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Review CNS pharmacokinetics of antifungal agents Shravan Kethireddy & David Andes† University of Wisconsin School of Medicine and Public Health, Madison 600 Highland Ave, H4/572, Madison, WI 53792, USA 1. Fungal infections and CNS involvement 2. Factors impacting CNS drug penetration and accumulation 3. Antifungal CNS pharmacokinetic and treatment investigations 4. Amphotericin B formulations 5. Flucytosine 6. Triazoles 7. Echinocandins 8. Expert opinion Expert Opin. Drug Metab. Toxicol. (2007) 3(4):573-581 a fo rm n fI o t h p o C ig r y UK d te The goal in treatment of infections is to achieve a beneficial effect whilei ib minimizing toxicity. It is widely recognized that the principles of pharmah cokinetics and pharmacodynamics are critical to determining an adequate o r dose–response relationship. There has been an increased involvement p of the y CNS to infection from opportunistic and endemic fungi over lthe last several t decades due to establishment of solid-organ and bone marrow transplantaric it has become tion as well as immunosuppression from HIV. In this tregard critical to define optimal dosing regimens by ansunderstanding of the nagent to the targeted CNS processes which govern delivery of an antifungal o i t is to: i) summarize published site of involvement. The objective of this review u experimental and clinical antifungal pharmacokinetics; and ii) examine the b i r relationship between CNS antifungal pharmacokinetics and efficacy. t s Examination of these studies reveal marked variability among antifungal i d drugs with regard to cerebrospinal fluid and brain parenchymal penetration. drelationship between CNS antifungal pharmaFormal examination of the n cokinetics and efficacy a The few experimental studies available g are limited. suggest that brainn parenchymal kinetics is a superior predictor of antifungal ti efficacy than cerebrospinal fluid concentrations. n i Keywords: antifungal Pr , central nervous system, cerebrospinal fluid, pharmacokinetics d. 1. Fungal infections and CNS involvement t L Outcome following invasive fungal infections is generally poor. When these pathogens breach the CNS, treatment success becomes even more dismal. The ability of antifungal drugs to achieve adequate concentrations in the tissues of the CNS is one of numerous factors that impact treatment outcome of these infections. All systemic fungal pathogens have been associated with CNS involvement. Those which most commonly disseminate to the CNS include Cryptococcus neoformans, Candida spp. and Aspergillus spp. (Table 1). One common factor to consider when designing an optimal antimicrobial therapy is where within an end organ does the pathogen reside? For example, common bacterial pathogens, such as Streptococcus pneumoniae, primarily produce disease of the meninges. Similar considerations for fungi are difficult since these pathogens do not respect the tissue compartments within the CNS. Histopathologic studies have demonstrated organism invasion of the meninges and parenchymal tissues with all fungal pathogens [1]. 2. Factors impacting CNS drug penetration and accumulation The pharmacologic goal of antimicrobial administration is to achieve adequate concentrations at the site of infection. For most tissue sites, serum drug concentrations provide an excellent surrogate of the interstitial tissue concentration where pathogens reside for most end organs. The tissues of the CNS and eye, however, are relatively protected tissue sites due to blood tissue barriers that limit diffusion of many molecules. Furthermore, there are tissue efflux pumps that can impact CNS 10.1517/17425225.3.4.573 © 2007 Informa UK Ltd ISSN 1742-5225 573 CNS pharmacokinetics of antifungal agents Table 1. Incidence of CNS involvement associated with invasive fungal infection. Organism CNS involvement Mortality Invasive candidiasis 3 – 64% 11 – 67% Invasive aspergillosis 4 – 6% 80 – 90% Cryptococosis 67 – 84% < 1% Histoplasmosis* 5 – 20% 20 – 40% Coccidioidomycosis* 25% 26% Blastomycosis‡ 40% 4.3 – 22% Zygomycosis 12% 79 – 98% Dematiacious (cladophialophora) 100% 71 – 74% Data taken from [37,49,63-66]. *Disseminated disease. ‡Patients with HIV/AIDS. accumulation for many drugs. In order for drugs to enter the cerebrospinal fluid (CSF) and parenchyma of the brain, the compounds need to traverse either the epithelial layer of the choroid plexus or the cerebral endothelium. This tissue barrier is structurally different from other blood tissue barriers due to the size of the intercellular connections through which drugs pass. All other tissue sites possess fenestrated cell connections