Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis

Pappas, Peter G.; Rotstein, Coleman; Betts, Robert F.; Nucci, Márcio; Talwar, Deepak; Waele, Jan J. De; Vázquez, José Antonio; Dupont, B.; Horn, David L.; Ostrosky-Zeichner, Luis; Reboli, Annette C.; Suh, Byungse; Digumarti, Raghunadharao; Wu, Chunzhang; Kovanda, Laura; Arnold, L; Buell, Donald N.

doi:10.1086/520980

Cited by 579 publications

(536 citation statements)

References 31 publications

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“…In fact, the clinical significance of paradoxical growth during echinocandin therapy of candidiasis is unproven. In two clinical trials, there were no differences in responses to echinocandins among patients with candidiasis who received high-or low-dose regimens (150 versus 100 mg of micafungin/day and 150 mg/day versus a 70-mg load, followed by 50 mg of caspofungin/day) (4,21). In a mouse model of systemic candidiasis, only one of four C. albicans isolates that demonstrated a paradoxical effect in vitro showed a similar pattern in vivo with a higher fungal burden recovered from mice treated with high-dose caspofungin (20 mg/kg).…”

Section: Discussionmentioning

confidence: 99%

Paradoxical Effect of Caspofungin against Candida Bloodstream Isolates Is Mediated by Multiple Pathways but Eliminated in Human Serum

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et al. 2011

Antimicrob Agents Chemother

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Paradoxical growth of Candida in vitro at echinocandin concentrations exceeding the MIC is well described, but the clinical relevance is unknown. We assessed echinocandin paradoxical effects against Candida bloodstream isolates (BSI) in the presence or absence of human serum and investigated regulatory mechanisms. As determined by broth microdilution, a paradoxical effect was evident for 60% (18/30), 23% (7/30), and 13% (4/30) of Candida albicans BSI exposed to caspofungin, anidulafungin, and micafungin, respectively, at achievable human serum concentrations (<8 g/ml). A paradoxical effect was not evident among 34 C. glabrata BSI and was observed only for caspofungin against C. parapsilosis (4%, 1/23). As determined in time-kill studies, a caspofungin paradoxical effect was demonstrated by C. albicans (2/3), C. glabrata (1/3), and C. parapsilosis (1/3), including BSI that were determined to be negative by microdilution. In 50% human serum, a paradoxical effect was eliminated at caspofungin concentrations up to 64 g/ml for 100% (8/8) of the C. albicans BSI. A caspofungin paradoxical effect was also eliminated by chitin synthase inhibitor nikkomycin Z and at achievable concentrations of calcineurin pathway inhibitors, tacrolimus and cyclosporine. Moreover, these agents were synergistic with caspofungin against 100, 100, and 88% (7/8) of C. albicans, respectively, and exerted their own paradoxical effects. Finally, paradoxical growth was eliminated in C. albicans irs4-and inp51-null mutants, which lack phosphatidylinositol-(4,5)-bisphosphate 5 -phosphatase. Our findings suggest that the paradoxical effect is unlikely to be important in vivo but remains an important tool to study cell wall stress responses. We implicate the Irs4-Inp51 phosphatidylinositol-(4,5)-bisphosphate 5 -phosphatase as a novel regulator of paradoxical growth.The echinocandins have emerged as frontline agents for the treatment of invasive candidiasis (20). These agents exert concentration-dependent fungicidal effects through noncompetitive inhibition of ␤-1-3-glucan synthase, an enzyme that produces a major constituent of the fungal cell wall. Echinocandins are well tolerated in humans at up to three times the standard doses (4), a circumstance that has created interest in exploring the use of high-dose regimens to maximize clinical efficacy. Along these lines, concerns have been expressed about the possible therapeutic implications of an in vitro paradoxical effect, in which certain Candida isolates exhibit increased growth in the presence of echinocandin concentrations above the minimum inhibitory concentration (MIC). Although the paradoxical effect is typically apparent in vitro at concentrations that are achievable in human serum with conventional dosing strategies, the clinical relevance of the phenomenon in the treatment of patients with candidiasis is unproven.To date, paradoxical effects have been demonstrated against Candida albicans, C. parapsilosis, C. krusei, C. tropicalis, and C. dubliniensis isolates (3,5,10,16,23,25,28). Moreover...

