Prophylaxis with nebulized liposomal amphotericin B for Aspergillus infection in lung transplant patients does not cause changes in the lipid content of pulmonary surfactant

doi:10.1016/j.healun.2012.11.013

The Journal of Heart and Lung Transplantation

Volume 32, Issue 3, March 2013, Pages 313-319

https://doi.org/10.1016/j.healun.2012.11.013 Get rights and content

Background

Prophylaxis with inhaled liposomal amphotericin B has proven to be safe and effective for preventing infection due to Aspergillus spp in lung transplant recipients. However, the liposome contains a large quantity of phospholipids, and inhalation of these substances could potentially change the composition of pulmonary surfactant. The aim of this study was to determine the lipid composition of pulmonary surfactant in patients receiving inhaled liposomal amphotericin B prophylaxis.

Methods

A prospective, open, controlled multicenter study was conducted in 2 groups: 19 lung transplant recipients who received regular prophylaxis with inhaled amphotericin B (study group) and 19 recipients who did not receive inhaled prophylaxis (control group). From both groups, 15 ml of the third aliquot of bronchoalveolar lavage fluid was obtained and phospholipid content determined in the active fraction of surfactant (large aggregates) and in the inactive fraction (small aggregates). Large aggregate cholesterol content was also determined.

Results

Patient demographic data and characteristics were similar in the 2 groups. No between-group differences in median phospholipid content were found for large aggregates (study group, 0.4 [range, 0.18–1.9] μmol vs controls, 0.36 [range 2.15–0.12] μmol; p = 0.69) or small aggregates (study group, 0.23 [range, 0.1–0.58] μmol vs controls, 0.29 [range, 0.18–0.65] μmol; p = 0.33). The small aggregate-to-large aggregate phospholipid ratio, commonly used as a marker of alveolar injury, showed no differences between the groups (study group, 0.56 vs controls, 0.69; p = 0.28). Nor were there differences in the cholesterol content of large aggregates (study group, 0.04 μmol [range 0.01–0.1] vs controls, 0.04 μmol [range 0.02–0.27); p = 0.13).

Conclusions

These results seem to indicate that prophylaxis with nebulized liposomal amphotericin B does not cause changes in the lipid content of pulmonary surfactant.

Section snippets

Methods

This study was approved by the Ethics Committee of Hospital Universitari Vall d’Hebron and the Research Committee of Hospital Universitario Puerta de Hierro. Patients who took part in the study gave informed consent for participation.

Results

Patient characteristics are reported in Table 1. The 2 study groups did not differ with respect to demographic variables or characteristics (Table 1). Patients received a median of 24 n-LAB doses (range, 6–128) before BAL was obtained, which represents a median cumulative amphotericin B dose of 600 mg (range, 150–3,200 mg). The median of timing of BAL in relationship with the LAB dose was 3 days (range, 0.5–15 days).

The median phospholipid content of LA was 0.40 μmol (range, 0.18–1.9 μmol) in

Discussion

The negative result obtained—no differences between groups—is a new piece of the puzzle providing additional information about safety in this type of prophylaxis. In this study evaluating the effect of inhaled LAB on human pulmonary surfactant, we found no differences in the lipid composition of surfactant between lung transplant recipients who received LAB and those who did not. The content of phospholipids in the LA (active fraction) and the SA (inactive fraction) was similar in the 2 groups.

Disclosure statement

This study was supported by a Spanish Society of Pneumology and Thoracic Surgery grant (2005).

