The Eagle-Like Effect of the Echinocandins: Is It Relevant for Clinical Decisions?

Stover, Kayla R.; Cleary, John D.

doi:10.1007/s12281-015-0221-6

Cited by 7 publications

(3 citation statements)

References 31 publications

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“…Consequently, a higher dose of micafungin could be considered in critically ill patients with a suspected or proven Candida infection with an MIC above 0.016 mg/liter. Increasing the dosage for all patients, however, might lead to an exposure above an AUC/MIC ratio of 12,000, which resulted in a worse outcome, possibly due to a previously described "eagle effect" inherent to echinocandins, although the clinical relevance of this effect is heavily debated (18,20).…”

Section: Discussionmentioning

confidence: 99%

Micafungin Plasma Levels Are Not Affected by Continuous Renal Replacement Therapy: Experience in Critically Ill Patients

Vossen

Knafl

Haidinger³

et al. 2017

Antimicrob Agents Chemother

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Critically ill patients often experience acute kidney injury and the need for renal replacement therapy in the course of their treatment in an intensive care unit (ICU). These patients are at an increased risk for candidiasis. Although there have been several reports of micafungin disposition during renal replacement therapy, to this date there are no data describing the elimination of micafungin during high-dose continuous venovenous hemodiafiltration with modified AN69 membranes. The aim of this prospective open-label pharmacokinetic study was to assess whether micafungin plasma levels are affected by continuous hemodiafiltration in critical ill patients using the commonly employed AN69 membrane. A total of 10 critically ill patients with micafungin treatment due to suspected or proven candidemia were included in this trial. Prefilter/postfilter micafungin clearance was measured to be 46.0 ml/min (Ϯ21.7 ml/min; n ϭ 75 individual time points), while hemofilter clearance calculated by the sieving coefficient was 0.0038 ml/min (Ϯ0.002 ml/min; n ϭ 75 individual time points). Total body clearance was measured to be 14.0 ml/min (Ϯ7.0 ml/min; n ϭ 12). The population area under the curve from 0 to 24 h (AUC 0 -24 ) was calculated as 158.5 mg · h/liter (Ϯ79.5 mg · h/liter; n ϭ 13). In spite of high protein binding, no dose modification is necessary in patients receiving continuous venovenous hemodiafiltration with AN69 membranes. A dose elevation may, however, be justified in certain cases. (This study has been registered at ClinicalTrials.gov under identifier NCT02651038.)

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Section: Discussionmentioning

confidence: 99%

Micafungin Plasma Levels Are Not Affected by Continuous Renal Replacement Therapy: Experience in Critically Ill Patients

Vossen

Knafl

Haidinger³

et al. 2017

Antimicrob Agents Chemother

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“…Contrariwise, 5h displayed no candidacidal action (lg R ≤ 0.43 in Table 3 ). Moreover, a paradoxical growth phenomenon of the reference strain SC5314 [ 26 ] was noted for the following derivatives: 4f , 4h , 5a, and 5g – i ( Figures S5, S7, S9, S11 and S12 ) as well as 5b , 5e – f , 5h , 5j ( Table 2 ). Briefly, we noted a slow decrease in the viable cell growth at higher concentrations (e.g., %I = 53 ± 8 at 16 µg/mL for 5b ) vs. the lowest concentrations at which the cell growth was substantially inhibited (e.g., %I = 95 ± 8 at 8 µg/mL for 5b ).…”

Section: Resultsmentioning

confidence: 99%

The Antifungal Action Mode of N-Phenacyldibromobenzimidazoles

et al. 2021

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Our study aimed to characterise the action mode of N-phenacyldibromobenzimidazoles against C. albicans and C. neoformans. Firstly, we selected the non-cytotoxic most active benzimidazoles based on the structure–activity relationships showing that the group of 5,6-dibromobenzimidazole derivatives are less active against C. albicans vs. 4,6-dibromobenzimidazole analogues (5e–f and 5h). The substitution of chlorine atoms to the benzene ring of the N-phenacyl substituent extended the anti-C. albicans action (5e with 2,4-Cl2 or 5f with 3,4-Cl2). The excellent results for N-phenacyldibromobenzimidazole 5h against the C. albicans reference and clinical isolate showed IC50 = 8 µg/mL and %I = 100 ± 3, respectively. Compound 5h was fungicidal against the C. neoformans isolate. Compound 5h at 160–4 µg/mL caused irreversible damage of the fungal cell membrane and accidental cell death (ACD). We reported on chitinolytic activity of 5h, in accordance with the patterns observed for the following substrates: 4-nitrophenyl-N-acetyl-β-d-glucosaminide and 4-nitrophenyl-β-d-N,N′,N″-triacetylchitothiose. Derivative 5h at 16 µg/mL: (1) it affected cell wall by inducing β-d-glucanase, (2) it caused morphological distortions and (3) osmotic instability in the C. albicans biofilm-treated. Compound 5h exerted Candida-dependent inhibition of virulence factors.

