An introduction to the future of echinocandin therapy

An introduction to the future of echinocandin therapy Since their introduction, nearly 20 years ago, echinocandins have become a cornerstone in invasive candidiasis treatment and one of the main classes of antifungal treatment and prophylaxis.1,2 However, the unmet and evolving needs in antifungal therapy call for improvements to current approaches and the development of new options. In addition to ensuring safety and efficacy, there are concerns about resistance, and advances in the treatment of underlying disease (the increasingly diverse polypharmacy of immunosuppressive and immunomodulatory agents, chemotherapies and biologics; risks and management of drug–drug interactions; longer life expectancies and the need for longer durations of prophylaxis to prevent late-onset infections) further raise the demands placed on modern antifungal therapy. This Supplement to the Journal of Antimicrobial Chemotherapy presents an outlook on the future of echinocandin therapy with these goals in mind: how might current use be improved, and how might newer options augment treatment and prophylaxis strategies in the future? In the first paper, Lamoth and colleagues3 review the changing epidemiology of invasive candidiasis. In addition to antifungal resistance concerns and shifts in distribution to non-albicans species, recent developments in Candida auris have raised questions about the current antifungal armoury. Although the importance of C. auris is not yet fully understood, echinocandin therapy may help answer the international call to arms that has been raised to meet the challenge.4 The emergence of C. auris is the latest example of a dynamic landscape that will require novel agents and stewardship practices to address the challenges of evolving mycoses. The next article in the Supplement, ‘What has changed in the treatment of invasive candidiasis? A look at the past 10 years and ahead’,5 takes a longitudinal view, from the past decade of experience in treating invasive candidiasis to the latest evidence that may inform future practice. Advances in diagnostic methods, approaches to prophylactic, pre-emptive and empirical therapy, and new drugs in development, including the novel once-weekly echinocandin rezafungin acetate (previously CD101),6–13 are poised to benefit the overarching goal of treatment: timely initiation of safe and efficacious antifungal therapy. The third paper, by Mourad and Perfect,14 reviews the tolerability of current and investigational agents, as part of the evaluation of risks versus benefits that may influence treatment selection. The ‘silent epidemic’ of antifungal underdosing is an emerging but critical item on the antifungal research agenda and is discussed in two articles in the Supplement. First, Pea and Lewis15 review the departure from a one-size-fits-all approach to individualized therapy based on the pharmacokinetic/pharmacodynamic (PK/PD) profile of a drug and patient-specific factors, such as polymorphisms, concomitant medications and drug–drug interaction risks, and special population considerations (for example, obesity, renal impairment/dialysis, hepatic impairment). Next, Bader and colleagues16 focus on echinocandin dosing and present a review of recent PK/PD research on current and investigational echinocandins in their paper ‘We can do better: a fresh look at echinocandin dosing’. Their findings overall, and specifically with a single-dose regimen of rezafungin acetate, may have significant implications for PK/PD-optimized antifungal dosing, the treatment of resistant isolates, and situations requiring longer durations of therapy. Use of antifungal prophylaxis has increased and will likely continue with advances in the treatment of underlying diseases that render patients immunodeficient and at increased risk of opportunistic fungal infection. Echinocandin use in prophylaxis has been limited by dosing requirements, but their safety, efficacy and predictable pharmacokinetics relative to other agents and the potential availability of newer agents with additional dosing options and expanded coverage (Pneumocystis pneumonia, for instance) suggest a greater role in the future of echinocandin therapy. These topics are discussed by Giannella and colleagues17 in their review of echinocandin prophylaxis in liver, lung and other solid organ transplant recipients, and by Epstein and colleagues18 in their review of the experience with and rationale for echinocandin prophylaxis in HSCT recipients and patients with haematological malignancies. The final article in this Supplement, ‘Biofilms and beyond: expanding echinocandin utility’,19 reviews leading areas of echinocandin research, from the development of new agents to additional applications for use, such as in the treatment of biofilms, dermatophytes and C. auris. Nascent findings relating to the mycobiome represent a truly novel and intriguing area of study. These active research efforts reflect the potential of the class and portend well for the future of echinocandin therapy. Funding This article is part of a supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) and funded by Cidara Therapeutics. Transparency declarations Dr Bassetti has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Cidara, Gilead, Menarini, MSD, Pfizer, The Medicines Company, Tetraphase and Vifor.  