- Email: [email protected]
Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature
JCF-00985; No of Pages 3
Journal of Cystic Fibrosis xx (2013) xxx – xxx www.elsevier.com/locate/jcf
Short Communication
Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature J. Holle ⁎, M. Leichsenring, P.E. Meissner Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Eythstrasse 24, 89075 Ulm, Germany Received 1 September 2013; received in revised form 29 October 2013; accepted 30 October 2013 Available online xxxx
Abstract Scedosporium infections are rare complications in immunocompromised patients or patients with chronic pulmonary disease. While Scedosporium prolificans is resistant to most antimycotics, Scedosporium apiospermum is usually sensitive to voriconazole and posaconazole. Pharmacokinetics and efficacy of nebulized voriconazole have been described in a murine model previously. We report for the first time the safe and effective use of nebulized voriconazole for the treatment of severe pulmonary infection with Scedosporium apiospermum in an adolescent with cystic fribrosis. © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Scedosporium apiospermum; Cystic fibrosis; Antimycotic treatment; Fungal infections
Infections due to Scedosporium species in humans are rare and caused predominantly by S. apiospermum and S. prolificans. Invasive infections are mainly seen in immunodeficient patients, due to chronic steroid use, hematopoietic stem cell or solid organ transplantation or hematological malignancy. Predominantly not only the lungs, but also other sites of infection, for example, the central nervous system, bones and joints may be affected [1]. Moreover invasive pulmonary infections may also be rare complications in immune competent patients with chronic pulmonary disease [2]. Invasive fungal infections of the lung typically present with fever, productive cough, hemoptysis, tachypnea and malaise. Diagnostic criteria include clinical and radiological findings and furthermore histopathological examination, culture, molecular technologies and serology [1]. Therapy is difficult, as common antifungal drugs have varying levels of activity against S. apiospermum. S. prolifcans is usually resistant to most antifungal drugs. A large retrospective study provides support for the use of voriconazole for the treatment of infections with S. apiospermum [3].
⁎ Corresponding author Tel.: +49 731 500 57230; fax: +49 731 500 57334. E-mail address: [email protected] (J. Holle).
We report the case of a seventeen year old patient with cystic fibrosis and severe respiratory failure due to an infection with S. apiospermum. Initially the patient had stable lung function with a forced exspiratory volume (FEV1) of 60% and a chronic colonization with Stenotrophomonas maltophilia and Staphylococcus aureus. Secondary to clinical worsening, a drop in lung function (FEV1 of 40%) and a rise in aspergillus antibodies and IgE levels (maximum 3499 kU/l) without detection of aspergillus antigen in the blood, the patient was suspected to have allergic bronchopulmonary aspergillosis (ABPA) and was treated accordingly with prednisolone (2.0 mg/kg body weight per day for 14 days, followed by a slow taper) and itraconazole (200 mg twice daily). After 4 weeks his clinical condition worsened significantly, accompanied by a rise in inflammatory parameters and hemoptysis. Within 2–3 days he developed respiratory failure type two with hypercapnia, hypoxia and oxygen requirement of up to 5–6 l/min via nasal prongs and a further drop of FEV1 to 19%. While the chest X-ray demonstrated new bilateral infiltrates, the CT scan of the chest revealed severe cavernous pulmonary destruction (Fig. 1A). Finally S. apiospermum was isolated from bronchoalveolar lavage (BAL) and identified by sequencing 18S ribosomal RNA. In BAL and several sputum specimens, no other microorganism, which could have explained this respiratory deterioration, was detected.
1569-1993/$ -see front matter © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcf.2013.10.014 Please cite this article as: Holle J, et al, Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature, J Cyst Fibros (2013), http://dx.doi.org/10.1016/j.jcf.2013.10.014
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J. Holle et al. / Journal of Cystic Fibrosis xx (2013) xxx–xxx
The detected S. apiospermum was resistant against itraconazole and caspofungin with a minimum inhibitory concentration (MIC) higher than 32 μg/ml, intermediate resistant against amphotericin B (MIC 2 μg/ml) and sensitive against voriconazole with a MIC of less than 0.047 μg/ml. These breakpoints were determined due to our experience with MIC values of antifungal agents in other invasive fungal infections, for example infections due to Candida species or Aspergillus species. S. apiospermum had been detected in the patient sputum occasionally 3 years prior to his deterioration. Systemic treatment with parenteral voriconazole (8 mg/kg body weight per day in two doses) and liposomal amphotericin B (3 mg/kg body weight per day once daily) was started
Fig. 1. Initial CT-scan of the chest revealed severe cavernous pulmonary destruction (A). After 3 weeks of parenteral treatment with voriconazole and liposomal amphotericin B infiltrates still increased on the CT-scan (B). After adding nebulized treatment with voriconazole to its systemic application, six weeks later his clinical condition and the CT-scan improved (C).
