Nebulized Liposomal Amphotericin B Prophylaxis for Aspergillus Infection in Lung Transplantation: Pharmacokinetics and Safety

Monforte, Vı́ctor; Ussetti, Piedad; López, Rosa María; Gavaldá, Joan; Bravo, Carles; Pablo, Alicia de; Pou, Leonor; Pahissa, Albert; Morell, Ferrán; Román, Antonio

doi:10.1016/j.healun.2008.11.004

Cited by 99 publications

(87 citation statements)

References 25 publications

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“…The number of complaints vs the number of doses administered was 1.2% and 1.0%, respectively. 12 In a previous study, 16 we found no changes in the mean FEV 1 value before and after n-LAB. A significant FEV 1 decrease (14%) was observed in only 1 of 22 patients, who, nonetheless, remained asymptomatic.…”

Section: Discussionmentioning

confidence: 53%

“…12,15 Other forms of amphotericin B, such as nebulized liposomal amphotericin B (n-LAB) could also be used as prophylaxis. In a previous pharmacokinetic study, 16 we found high concentrations of amphotericin B in the respiratory tract of lung transplant patients 14 days after a 25-mg dose of n-LAB. No significant systemic absorption of amphotericin B was detected, and no effect was observed on respiratory function measured by spirometry.…”

mentioning

confidence: 62%

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Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation

Monforte

Ussetti

Gavaldá

et al. 2010

The Journal of Heart and Lung Transplantation

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100

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Section: Discussionmentioning

confidence: 53%

mentioning

confidence: 62%

Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation

Monforte

Ussetti

Gavaldá

et al. 2010

The Journal of Heart and Lung Transplantation

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100

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“…Concentrations of amphotericin B in bronchoalveolar lavage specimens remained high enough to inhibit the growth of most Aspergillus species over a 14-day treatment period [151]. Similar to findings from studies involving amphotericin B deoxycholate and Abelcet Ò , serum concentrations of amphotericin B following aerosolized administration of AmBisome Ò were undetectable in all but one patient, and that patient's concentration was 0.1 lg/mL (slightly above the lower limit of quantitation) [151]. Overall, these results demonstrate the superior pharmacokinetic profile of aerosolized amphotericin B formulations as compared with parenterally administered amphotericin B for the treatment of pulmonary fungal infections.…”

Section: Amphotericinmentioning

confidence: 97%

“…The pharmacokinetics of a colloidal dispersion of amphotericin B (AmBisome Ò ) were investigated in 27 patients who received 50 mg of AmBisome Ò three times per week [151]. Concentrations of amphotericin B in bronchoalveolar lavage specimens remained high enough to inhibit the growth of most Aspergillus species over a 14-day treatment period [151].…”

Section: Amphotericinmentioning

confidence: 99%

Clinical Pharmacokinetics of Inhaled Antimicrobials

2015

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Administration of inhaled antimicrobials affords the ability to achieve targeted drug delivery into the respiratory tract, rapid entry into the systemic circulation, high bioavailability and minimal metabolism. These unique pharmacokinetic characteristics make inhaled antimicrobial delivery attractive for the treatment of many pulmonary diseases. This review examines recent pharmacokinetic trials with inhaled antibacterials, antivirals and antifungals, with an emphasis on the clinical implications of these studies. The majority of these studies revealed evidence of high antimicrobial concentrations in the airway with limited systemic exposure, thereby reducing the risk of toxicity. Sputum pharmacokinetics varied widely, which makes it challenging to interpret the result of sputum pharmacokinetic studies. Many no vel inhaled antimicrobial therapies are currently under investigation that will require detailed pharmacokinetic studies, including combination inhaled antimicrobial therapies, inhaled nanoparticle formulations of several antibacterials, inhaled non-antimicrobial adjuvants, inhaled antiviral recombinant protein therapies and semi-synthetic inhaled antifungal agents. Additionally, the development of new inhaled delivery devices, particularly for mechanically ventilated patients, will result in a pressing need for additional pharmacokinetic studies to identify optimal dosing regimens.