The author received no compensation for contributing to the supplement. This article was developed and published based on the author’s approval. References 1 Cornely OA, Bassetti M, Calandra T et al.   ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect  2012; 18 Suppl 7: 19– 37. Google Scholar CrossRef Search ADS PubMed  2 Pappas PG, Kauffman CA, Andes DR et al.   Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis  2016; 62: e1– 50. Google Scholar CrossRef Search ADS PubMed  3 Lamoth F, Lockhart SR, Berkow EL et al.   Changes in the epidemiological landscape of invasive candidiasis. J Antimicrob Chemother  2018; 73 Suppl 1: i4– i13. 4 Clancy CJ, Nguyen MH. Emergence of Candida auris: an international call to arms. Clin Infect Dis  2017; 64: 141– 3. http://dx.doi.org/10.1093/cid/ciw696 Google Scholar CrossRef Search ADS PubMed  5 Bassetti M, Righi E, Montravers P et al.   What has changed in the treatment of invasive candidiasis? A look at the past 10 years and ahead. J Antimicrob Chemother  2018; 73 Suppl 1: i14– i25. 6 Ong V, Hough G, Schlosser M et al.   Preclinical evaluation of the stability, safety, and efficacy of CD101, a novel echinocandin. Antimicrob Agents Chemother  2016; 60: 6872– 9. http://dx.doi.org/10.1128/AAC.00701-16 Google Scholar CrossRef Search ADS PubMed  7 Sandison T, Ong V, Lee J et al.   Safety and pharmacokinetics of CD101 IV, a novel echinocandin, in healthy adults. Antimicrob Agents Chemother  2017; 61: pii=e01627-16. 8 Zhao Y, Perez WB, Jimenez-Ortigosa C et al.   CD101: a novel long-acting echinocandin. Cell Microbiol  2016; 18: 1308– 16. http://dx.doi.org/10.1111/cmi.12640 Google Scholar CrossRef Search ADS PubMed  9 Pfaller MA, Messer SA, Rhomberg PR et al.   Activity of a long-acting echinocandin (CD101) and seven comparator antifungal agents tested against a global collection of contemporary invasive fungal isolates in the SENTRY 2014 antifungal surveillance program. Antimicrob Agents Chemother  2017; 61: pii=e02045-16. 10 Pfaller MA, Messer SA, Rhomberg PR et al.   Activity of a long-acting echinocandin, CD101, determined using CLSI and EUCAST reference methods, against Candida and Aspergillus spp., including echinocandin- and azole-resistant isolates. J Antimicrob Chemother  2016; 71: 2868– 73. Google Scholar CrossRef Search ADS PubMed  11 Hall D, Bonifas R, Stapert L et al.   In vitro potency and fungicidal activity of CD101, a novel echinocandin, against recent clinical isolates of Candida spp. Diagn Microbiol Infect Dis  2017; 89: 205– 11. http://dx.doi.org/10.1016/j.diagmicrobio.2017.07.007 Google Scholar CrossRef Search ADS PubMed  12 Zhao Y, Prideaux B, Nagasaki Y et al.   Unraveling drug penetration of echinocandin antifungals at the site of infection in an intra-abdominal abscess model. Antimicrob Agents Chemother  2017; 61: pii=e01009-17. 13 Lakota EA, Bader JC, Ong V et al.   Pharmacological basis of CD101 efficacy: exposure shape matters. Antimicrob Agents Chemother  2017; 61: pii=e00758-17. 14 Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J Antimicrob Chemother  2018; 73 Suppl 1: i26– i32. 15 Pea F, Lewis RE. Overview of antifungal dosing in invasive candidiasis. J Antimicrob Chemother  2018; 73 Suppl 1: i33– i43. 16 Bader JC, Bhavnani SM, Andes DR et al.   We can do better: a fresh look at echinocandin dosing. J Antimicrob Chemother  2018; 73 Suppl 1: i44– i50. 17 Giannella M, Husain S, Saliba F et al.   Use of echinocandin prophylaxis in solid organ transplantation. J Antimicrob Chemother  2018; 73 Suppl 1: i51– i59. 18 Epstein DJ, Seo SK, Brown JM et al.   Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies. J Antimicrob Chemother  2018; 73 Suppl 1: i60– i72. 19 Larkin EL, Dharmaiah S, Ghannoum MA. Biofilms and beyond: expanding echinocandin utility. J Antimicrob Chemother  2018; 73 Suppl 1: i73– i81. © The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

An introduction to the future of echinocandin therapy

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Oxford University Press
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© The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0305-7453
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1460-2091
D.O.I.
