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Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality
ARTICLE IN PRESS International Journal of Antimicrobial Agents ■■ (2016) ■■–■■
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j a n t i m i c a g
Letter to the Editor Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality Sir, Invasive pulmonary aspergillosis (IPA) is primarily caused by inhalation of fungal spores. Thus, it is essential to maintain a high concentration of antifungal agents in lung tissues to prevent spore germination. Therefore, an easy and convenient way to deliver amphotericin B (AmB) to the lungs is of vital importance. An AmB inhalation powder has been developed for several years. It has been shown to have favourable pharmacokinetic properties and appears to be effective in animal models. Unfortunately, there are only a few clinical trials being conducted, leading to a lack of evidence on the pulmonary pharmacokinetics, efficacy and safety of this delivery route. In a recent issue of International Journal of Antimicrobial Agents, a prospective cohort study involving acute myeloid leukaemia patients found that liposomal amphotericin B inhalation resulted in a significant reduction in the rate of IPA [1]. In their latest guidelines for diagnosis and management of aspergillosis, the Infectious Diseases Society of America (IDSA) recommended AmB nebulisation for IPA prophylaxis in patients with prolonged neutropenia and/ or lung transplantation (weak recommendation; low-quality evidence) [2]. Another guideline from the Society of Infectious Diseases Pharmacists (SIDP) stated that based on the results from randomised studies, including one that demonstrated lack of benefit, routine use of nebulised AmB was not recommended (level B-I) [3]. Thus, the clinical benefits of AmB nebulisation are still open to debate. It is well known that for aerosolised AmB to take effect, the administration technique must be customised, aiming to achieve therapeutic concentrations at the site of infection deep in the respiratory tract. Furthermore, to attenuate adverse effects such as cough and bronchoconstriction, aerosolised drug solutions should have an osmolality close to 310 mOsm/L and a pH of 3.0–10.0. However, instruments such as the Respirgard II Filtered Medication Nebulizer and Pari Boy® or Pari IS II are not available in most countries in Asia and Africa. The breath-actuated jet nebuliser currently widely used in clinical practice is not able to produce particle sizes with adapted mass median aerodynamic diameter (MMAD). In China, most lung transplantation patients in home care use inhalation of AmB via an oxygen tank, which is not supported by evidence. In most academic teaching hospitals, only the blood concentration of vancomycin and etimicin can be routinely measured. Therapeutic concentrations of AmB in tissues cannot be routinely measured. Therefore, it remains largely unknown whether the use of AmB inhalation can benefit patients with regard to safety and efficacy. One meta-analysis involving six animal studies and two clinical trials (768 high-risk patients) indicated that prophylactic use of aerosolised AmB effectively reduced the incidence of IPA among
high-risk patients [4]. However, there was no consensus on dosing and timing of AmB administration in the studies included. Furthermore, time points of IPA determination were not consistent across studies. Publication bias of studies with positive results that are more likely to be published should also be considered in the interpretation of the meta-analysis. Pharmacological profiles of AmB are largely dependent on its formulation, and thus the formulation of AmB is responsible for its clinical efficacy. Although subgroup analysis of animal studies in this meta-analysis showed no significant difference between amphotericin B deoxycholate (AmBD) and lipidassociated AmB formulations, there is no clinical evidence on the difference in clinical efficacies between different AmB formulations for nebulisation [4]. A worldwide survey on antifungal prophylaxis in patients undergoing lung transplantation also revealed that inhaled lipid formulations of AmB were thought to be effective and were increasingly being used in clinical practice [5]. Therefore, lipid formulations may be more effective than AmBD in preventing IPA [5]. Further studies comparing the effects of these various formulations on the prevention of IPA are also needed. The SIDP guidelines recommended that triazoles were preferred agents for the treatment and prevention of invasive aspergillosis in most patients (strong recommendation; highquality evidence) [3]. However, it remains unknown whether inhaled voriconazole is superior to aerosolised AmB. Clinical trials comparing azoles and inhaled AmB are urgently needed to settle down the dispute on which agent and administration method are effective for IPA prophylaxis. Meanwhile, the cost effectiveness of different antifungal agents should be taken into consideration when designing future trials. In conclusion, although aerosolised formulations of AmB are an attractive option to prevent IPA in high-risk patients, there is no consensus on the technique, dosing or timing of aerosolised AmB administration. Standardised procedures for inhalation therapy need to be specified. Otherwise, the potential benefit of nebulisation can only be an impression for clinicians. Funding: None. Competing interests: None declared. Ethical approval: Not required.