for which the space between cells is 100 Å, allowing ready diffusion of most pharmacologic molecules. However, to gain access to the CNS, drugs must traverse tight junctions which are much smaller (20 Å) and preclude diffusion of large molecular weight (MW) drugs. The blood–brain barrier is one of these tissue barriers and is composed of the layer of endothelium from the vessels surrounding the brain and spinal cord. The endothelial cells are linked by tight junctions with only 0.02% of the capillaries possessing fenestrations [2]. The choroid plexus makes up a second drug barrier termed the blood–CSF barrier [9]. Although the capillary membrane at the choroid plexus is mostly fenestrated, the ependymal cell layer of the plexus which contacts the CSF is constituted by tight junctions that similarly limit large molecule transport [3]. Once a compound traverses the CNS tissue barriers, there are efflux pumps (P-glycoprotein [P-gp]) in the choroid plexus that can impact the ability of drugs to accumulate in the CNS. There are several physiochemical properties that impact the ability of drugs to traverse the CNS tissue barrier. These factors include: compound i) molecular size; ii) lipophilicity; iii) plasma protein binding; iv) efflux pump affinity; v) molecular charge; and vi) cerebral blood flow. The impact of molecular size is intuitive, the larger the molecule the less it would be expected to be able to traverse the tight junctions of the CNS tissue barrier. The diffusion coefficient is an estimate of the ability of a compound to penetrate the CNS serum barrier and is approximately proportional to the reciprocal of the square root of the molecular mass. Doubling the size of a 574 drug from a MW of 250 – 400 Da can decrease permeation by 100-fold [4,5]. The upper limit of MW to allow for efficient diffusion is 300 – 400 Da [4]. Among the available antifungal agents, one would expect that a small molecule such as flucytosine (120 g/mol) would diffuse easily due to its small MW (Table 2). Conversely, the large MW of the cyclic hexapeptide echinocandin molecules would be anticipated to limit penetration of drugs such as caspofungin, anidulafungin and micafungin. The MW of each of the echinocandins exceeds 1000 g/mol. Polyene and triazole molecules are of intermediate-to-large size. Although the MW of the parent amphotericin B molecule is identical among the four preparations (amphotericin B deoxycholate, liposomal amphotericin B, amphotericin B lipid complex and amphotericin B colloidal dispersion), the particle size of the complex varies markedly. Among the lipid preparations, the liposomal product is two orders of magnitude smaller than other lipid associated preparations. Among the triazoles, fluconazole and voriconazole would appear to have an advantage over either itraconazole or posaconazole for CNS diffusion due to their lower MW (Table 2). A second drug property that impacts penetration into the CNS is binding to plasma protein. The large size of serum proteins, such as albumin, precludes penetration of protein bound molecules. In the absence of inflammation, there is very little albumin in the CSF (CSF:serum albumin ratio of 1:200). Plasma protein binding varies widely among the antifungal agents. The amphotericin B preparations and each of the echinocandins exhibit binding to albumin in excess of 95%. Conversely, protein binding to flucytosine is negligible. Among the triazole compounds, fluconazole is least impacted by protein binding (10%), voriconazole is intermediate (58%), and both itraconazole and posaconazole exhibit a very high degree of binding (> 98%). The lower protein bound drugs would be expected to penetrate more readily than those bound to a higher degree. A third drug property that governs permeation across the CNS tissue barrier is molecule lipophilicity. Capillaries of the brain are devoid of aqueous pores to facilitate aqueous diffusion, thus lipid diffusion becomes a critical determinant of drug penetration. The permeability coefficient for lipid diffusion is known as the lipid:aqueous partition or the octanol:water partition (Log P) [6,7]. Drugs which readily enter the CNS compartments often possess an octanol:water partition coefficient of ∼ 1. However, highly lipophilic compounds also frequently demonstrate a high level of binding to serum proteins. Thus, drug properties of lipophilicity and protein binding can be conflicting characteristics in regard to CNS penetration. Among the antifungal drugs, the two triazole compounds, itraconazole and posaconazole, possess high lipophilicity. However, as discussed, this physiochemical characteristic is associated with high affinity for