10.1093/jac/dkx443
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Abstract

Since their introduction, nearly 20 years ago, echinocandins have become a cornerstone in invasive candidiasis treatment and one of the main classes of antifungal treatment and prophylaxis.1,2 However, the unmet and evolving needs in antifungal therapy call for improvements to current approaches and the development of new options. In addition to ensuring safety and efficacy, there are concerns about resistance, and advances in the treatment of underlying disease (the increasingly diverse polypharmacy of immunosuppressive and immunomodulatory agents, chemotherapies and biologics; risks and management of drug–drug interactions; longer life expectancies and the need for longer durations of prophylaxis to prevent late-onset infections) further raise the demands placed on modern antifungal therapy. This Supplement to the Journal of Antimicrobial Chemotherapy presents an outlook on the future of echinocandin therapy with these goals in mind: how might current use be improved, and how might newer options augment treatment and prophylaxis strategies in the future? In the first paper, Lamoth and colleagues3 review the changing epidemiology of invasive candidiasis. In addition to antifungal resistance concerns and shifts in distribution to non-albicans species, recent developments in Candida auris have raised questions about the current antifungal armoury. Although the importance of C. auris is not yet fully understood, echinocandin therapy may help answer the international call to arms that has been raised to meet the challenge.4 The emergence of C. auris is the latest example of a dynamic landscape that will require novel agents and stewardship practices to address the challenges of evolving mycoses. The next article in the Supplement, ‘What has changed in the treatment of invasive candidiasis? A look at the past 10 years and ahead’,5 takes a longitudinal view, from the past decade of experience in treating invasive candidiasis to the latest evidence that may inform future practice. Advances in diagnostic methods, approaches to prophylactic, pre-emptive and empirical therapy, and new drugs in development, including the novel once-weekly echinocandin rezafungin acetate (previously CD101),6–13 are poised to benefit the overarching goal of treatment: timely initiation of safe and efficacious antifungal therapy. The third paper, by Mourad and Perfect,14 reviews the tolerability of current and investigational agents, as part of the evaluation of risks versus benefits that may influence treatment selection. The ‘silent epidemic’ of antifungal underdosing is an emerging but critical item on the antifungal research agenda and is discussed in two articles in the Supplement. First, Pea and Lewis15 review the departure from a one-size-fits-all approach to individualized therapy based on the pharmacokinetic/pharmacodynamic (PK/PD) profile of a drug and patient-specific factors, such as polymorphisms, concomitant medications and drug–drug interaction risks, and special population considerations (for example, obesity, renal impairment/dialysis, hepatic impairment). Next, Bader and colleagues16 focus on echinocandin dosing and present a review of recent PK/PD research on current and investigational echinocandins in their paper ‘We can do better: a fresh look at echinocandin dosing’. Their findings overall, and specifically with a single-dose regimen of rezafungin acetate, may have significant implications for PK/PD-optimized antifungal dosing, the treatment of resistant isolates, and situations requiring longer durations of therapy. Use of antifungal prophylaxis has increased and will likely continue with advances in the treatment of underlying diseases that render patients immunodeficient and at increased risk of opportunistic fungal infection. Echinocandin use in prophylaxis has been limited by dosing requirements, but their safety, efficacy and predictable pharmacokinetics relative to other agents and the potential availability of newer agents with additional dosing options and expanded coverage (Pneumocystis pneumonia, for instance) suggest a greater role in the future of echinocandin therapy. These topics are discussed by Giannella and colleagues17 in their review of echinocandin prophylaxis in liver, lung and other solid organ transplant recipients, and by Epstein and colleagues18 in their review of the experience with and rationale for echinocandin prophylaxis in HSCT recipients and patients with haematological malignancies. The final article in this Supplement, ‘Biofilms and beyond: expanding echinocandin utility’,19 reviews leading areas of echinocandin research, from the development of new agents to additional applications for use, such as in the treatment of biofilms, dermatophytes and C. auris. Nascent findings relating to the mycobiome represent a truly novel and intriguing area of study. These active research efforts reflect the potential of the class and portend well for the future of echinocandin therapy. Funding This article is part of a supplement sponsored by Cidara Therapeutics, Inc. Editorial support was provided by T. Chung (Scribant Medical) and funded by Cidara Therapeutics. Transparency declarations Dr Bassetti has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Cidara, Gilead, Menarini, MSD, Pfizer, The Medicines Company, Tetraphase and Vifor.  