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“…AMB was undetectable in plasma of all but one patient, suggesting a poor systemic absorption and penetration into deeper lung compartments (20).…”

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confidence: 92%

Pulmonary Epithelial Lining Fluid Concentrations after Use of Systemic Amphotericin B Lipid Formulations

Weiler

Falkensammer²,

Hammerer-Lercher³

et al. 2009

Antimicrob Agents Chemother

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Amphotericin B (AMB) concentrations were determined in pulmonary epithelial lining fluid (ELF) of 44 critically ill patients, who were receiving treatment with liposomal AMB (LAMB) (n ‫؍‬ 11), AMB colloidal dispersion (ABCD) (n ‫؍‬ 28), or AMB lipid complex (ABLC) (n ‫؍‬ 5). Mean AMB levels (؎ standard errors of the means) in ELF amounted to 1.60 ؎ 0.58, 0.38 ؎ 0.07, and 1.29 ؎ 0.71 g/ml in LAMB-, ABCD-, and ABLC-treated patients, respectively (differences are not significant).Invasive pulmonary mycoses exhibit a high mortality, particularly in critically ill patients (19). Amphotericin B (AMB) lipid formulations-liposomal AMB (AmBisome; Gilead) (LAMB), AMB colloidal dispersion (Amphotec [Three Rivers] and Amphocil [Torrex-Chiesi]) (ABCD), and AMB lipid complex (Abelcet; Zeneus) (ABLC)-display differences in plasma pharmacokinetics and tissue distribution (15,26,28). During treatment with AMB lipid formulations, AMB concentrations were investigated in epithelial lining fluid (ELF), which is a well-established model for pulmonary drug penetration (1-4, 6-10, 12, 17).This study was approved by the local ethics committee. Patients on lipid-formulated AMB requiring bronchoalveolar lavage (BAL) were enrolled (Table 1). AMB concentrations were assessed in 8-ml aliquots of BAL samples obtained by a standard procedure (16). BAL fluid was concentrated by evaporation, and AMB was quantified by high-performance liquid chromatography as described previously, with modifications for BAL samples (13). The concentrations were assessed by using a linear standard curve (R between 0.995 and 0.999), obtained from standards comprising 0.9% saline solution spiked with AMB. The lower detection limit of AMB in BAL fluid was 0.005 g/ml. The assay has been found to be linear over the concentration range of 0.005 to 2.5 g/ml for AMB in BAL fluid. The intraday and interday precisions were 3.2% and 4.7%, respectively. AMB concentrations in ELF were calculated by the urea dilution method (23), AMB ELF ϭ AMB BAL ϫ (urea PLA /urea BAL ), where AMB ELF is the AMB concentration in ELF, AMB BAL is the AMB concentration in BAL fluid, urea PLA is the urea concentration in plasma, and urea BAL is the urea concentration in BAL fluid (23). Two ml of the BAL fluid was separated for urea quantification, which was performed using an enzymatic assay (urea/blood urea nitrogen; Roche) as with plasma.Arterial blood samples were simultaneously taken for measurement of plasma AMB and urea concentrations. In patients on LAMB or ABCD therapy, the lipid-associated fractions were separated from AMB that had been liberated from its lipid encapsulation. AMB was measured with high-performance liquid chromatography as described previously (13).Statistical analysis was performed using the Statistica software program, version 5. The differences between total AMB concentrations in plasma and in ELF were analyzed by using the Wilcoxon matched pairs test. For comparisons between the lipid formulations, the Mann-Whitney U test was applied.Forty-four patients were enrolled:...

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Nebulized Liposomal Amphotericin B Prophylaxis for Aspergillus Infection in Lung Transplantation: Pharmacokinetics and Safety

Cited by 99 publications

References 25 publications

Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation

Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation

Clinical Pharmacokinetics of Inhaled Antimicrobials

Pulmonary Epithelial Lining Fluid Concentrations after Use of Systemic Amphotericin B Lipid Formulations

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