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

References (41)

C.F. Neoh et al.
Antifungal prophylaxis in lung transplantation—a world-wide survey
Am J Transplant
(2011)
J.S. Dummer et al.
A survey of anti-fungal management in lung transplantation
J Heart Lung Transplant
(2004)
J.M. Borro et al.
Efficiency and safety of inhaled amphotericin B lipid complex (Abelcet) in the prophylaxis of invasive fungal infections following lung transplantation
Transplant Proc
(2008)
T.E. Corcoran et al.
Aerosol deposition of lipid complex amphotericin-B (Abelcet) in lung transplant recipients
Am J Transplant
(2006)
V. Monforte et al.
Nebulized amphotericin B prophylaxis for Aspergillus infection in lung transplantation: study of risk factors
J Heart Lung Transplant
(2001)
H. Reichenspurner et al.
Significant reduction in the number of fungal infections after lung-, heart-lung, and heart transplantation using aerosolized amphotericin B prophylaxis
Transplant Proc
(1997)
V. Monforte et al.
Feasibility, tolerability, and outcomes of nebulized liposomal amphotericin B for Aspergillus infection prevention in lung transplantation
J Heart Lung Transplant
(2010)
V. Monforte et al.
Nebulized liposomal amphotericin B prophylaxis for Aspergillus infection in lung transplantation: pharmacokinetics and safety
J Heart Lung Transplant
(2009)
B.C. Cahill et al.
Aspergillus airway colonization and invasive disease after lung transplantation
Chest
(1997)
F.D. Kermeen et al.
Resolution of severe ischemia-reperfusion injury post-lung transplantation after administration of endobronchial surfactant
J Heart Lung Transplant
(2007)

M. Struber et al.

Effects of exogenous surfactant instillation in clinical lung transplantation: a prospective, randomized trial

J Thorac Cardiovasc Surg

(2007)

B.P. van Putte et al.

Exogenous surfactant attenuation of ischemia-reperfusion injury in the lung through alteration of inflammatory and apoptotic factors

J Thorac Cardiovasc Surg

(2009)

A.A. Gal et al.

Cytopathology of pulmonary alveolar proteinosis complicating lung transplantation

J Heart Lung Transplant

(2004)

F. D’Ovidio et al.

The effect of reflux and bile acid aspiration on the lung allograft and its surfactant and innate immunity molecules SP-A and SP-D

Am J Transplant

(2006)

S. Husain et al.

Variation in antifungal prophylaxis strategies in lung transplantation

Transpl Infect Dis

(2006)

S. Husain et al.

Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients

Transplantation

(2010)

R.H. Drew et al.

Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients

Transplantation

(2004)

V. Monforte et al.

Nebulized amphotericin B concentration and distribution in the respiratory tract of lung-transplanted patients

Transplantation

(2003)

S.M. Palmer et al.

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients

Transplantation

(2001)

C.M. Lowry et al.

Safety of aerosolized liposomal versus deoxycholate amphotericin B formulations for prevention of invasive fungal infections following lung transplantation: a retrospective study

Transpl Infect Dis

(2007)

Cited by (38)