intravenously without improvement of his clinical condition. After 3 weeks, in a follow up CT scan of the chest even an aggravation of the cavernous destruction was seen (Fig. 1B). Confronted with the severity of the disease, the literature was reviewed for further treatment options. In animal models with invasive pulmonary aspergillosis improved survival had been reported when both inhaled and systemic amphotericin B was administered, compared to systemic administration alone [4]. Some investigators described the prophylactic nebulization of amphotericin B in immunodeficient patients, for example after lung transplantation. However, due to small numbers, there is still insufficient data to determine the effectiveness of such a treatment and to recommend its routine use [5,6]. Characterization and pharmacokinetics of aerosolized aqueous voriconazole solution has been described recently by Tolman et al. [7,8]. Voriconazole, dissolved with sulfobutyl ether-βcyclodextrin, is commercially available as Vfend® for intravenous use. Reconstituted with sterile water to a concentration of 6.25 mg/ml voriconazole and 100 mg/ml sulfobutyl ether-βcyclodextrin, the solution is isotonic with a mass median aerodynamic diameter of 2.98 μm and a fine particle fraction of 71.7% [7], suggesting an appropriate distribution of the nebulized droplets also into more distal areas of the lung. In mice, high lung deposition as well as an increase in plasma concentrations was observed, following single and multiple inhaled doses [7]. In a murine model with immunocompromised animals with invasive pulmonary aspergillosis, mice that were prophylactically nebulized with voriconazole had a survival advantage over controls and even those treated with amphotericin B intraperitoneally [8]. Based on these data, we started a treatment with nebulized voriconazole (Vfend®, 40 mg, once daily) in addition to systemic application in order to reach maximum drug concentrations in the lungs. The additional treatment with nebulized voriconazole was very well tolerated without any side effects, especially no increased airway obstruction. Drug plasma concentration of voriconazole was measured before and after parenteral and also after nebulized application of voriconazole. No toxic increase of drug plasma concentration after nebulization could be detected and peak plasma levels ranged between 1500 and 5000 μg/l. Additional treatment with omeprazole, which was initially administered because of hemoptysis, did not influence the plasma level of voriconazole significantly and no dose modification was necessary. The patient's respiratory situation improved already two weeks after the start of voriconazole nebulization. In the following months, further respiratory stabilization (FEV1 of 30% with minimal oxygen requirement) and regression of the infection also on follow up CT-scans (Fig. 1C) was achieved. The nebulizations and the intravenous treatment were continued until successful lung transplantation 3 months later. In follow up investigations S. apiospermum was detected only once in secretions from the nostrils shortly after transplantation, but it was not detected in several bronchoalveolar lavages afterwards. Oral voriconazole was continued (400 mg twice daily) for another year post transplantation and despite immunosupression, no relapse of the Scedosporium infection
Please cite this article as: Holle J, et al, Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature, J Cyst Fibros (2013), http://dx.doi.org/10.1016/j.jcf.2013.10.014
J. Holle et al. / Journal of Cystic Fibrosis xx (2013) xxx–xxx
or colonization did occur in the following 2 years. The patient is currently still in stable respiratory situation (FEV1 of 80%) without any signs of bronchiolitis obliterans. To our knowledge this is the first report of the safe and effective use of nebulized voriconazole in addition to systemic application for the treatment of severe pulmonary infection with S. apiospermum in a patient with cystic fribrosis. After we had treated our patient with nebulized voriconazole, recently also Hilberg et al. reported three patients with invasive, pulmonary aspergillosis who had been successfully treated with inhaled voriconazole alone because of severe side effects of systemic treatment [9]. Although there is still limited experience, nebulized application of voriconazole as described above, seems to be a safe treatment option in patients with severe fungal infections, where exclusive systemic application is not sufficient or not tolerated because of side effects. Larger clinical trials and further investigations will be necessary to prove the efficacy of nebulized voriconazole in the treatment of pulmonary fungal infections. Declaration of the authors The authors declare that they have no conflicts of interest and the manuscript has been written without further funding source or affiliations.