The author received no compensation for contributing to the supplement. This article was developed and published based on the author’s approval. References 1 Cornely OA, Bassetti M, Calandra T et al.   ESCMID guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect  2012; 18 Suppl 7: 19– 37. Google Scholar CrossRef Search ADS PubMed  2 Pappas PG, Kauffman CA, Andes DR et al.   Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis  2016; 62: e1– 50. Google Scholar CrossRef Search ADS PubMed  3 Lamoth F, Lockhart SR, Berkow EL et al.   Changes in the epidemiological landscape of invasive candidiasis. J Antimicrob Chemother  2018; 73 Suppl 1: i4– i13. 4 Clancy CJ, Nguyen MH. Emergence of Candida auris: an international call to arms. Clin Infect Dis  2017; 64: 141– 3. http://dx.doi.org/10.1093/cid/ciw696 Google Scholar CrossRef Search ADS PubMed  5 Bassetti M, Righi E, Montravers P et al.   What has changed in the treatment of invasive candidiasis? A look at the past 10 years and ahead. J Antimicrob Chemother  2018; 73 Suppl 1: i14– i25. 6 Ong V, Hough G, Schlosser M et al.   Preclinical evaluation of the stability, safety, and efficacy of CD101, a novel echinocandin. Antimicrob Agents Chemother  2016; 60: 6872– 9. http://dx.doi.org/10.1128/AAC.00701-16 Google Scholar CrossRef Search ADS PubMed  7 Sandison T, Ong V, Lee J et al.   Safety and pharmacokinetics of CD101 IV, a novel echinocandin, in healthy adults. Antimicrob Agents Chemother  2017; 61: pii=e01627-16. 8 Zhao Y, Perez WB, Jimenez-Ortigosa C et al.   CD101: a novel long-acting echinocandin. Cell Microbiol  2016; 18: 1308– 16. http://dx.doi.org/10.1111/cmi.12640 Google Scholar CrossRef Search ADS PubMed  9 Pfaller MA, Messer SA, Rhomberg PR et al.   Activity of a long-acting echinocandin (CD101) and seven comparator antifungal agents tested against a global collection of contemporary invasive fungal isolates in the SENTRY 2014 antifungal surveillance program. Antimicrob Agents Chemother  2017; 61: pii=e02045-16. 10 Pfaller MA, Messer SA, Rhomberg PR et al.   Activity of a long-acting echinocandin, CD101, determined using CLSI and EUCAST reference methods, against Candida and Aspergillus spp., including echinocandin- and azole-resistant isolates. J Antimicrob Chemother  2016; 71: 2868– 73. Google Scholar CrossRef Search ADS PubMed  11 Hall D, Bonifas R, Stapert L et al.   In vitro potency and fungicidal activity of CD101, a novel echinocandin, against recent clinical isolates of Candida spp. Diagn Microbiol Infect Dis  2017; 89: 205– 11. http://dx.doi.org/10.1016/j.diagmicrobio.2017.07.007 Google Scholar CrossRef Search ADS PubMed  12 Zhao Y, Prideaux B, Nagasaki Y et al.   Unraveling drug penetration of echinocandin antifungals at the site of infection in an intra-abdominal abscess model. Antimicrob Agents Chemother  2017; 61: pii=e01009-17. 13 Lakota EA, Bader JC, Ong V et al.   Pharmacological basis of CD101 efficacy: exposure shape matters. Antimicrob Agents Chemother  2017; 61: pii=e00758-17. 14 Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J Antimicrob Chemother  2018; 73 Suppl 1: i26– i32. 15 Pea F, Lewis RE. Overview of antifungal dosing in invasive candidiasis. J Antimicrob Chemother  2018; 73 Suppl 1: i33– i43. 16 Bader JC, Bhavnani SM, Andes DR et al.   We can do better: a fresh look at echinocandin dosing. J Antimicrob Chemother  2018; 73 Suppl 1: i44– i50. 17 Giannella M, Husain S, Saliba F et al.   Use of echinocandin prophylaxis in solid organ transplantation. J Antimicrob Chemother  2018; 73 Suppl 1: i51– i59. 18 Epstein DJ, Seo SK, Brown JM et al.   Echinocandin prophylaxis in patients undergoing haematopoietic cell transplantation and other treatments for haematological malignancies. J Antimicrob Chemother  2018; 73 Suppl 1: i60– i72. 19 Larkin EL, Dharmaiah S, Ghannoum MA. Biofilms and beyond: expanding echinocandin utility. J Antimicrob Chemother  2018; 73 Suppl 1: i73– i81. © The Author 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Jan 1, 2018

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