Safety and usefulness of nebulized liposomal amphotericin B: Systematic scoping review
2023, Pulmonary Pharmacology and Therapeutics
Invasive fungal infections potentially result in fatal outcomes in immunocompromised hosts. Compared to intravenous administration, a nebulization therapy can achieve a high concentration of drug delivered in the respiratory tract, without a systematic absorption. We herein summarized the study findings on the safety and clinical utility of nebulized liposomal amphotericin B therapy.
According to the PRISMA Extension for Scoping Reviews, we performed a search on MEDLINE and EMBASE for articles with relevant keywords, including “inhaled liposomal amphotericin B″, “nebulized liposomal amphotericin B″, or “aerosolized liposomal amphotericin B″, from the inception of these databases to August 31, 2022.
Of the 172 articles found, 27 articles, including 13 case reports, 11 observational studies, and 3 clinical trials, were selected. Generally, findings showed that nebulized liposomal amphotericin B treatment appeared to be safe and without severe adverse effects. We found an accumulated evidence for the safety, tolerability, and effectiveness of nebulized liposomal amphotericin B prophylaxis among lung transplantation recipients; however, a randomized controlled study has yet to be reported. Data on hemato-oncological patients are relatively scarce; however, a randomized controlled study suggested the prophylactic effect of nebulized liposomal amphotericin B on invasive pulmonary aspergillosis. Observational and randomized controlled studies to evaluate therapeutic efficacy of the nebulized liposomal amphotericin B therapy have not been performed.
In conclusion, we found increasing evidence for the effectiveness of the inhalation therapy among patients after lung transplantation and with hemato-oncological diseases.
Filamentous fungi in the airway of patients with cystic fibrosis: Just spectators?
2021, Revista Iberoamericana de Micologia
Citation Excerpt :
Twenty six patients of the group with chronic filamentous fungus colonization (65%) received a protocolized long-term antifungal treatment during the three years of follow-up. The therapeutic protocol consisted in having inhaled amphotericin B lipid complex or azoles.15,23 The inhaled amphotericin B dose was 25 mg three times a week for two months, followed by a weekly dose for 6 months and, lastly, two doses per month until the end of the follow-up period.
There are important advances in the management of bacterial infection in patients with cystic fibrosis (CF), but there are many gaps in the field of fungal infections.
The aim of this study was to analyse whether chronic respiratory filamentous fungal colonization had clinical impact and whether antifungal treatment can change the disease.
The prospective, bicentric and descriptive study was carried out within a 3-year follow-up period, with four-month periodicity medical controls. Adult patients from two CF units of tertiary hospitals were included. Clinical, microbiological, analytical and spirometric variables were collected. Quality of life was evaluated in a subgroup, using the Spanish version of the Revised Cystic Fibrosis Quality of Life Questionnaire (CFQ-R). To statistically analyze the evolution of forced expiratory along time (volume of air blown out in 1 second -FEV₁-) and the forced vital capacity (FVC), mixed linear models were carried out.
From the ninety-eight patients under study, 40 suffered chronic filamentous fungal colonization. The presence of filamentous fungi in airway was associated to an annual fall of FEV₁ and FVC of 0.029 and 0.017 litres, respectively (p<0.001). In addition, worse quality of life based on CFQ-R, significant when concerning physical condition and emotional state, was also linked with the fungal colonization. Protocolized antifungal therapy, nebulized or oral, improved FEV₁ in 0.023 and 0.024 litres per year, respectively (p<0.001).
Chronic filamentous fungal colonization in patients with CF is associated with a significant annual decline of lung function that persists over time. Chronic antifungal therapy slows down this progression, mainly in the patient with more advanced disease.
Existen avances importantes en el manejo de la infección bacteriana en pacientes con fibrosis quística (FQ), pero hay muchas lagunas en el campo de las infecciones fúngicas.
El objetivo del estudio fue analizar si la colonización respiratoria crónica por hongos filamentosos tenía impacto clínico y si el tratamiento antifúngico modificaba la enfermedad.
Estudio prospectivo, bicéntrico y descriptivo con un seguimiento de 3 años y controles médicos cuatrimestrales. Se incluyeron pacientes adultos de dos Unidades de Fibrosis Quística de hospitales terciarios. Se recogieron datos de variables clínicas, microbiológicas, analíticas y espirométricas; en un subgrupo se evaluó la calidad de vida mediante el cuestionario específico para FQ (CFQ-R). Para analizar estadísticamente la evolución a lo largo del tiempo del volumen espiratorio máximo en el primer segundo (FEV₁) y la capacidad vital forzada (FVC) se realizaron modelos lineales mixtos.
De los 98 pacientes incluidos en el estudio, 40 presentaron colonización crónica por hongos filamentosos. La presencia de hongos filamentosos en la vía aérea se asoció a una caída anual del FEV₁ y FVC de 0,029 y 0,017 litros, respectivamente (p<0,001), además de a una peor calidad de vida según el CFQ-R, significativa en cuestiones como la capacidad física y el estado emocional. La terapia antifúngica protocolizada, nebulizada u oral, mejoraron el FEV₁ 0,023 y 0,024 litros al año, respectivamente (p<0,001).
La colonización crónica por hongos filamentosos en pacientes con FQ se asocia a una caída anual de la función pulmonar significativa que persiste en el tiempo. El tratamiento antifúngico protocolizado ralentiza este deterioro funcional, fundamentalmente en el paciente con enfermedad más avanzada.
Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline
2018, Clinical Microbiology and Infection
The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.
A cell impedance-based real-time in vitro assay to assess the toxicity of amphotericin B formulations
2017, Toxicology and Applied Pharmacology
Citation Excerpt :