serum albumin. The characteristics of protein binding and lipophilicity conflict in regard to CNS penetration, making pharmacokinetic predictions difficult. Expert Opin. Drug Metab. Toxicol. (2007) 3(4) Kethireddy & Andes Table 2. Physiochemical properties of antifungal agents. Molecular weight Log P % Protein binding to albumin P-glycoprotein substrate Fluconazole 309 2.17 10 + Itraconazole 705 6.99 98 ++ Voriconazole 349 2.56 58 + Posaconazole 700 6.1 99 + 5-FC 120 -0.89 5 - (*< AmB 924 0.95 > 95 - ABLC* 1.6 – 11 um 0.4 µm) 0.95 > 95 - L-AmB* 0.08 um 0.95 > 95 - ABCD 0.12 – 0.14 µm Caspofungin 1093 -2.8 98 - Anidulafungin 1140 0.21 98 - Micafungin 1291 -3.8 98 - Data taken from [6,67,68]. *Particle size. 5-FC: 5-Flurocytosine; ABCD: AmB colloidal dispersion; ABLC: AmB lipid complex; AmB: Amphotericin B; L-AmB: Liposomal AmB. Once within the CNS space, the drug must accumulate to achieve therapeutic concentrations. Efflux pumps at the CNS tissue barrier are capable of removing molecules from the CSF. Substrates of P-gp, a membrane bound P-ATPase efflux pump, has a high affinity for lipophilic molecules. These transporters protect the brain from toxic xenobiotics and also decrease entry of some therapeutic drugs into the CNS. The only antifungal compounds that serve as substrates for P-gp are drugs from the azole class. Among the triazole drugs, itraconazole exhibits the most significant affinity for this protein [8]. The understanding of these basic principles of CNS pharmacokinetics should allow prediction of antifungal penetration and accumulation. However, the complex and often conflicting nature of several of these physiochemical properties can make these predictions difficult. The studies examining the reliability of these predictions for CNS pharmacokinetics and treatment efficacy of antifungal drugs are considered herein. Antifungal CNS pharmacokinetic and treatment investigations 3. Interpretation of pharmacokinetic studies in the CNS requires consideration of several important experimental variables. First among these is the realization that the CNS is not a homogenous pharmacologic compartment. More simply put, CSF concentrations do not necessarily predict brain parenchymal or meningeal concentrations. In fact, there is even a lack of rapid equilibration within different CSF locations such as the lumbar cistern and ventricles. As a general rule, brain tissue concentrations are most often greater than those detected in the CSF. A second study variable that markedly impacts kinetic measurements is the presence of CNS inflammation, often associated with an infectious process. Inflammation can disrupt the CNS blood barrier tight junctions and enhance the ability of pharmaceutical agents to penetrate the CNS. Yet, the degree of inflammation is difficult to measure and accurately reproduce from study to study. Finally, it is critical to consider the manner in which CNS kinetic data are presented. Most studies report CSF concentrations relative to serum and include an estimate of penetration. It is not uncommon to find reports based on a single and simultaneous measurement of serum and the CSF, especially in human studies. It is important to recognize the amount of time necessary for equilibration of drug in the CSF. The time to peak serum concentrations is much earlier than the time to peak CSF concentration. With these caveats in mind, the most valid parameters of drug entry into the CSF include: i) CSF:serum concentration ratio at steady-state; and ii) CSF: serum ratio of the area under the concentration–time curve. There are several study types that allow one to understand and predict the likelihood of adequate antifungal CNS pharmacokinetics for treatment of CNS fungal infections. These investigations include both animal models and human trials (Tables 3 and 4). The study designs include: i) measurement of antifungal drug concentrations in CSF or brain parenchyma, with or without CNS inflammation; ii) measurement of CNS concentration and correlation with antifungal treatment effect; and iii) examination of antifungal treatment effect without CNS drug concentration measurements. Several assay methodologies have been used measure of CNS antifungal concentrations including microdialysis, postmortem tissue samples, positron emission tomography (PET) imaging and, most commonly, CSF sampling. Unfortunately, there is significant heterogeneity in study design for antifungal CNS kinetics which makes comparison across studies and drugs somewhat Expert Opin. Drug Metab. Toxicol. (2007) 3(4) 575 CNS pharmacokinetics of antifungal agents Table 3. CNS pharmacokinetics of antifungal agents in animal models. CSF concentration Brain concentration Ref. Fluconazole 42 – 84% (75%) 50 – 100% [24,26,30,34,35,69] Itraconazole < 1% (< 1%) Hydroxy itraconazole found in one study [30,34,35] [39] Voriconazole 68 – 100% Detectable in guinea-pig brain Posaconazole NA NA 5-FC NA NA AmB < 1% 3% (18%) [9,10,17] ABLC < 1% (27%) [10] ABCD < 1% (22%) [10] L-AmB < 1% (3%) [10] Caspofungin 0 10 – 20% [50] Anidulafungin 0 9 – 15% [51] Micafungin 0 8 – 18% [58,70] Value in parentheses represents study in presence of CNS infection. 