Assessment of the Paradoxical Effect of Caspofungin in Therapy of Candidiasis

Clemons, Karl V.; Espiritu, Marife; Parmar, Rachana; Stevens, David A.

doi:10.1128/aac.50.4.1293-1297.2006

Cited by 98 publications

(40 citation statements)

References 25 publications

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“…In a neutropenic mouse model of invasive pulmonary aspergillosis, a modest PE (increased fungal burden) occurred with CAS but not MICA [12]. However, in a murine model of disseminated candidiasis, C. albicans strains that demonstrated an in vitro PE of CAS did not display a consistent PE in vivo [33]. It should be noted that the PE can be eliminated in the presence of 50% serum in vitro [34,35], and thus the findings of this study must be interpreted cautiously from a clinical standpoint.…”

Section: Discussionmentioning

confidence: 99%

Paradoxical antifungal activity and structural observations in biofilms formed by echinocandin-resistant Candida albicans clinical isolates

Walraven

Bernardo²,

Wiederhold

et al. 2013

Medical Mycology

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Echinocandin-resistant clinical isolates of Candida albicans have been reported, and key-hot spot mutations in the FKS1 gene, which encodes a major glucan synthase subunit, have been identified in these (caspofungin-resistant [CAS-R]) strains. Although these mutations result in phenotypic resistance to echinocandins in planktonic cells, there is little data on antifungal susceptibilities of CAS-R C. albicans strains within biofilms. Thus, we analyzed biofilms formed by 12 C. albicans CAS-R clinical strains in which we previously identified FKS1 hot-spot mutations and compared the sessile antifungal and paradoxical activity of anidulafungin (ANID), caspofungin (CAS), and micafungin (MICA). Biofilms were formed in a 96-well static microplate model and assayed using both tetrazolium-salt reduction and crystal violet assays, as well as examination by scanning electron microscopy. We first sought to assess biofilm formation and structure in these fks1 mutants and found that the biofilm mass and metabolic activities were reduced in most of the fks1 mutants as compared with reference strain SC5314. Structural analyses revealed that the fks1 mutant biofilms were generally less dense and had a clear predominance of yeast and pseudohyphae, with unusual “pit”-like cell surface structures. We also noted that sessile minimum inhibitory concentrations (MICs) to ANID, CAS, and MICA were higher than planktonic MICs of all but one strain. The majority of strains demonstrated a paradoxical effect (PE) to particular echinocandins, in either planktonic or sessile forms. Overall, biofilms formed by echinocandin-resistant clinical isolates demonstrated varied PEs to echinocandins and were structurally characterized by a preponderance of yeast, pseudohyphae, and pit-like structures.

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Section: Discussionmentioning

confidence: 99%

Paradoxical antifungal activity and structural observations in biofilms formed by echinocandin-resistant Candida albicans clinical isolates

Walraven

Bernardo²,

Wiederhold

et al. 2013

Medical Mycology

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“…Combination therapy with available drugs has only achieved moderate recognition in view of potential deleterious side effects (Mougdal et al. 2005; Clemons et al. 2006).…”

Section: Discussionmentioning

confidence: 99%

Enhanced activity of antifungal drugs using natural phenolics against yeast strains of Candida and Cryptococcus

Faria

Kim

Gonçalves

et al. 2011

Letters in Applied Microbiology

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Aims: Determine whether certain, natural phenolic compounds enhance activity of commercial antifungal drugs against yeast strains of Candida and Cryptococcus neoformans. Methods and Results: Twelve natural phenolics were examined for fungicidal activity against nine reference strains of Candida and one of C. neoformans. Six compounds were selected for synergistic enhancement of antifungal drugs, amphotericin B (AMB), fluconazole (FLU) and itraconazole (ITR). Matrix assays of phenolic and drug combinations conducted against one reference strain, each, of Candida albicans and C. neoformans showed cinnamic and benzoic acids, thymol, and 2,3‐ and 2,5‐dihydroxybenzaldehydes (‐DBA) had synergistic interactions depending upon drug and yeast strain. 2,5‐DBA was synergistic with almost all drug and strain combinations. Thymol was synergistic with all drugs against Ca. albicans and with AMB in C. neoformans. Combinations of benzoic acid or thymol with ITR showed highest synergistic activity. Of 36 combinations of natural product and drug tested, none were antagonistic. Conclusions: Relatively nontoxic natural products can synergistically enhance antifungal drug activity, in vitro. Significance and Impact of the Study: This is a proof‐of‐concept, having clinical implications. Natural chemosensitizing agents could lower dosages needed for effective chemotherapy of invasive mycoses. Further studies against clinical yeast strains and use of animal models are warranted.