As the portal of entry of mold spores is mainly the respiratory tract, antifungal administration through the pulmonary route has been proposed to directly target the fungus while reducing systemic toxicity compared with intravenous administration (Ruijgrok 2001; Takazono 2009). Experimental and clinical studies have suggested the utility of liposomal amphotericin B (L-AmB) aerosols for the prophylaxis of invasive aspergillosis (Palmer et al., 2001; Ruijgrok et al., 2001; Drew et al., 2004; Gavalda et al., 2005; Lowry et al., 2007; Rijnders et al., 2008; Takazono et al., 2009; Monforte et al., 2013). However, even inhaled L-AmB has been shown to present some side effects the origin of which is not yet clear: in a randomized placebo-controlled trial, coughing was reported to be more frequent in patients on L-AmB inhalation than in patients on placebo inhalation (Slobbe et al., 2008).
Aerosolized liposomal amphotericin B (L-AmB) has been investigated as prophylaxis against invasive aspergillosis. However, the clinical results are controversial and some trials suggest that toxicity could be a limitation for wider use. Our aim was to assess the dynamics of cell toxicity induced in a human alveolar epithelial cell line (A549) after exposure to L-AmB (50 to 400 μg/ml) or amphotericin B deoxycholate (D-AmB; 50 to 200 μg/ml) by monitoring real-time A549 cell viability using an impedance-based technology. Results were expressed as cell index values integrating cell adhesion, proliferation, and survival. In parallel, the gene expression of proinflammatory cytokines was quantified at 6 and 24 h after drug addition by real-time RT-PCR on cell lysates. No sustained reduction of cell indexes was observed with L-AmB or empty liposomes, even at 400 μg/ml. Only the highest concentration tested of L-AmB (400 μg/ml) yielded transient significant 6-fold and 4-fold induction of TNF-α and IL-8 mRNAs, respectively. In contrast, D-AmB induced a decrease in cell indexes and only the 50 μg/ml concentration of D-AmB was followed by cell recovery, higher concentrations leading to cell death. Significant 4-fold, 7-fold and 3-fold inductions of TNF-α, IL-8 and IL-33 mRNAs were also observed at 6 h with 50 μg/ml of D-AmB. In conclusion, continuous cell impedance measurement showed no toxicity on overall cellular behavior although a slight proinflammatory cytokine expression is possible after L-AmB challenge. Real-time kinetics of cell impedance is an interesting tool for initial screening of cell toxicity.
Aerosolized amphotericin B as prophylaxis for invasive pulmonary aspergillosis: A meta-analysis
2015, International Journal of Infectious Diseases
Citation Excerpt :
They also found that nebulized L-AMB does not change the lipid content of pulmonary surfactant. This agent safely and effectively prevents Aspergillus spp infection in lung transplant recipients.31 Different AMB formulations may have different clinical effects because each has a distinct pharmacological profile.
Invasive pulmonary aspergillosis (IPA) is associated with high mortality in high-risk (immunosuppressed) patients. Many studies have investigated whether prophylactic inhalation of amphotericin B (AMB) reduces the incidence of IPA, but no definitive conclusions have been reached. The present meta-analysis was performed to evaluate the efficacy of prophylactic inhalation of AMB for the prevention of IPA.
MEDLINE and other databases were searched for relevant articles published until December 2013. Randomized controlled trials that compared aerosolized AMB with placebo were included. Two reviewers independently assessed and extracted the data of all trials.
Six animal studies and two clinical trials involving 768 high-risk patients were eligible. The animal studies showed lower overall mortality rate among animals that underwent aerosolized AMB prophylaxis (odds ratio (OR) 0.13, 95% confidence interval (CI) 0.08–0.21). Similarly, the clinical trials showed a lower incidence of IPA among patients who underwent aerosolized AMB prophylaxis (OR 0.42, 95% CI 0.22–0.79).
This analysis provides evidence supporting the notion that the prophylactic use of aerosolized AMB effectively reduces the incidence of IPA among high-risk patients.
Nebulized Therapy. SEPAR Year
2014, Archivos de Bronconeumologia
Citation Excerpt :
Inhaled amphotericin is the most common preventive strategy.104 It has good distribution at pulmonary level105 without modifying surfactant lipid levels,106 and has very low systemic absorption. It comes in 3 presentations: amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B.
Inhaled drugs are deposited directly in the respiratory tract. They therefore achieve higher concentrations with faster onset of action and fewer side effects than when used systemically. Nebulized drugs are mainly recommended for patients that require high doses of bronchodilators, when they need to inhale drugs that only exist in this form (antibiotics or dornase alfa) or when they are unable to use other inhalation devices. Technological development in recent years has led to new devices that optimize pulmonary deposits and reduce the time needed for treatment. In this review we focus solely on drugs currently used, or under investigation, for nebulization in adult patients, basically bronchodilators, inhaled steroids, antibiotics, antifungals, mucolytics and others such as anticoagulants, prostanoids, and lidocaine.
Los fármacos inhalados se depositan directamente en el tracto respiratorio, con lo que se alcanzan altas concentraciones, con un inicio de acción más rápido y con menores efectos secundarios que si se emplea la vía sistémica. Los fármacos nebulizados se recomiendan fundamentalmente en pacientes que requieren dosis altas de broncodilatadores, cuando precisan inhalar fármacos que solo pueden administrarse nebulizados (como los antibióticos o la dornasa alfa) y si no son capaces de utilizar otros dispositivos de inhalación. El desarrollo tecnológico de los últimos años ha permitido contar con dispositivos que optimizan el depósito pulmonar y disminuyen el tiempo necesario para realizar el tratamiento. En esta revisión nos ceñiremos únicamente a aquellos fármacos que se administran –o están en investigación– en nebulización en pacientes adultos; fundamentalmente a los broncodilatadores, corticoides inhalados, antibióticos, antifúngicos, mucolíticos y otros como los prostanoides, los anticoagulantes o la lidocaína.