5-FC: 5-Flurocytosine; ABCD: AmB colloidal dispersion; ABLC: AmB lipid complex; AmB: Amphotericin B; CSF: Cerebrospinal fluid; L-AmB: Liposomal AmB; NA: Not applicable. difficult. The available literature for each of the antifungal drugs from animal models is listed in Table 3. 4. Amphotericin B formulations The CNS pharmacokinetics of amphotericin B (AmB) deoxycholate and the lipid-associated preparations have been examined in experimental studies using rabbit models both with and without CNS infection [9,10]. Systemic administration of each of the formulations did not produce measurable concentrations in the CSF regardless of CNS inflammation due to candida or cryptococcal meningitis. However, detectable brain parenchymal concentrations were observed even in the absence of CNS infection. Brain concentrations in non-infected animals ranged 3 – 27% of those observed in rabbit serum. The penetration of these compounds was enhanced in presence of infection two- to fourfold. The tissue concentrations observed with common dosing regimens would be expected to effectively inhibit the growth of or kill invading fungi. The degree of penetration in a Candida meningitis model was similar among AmB, AmB lipid complex (ABLC) and AmB colloidal dispersion (ABCD). The penetration of LAmB relative to serum concentrations was lower than the other preparations. However, the kinetics of liposomal AmB (L-AmB) are characterized by very high serum concentrations which are more than 30-fold greater than each of the other amphotericin B formulations. Thus, the absolute concentrations of L-AmB in the brains of rabbits in this model were significantly higher than the other preparation (L-AmB brain tissue concentrations 3.6- to 5.2-fold greater than AmB, ABLC, ABCD). Interestingly these differences in brain parenchymal concentrations favoring the L-AmB formulation were associated with enhanced therapeutic efficacy in this model. The investigators observed 576 a strong correlation between the maximal (peak concentration) and total (AUC) AmB concentration in the brain tissue and Candida burden in brain tissue at the end of therapy. This concentration-dependent pharmacodynamic relationship is similar to that observed for these antifungals in other infection sites. Human CNS pharmacokinetic evaluation of AmB and ABLC are limited to a report of CSF concentrations in a small series of patients with CNS infections. Similar to animal model studies, concentrations in CSF were either undetectable or very low relative to serum AmB levels. Limited CSF accumulation of amphotericin B led to the development of intrathecal therapy for several CNS fungal infections [11,12]. However, despite the lack of measurable CSF amphotericin B concentrations, there is a large clinical experience of successful use of these products for treatment of CNS fungal infections [13-15]. In fact, amphotericin B remains the standard of treatment for certain CNS infections, such as cryptococcal meningitis [16]. Similarly, there are numerous animal model treatment studies demonstrating efficacy with these polyene drugs [9,10,17-22]. Taken together, these data suggest a poor correlation between AmB CSF concentration and efficacy in treatment of CNS fungal infections. The experimental data from Groll et al. suggest that the ability of these drugs to achieve adequate brain parenchymal concentrations may better correlate with treatment efficacy than CSF measurements. 5. Flucytosine Both animal and human studies have examined the CNS pharmacokinetics of flucytosine. Bennett and associates accessed serum and CSF concentrations in animals and humans with CNS mycoses. Using a bioassay to measure drug concentrations they found that CSF concentrations in humans ranged Expert Opin. Drug Metab. Toxicol. (2007) 3(4) Kethireddy & Andes 17 – 62 µg/ml and were ∼ 74% of simultaneously determined serum concentrations [23]. These concentrations far exceed those associated with growth inhibition in vitro and would be anticipated to be adequate for efficacy. However, studies examining the relationship between CSF concentrations and therapeutic effect are unavailable. 