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“…well as MS12+pAVB107, MS12+pEPM901), moreover paradox effect was also observed at these strains, thus increasing the ITR concentration to more than 8 µg/ml did not resulted 90% growth inhibition. This phenomenon was also observed in Candida and Aspergillus species against echinocandins, but the mechanism still not clear, presumably induction of chitin synthesis is one of the possible mechanism of survival (Eagle and Musselman, 1948;Shields et al, 2011;Stover and Cleary, 2015). Increased susceptibility of these strains to CLO was also observed: MS12+pIPI/own, MS12+pHMG/hpRNA and MS12+pDMD/hpRNA showed susceptibility at 1 -4, 4 -16 and 2 -8 µg/ml to CLO, respectively, in comparision to the 32 µg/ml in the case of M.…”

Section: Investigation Of Macro-and Micromorphology Of the Transformantsmentioning

confidence: 96%

Functional characterization of the mevalonate-isoprenoid biosynthesis pathway genes in Mucor circinelloides

Kumar¹

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Alvarez et al., 2009). In addition, species of Rhizomucor, Apophysomyces, Saksenaea, Cunninghamella, Cokeromyces, and Syncephalastrum have also been described as caustaive agents of mucormycosis, but less cases have been reported (Gomes et al., 2011). Five major forms of mucormycosis occur, including rhino-orbito-cerebral, pulmonary, disseminated, cutaneous, and gastrointestinal, while species of Entomophthoromycotina generally cause locally manifested-cutaneous and subcutaneousand slowly progressive infections (Prabhu and Patel, 2004; Pfaller and Diekema, 2005). An increase in the number of mucormycosis has been observed in the last few decades, mainly because of the modern surgical interventions, immunosuppressive therapies and irresponsible use of antimicrobial agents (Ribes et al., 2000; Chayakulkeeree, et al., 2006; Ibrahim et al., 2012). According to Centers for Disease Control and Prevention USA (CDC, 2015) the overall mortality rate of mucormycosis found to be 54%. It was 46% among people with sinus infections, 76% for pulmonary infections, and 96% for disseminated mucormycosis (CDC, 2015). The most vulnerable group of these infections are immunocompromised patients, the major risk factors include neutropenia, cancer, corticosteroid treatment, diabetes mellitus in ketoacidosis, deferoxamine treatment, organ transplantation, and burn injury (Sugar, 2000; Sugar and Liu, 2000; Prabhu and Patel, 2004; Ibrahim et al., 2008). Phagocytes-primarily macrophages and neutrophils-have the most important role in host immune defence against fungi causing mucormycosis, thus longer neutropenia is one of the major risk for developing infection (Ibrahim et al, 2012; Morace and Borghi, 2012). Pulmonary alveolar macrophages play important role in defence against these fungi, because inhalation of the sporangiospores is one of the most common way of infection (van de Veerdonk et al., 2010). 3.3. Antifungal agents applied in clinics to treat fungal infections Only few antimycotic drugs were reported which are able to kill the Mucoromycotina fungi, whereas others merely only inhibit the growth of pathogens. The proper antifungal therapy and selection of drug should be based on several criteria, such as immune capability of the host, site of infection, characteristics of the infection (the fungal species and its susceptibility to different antifungal drugs), and pharmacokinetic characteristics of the antifungal drug (e.g., absorption, elimination, and toxicity) (Lepak et al., 2015). Mucorales are mostly resistant against widely used antifungal drugs used in clinics (such as against different azoles and echinocandins), thus generally, antifungal therapy need to be combined with surgical debridement of the necrotic regions.

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The Eagle-Like Effect of the Echinocandins: Is It Relevant for Clinical Decisions?

Cited by 7 publications

References 31 publications

Micafungin Plasma Levels Are Not Affected by Continuous Renal Replacement Therapy: Experience in Critically Ill Patients

Micafungin Plasma Levels Are Not Affected by Continuous Renal Replacement Therapy: Experience in Critically Ill Patients

The Antifungal Action Mode of N-Phenacyldibromobenzimidazoles

Functional characterization of the mevalonate-isoprenoid biosynthesis pathway genes in Mucor circinelloides

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