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References [1] Cortez KJ, Roilides E, Quiroz-Telles F, Meletiadis J, Antachopoulos C, Knudsen T, et al. Infections caused by Scedosporium spp. Clin Microbiol Rev 2008;21:157–97. [2] Borghi E, Latta R, Manca A, Montagna MT, Morace G. Chronic airway colonization by Scedosporium apiospermum with a fatal outcome in a patient with cystic fibrosis. Med Mycol 2010;49:108–13. [3] Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, et al. Global Scedosporium Study Group. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother 2008;52:1743–50. [4] Gavaldà J, Martín MT, López P, Gomis X, Ramírez JL, Rodríguez D, et al. Efficacy of nebulized liposomal amphotericin B in treatment of experimental pulmonary aspergillosis. Antimicrob Agents Chemother 2005;49:3028–30. [5] Le J, Schiller DS. Aerosolized delivery of antifungal agents. Curr Fungal Infect Rep 2010;4:96–102. [6] O'Riordan TG. Inhaled antimicrobial therapy: from cystic fibrosis to the flu. Respir Care 2010;45:836–45. [7] Tolman JA, Nelson NA, Son YJ, Bosselmann S, Wiederhold NP, Peters JI, et al. Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution. Eur J Pharm Biopharm 2009;72:199–205. [8] Tolman JA, Wiederhold NP, McConville JT, Najvar LK, Bocanegra R, Peters JI, et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother 2009;53:2613–5. [9] Hilberg O, Bendstrup E, Mortensen J, Andersen C. Inhaled voriconazole — an efficient treatment against invasive aspergillosis. Am J Respir Crit Care Med 2012;185:A6088.
Please cite this article as: Holle J, et al, Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature, J Cyst Fibros (2013), http://dx.doi.org/10.1016/j.jcf.2013.10.014
Journal of Cystic Fibrosis xx (2013) xxx – xxx www.elsevier.com/locate/jcf
Short Communication
Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature J. Holle ⁎, M. Leichsenring, P.E. Meissner Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Eythstrasse 24, 89075 Ulm, Germany Received 1 September 2013; received in revised form 29 October 2013; accepted 30 October 2013 Available online xxxx
Abstract Scedosporium infections are rare complications in immunocompromised patients or patients with chronic pulmonary disease. While Scedosporium prolificans is resistant to most antimycotics, Scedosporium apiospermum is usually sensitive to voriconazole and posaconazole. Pharmacokinetics and efficacy of nebulized voriconazole have been described in a murine model previously. We report for the first time the safe and effective use of nebulized voriconazole for the treatment of severe pulmonary infection with Scedosporium apiospermum in an adolescent with cystic fribrosis. © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. Keywords: Scedosporium apiospermum; Cystic fibrosis; Antimycotic treatment; Fungal infections
Infections due to Scedosporium species in humans are rare and caused predominantly by S. apiospermum and S. prolificans. Invasive infections are mainly seen in immunodeficient patients, due to chronic steroid use, hematopoietic stem cell or solid organ transplantation or hematological malignancy. Predominantly not only the lungs, but also other sites of infection, for example, the central nervous system, bones and joints may be affected [1]. Moreover invasive pulmonary infections may also be rare complications in immune competent patients with chronic pulmonary disease [2]. Invasive fungal infections of the lung typically present with fever, productive cough, hemoptysis, tachypnea and malaise. Diagnostic criteria include clinical and radiological findings and furthermore histopathological examination, culture, molecular technologies and serology [1]. Therapy is difficult, as common antifungal drugs have varying levels of activity against S. apiospermum. S. prolifcans is usually resistant to most antifungal drugs. A large retrospective study provides support for the use of voriconazole for the treatment of infections with S. apiospermum [3].
⁎ Corresponding author Tel.: +49 731 500 57230; fax: +49 731 500 57334. E-mail address: [email protected] (J. Holle).