References [1] Chong GL, Broekman F, Polinder S, Doorduijn JK, Lugtenburg PJ, Verbon A, et al. Aerosolised liposomal amphotericin B to prevent aspergillosis in acute myeloid leukaemia: efficacy and cost effectiveness in real-life. Int J Antimicrob Agents 2015;46:82–7. [2] Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1–60. [3] Le J, Ashley ED, Neuhauser MM, Brown J, Gentry C, Klepser ME, et al. Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2010;30:562–84.
http://dx.doi.org/10.1016/j.ijantimicag.2016.11.007 0924-8579/© 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
Please cite this article in press as: Yuetian Yu, Cheng Zhu, Chunyan Liu, Yuan Gao, Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality, International Journal of Antimicrobial Agents (2016), doi: 10.1016/j.ijantimicag.2016.11.007
ARTICLE IN PRESS 2
Letter to the Editor / International Journal of Antimicrobial Agents ■■ (2016) ■■–■■
[4] Xia D, Sun WK, Tan MM, Zhang M, Ding Y, Liu ZC, et al. Aerosolized amphotericin B as prophylaxis for invasive pulmonary aspergillosis: a meta-analysis. Int J Infect Dis 2015;30:78–84. [5] Neoh CF, Snell GI, Kotsimbos T, Levvey B, Morrissey CO, Slavin MA, et al. Antifungal prophylaxis in lung transplantation—a world-wide survey. Am J Transplant 2011;11:361–6.
Yuetian Yu 1 Department of Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China Cheng Zhu 1 Department of Emergency Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
1 These two authors contributed equally to this article.
Chunyan Liu Department of Emergency Medicine, Min Hang Central Hospital, School of Medicine, Fu Dan University, Shanghai, China Yuan Gao * Department of Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China * Corresponding author. Department of Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China. Fax: +86 21 5875 2345. E-mail address: [email protected] (Y. Gao) 30 September 2016 12 November 2016
Please cite this article in press as: Yuetian Yu, Cheng Zhu, Chunyan Liu, Yuan Gao, Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality, International Journal of Antimicrobial Agents (2016), doi: 10.1016/j.ijantimicag.2016.11.007
Contents lists available at ScienceDirect
International Journal of Antimicrobial Agents j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / i j a n t i m i c a g
Letter to the Editor Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality Sir, Invasive pulmonary aspergillosis (IPA) is primarily caused by inhalation of fungal spores. Thus, it is essential to maintain a high concentration of antifungal agents in lung tissues to prevent spore germination. Therefore, an easy and convenient way to deliver amphotericin B (AmB) to the lungs is of vital importance. An AmB inhalation powder has been developed for several years. It has been shown to have favourable pharmacokinetic properties and appears to be effective in animal models. Unfortunately, there are only a few clinical trials being conducted, leading to a lack of evidence on the pulmonary pharmacokinetics, efficacy and safety of this delivery route. In a recent issue of International Journal of Antimicrobial Agents, a prospective cohort study involving acute myeloid leukaemia patients found that liposomal amphotericin B inhalation resulted in a significant reduction in the rate of IPA [1]. In their latest guidelines for diagnosis and management of aspergillosis, the Infectious Diseases Society of America (IDSA) recommended AmB nebulisation for IPA prophylaxis in patients with prolonged neutropenia and/ or lung transplantation (weak recommendation; low-quality evidence) [2]. Another guideline from the Society of Infectious Diseases Pharmacists (SIDP) stated that based on the results from randomised studies, including one that demonstrated lack of benefit, routine use of nebulised AmB was not recommended (level B-I) [3]. Thus, the clinical benefits of AmB nebulisation are still open to debate. It is well known that for aerosolised AmB to take effect, the administration technique must be customised, aiming to achieve therapeutic concentrations at the site of infection deep in the respiratory tract. Furthermore, to attenuate adverse effects such as cough and bronchoconstriction, aerosolised drug solutions should have an osmolality close to 310 mOsm/L and a pH of 3.0–10.0. However, instruments such as the Respirgard II Filtered Medication Nebulizer and Pari Boy® or Pari IS II are not available in most countries in Asia and Africa. The breath-actuated jet nebuliser currently widely used in clinical practice is not able to produce particle sizes with adapted mass median aerodynamic diameter (MMAD). In China, most lung transplantation patients in home care use inhalation of AmB via an oxygen tank, which is not supported by evidence. In most academic teaching hospitals, only the blood concentration of vancomycin and etimicin can be routinely measured. Therapeutic concentrations of AmB in tissues cannot be routinely measured. Therefore, it remains largely unknown whether the use of AmB inhalation can benefit patients with regard to safety and efficacy. One meta-analysis involving six animal studies and two clinical trials (768 high-risk patients) indicated that prophylactic use of aerosolised AmB effectively reduced the incidence of IPA among