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Section: Discussionmentioning

confidence: 99%

Paradoxical Effect of Caspofungin against Candida Bloodstream Isolates Is Mediated by Multiple Pathways but Eliminated in Human Serum

Shields

Press

et al. 2011

Antimicrob Agents Chemother

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“…Also voriconazole and caspofungin were shown to be as effective as dAmB but less toxic [22,23]. Subsequently, in two randomized trials, micafungin was shown to be as effective as caspofungin and as liposomal amphotericin B (LAmB) [24,25].…”

Section: Invasive Candidiasismentioning

confidence: 99%

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

et al. 2017

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Purpose:To describe concisely the current standards of care, major recent advances, common beliefs that have been contradicted by recent trials, areas of uncertainty, and clinical studies that need to be performed over the next decade and their expected outcomes with regard to Candida and Aspergillus infections in non-neutropenic patients in the ICU setting. Methods:A systematic review of the medical literature taking account of national and international guidelines and expert opinion. Results:Severe invasive fungal infections (IFIs) are becoming increasingly frequent in critically ill patients. Approximately 80% of IFIs are due to Candida spp. and 0.3-19% to Aspergillus spp. Recent observations emphasize the necessity of building a worldwide sentinel network to monitor the emergence of new fungal species and changes in susceptibility. Robust data on the attributable mortality are essential for the design of clinical studies with mortality endpoints. Although early antifungal therapy for Candida has been recommended in patients with risk factors, sepsis of unknown cause, and positive Candida serum biomarkers [β-1 → 3-d-glucan (BDG) and Candida albicans germ tube antibody (CAGTA)], its usefulness and influence on outcome need to be confirmed. Future studies may specifically address the optimal diagnostic and therapeutic strategies for patients with abdominal candidiasis. Better knowledge of the pharmacokinetics of antifungal molecules and tissue penetration is a key issue for intensivists. Regarding invasive aspergillosis, further investigation is needed to determine its incidence in the ICU, its relationship with influenza outbreaks, the clinical impact of rapid diagnosis, and the significance of combination treatment. Conclusions:Fundamental questions regarding IFI have to be addressed over the next decade. The clinical studies described in this research agenda should provide a template and set priorities for the clinical investigations that need to be performed.

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“…It must however be underlined that, beside toxicity, the efficacy between the two drugs showed no significant differences. Pappas et al [25] compared two dosages of micafungin to caspofungin. The results showed that 100 mg daily and 150 mg daily were non-inferior to a standard dosage of caspofungin for the treatment of candidemia.…”

Section: Treatment Of Documented Infectionmentioning

confidence: 99%

Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment

et al. 2008

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Background: Invasive candidiasis and candidemia are frequently encountered in the nosocomial setting particularly in the intensive care unit (ICU). Objective and methods: To review the current management of invasive candidiasis and candidemia in non-neutropenic adult ICU patients based on a review of the literature and an European expert panel discussion. Results and conclusions: Empiric and directed treatment for invasive candidiasis are predicated on the hemodynamic status of the patient. Unstable patients may benefit from broad-spectrum antifungal agents, which can be narrowed once the patient has stabilized and the identity of the infecting species is established. In stable patients, a more classical approach using fluconazole may be satisfactory provided that the patient is not colonized Intensive Care Med

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Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis

Abstract: Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.

Cited by 579 publications

References 31 publications

Paradoxical Effect of Caspofungin against Candida Bloodstream Isolates Is Mediated by Multiple Pathways but Eliminated in Human Serum

Paradoxical Effect of Caspofungin against Candida Bloodstream Isolates Is Mediated by Multiple Pathways but Eliminated in Human Serum

Intensive care medicine research agenda on invasive fungal infection in critically ill patients

Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment

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