whereas the new cost- and labor-intensive imaging techniques are not readily applicable in clinical routine settings for
PK studies and are available only for a small number of compounds, in vivo MD offers the opportunity to study the distributions of a large variety of chemical entities in many different
clinical settings. Under appropriate ethical conditions, in vivo
MD is feasible for virtually every human tissue. The particular
advantage of MD in studies of anti-infective agents, however,
relates to the fact that MD allows for the online measurement
of the unbound, i.e., pharmacologically active, drug fraction in
the ISF, i.e., the space which directly surrounds the target
structures. Conceptually, MD thus represents the sole scientific tool currently available with the ability to satisfy the abovestated regulatory requirements (58, 159), and its use as a tool
in clinical PK studies of anti-infective agents has been discussed by FDA advisory committees (59).
(a) Animal studies with MD. To date, MD has been used to
measure in animals the tissue PK of various antimicrobial
agents, including quinolones (123, 171), such as pefloxacin
(171); chloramphenicol (160, 161, 168); ␤-lactams, such as
cephalosporins, notably, cefazolin (165), cephalexin (166), cefotaxime (167), cefmetazole (162), cefuroxime (164), cephalothin (28), ceftriaxone (66, 85, 124, 163), ceftazidime (66, 169,
178), cephaloridine (170), cefamandole (194), cefoperazone
(29), and cefaclor (40); penicillins, notably, penicillin G (27),
piperacillin and tazobactam (37, 118), amoxicillin (148), and
ampicillin (R. J. Sawchuk, Y. Huang, and G. S. Giebnik, Abstr.
2nd Int. Symp. Microdialysis Drug Res. Dev., abstr. 7, 2000);
VOL. 48, 2004
that is not possible with conventional ganciclovir implants
(178).
The issue of lung penetration was addressed for several
antibiotics, e.g., cefaclor (40), cefminox, the ␤-lactam SY5555,
and faropenem (38). It was shown that unbound concentrations in ISF in the lungs, muscle, and liver for these compounds
were close to the unbound concentrations in plasma. Total
tissue drug concentrations also differed widely among the tissues studied (38). Another group applied MD for intrabronchial measurements of tobramycin and gentamicin (49). The
mean values for penetration ratios into the epithelial lining
fluid were 0.36 for gentamicin and 0.56 for tobramycin. The
results demonstrated that MD lends itself to intrabronchial
and intrapulmonary measurements either as an extension of
other techniques, such as bronchoalveolar lavage, or as a practical alternative to other techniques.
For soft tissues, it was shown that total concentrations in
plasma were much higher than concentrations in ISF for ceftriaxone (Fig. 4). After determination of nonlinear protein binding by MD and inclusion of those parameters in the PK model,
however, it was possible to predict free drug concentrations in
the interstitial space from concentrations in plasma for any
given dose. Follow-up studies on the PK of piperacillin and
tazobactam (37, 118), alone and in combination, showed that
piperacillin PK were not influenced by the coadministration of
tazobactam. Again, it was possible to calculate concentrations
in ISF for both drugs based on the protein-bound fraction, and
the data showed good agreement with measured ISF concentrations.
MD has been frequently applied to measurements of antibiotics in fluids, such as bile and blood. Although it is generally
preferable to sample and analyze these fluids directly, the
volume of body fluid that can be obtained from small experi-
1447
mental animals is usually limited. Since MD enables long-term
measurements without net fluid loss, it offers a promising alternative to direct sampling for these purposes.
Another interesting and promising approach in this regard is
the use of MD for the middle ear fluid of chinchillas—a model
which closely resembles the anatomy in the middle ear of
human infants. It was shown that for ampicillin, concentrations
in the middle ear fluid were only 30% the corresponding concentrations in plasma (Sawchuk et al., Abstr. 2nd Int. Symp.
Microdialysis Drug Res. Dev., abstr. 7).
Apart from mere PK measurements, MD may also be used
to quantify and monitor biochemical surrogate markers for
side effects, e.g., the time course of the changes in perilymphatic glutamate during the application of kanamycin in cases
of aminoglycoside-induced ototoxicity (95).
(b) Human studies with MD. To date, MD has been used to
measure in humans the tissue PK of various antimicrobial
agents, including gentamicin (93, 107), ciprofloxacin (24),
moxifloxacin (114), fleroxacin (107), cefodizime (107, 110),
cefpirome (107, 110), piperacillin (22), dirithromycin (107),
cefaclor (41), and fosfomycin (62), and antiviral agents, such as
penciclovir (19), in the soft tissues of healthy volunteers.