We report the case of a seventeen year old patient with cystic fibrosis and severe respiratory failure due to an infection with S. apiospermum. Initially the patient had stable lung function with a forced exspiratory volume (FEV1) of 60% and a chronic colonization with Stenotrophomonas maltophilia and Staphylococcus aureus. Secondary to clinical worsening, a drop in lung function (FEV1 of 40%) and a rise in aspergillus antibodies and IgE levels (maximum 3499 kU/l) without detection of aspergillus antigen in the blood, the patient was suspected to have allergic bronchopulmonary aspergillosis (ABPA) and was treated accordingly with prednisolone (2.0 mg/kg body weight per day for 14 days, followed by a slow taper) and itraconazole (200 mg twice daily). After 4 weeks his clinical condition worsened significantly, accompanied by a rise in inflammatory parameters and hemoptysis. Within 2–3 days he developed respiratory failure type two with hypercapnia, hypoxia and oxygen requirement of up to 5–6 l/min via nasal prongs and a further drop of FEV1 to 19%. While the chest X-ray demonstrated new bilateral infiltrates, the CT scan of the chest revealed severe cavernous pulmonary destruction (Fig. 1A). Finally S. apiospermum was isolated from bronchoalveolar lavage (BAL) and identified by sequencing 18S ribosomal RNA. In BAL and several sputum specimens, no other microorganism, which could have explained this respiratory deterioration, was detected.
1569-1993/$ -see front matter © 2013 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jcf.2013.10.014 Please cite this article as: Holle J, et al, Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature, J Cyst Fibros (2013), http://dx.doi.org/10.1016/j.jcf.2013.10.014
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J. Holle et al. / Journal of Cystic Fibrosis xx (2013) xxx–xxx
The detected S. apiospermum was resistant against itraconazole and caspofungin with a minimum inhibitory concentration (MIC) higher than 32 μg/ml, intermediate resistant against amphotericin B (MIC 2 μg/ml) and sensitive against voriconazole with a MIC of less than 0.047 μg/ml. These breakpoints were determined due to our experience with MIC values of antifungal agents in other invasive fungal infections, for example infections due to Candida species or Aspergillus species. S. apiospermum had been detected in the patient sputum occasionally 3 years prior to his deterioration. Systemic treatment with parenteral voriconazole (8 mg/kg body weight per day in two doses) and liposomal amphotericin B (3 mg/kg body weight per day once daily) was started
Fig. 1. Initial CT-scan of the chest revealed severe cavernous pulmonary destruction (A). After 3 weeks of parenteral treatment with voriconazole and liposomal amphotericin B infiltrates still increased on the CT-scan (B). After adding nebulized treatment with voriconazole to its systemic application, six weeks later his clinical condition and the CT-scan improved (C).
intravenously without improvement of his clinical condition. After 3 weeks, in a follow up CT scan of the chest even an aggravation of the cavernous destruction was seen (Fig. 1B). Confronted with the severity of the disease, the literature was reviewed for further treatment options. In animal models with invasive pulmonary aspergillosis improved survival had been reported when both inhaled and systemic amphotericin B was administered, compared to systemic administration alone [4]. Some investigators described the prophylactic nebulization of amphotericin B in immunodeficient patients, for example after lung transplantation. However, due to small numbers, there is still insufficient data to determine the effectiveness of such a treatment and to recommend its routine use [5,6]. Characterization and pharmacokinetics of aerosolized aqueous voriconazole solution has been described recently by Tolman et al. [7,8]. Voriconazole, dissolved with sulfobutyl ether-βcyclodextrin, is commercially available as Vfend® for intravenous use. Reconstituted with sterile water to a concentration of 6.25 mg/ml voriconazole and 100 mg/ml sulfobutyl ether-βcyclodextrin, the solution is isotonic with a mass median aerodynamic diameter of 2.98 μm and a fine particle fraction of 71.7% [7], suggesting an appropriate distribution of the nebulized droplets also into more distal areas of the lung. In mice, high lung deposition as well as an increase in plasma concentrations was observed, following single and multiple inhaled doses [7]. In a murine model with immunocompromised animals with invasive pulmonary aspergillosis, mice that were prophylactically nebulized with voriconazole had a survival advantage over controls and even those treated with amphotericin B intraperitoneally [8]. Based on these data, we started a treatment with nebulized voriconazole (Vfend®, 