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Antimicrobial Agents and Chemotherapy, November 2007, p. 4211-4213, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01087-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Penetration of Amphotericin B Lipid Formulations into Pleural Effusion{triangledown}

Stefan Weiler,1 Rosa Bellmann-Weiler,2 Michael Joannidis,3 and Romuald Bellmann1,3*

Clinical Pharmacokinetics Unit, Inflammation Research Laboratory,1 Infectious Diseases Unit,2 Medical Intensive Care Unit, Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical School, Innsbruck, Austria3

Received 18 August 2007/ Returned for modification 22 August 2007/ Accepted 24 August 2007


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ABSTRACT
 
The penetration of the amphotericin B (AMB) lipid formulations (liposomal AMB, AMB colloidal dispersion, and AMB lipid complex formulations) into pleural effusions in seven critically ill patients was assessed. AMB was detected in all pleural effusion samples at concentrations ranging from 0.02 to 0.43 µg/ml. The penetration ratio was 3 to 44%.


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TEXT
 
Invasive fungal infections are a major cause of morbidity and mortality in immunocompromised patients, particularly when the pleural compartment is affected (9). Although many studies on the penetration of antibacterial agents into pleural effusions have been performed, less attention has been paid to target site concentrations of antimycotic drugs in pleural effusions (2, 8, 12, 15-17, 22, 23). Amphotericin B (AMB) lipid formulations have been introduced in therapy to reduce the toxicity of AMB. The lipid moieties of liposomal AMB (LAMB), the AMB colloidal dispersion formulation (ABCD), and the AMB lipid complex (ABLC) exhibit different compositions, structures, and particle sizes, which are reflected in different plasma pharmacokinetics and degrees of lung penetration (1, 7, 19, 21). The aim of the present study was to investigate AMB penetration into pleural effusions during treatment with LAMB, ABCD, or ABLC.

The study was approved by the local ethics committee. We determined AMB levels in specimens from seven critically ill patients treated with LAMB (one patient [two sample sets]), ABCD (five patients), or ABLC (one patient) for suspected invasive fungal infection. Demographic and clinical characteristics of the enrolled patients are shown in Table 1. LAMB (AmBisome; Gilead, San Dimas, CA), ABCD (Amphocil; Torrex-Chiesi Pharma, Vienna, Austria), and ABLC (Abelcet; Elan Pharma International Limited, Athlone, Ireland) were dissolved as recommended by the manufacturers and administered intravenously at doses of 3 to 5 mg/kg of body weight over 4 h once a day. Aliquots of pleural effusions were taken during therapeutic thoracentesis. Blood samples were drawn simultaneously from an arterial line and were centrifuged immediately. The plasma and the pleural effusion samples were stored frozen at –80°C. Samples were purified and concentrated. The lipid-associated fractions of LAMB and ABCD were separated from AMB that had been liberated from its lipid encapsulation (comprising free and protein-bound AMB) by C18 solid-phase extraction as described previously (with modifications for pleural effusion samples) (3). For ABLC, this separation technique is not feasible. Pleural effusion and plasma specimens were analyzed by reversed-phase high-performance liquid chromatography using a LiChrosorb-RP-8 column, UV detection ({lambda} = 405 nm), and acetonitrile-methanol-0.010 M NaH2PO4 buffer (41:10:49, vol/vol) as the mobile phase (3). The detection limit was 0.005 µg/ml. The intra-assay coefficient of variation was 2.06%. The concentrations were assessed by means of a linear standard curve (R, 0.998 to 0.999) obtained by using external standards comprising pleural effusion samples spiked with AMB. Total AMB concentrations were obtained by adding the concentrations of liberated and lipid-associated AMB. The penetration ratio was defined as follows: AMB concentration in pleural effusion sample/simultaneous AMB level in plasma sample, expressed as a percentage. Statistical calculations were performed using Statistica 5.1 (1997; StatSoft, Inc., Tulsa, OK). The Wilcoxon matched-pair test was used to analyze the differences between total AMB concentrations in plasma and pleural effusion samples.


