Caspofungin Increases Fungal Chitin and Eosinophil and γδ T Cell-Dependent Pathology in Invasive Aspergillosis.

The polysaccharide-rich fungal cell wall provides pathogen-specific targets for antifungal therapy and distinct molecular patterns that stimulate protective or detrimental host immunity. The echinocandin antifungal caspofungin inhibits synthesis of cell wall ß-1,3-glucan and is used for prophylactic therapy in immune-suppressed individuals. However, breakthrough infections with fungal pathogen Aspergillus fumigatus are associated with caspofungin prophylaxis. In this study, we report in vitro and in vivo increases in fungal surface chitin in A. fumigatus induced by caspofungin that was associated with airway eosinophil recruitment in neutropenic mice with invasive pulmonary aspergillosis (IA). More importantly, caspofungin treatment of mice with IA resulted in a pattern of increased fungal burden and severity of disease that was reversed in eosinophil-deficient mice. Additionally, the eosinophil granule proteins major basic protein and eosinophil peroxidase were more frequently detected in the bronchoalveolar lavage fluid of lung transplant patients diagnosed with IA that received caspofungin therapy when compared with azole-treated patients. Eosinophil recruitment and inhibition of fungal clearance in caspofungin-treated mice with IA required RAG1 expression and γδ T cells. These results identify an eosinophil-mediated mechanism for paradoxical caspofungin activity and support the future investigation of the potential of eosinophil or fungal chitin-targeted inhibition in the treatment of IA.

Role of caspofungin in restoring the impaired phagocyte-dependent innate immunity towards Candida albicans in chronic haemodialysis patients.

Phagocyte-dependent cellular immunity in chronic kidney disease patients undergoing haemodialysis treatment is frequently impaired owing to the uraemic state, resulting in an intrinsic susceptibility to developing invasive fungal infections with high mortality rates. Since synergism between phagocytic cells and antifungal drugs may be crucial for successful therapy, the aim of this study was to evaluate the effects exerted by caspofungin (CAS) on the functional activities of polymorphonuclear cells (PMNs) in haemodialysed patients (HDs) towards Candida albicans compared with those of PMNs from healthy subjects (HSs). PMNs were separated from venous blood samples of 66 HDs and 30 HSs (as controls), and measurement of phagocytic and intracellular fungicidal activities of HD-PMNs and HS-PMNs was performed in the presence of CAS at the minimum inhibitory concentration (MIC) and at sub-MICs. CAS-free controls were also included. In the drug-free test condition, no significant difference between the phagocytic activity of HD-PMNs and HS-PMNs was detected. In contrast, a progressive decline in the intracellular killing activity of HD-PMNs against proliferating yeasts was observed. CAS at MIC and sub-MIC levels was able to improve significantly the intracellular fungicidal activity of HD-PMNs against C. albicans, restoring their functionality. These findings provide evidence that CAS exerts a synergistic effect on HD-PMNs against C. albicans, being able to strength the depressed intracellular killing activity. These results corroborate the use of CAS as an effective therapeutic option for the treatment of invasive fungal infections in HDs, in whom even a marginal influence of antifungal drugs on host response may have a relevant effect.

Micafungin-induced thrombotic thrombocytopenic purpura: a case report and review of the literature.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening multisystem disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia accompanied by microvascular thrombosis that causes variable degrees of tissue ischemia and infarction leading to organ dysfunction. Drug-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome has been recognized for several years. The most commonly implicated drugs are mitomycin C, cyclosporine, quinine, clopidogrel, and ticlopidine. Recent advances have suggested that like in idiopathic TTP, the most likely pathogenesis for drug-induced TTP is either an immune-mediated phenomenon involving the ADAMTS13 metalloprotease or direct endothelial toxicity. In this communication, we report a case of micafungin-induced TTP. Micafungin is a new antifungal drug of the Echinocandins group. Whether micafungin induces autoantibodies against ADAMTS13 or not, this needs further evaluation, but TTP should be recognized as a possible complication of micafungin. Clinicians should be alert to this adverse effect of micafungin and monitor platelet counts in patients receiving this drug.

Immediate cross-hypersensitivity between micafungin and caspofungin: a case report.

A hematopoietic stem cell transplant patient with a history of immediate drug hypersensitivity reaction to micafungin was considered for a caspofungin trial. A caspofungin intradermal skin test was performed. The result was positive, suggesting the presence of cross-reactivity and that the cyclic peptide nucleus chemical structure shared between echinocandins is the site of IgE recognition. It is recommended to avoid challenging patients with history of immediate hypersensitivity to one echinocandin with another.

Micafungin-induced immune hemolysis attacks.

The echinocandins provide an attractive new option for prophylactic and empirical treatment of invasive fungal infections in patients with neutropenia after intensive cytotoxic chemotherapy or hematopoietic stem cell transplantation. We present two patients with hematological diseases who experienced massive intravascular hemolysis followed by renal failure after administration of micafungin. In indirect antiglobulin test, significant agglutination was observed when red blood cells were exposed to the mixture of micafungin and either of the patients' plasma samples, indicating that production of antibodies directed against both micafungin and red blood cell membrane induced hemolysis attack. Micafungin-mediated immune hemolysis represents an uncommon but life-threatening adverse reaction leading to renal failure.