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“…Finally, echinocandin action results in compensatory increases in chitin synthesis, which serves to maintain the structural integrity of the cell wall, as chitin replaces β-1,3 glucan [92], and cell wall mutants with enhanced chitin contents are less susceptible to echinocandins both in vitro [96, 92, 97, 93] and in vivo [98]. Elevated chitin and adaptive responses have been linked to paradoxical growth whereby susceptible cells show growth at very high levels of drug [99] [100] [101]. It has been proposed that sphingolipids can interact with echinocandins near their target and differentially decrease sensitivity to caspofungin while increasing sensitivity to micafungin [102, 103].…”

Section: Mechanism Of Acquired Resistancementioning

confidence: 99%

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

Perlin

2014

Drugs

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This article addresses the emergence of echinocandin resistance among Candida species, mechanisms of resistance, factors that promote resistance and confounding issues surrounding standard susceptibility testing. Fungal infections remain a significant cause of global morbidity and mortality, especially among patients with underlying immunosupression. Antifungal therapy is a critical component of patient management for acute and chronic diseases. Yet, therapeutic choices are limited due to only a few drug classes available to treat systemic disease. Moreover, the problem is exacerbated by the emergence of antifungal resistance, which has resulted in difficult to manage multidrug resistant strains. Echinocandin drugs are now the preferred choice to treat a range of candidiasis. These drugs target and inhibit the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a key cell wall polymer. Therapeutic failures involving acquisition of resistance among susceptible organisms like Candida albicans is largely a rare event. However, in recent years, there is an alarming trend of increased resistance among strains of Candida glabrata, which in many cases are also resistant to azole drugs. Echinocandin resistance is always acquired during therapy and the mechanism of resistance is well established to involve amino acid changes in “hot-spot regions of the Fks subunits carrying the catalytic portion of glucan synthase. These changes significantly decrease the sensitivity of the enzyme to drug resulting in higher MIC values. A range of drug responses, from complete to partial refractory response, is observed depending on the nature of the amino acid substitution, and clinical responses are recapitulated in pharmacodynamic models of infection. The cellular processes promoting the formation of resistant Fks strains involve complex stress response pathways, which yield a variety of adaptive compensatory genetic responses. Stress-adapted cells become drug tolerant and can form stable drug resistant FKS mutations with continued drug exposure. A major concern for resistance detection is that classical broth microdilution techniques show significant variability among clinical microbiology laboratories for certain echinocandin drugs and Candida species. The consequence is that susceptible strains are misclassified according to established clinical breakpoints, and this has led to confusion in the field. Clinical factors that appear to promote echinocandin resistance include the expanding use of antifungal agents for empiric therapy and prophylaxis. Furthermore, host reservoirs such as biofilms in the gastrointestinal tract or intra-abdominal infections can seed development of resistant organisms during therapy. A fundamental understanding of the primary molecular resistance mechanism, along with cellular and clinical factors that promote resistance emergence, is critical to develop better diagnostic tools and therapeutic strategies to overcome and prevent echinocandin resistance.

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Assessment of the Paradoxical Effect of Caspofungin in Therapy of Candidiasis

Cited by 98 publications

References 25 publications

Paradoxical antifungal activity and structural observations in biofilms formed by echinocandin-resistant Candida albicans clinical isolates

Paradoxical antifungal activity and structural observations in biofilms formed by echinocandin-resistant Candida albicans clinical isolates

Enhanced activity of antifungal drugs using natural phenolics against yeast strains of Candida and Cryptococcus

Echinocandin Resistance, Susceptibility Testing and Prophylaxis: Implications for Patient Management

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