6. Triazoles The available triazole antifungal agents (fluconazole, voriconazole, itraconazole and posaconazole) exhibit variable physiochemical characteristics and, not surprisingly, differ in CNS pharmacokinetics. The pharmacokinetics of each of these compounds in the CSF and brain parenchyma has been extensively examined in animal models both with and without CNS infection. Among the triazoles, fluconazole achieves the highest concentrations in the CSF. Even in models with an intact CNS blood barrier, concentrations were in the range of 42 – 84% of those observed in serum. For example, Madu et al. found that CSF concentrations of fluconazole were 84.3% of those observed in serum following intravenous administration of drug to healthy rabbits [24]. Achievable concentrations are even greater in the presence of CNS infection. Several human CSF kinetics studies with fluconazole report similar findings. For example, Foulds et al. examined the fluconazole concentration in serum and CSF in patients without meningeal inflammation [25]. CSF concentrations were in the range of 52 – 62% of those in serum at steady-state. Study of brain tissue fluconazole kinetics demonstrated a concentration profile that closely approximates that observed in the CSF. Using intracerebral microdialysis in rats, Yang et al. found that fluconazole rapidly reaches equilibrium between the plasma and brain extracellular fluid with an average brain distribution coefficient of 0.60 [26]. Thaler and colleagues examined fluconazole penetration by HPLC analysis in non-inflammed human cerebral tissue and found an average brain/plasma ratio of 1.33, indicating nearly complete equilibration with serum [27]. PET scan imaging of 18F-labeled fluconazole in healthy human volunteers revealed relatively homogenous distribution of the drug throughout the brain with calculated values in the range of 4.15 – 5.48 µg/ml [28]. In a murine histoplasmosis meningitis model, Haynes et al. reported brain parenchymal fluconazole concentrations as high as 13.85 µg/ml following dose levels relevant to those used in patients [18]. These concentrations are several-fold higher than that needed to inhibit growth (minimum inhibitory concentration [MIC90]) of Histoplasma spp. [29]. The ability of fluconazole to achieve concentrations in the various CNS compartments greater than the MIC90 of common fungal pathogens would suggest it would be effective in therapy of these infections. Indeed, multiple experimental and clinical trial studies with fluconazole for treatment of susceptible Candida, Cryptococcal and endemic fungi demonstrate the successful use of this triazole [22,30-33]. The kinetics of itraconazole has been similarly investigated. Both animal models and human studies of CSF pharmacokinetics report nearly undetectable concentrations [30,34-36]. These findings would not be terribly surprising given the larger MW and high protein binding. However, study of brain parenchymal concentrations demonstrate that itraconazole does accumulate in this tissue space. Haynes et al. found brain parenchymal concentrations of the microbiologically active itraconazole metabolite (hydroxyl-itraconazole) approaching those measured in the serum of mice with Histoplasma meningitis [18]. Several CNS fungal infection models have undertaken comparative CSF kinetic and efficacy studies with fluconazole and itraconazole [30,34-36]. The kinetic results from these investigations confirm those discussed above for which fluconazole would appear to have an advantage based on CSF concentrations. However, despite the lack of appreciable CSF concentrations of itraconazole, therapeutic efficacy is similar to that observed for fluconazole in cryptococcal, Coccidioides and Histoplasma meningitis models. For example, Sorensen and colleagues measured serum and CSF concentrations of fluconazole and itraconazole in a rabbit Coccidioides meningitis model [30]. Itraconazole CSF concentrations were undetectable; however, fluconazole concentrations exceeded the Coccidiodes spp. MIC90. Despite this marked difference in CSF concentrations, there was no difference in the ability of either treatment to reduce the burden of organisms in the spinal cord and brain of these mice. It is hypothesized that the activity of itraconazole in this model is due to a combination of higher concentrations in the target tissues of the brain parenchyma and the lower MIC values for this drug organism combination [37]. An animal model study of Histoplasma CNS infection also supports this theory [18]. Haynes et al. compared the CNS kinetics and efficacy of several antifungals in a murine model. They similarly found undetectable itraconazole concentrations in the