high-risk patients [4]. However, there was no consensus on dosing and timing of AmB administration in the studies included. Furthermore, time points of IPA determination were not consistent across studies. Publication bias of studies with positive results that are more likely to be published should also be considered in the interpretation of the meta-analysis. Pharmacological profiles of AmB are largely dependent on its formulation, and thus the formulation of AmB is responsible for its clinical efficacy. Although subgroup analysis of animal studies in this meta-analysis showed no significant difference between amphotericin B deoxycholate (AmBD) and lipidassociated AmB formulations, there is no clinical evidence on the difference in clinical efficacies between different AmB formulations for nebulisation [4]. A worldwide survey on antifungal prophylaxis in patients undergoing lung transplantation also revealed that inhaled lipid formulations of AmB were thought to be effective and were increasingly being used in clinical practice [5]. Therefore, lipid formulations may be more effective than AmBD in preventing IPA [5]. Further studies comparing the effects of these various formulations on the prevention of IPA are also needed. The SIDP guidelines recommended that triazoles were preferred agents for the treatment and prevention of invasive aspergillosis in most patients (strong recommendation; highquality evidence) [3]. However, it remains unknown whether inhaled voriconazole is superior to aerosolised AmB. Clinical trials comparing azoles and inhaled AmB are urgently needed to settle down the dispute on which agent and administration method are effective for IPA prophylaxis. Meanwhile, the cost effectiveness of different antifungal agents should be taken into consideration when designing future trials. In conclusion, although aerosolised formulations of AmB are an attractive option to prevent IPA in high-risk patients, there is no consensus on the technique, dosing or timing of aerosolised AmB administration. Standardised procedures for inhalation therapy need to be specified. Otherwise, the potential benefit of nebulisation can only be an impression for clinicians. Funding: None. Competing interests: None declared. Ethical approval: Not required.
References [1] Chong GL, Broekman F, Polinder S, Doorduijn JK, Lugtenburg PJ, Verbon A, et al. Aerosolised liposomal amphotericin B to prevent aspergillosis in acute myeloid leukaemia: efficacy and cost effectiveness in real-life. Int J Antimicrob Agents 2015;46:82–7. [2] Patterson TF, Thompson GR 3rd, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis 2016;63:e1–60. [3] Le J, Ashley ED, Neuhauser MM, Brown J, Gentry C, Klepser ME, et al. Consensus summary of aerosolized antimicrobial agents: application of guideline criteria. Insights from the Society of Infectious Diseases Pharmacists. Pharmacotherapy 2010;30:562–84.
http://dx.doi.org/10.1016/j.ijantimicag.2016.11.007 0924-8579/© 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.
Please cite this article in press as: Yuetian Yu, Cheng Zhu, Chunyan Liu, Yuan Gao, Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality, International Journal of Antimicrobial Agents (2016), doi: 10.1016/j.ijantimicag.2016.11.007
ARTICLE IN PRESS 2
Letter to the Editor / International Journal of Antimicrobial Agents ■■ (2016) ■■–■■
[4] Xia D, Sun WK, Tan MM, Zhang M, Ding Y, Liu ZC, et al. Aerosolized amphotericin B as prophylaxis for invasive pulmonary aspergillosis: a meta-analysis. Int J Infect Dis 2015;30:78–84. [5] Neoh CF, Snell GI, Kotsimbos T, Levvey B, Morrissey CO, Slavin MA, et al. Antifungal prophylaxis in lung transplantation—a world-wide survey. Am J Transplant 2011;11:361–6.
Yuetian Yu 1 Department of Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China Cheng Zhu 1 Department of Emergency Medicine, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
1 These two authors contributed equally to this article.
Chunyan Liu Department of Emergency Medicine, Min Hang Central Hospital, School of Medicine, Fu Dan University, Shanghai, China Yuan Gao * Department of Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China * Corresponding author. Department of Critical Care Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 145 Middle Shandong Road, Shanghai 200001, China. Fax: +86 21 5875 2345. E-mail address: [email protected] (Y. Gao) 30 September 2016 12 November 2016
Please cite this article in press as: Yuetian Yu, Cheng Zhu, Chunyan Liu, Yuan Gao, Amphotericin B nebulisation for invasive pulmonary aspergillosis prophylaxis: the conflict of ideality and reality, International Journal of Antimicrobial Agents (2016), doi: 10.1016/j.ijantimicag.2016.11.007