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  		TABLE 1. Demographic and clinical characteristics of patientsa

AMB concentrations in plasma and pleural effusion samples and the penetration ratios are displayed in Table 2. Liberated AMB could be detected in all samples of pleural effusions and plasma. In pleural effusion samples, total AMB concentrations were significantly lower than the total concentrations in plasma samples (P = 0.03). Concentrations of the lipid-associated fractions of ABCD and LAMB, measured in pleural effusion samples, were very low (<0.03 µg/ml; in four samples, they were even below the detection limit). The highest AMB concentration in a pleural effusion was found in a sample from patient 1 (0.43 µg/ml), who had been treated with LAMB at a daily dose of 300 mg for 4 days. AMB concentrations in pleural effusions correlated positively with the cumulative dose administered to patients treated with ABCD (R = 0.96; P = 0.01). The AMB concentration in the pleural effusion from patient 7, who had received a cumulative dose of 12,750 mg of ABLC, reached 0.18 µg/ml (penetration ratio, 44%). The respective level in plasma was as low as 0.4 µg/ml.


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  		TABLE 2. Concentrations of AMB in plasma and pleural effusion samplesa

Since several mycoses, such as candidiasis, aspergillosis, blastomycosis, histoplasmosis, cryptococcosis, and coccidioidomycosis, can cause pleural manifestations (5, 6, 9, 11, 13, 20), AMB concentrations in pleural effusions can be crucial for clinical response. After treatment with AMB lipid formulations, AMB concentrations were substantially lower in pleural effusions than in plasma samples and lung tissue (19). However, the small number of patients, the different underlying clinical conditions of the patients, and the differences in cumulative doses are clear limitations of our study and preclude a comparison among the lipid formulations.

Median intraperitoneal levels of AMB previously amounted to 0.12 µg/ml in samples from critically ill patients during intravenous treatment with AMB deoxycholate (18), which is comparable to our results for pleural effusion samples. In noninfected rabbits, total AMB concentrations were much lower in alveolar epithelial lining fluid than in lung tissue (7). By the separation of lipid-associated and liberated AMB, we could show that only AMB that has been liberated from its lipid encapsulation penetrates into pleural effusions.

The MIC of AMB has been reported to range from 0.125 to 1 mg/liter for Candida spp. (14), from 0.25 to 4 mg/liter for Aspergillus spp., and from <0.03 to 2 mg/liter for relevant dimorphic fungi, such as Blastomyces dermatitidis and Histoplasma capsulatum (4). Thus, the MIC may exceed in some cases the pleural AMB concentrations that are achieved by therapeutic dosage. Samples from patients 1 and 6, which exhibited the highest levels of AMB in pleural effusions, met the criteria for an exudate (10). This finding may indicate that the presence of local inflammation increases the penetration of AMB into pleural effusions. However, none of our patients suffered from fungal empyema thoracis. Recently, voriconazole was found to achieve penetration ratios of 45 to 95% in cases of pleural empyema caused by Aspergillus fumigatus (15).

In conclusion, AMB levels in pleural effusions were in the range of—or even below-the MICs of AMB for most relevant pathogens after the administration of AMB lipid formulations. Therefore, long-term treatment with high doses of AMB lipid formulations will be required for the eradication of fungal infection from pleural effusions, and alternative therapeutic strategies have to be considered. Further clinical studies are required to elucidate the penetration of antimycotics into pleural effusions.


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ACKNOWLEDGMENTS
 
This study was supported by the Tiroler Wissenschaftsfonds and Torrex-Chiesi Pharma, Austria.


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FOOTNOTES
 
* Corresponding author. Mailing address: Division of General Internal Medicine, Department of Internal Medicine, Innsbruck Medical School, Anichstrasse 35, A-6020 Innsbruck, Austria. Phone: 43 512 504 81389. Fax: 43 512 504 24199. E-mail: romuald.bellmann{at}i-med.ac.at Back

{triangledown} Published ahead of print on 4 September 2007. Back


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Antimicrobial Agents and Chemotherapy, November 2007, p. 4211-4213, Vol. 51, No. 11
0066-4804/07/$08.00+0     doi:10.1128/AAC.01087-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.




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