CSF but parenchymal concentrations that are higher than the MIC of the infecting organisms. Similar to other groups comparing the efficacy of fluconazole and itraconazole in these CNS infection models, they reported no difference in efficacy in this CNS endemic fungal infection model. More importantly, most comparable clinical trials have also not demonstrated differences in treatment efficacy for CNS fungal infections. Two cryptococcal meningitis trials comparing the efficacy of fluconazole and itraconazole for consolidation therapy have observed therapeutic equivalence [16,38]. However, these patient trials have not included CNS pharmacokinetic evaluation. Taken together, these animal models and clinical trials point to discordance between triazole CSF concentrations and treatment efficacy similar to that observed for AmB. Although brain parenchymal concentrations were not examined in the animal model treatment studies, one certainly wonders if the ability of itraconazole to accumulate in this tissue accounts for efficacy in these models. The newer triazole voriconazole is structurally related to fluconazole, whereas posaconazole is similar in structure to itraconazole. Lutsar and colleagues studied voriconazole concentrations in the CSF and brain in uninfected guinea-pigs and in the CSF of humans with a wide range of CNS Expert Opin. Drug Metab. Toxicol. (2007) 3(4) 577 CNS pharmacokinetics of antifungal agents Table 4. CNS pharmacokinetics of antifungal agents in humans. CSF concentration Brain concentration Ref. Fluconazole 52 – 82% (70 – 89%) 116% [18,25,31,71] Itraconazole (< 10%) NA [42] Voriconazole (38 – 68%) 1.2 – 1.9 µg/g [39, 40, 42-44] Posaconazole NA NA 5-FC 74% NA [23] AmB (0 – 4%) NA [72] ABLC (< 1%) NA [13] ABCD NA NA L-AmB NA NA Caspofungin NA NA Anidulafungin NA NA Micafungin NA NA 7. Value in parentheses represents study in presence of CNS infection. 5-FC: 5-Flurocytosine; ABCD: AmB colloidal dispersion; ABLC: AmB lipid complex; AmB: Amphotericin B; CSF: Cerebrospinal fluid; L-AmB: Liposomal AmB; NA: Not applicable. fungal disease. In animals without CNS infection, CSF concentrations were very similar to those observed in serum. Among a group of 14 patients with invasive fungal infections, CSF concentrations of voriconazole were nearly half (46%) of those reported concomitantly in serum [39]. Brain tissue levels of voriconazole have also been reported in a patient with an intracerebral aspergillosis [40]. Drug concentrations in biopsies ranged 1.2 – 1.9 µg/g, indicating that voriconazole also accumulates in the brain parenchyma. These concentrations are above or near the MIC90 for most target fungal pathogens [41]. Other anecdotal publications also include measurement of voriconazole concentration in CSF or brain tissue and report similar findings. In humans treated for CNS aspergillosis, CSF concentrations have been measured in 38 – 68% of those observed in plasma [42-44]. Although clinical experience with voriconazole in treatment of CNS fungal infections is small, the limited reports suggest efficacy [41]. The most recently approved triazole, posaconazole, has not been evaluated as extensively with regard to CNS efficacy and no published or presented CNS kinetic studies are available at this time. However, the in vivo activity of posaconazole has been investigated in several animal models of CNS fungal infections with Aspergillus, Cryptococcus and Phaeohyphomycosis. In these studies, posaconazole was administered using clinically relevant dosing regimens and compared with either AmB or another triazole. Without exception, outcome following posaconazole therapy as measured by survival or fungal CNS burden was equivalent or superior to the other therapies [45-48]. 578 For example, Imai et al. found posaconazole therapy of CNS aspergillosis in neutropenic mice to be equivalent to AmB at reducing brain parenchymal organism burden [46]. It will be important for future studies to include kinetic investigation in the CNS. Given the structural similarities to itraconazole, one would anticipate low CSF concentrations, but significant accumulation in the brain parenchyma. Few anecdotal reports detail successful use of posaconazole for CNS fungal infections in humans [49]. Echinocandins The CNS pharmacokinetics of each of the three available echinocandin compounds, caspofungin, micafungin and anidulafungin, has been studied in detail using a non-infected rabbit model [50-52]. In each instance, the investigators have reported undetectable CSF concentrations even using dose levels far exceeding those used in current clinical regimens. However, these same investigations found brain parenchymal