REGISTER
LOG IN
HOME
RESOURCES
Publications
Conference Calendar
Past Quiz Results
ARTICLES
First-ever Study of Mycology Lab Practices in Asia
Fereydounia khargensis: A New Opportunistic Yeast Reported from Malaysia
9 Years of MMTN: Improving Fungal Disease Management in Asia Pacific
Echinocandins: Clinicians' Guide
Fungemia blood culture media
Deep dermatophytosis
AFWG Education Module 4: Is Antifungal Susceptibility Testing Useful for Clinical Management?
AFWG Education Module 5: TDM of Antifungal Agents - Essential or Optional?
AFWG Education Module 6: Antifungal Stewardship
Itraconazole: A Quick Guide for Clinicians
Evolving Fungal Landscape in Asia
Laboratory Diagnosis of Pythiosis
ICMR Issues C. auris Advisory
Strengths and Limitations of Imaging for Diagnosis of IFI
Candidemia: Lessons Learned from Asian Studies for Intervention
Pivotal Asian Invasive Mold Study
Mycetoma in Asia: Still veiled in mystery
Cryptococcosis
New Antifungal Agents
Making Precise Diagnoses: Experience from the Laboratory Skills Enhancement Course
AFWG Online Education Module 3: Optimizing Dosing in IFI Management
AFWG Online Education Module 2: Antifungal Prophylaxis in Solid Organ Transplantation
AFWG Education Module 1: The Value of Clinical Mycology Laboratories
Cryptococcosis in HIV and non-HIV infected patients
Human Pythiosis
AFWGOnline Privacy Policy has been Updated
Recent Advances of Fungal Diagnostics in Asian Laboratories
Deep Dermatophytosis: A Case Report
Emerging yeast infections in Asia
Championing Medical Mycology: Thoughts on the AFWG Laboratory Skills Enhancement Course
Mucormycosis and Pythiosis – New Insights
AML and the high risk of multiple infectious complications
Do We Need Modification of Recent IDSA & ECIL Guidelines while Managing Patients in Asia?
A hospital’s experience with candidemia and empirical therapy
Fungal Academy 2015
Fluconazole in 2015
Fungal isolation protocol
Influencing Aspergillus
Fungal Asthma
Aspergillus
Laboratory Diagnosis of IPA
Two-Hot-to-Handle
Voriconazole
Educational Organizations
Literature Updates
 

Articles

New Antifungal Agents

Share this
page



Share
this page

Dr Atul Patel, MD, FIDSA
Chief Consultant and Director
Infectious Diseases Clinic
Vedanta Institute of Medical Sciences
Ahmedabad, India

There remains a pressing need for new antifungal agents, for a wide variety of reasons – including an increasing incidence of invasive fungal infection (IFI), high levels of associated mortality, limitations among existing agents (eg, toxicity, drug-drug interactions and resistance), and the need for agents against difficult-to-treat infections like Scedosporium and Fusarium.

A number of potent new agents are currently in Phase 1 and 2 development, many of which offer a broad spectrum of activity and potential synergy with approved antifungals (Table).1 In addition, several drugs that have been approved for indications outside fungal infection – such as cyclosporine/tacrolimus/rapamycin, rifampin and verapamil – have potentially broad-spectrum antifungal activity that could be useful in combination with existing treatments.1 The antidepressant sertraline has also shown promising activity against cryptococcal meningitis.2,3

Table. New antifungal agents in the pipeline1

Compound

Activity

Target

Stage

APX001

Glycosyl phosphatidylinositol synthesis

  • Broad-spectrum potency against pathogens including Mucorales, Candida spp., Aspergillus spp., Fusarium spp. and Scedosporium spp.
  • Synergizes with approved antifungals

Phase 1,
Phase 2

AR 12

Probably blocks fungal acetyl-CoA synthetase 1; increases host immune response by downregulating host chaperone proteins

  • Cryptococcus neoformans
  • Candida albicans
  • Mucorales molds
  • Hyalohyphomycosis, including those caused by Fusarium spp. and Scedosporium spp.

Phase 1

Efungumab

Hsp90

  • Candida spp.

Phase 2

MGCD290

Hos2

  • Broad spectrum
  • Synergizes with approved antifungals

Phase 2

Nikkomycin Z

Chitin synthase

  • Coccidioidomycosis, histoplasmosis and blastomycosis
  • Synergizes with approved antifungals

Phase 1

 

Newer formulations of posaconazole

Among currently approved antifungal agents, 2 new formulations of posaconazole have potential to improve the usability of this compound. The major drawback of the older, oral-suspension formulation was the requirement of frequent dosing (4 times daily during week 1 followed by twice daily), preferably following a full meal, to ensure adequate oral absorption.4 This was needed because absorption requires dissolution of the drug in the stomach, which is maximized by taking smaller, more frequent doses with food, to lower the gastric pH and prolong residence time.

The new formulations of posaconazole – a delayed-release tablet and an injectable preparation – circumvent these absorption problems. The tablet formulation uses pH-sensitive polymers to release posaconazole at a controlled rate in the duodenum, thereby improving the absorption profile and allowing once-daily maintenance dosing.4 However, it has the downside of disallowing division/crushing of the tablet, thus preventing administration through a gastric feeding tube. The injectable formulation has the advantage of early achievement of steady-state plasma levels, but must be administered via a central line and may be contraindicated in patients with renal impairment.4

Isavuconazole

Isavuconazole is a recently approved, second-generation triazole antifungal agent, available in oral and intravenous (IV) formulations. The oral preparation has high bioavailability, and absorption is not significantly affected by food intake.5 It is approved for use against IA and mucormycosis,5 although efficacy against the latter appears to be similar to amphotericin B.6

In vitro data suggest that isavuconazole has broad-spectrum antifungal activity, including against Candida spp., Cryptococcus neoformans and Trichosporon spp.7 However, it has little or no activity against difficult-to-treat Scedosporium prolificans and Fusarium spp. 

It has many potential advantages over other azole antifungals5,7,8:

  • High prodrug water solubility, obviating the need for cyclodextrin (which is associated with nephrotoxicity) in the IV formulation;
  • High oral bioavailability, which therefore allows for 1-to-1 dosage conversions from the IV formulation;
  • A prolonged half-life of >75 hours, allowing for convenient once-daily dosing;
  • Predictable, linear pharmacokinetics with no relevant food effect; and
  • Potentially fewer drug-drug interactions than other azoles, although it should not be administered with strong inducers or inhibitors of CYP3A4.

Isavuconazole therefore represents a valuable new option within the antifungal armamentarium.

References

  1. Perfect JR. Nat Rev Drug Discov 2017;16:603-616.
  2. Veringa A, et al. Lancet Infect Dis 2016;16:1111.
  3. Rhein J, et al. Lancet Infect Dis 2016;16:809-818.
  4. Merck Sharp & Dohme Corp. Noxafil® prescribing information. November 2015. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2015/022003s018s020,0205053s002s004,0205596s001s003lbl.pdf. Accessed September 2017.
  5. Astellas Pharma US, Inc. Cresemba® prescribing information. March 2015. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf. Accessed September 2017.
  6. Marty FM, et al. Lancet Infect Dis 2016;16:828-837.
  7. Pettit NN, Carver PL. Ann Pharmacother 2015;49:825-842.
  8. Falci DR, Pasqualotto AC. Infect Drug Resist 2013;6:163-174.
SIGN UP FOR NEWSLETTER
SIGN UP

This field is required. Please enter your email address.
Thank you for signing up for the AFWG newsletter.
You have previously subscribed for AFWG newsletter.