Invasive Fungal Infections in Patients with Hematological Malignancies: Emergence of Resistant Pathogens and New Antifungal Therapies

Invasive fungal infections caused by drug-resistant organisms are an emerging threat to heavily immunosuppressed patients with hematological malignancies. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance. The extended use of central venous catheters, the nonlinear pharmacokinetics of certain antifungal agents, neutropenia, other forms of intense immunosuppression, and drug toxicities are other contributing factors. The widespread use of agricultural and industrial fungicides with similar chemical structures and mechanisms of action has resulted in the development of environmental reservoirs for some drug-resistant fungi, especially azole-resistant Aspergillus species, which have been reported from four continents. The majority of resistant strains have the mutation TR34/L98H, a finding suggesting that the source of resistance is the environment. The global emergence of new fungal pathogens with inherent resistance, such as Candida auris, is a new public health threat. The most common mechanism of antifungal drug resistance is the induction of efflux pumps, which decrease intracellular drug concentrations. Overexpression, depletion, and alteration of the drug target are other mechanisms of resistance. Mutations in the ERG11 gene alter the protein structure of C-demethylase, reducing the efficacy of antifungal triazoles. Candida species become echinocandin-resistant by mutations in FKS genes. A shift in the epidemiology of Candida towards resistant non-albicans Candida spp. has emerged among patients with hematological malignancies. There is no definite association between antifungal resistance, as defined by elevated minimum inhibitory concentrations, and clinical outcomes in laca direnli organizmalarn neden olduu invaziv mantar enfeksiyonlar, ar immn basklanma altndaki hematolojik kanserli hastalar iin bir tehdittir. Profilaktik, ampirik ve nleyici tedaviler gibi gncel anti-fungal tedavi yaklamlar, diren geliiminde byk bir itici g olan anti-fungal ajanlara uzun sreli maruz kalma ile sonulanmaktadr. Santral venz kateterlerin uzun sreli kullanm, baz anti-fungal ajanlarn dorusal olmayan farmakokinetii, ntropeni, youn immn basklamann farkl formlar ve ila toksisitesi diren geliimine katkda bulunan dier faktrlerdir. Benzer kimyasal yaplara ve etki mekanizmalarna sahip, tarmsal ve endstriyel fungisitlerin yaygn kullanm, drt ktadan bildirilen baz ilaca direnli mantarlar, zellikle azole dayankl Aspergillus trleri iin evresel kaynaklarn gelimesine neden olmaktadr. Direnli sularn ounda bulunan TR34 / L98H mutasyonu, direncin evresel kaynakl olduunu dndrmektedir. Candida auris gibi doal direnli yeni fungal patojenlerin ortaya kmas, yeni bir halk sal tehdididir