Following the first publication on the use of MD for clinical
antibiotic studies in 1995 (107), MD has been used to address
various questions in anti-infective agent research, such as the
influence of protein binding (110), of PK surrogate markers in
tissues, and of different administration schedules and galenic
formulations (73) on antibiotic distributions in various tissues.
In addition, it was shown, in principle, that the concept of
markers of PK and pharmacodynamics (PD), e.g., the time
above the MIC (T⬎MIC), the AUC/MIC ratio, the ratio of the
maximum concentration of drug in serum (Cmax) to the MIC,
or the area under the inhibitory curve, for the evaluation of
antibiotic regimens, originally developed for serum PK, can be
extended to peripheral tissue PK by means of MD (41, 107,
114).
MD studies showed that the concentrations in ISF of selected antibiotics, e.g., fleroxacin (107), ciprofloxacin (24), or
dirithromycin (107), correspond to unbound concentrations in
plasma and are much lower than concentrations reported from
whole-tissue biopsy specimens. For cefpirome, it was shown
that in soft tissue infections with selected bacteria, continuous
infusion may substantially prolong the T⬎MIC at the target
site (73). Similarly, a comparative study on an immediate- or a
modified-release formulation of cefaclor revealed that the
T⬎MIC at the target site can be substantially prolonged when
an antibiotic is administered as a sustained-release product
(73).
Altogether, these studies with healthy volunteers led to a
reappraisal of formerly believed concepts about the tissue penetration of antimicrobial drugs. Concentrations of ␤-lactams
and aminoglycosides in ISF are mostly in the range of free
concentrations in serum (110) (Fig. 3), whereas for quinolones
and macrolides, target site concentrations are considerably
lower than those predicted from tissue biopsy specimens (107).
The results of these MD studies further demonstrated that
concentrations of antimicrobial agents at target sites may be
subinhibitory even though effective concentrations are attained
in serum (24).
In patients, MD was used to quantify the effects of obesity
FIG. 4. Under physiological conditions, tissue drug distribution can
be predicted from unbound plasma drug concentrations. Mean drug
concentration-time profiles were plotted for ceftriaxone in plasma
(closed triangles; total concentration) and the ISF (open triangles;
unbound concentration) after a single intravenous bolus administration of 50 mg/kg of body weight to rats. The line for tissue data
indicates the predicted tissue drug level based on plasma PK parameters and protein binding values. The data are presented as means and
standard deviations. The data are from reference 85.
MINIREVIEW
1448
MINIREVIEW
for compromised patients (22, 80, 157). In particular cardiac
surgery and intensive care procedures significantly lowered
tissue AUC/serum AUC ratios in the patients, and inadequate
target site concentrations were frequently attained (22) (Fig.
4). In a follow-up study on patients with septic shock, these
findings were even more pronounced, as piperacillin concentrations in soft tissue ISF were up to 10-fold lower than corresponding free concentrations in plasma (80). Piperacillin
concentrations in subcutaneous adipose tissue in patients with
septic shock did not exceed values below the MICs for a large
range of relevant pathogens. It thus appears that capillary
damage associated with septicemia or postoperative trauma
significantly affects drug concentrations. This finding may have
clinical implications in that current dosing guidelines might
result in inadequate target site concentrations and could lead
to therapeutic failure in some patients.
INTEGRATION OF DISTRIBUTION STUDIES IN PK-PD
STUDIES OF ANTI-INFECTIVE AGENTS
The traditional approach to linking antibiotic concentrations
to antibiotic effects is to relate a static parameter, the MIC, to
the concentration in serum. This approach is usually applied by
using cumulative PK-PD variables, such as AUC/MIC ratios,
T⬎MIC, or Cmax/MIC ratios (20, 44). However, these approaches do not take into account the complex interactions
among an administered drug, a host, and an infective agent,
since in practice, a PD effect in vivo is the result of a dynamic
exposure of the infective agent to the unbound drug fraction at
the relevant target site rather than a static interaction of two
variables. Therefore, several authors proposed that PK be
linked to PD in a more dynamic way by using several PK-PD
models (35, 39, 42, 44, 119).
All of the above techniques not only may provide information on PK but also may lend themselves to studies of antibiotic
PD. This is particularly true for MD, as it monitors free antibiotic concentrations in the fluid which directly surrounds the
infective agent; the antimicrobial effect linked to the time-drug
concentration profile obtained by MD may be simulated easily
in an in vitro setting with bacterial cultures. This dynamic
simulation may thus provide a rational approach to describing
and predicting PD at a relevant target site. Some recent publications described an MD-based in vivo PK-in vitro PD model
(39) that is based on a previously described modified maximum
effect (Emax) model (42, 119) and that may be used to predict
drug effects at the target site.