concentrations in the range of 10 – 20% of those measured in serum. For example, Groll et al. performed extensive tissue distribution studies with anidulafungin in healthy rabbits [51]. Although a CSF assay for anidulafungin did not identify a measurable amount of drug, brain parenchymal concentrations ranged 0.24 – 3.9 µg/g over a dose range of 0.5 – 10 mg/kg [51]. These tissue concentrations exceed the MIC90 of fungal pathogens in the echinocandin spectrum and would be anticipated to be sufficient for treatment success. This same research group has undertaken similar investigation of the CNS kinetics of caspofungin and micafungin and report nearly identical findings [50,52]. Numerous animal model studies have examined the efficacy of each of the echinocandin drugs in CNS fungal infection models [53-57]. Comparative studies using these models have examined echinocandin efficacy relative to other antifungal drugs and have demonstrated therapeutic equivalence. For example, Imai and colleagues compared the efficacy of conventional amphotericin, ABLC and caspofungin in a murine model of CNS aspergillosis [53]. Caspofungin prolonged survival in > 80% of infected animals when compared to controls [53]. Similar observations were made by Ibrahim and colleagues in a murine model of zygomycosis [54]. Singh et al. and Hussain et al. both found clinical efficacy of caspofungin in murine models of CNS aspergillosis and azole resistant candida meningitis, respectively [55,56]. Each of these studies did not include pharmacokinetic assays. However, in a recent study by Hope et al., micafungin was evaluated in a rabbit model of Candida meningoencephalitis. in which detailed kinetic evaluation was incorporated [58]. Similar to previous kinetic evaluation of micafungin, CSF concentrations were undetectable. However, parenchymal and meningeal concentrations of micafungin exceeded the MIC90 of the infecting organisms. In fact, the micafungin concentrations in the meningeal tissues were 10-fold greater than the brain parenchyma. The relationship between parenchymal micafungin concentrations and reduction in CNS Candida burden in Expert Opin. Drug Metab. Toxicol. (2007) 3(4) Kethireddy & Andes these experiments were strong. Furthermore, the tissue concentrations in these infected animals were nearly 30% greater than those previously observed in models without CNS inflammation [58]. Human CNS kinetic data with these compounds are not available. However, there are anecdotes and small case series suggesting clinical efficacy of caspofungin for patients with CNS fungal infection [59-62]. 8. Expert opinion Understanding the pharmacokinetics of antimicrobial compounds at the site of infection is important to optimize drug choice and dosing regimen design. The CNS represents a critical tissue site due to poor outcome of fungal infection at this site and variable kinetics due to the CNS blood barrier. The CSF kinetics of all available antifungals has been characterized in the CSF and brain parenchyma in animal models. Kinetics of these drugs differs markedly in the CSF. 1. 2. • 3. 4. 5. 6. 7. 8. DE LANGE ECM DM: Consideration in the use of cerebrspinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting. Clin. Pharmacokinet. (2002) 41(10):691-703. PARDRIDGE: Blood–brain barrier drug targeting: the future of brain drug development. Mol. Interven. (2003) 3(2):90-105. 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Agents Chemother. (2005) 49(12):5092-5098. Infect. Dis. Clin. North Am. (1999) 13(3):595-611. Bibliography Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers. However, each of the available drugs has been demonstrated to accumulate in the brain parenchyma at concentrations exceeding the MIC90 values of most infecting pathogens. Fewer clinical studies are available to corroborate these data. Investigation of the relationship between CNS antifungal concentrations and outcome are even more uncommon. However, the available data suggest a poor relationship between antifungal CSF concentration and outcome. Conversely, efficacy in these studies has been reasonably correlated with brain parenchymal antifungal penetration. Additional studies defining the relationship between antifungal concentrations in the CNS and treatment efficacy will be critical for optimal therapy of these increasingly common infections. 9. 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Affiliation Shravan Kethireddy & David Andes† †Author for correspondence University of Wisconsin School of Medicine and Public Health, Madison 600 Highland Ave, H4/572, Madison, WI 53792, USA Tel: +1 608 263 1545; Fax: +1 608 263 4464; E-mail: [email protected] 581