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Original clinical scienceProphylaxis with nebulized liposomal amphotericin B for Aspergillus infection in lung transplant patients does not cause changes in the lipid content of pulmonary surfactant

Background

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Disclosure statement

Am J Transplant

J Heart Lung Transplant

Transplant Proc

Am J Transplant

J Heart Lung Transplant

Transplant Proc

J Heart Lung Transplant

J Heart Lung Transplant

Chest

J Heart Lung Transplant

J Thorac Cardiovasc Surg

J Thorac Cardiovasc Surg

J Heart Lung Transplant

Am J Transplant

Variation in antifungal prophylaxis strategies in lung transplantation

Transpl Infect Dis

Intrapulmonary disposition of amphotericin B after aerosolized delivery of amphotericin B lipid complex (Abelcet; ABLC) in lung transplant recipients

Transplantation

Comparative safety of amphotericin B lipid complex and amphotericin B deoxycholate as aerosolized antifungal prophylaxis in lung-transplant recipients

Transplantation

Nebulized amphotericin B concentration and distribution in the respiratory tract of lung-transplanted patients

Transplantation

Safety of aerosolized amphotericin B lipid complex in lung transplant recipients

Transplantation

Safety of aerosolized liposomal versus deoxycholate amphotericin B formulations for prevention of invasive fungal infections following lung transplantation: a retrospective study

Transpl Infect Dis

Original clinical science
Prophylaxis with nebulized liposomal amphotericin B for Aspergillus infection in lung transplant patients does not cause changes in the lipid content of pulmonary surfactant