Experimental Central Nervous System Aspergillosis Therapy: Efficacy, Drug Levels and Localization, Immunohistopathology, and Toxicity

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>We have shown previously that high-dose lipid amphotericin preparations are not more efficacious than lower doses in aspergillosis. We studied toxicity, drug concentrations and localization, and quantitative infection concurrently, using a 4-day model of central nervous system (CNS) aspergillosis to assess early events. Mice given<jats:named-content xmlns:xlink="http://www.w3.org/1999/xlink" content-type="genus-species" xlink:type="simple">Aspergillus fumigatus</jats:named-content>conidia intracerebrally, under a cyclophosphamide immunosuppressive regimen, were treated for 3 days (AmBisome at 3 or 10 mg/kg of body weight, Abelcet at 10 mg/kg, amphotericin B deoxycholate at 1 mg/kg, caspofungin at 5 mg/kg, or voriconazole at 40 mg/kg). Sampling 24 h after the last treatment showed that AmBisome at 3 but not at 10 mg/kg, as well as Abelcet, caspofungin, and voriconazole, reduced brain CFU. All regimens reduced renal infection. Minor renal tubular changes occurred with AmBisome or Abelcet therapy, whereas heart, lung, and brain showed no drug toxicity. Amphotericin B tissue and serum concentrations did not correlate with efficacy. Endothelial cell activation (ICAM-1 and P-selectin in cerebral capillaries) occurred during infection. Amphotericin B derived from AmBisome and Abelcet localized in activated endothelium and from Abelcet in intravascular monocytes. In 10-day studies dosing uninfected mice, minor renal tubular changes occurred after AmBisome or Abelcet at 1, 5, or 10 mg/kg with or without cyclophosphamide treatment; nephrosis occurred only with Abelcet in cyclophosphamide-treated mice. Hepatotoxicity occurred with AmBisome and Abelcet but was reduced in cyclophosphamide-treated mice. Marked CFU reduction by AmBisome at 3 mg/kg occurred in association with relatively more intense inflammation. Abelcet renal localization appears to be a precursor to late nephrotoxicity. Hepatotoxicity may contribute to high-dose Abelcet and AmBisome failures. Our novel observation of endothelial amphotericin localization during infection may contribute to amphotericin mechanism of efficacy.</jats:p>

Tissue Penetration of Antifungal Agents

“…There must be colocalization of "drug and bug" within tissue beds and tissue subcompartments. Such considerations are relevant at the level of the organ and tissue subcompartments but may be elucidated further at the cellular and even molecular levels (25,26,27,28,29).…”

“…The potential reasons that tissue homogenates may provide inaccurate information regarding the "true" concentration at the site of infection include (i) discordance between intra-and extracellular drug concentrations versus where the pathogen is actually located, e.g., for posaconazole (33); (ii) multifocal versus diffuse disease, resulting in altered drug penetration at the site of infection compared with the normal contiguous tissue, e.g., pulmonary aspergilloma (257) or cerebral cryptococcoma (Fig. 6); (iii) the concentration of total versus biologically active drug, e.g., free amphotericin B versus drug that remains complexed to lipid (29,52,53,54); and (iv) incomplete extraction of drug from tissue, e.g., for amphotericin B (29,52,53,54).…”

“…(ii) physiological factors, such as inflammation, which may increase tissue permeability, i.e., by disruption of normal physiological barriers such as the blood-brain barrier (29,40); the underlying disease (41), which may result in a range of effects, including modification of plasma protein composition and hence drug binding (42,43,44); the recruitment of drug-containing phagocytic cells, i.e., the "dump truck phenomenon," which may increase drug concentrations at the site of infection (12,13,32,45,46); drug export via pumps, e.g., for itraconazole and P-glycopro- Fluid multiples are from g/ml concentrations. *, autopsy data; in these cases, the multiples are based on plasma C max values at the same dose in volunteers (188).…”

Very-High-Dose Caspofungin Combined with Voriconazole To Treat Central Nervous System Aspergillosis: Substantial Penetration of Caspofungin into Cerebrospinal Fluid

“…These data are in line with data from experimental studies showing that brain caspofungin levels are higher in infected animals (8) and with numerous data showing that the penetration of hydrophilic antiinfective drugs increases with the intensity of blood-brain barrier inflammation. Moreover, in an animal model of CNS aspergillosis, caspofungin significantly reduced the fungal burden (9).…”

Chronic Invasive Aspergillus Sinusitis and Otitis with Meningeal Extension Successfully Treated with Voriconazole

“…It has good penetration across the blood-brain barrier, and its CNS concentrations exceed inhibitory concentrations for Aspergillus spp. (19,20). However, the Infectious Diseases Society of America recommends surgery in combination with antifungal therapy for osteomyelitis and cerebral lesions.…”