40 mg, once daily) in addition to systemic application in order to reach maximum drug concentrations in the lungs. The additional treatment with nebulized voriconazole was very well tolerated without any side effects, especially no increased airway obstruction. Drug plasma concentration of voriconazole was measured before and after parenteral and also after nebulized application of voriconazole. No toxic increase of drug plasma concentration after nebulization could be detected and peak plasma levels ranged between 1500 and 5000 μg/l. Additional treatment with omeprazole, which was initially administered because of hemoptysis, did not influence the plasma level of voriconazole significantly and no dose modification was necessary. The patient's respiratory situation improved already two weeks after the start of voriconazole nebulization. In the following months, further respiratory stabilization (FEV1 of 30% with minimal oxygen requirement) and regression of the infection also on follow up CT-scans (Fig. 1C) was achieved. The nebulizations and the intravenous treatment were continued until successful lung transplantation 3 months later. In follow up investigations S. apiospermum was detected only once in secretions from the nostrils shortly after transplantation, but it was not detected in several bronchoalveolar lavages afterwards. Oral voriconazole was continued (400 mg twice daily) for another year post transplantation and despite immunosupression, no relapse of the Scedosporium infection
Please cite this article as: Holle J, et al, Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature, J Cyst Fibros (2013), http://dx.doi.org/10.1016/j.jcf.2013.10.014
J. Holle et al. / Journal of Cystic Fibrosis xx (2013) xxx–xxx
or colonization did occur in the following 2 years. The patient is currently still in stable respiratory situation (FEV1 of 80%) without any signs of bronchiolitis obliterans. To our knowledge this is the first report of the safe and effective use of nebulized voriconazole in addition to systemic application for the treatment of severe pulmonary infection with S. apiospermum in a patient with cystic fribrosis. After we had treated our patient with nebulized voriconazole, recently also Hilberg et al. reported three patients with invasive, pulmonary aspergillosis who had been successfully treated with inhaled voriconazole alone because of severe side effects of systemic treatment [9]. Although there is still limited experience, nebulized application of voriconazole as described above, seems to be a safe treatment option in patients with severe fungal infections, where exclusive systemic application is not sufficient or not tolerated because of side effects. Larger clinical trials and further investigations will be necessary to prove the efficacy of nebulized voriconazole in the treatment of pulmonary fungal infections. Declaration of the authors The authors declare that they have no conflicts of interest and the manuscript has been written without further funding source or affiliations.
3
References [1] Cortez KJ, Roilides E, Quiroz-Telles F, Meletiadis J, Antachopoulos C, Knudsen T, et al. Infections caused by Scedosporium spp. Clin Microbiol Rev 2008;21:157–97. [2] Borghi E, Latta R, Manca A, Montagna MT, Morace G. Chronic airway colonization by Scedosporium apiospermum with a fatal outcome in a patient with cystic fibrosis. Med Mycol 2010;49:108–13. [3] Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, et al. Global Scedosporium Study Group. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother 2008;52:1743–50. [4] Gavaldà J, Martín MT, López P, Gomis X, Ramírez JL, Rodríguez D, et al. Efficacy of nebulized liposomal amphotericin B in treatment of experimental pulmonary aspergillosis. Antimicrob Agents Chemother 2005;49:3028–30. [5] Le J, Schiller DS. Aerosolized delivery of antifungal agents. Curr Fungal Infect Rep 2010;4:96–102. [6] O'Riordan TG. Inhaled antimicrobial therapy: from cystic fibrosis to the flu. Respir Care 2010;45:836–45. [7] Tolman JA, Nelson NA, Son YJ, Bosselmann S, Wiederhold NP, Peters JI, et al. Characterization and pharmacokinetic analysis of aerosolized aqueous voriconazole solution. Eur J Pharm Biopharm 2009;72:199–205. [8] Tolman JA, Wiederhold NP, McConville JT, Najvar LK, Bocanegra R, Peters JI, et al. Inhaled voriconazole for prevention of invasive pulmonary aspergillosis. Antimicrob Agents Chemother 2009;53:2613–5. [9] Hilberg O, Bendstrup E, Mortensen J, Andersen C. Inhaled voriconazole — an efficient treatment against invasive aspergillosis. Am J Respir Crit Care Med 2012;185:A6088.
Please cite this article as: Holle J, et al, Nebulized voriconazole in infections with Scedosporium apiospermum — Case report and review of the literature, J Cyst Fibros (2013), http://dx.doi.org/10.1016/j.jcf.2013.10.014