Echinocandin Antifungal Drugs in Fungal Infections View Full Text


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Article Info

DATE

2011-01

AUTHORS

Sharon C. -A. Chen, Monica A. Slavin, Tania C. Sorrell

ABSTRACT

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections.The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤2 mg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC90) values are typically <2 mg/mL but 100-fold higher MIC90 values are seen with Candida parapsilosis (1–2mg/mL) and Candida guilliermondii (1–4 mg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed.Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2mg/mL. Of the three echinocandins, the in vitro ‘paradoxical effect’ (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin.All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9–20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors.All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only mica-fungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutro-penia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use. More... »

PAGES

11-41

References to SciGraph publications

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  • 2008-07-19. A clinical cohort trial of antifungal combination therapy: efficacy and toxicity in haematological cancer patients in ANNALS OF HEMATOLOGY
  • 2004-09. Newer Systemic Antifungal Agents in DRUGS
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  • 2007-10-11. Economic evaluation of caspofungin vs liposomal amphotericin B for empirical therapy of suspected systemic fungal infection in the German hospital setting in ANNALS OF HEMATOLOGY
  • 2010-08-12. Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort in EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES
  • 2009-01-27. Caspofungin for prevention of intra-abdominal candidiasis in high-risk surgical patients in INTENSIVE CARE MEDICINE
  • 2010-06-22. Caspofungin Use in Daily Clinical Practice for Treatment of Invasive Aspergillosis: Results of a Prospective Observational Registry in BMC INFECTIOUS DISEASES
  • 2009-01-12. An early CT-diagnosis-based treatment strategy for invasive fungal infection in allogeneic transplant recipients using caspofungin first line: an effective strategy with low mortality in BONE MARROW TRANSPLANTATION
  • 2010-01-11. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study in BONE MARROW TRANSPLANTATION
  • 2008-11-29. Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation in INTERNATIONAL JOURNAL OF HEMATOLOGY
  • 2004-05-03. Safety of the concomitant use of caspofungin and cyclosporin A in patients with invasive fungal infections in BONE MARROW TRANSPLANTATION
  • 2007-05-28. Efficacy of caspofungin as secondary prophylaxis in patients undergoing allogeneic stem cell transplantation with prior pulmonary and/or systemic fungal infection in BONE MARROW TRANSPLANTATION
  • 2009-06-19. Cost-effectiveness of micafungin as an alternative to fluconazole empiric treatment of suspected ICU-acquired candidemia among patients with sepsis: a model simulation in CRITICAL CARE
  • 2005-10-13. Experience with Caspofungin in the Treatment of Persistent Fungemia in Neonates in JOURNAL OF PERINATOLOGY
  • 2010-05-01. Use of Antifungal Combination Therapy: Agents, Order, and Timing in CURRENT FUNGAL INFECTION REPORTS
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    http://scigraph.springernature.com/pub.10.2165/11585270-000000000-00000

    DOI

    http://dx.doi.org/10.2165/11585270-000000000-00000

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/21175238


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    30 schema:description This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections.The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤2 mg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC90) values are typically <2 mg/mL but 100-fold higher MIC90 values are seen with Candida parapsilosis (1–2mg/mL) and Candida guilliermondii (1–4 mg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp., although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed.Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2mg/mL. Of the three echinocandins, the in vitro ‘paradoxical effect’ (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin.All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9–20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors.All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only mica-fungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutro-penia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.
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