This three-step approach is based on (i) the in vivo measurement of ISF drug PK at the target site and (ii) the subsequent PD simulation of the time-drug concentration profile in
an in vitro setting. In a third step, the data are analyzed with an
integrated PK-PD model to link unbound antibiotic concentrations to bacterial killing rates by using Emax. Such experiments enable the simulation of different dosing scenarios without the need for large clinical trials (24, 39, 41, 42, 73, 119).
These data could provide strong support for PK-PD modeling
procedures, might assist in dose optimization, and might replace current concepts for establishing dosing guidelines for
selected tissue infections. This approach is also in accordance
with the current reasoning of regulatory authorities, such as
the FDA and the EMEA, which not only require measure-
(72), surgery (22), intensive care procedures (22, 80), and septicemia (80) on peripheral drug distribution; to study the effects of inflammation on antibiotic penetration into foot lesions in patients with diabetes (89, 112) and dermatological
conditions (107); and to measure antibiotic penetration into
the lungs (70) and the brain (25, 105).
In a study on the distribution of phenoxymethylpenicillin in
patients with cellulitis (107), no difference could be detected in
the time courses of phenoxymethylpenicillin in inflamed dermis versus noninflamed dermis. Similarly, there was no significant difference in the penetration of ciprofloxacin (112) or
fosfomycin (89) into unaffected tissue and acutely inflamed
foot lesions. In contrast, significantly reduced target site penetration was observed for ciprofloxacin in patients with arterial
occlusive disease (82) and for fosfomycin in patients with longterm diabetes mellitus (89), probably due to impaired capillary
density. Thus, it appears that local blood flow and alterations
in the capillary surface area are important determinants of
concentrations in ISF, whereas acute inflammatory events
seem to have little influence on tissue penetration. These observations are in clear contrast to reports on the increase in the
target site availability of antibiotics by macrophage drug uptake and the preferential release of antibiotics at the target site
(140), a concept which is also used as a marketing strategy by
the drug industry.
Recently, Hollenstein et al. (72) addressed the issue of tissue
penetration of ciprofloxacin in obese subjects with a mean
weight of 122 kg and age- and sex-matched lean control subjects and found ⬃50% lower tissue AUC/plasma AUC ratios in
obese subjects. Thus, the process of penetration into the ISF is
markedly impaired in obese subjects, most likely because of a
reduced capillary permeability surface area in fat tissue (72).
Apart from studies in easily accessible soft tissues, MD has
been adopted for measurements in other organs, including the
lungs and the brain. The application of clinical lung MD was
shown in a study of cefpirome (70) penetration into lung ISF in
patients undergoing lung surgery due to malignancies. Such
pilot studies, which have opened the opportunity for future
studies on antibiotic penetration in the lungs, have provided
evidence for the feasibility of lung MD and have shown that
drug distribution in the unaffected lung is driven by unrestricted diffusion. Mindermann et al. published the first report
on the study of antibiotic PK in the human brain by MD in
1998 (105). They determined the in vivo penetration of rifampin into various compartments of the human brain in patients undergoing craniotomy for resection of primary brain
tumors. Rifampin concentrations in all compartments exceeded the MICs for staphylococci and streptococci. However,
concentrations in ISF might have been below the MICs for
some mycobacterial strains. In another recent study, the intracerebral penetration of fosfomycin was studied by MD in intensive care patients with intracerebral hemorrhage requiring
neurosurgical intensive care, including cerebrospinal fluid
drainage (25). Intracerebral Cmaxs of fosfomycin were above
the MICs for clinically relevant bacteria causing CNS infections and ranged between 13 and 79 ␮g/ml. Fosfomycin therefore might qualify as a therapeutic option in the treatment of
CNS infections, such as meningitis, meningoencephalitis, or
brain abscesses.
A significant problem with antibiotic penetration was shown
VOL. 48, 2004
MINIREVIEW
ments of the distribution of antibiotics to unaffected and infected target sites but also require the unbound drug concentration at the site of action to be related to the in vitro
susceptibility of the infecting microorganism (58, 159).
CONCLUSIONS AND OUTLOOK
ACKNOWLEDGMENT
This work was sponsored by the Austrian Science Fund (grant no.
J-1895-Med to M. Müller).
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