In Vitro Activity of the New Echinocandin Antifungal, MK-0991, against Common and Uncommon Clinical Isolates of Candida Species

Barchiesi, Francesco; Schimizzi, Anna Maria; Fothergill, Annette W.; Scalise, Giorgio; Rinaldi, Michael G.

doi:10.1007/pl00015011

EJCMID

1999

DOI: 10.1007/pl00015011

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In Vitro Activity of the New Echinocandin Antifungal, MK-0991, against Common and Uncommon Clinical Isolates of Candida Species

Francesco Barchiesi

Anna Maria Schimizzi

Annette W. Fothergill

et al.

Abstract: A broth macrodilution method, performed as recommended by the National Committee for Clinical Laboratory Standards, was used for comparative testing of the new echinocandin antifungal agent MK-0991 and fluconazole against 50 yeast isolates belonging to 12 species of Candida. MK-0991 was shown to be highly effective against both fluconazole-susceptible and -resistant Candida spp., yielding minimum inhibitory concentrations ranging from ^0.19 to 0.78 mg/ml. Fungicidal activity was exerted at ^1.5 mg/ml for 73% o… Show more

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Cited by 43 publications

(31 citation statements)

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“…As caspofungin specifically targets the fungal cell wall as opposed to the fungal cell membrane, this echinocandin retains activity against clinical Candida isolates with documented resistance to either the azoles or the polyenes (4,14,17,29). In several phase II/III trials, caspofungin has exhibited efficacy outcomes comparable to those of amphotericin B deoxycholate or fluconazole for the treatment of esophageal candidiasis (3,30,31).…”

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confidence: 99%

Caspofungin Susceptibility Testing of Isolates from Patients with Esophageal Candidiasis or Invasive Candidiasis: Relationship of MIC to Treatment Outcome

Kartsonis

Killar

Mixson

et al. 2005

Antimicrob Agents Chemother

131

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The caspofungin clinical trial database offers an opportunity to assess susceptibility results for Candida pathogens obtained from patients with candidiasis and allows for correlations between efficacy outcomes and MICs. Candida isolates have been identified from patients enrolled in four studies of esophageal candidiasis and two studies of invasive candidiasis. The MICs of caspofungin for all baseline isolates were measured at a central laboratory using NCCLS criteria (document M-27A); MICs for caspofungin were defined as the lowest concentration inhibiting prominent growth at 24 h. MICs were then compared to clinical and microbiological outcomes across the two diseases. Susceptibility testing for caspofungin was performed on 515 unique baseline isolates of Candida spp. obtained from patients with esophageal candidiasis. MICs for caspofungin ranged from 0.008 to 4 g/ml; the MIC 50 and MIC 90 were 0.5 and 1.0 g/ml, respectively. Susceptibility testing was also performed on 231 unique baseline isolates of Candida spp. from patients with invasive candidiasis. The majority (ϳ96%) of MICs were between 0.125 and 2 g/ml, with MIC 50 and MIC 90 for caspofungin being 0.5 and 2.0 g/ml, respectively. Overall, caspofungin demonstrated potent in vitro activity against clinical isolates of Candida species. A relationship between MIC for caspofungin and treatment outcome was not seen for patients with either esophageal candidiasis or invasive candidiasis. Patients with isolates for which the MICs were highest (>2 g/ml) had better outcomes than patients with isolates for which the MICs were lower (<1 g/ml). Additionally, no correlation between MIC and outcome was identified for specific Candida species.Caspofungin is a parenteral echinocandin antifungal with known fungicidal activity against Candida species (1, 2, 5, 8, 9). As caspofungin specifically targets the fungal cell wall as opposed to the fungal cell membrane, this echinocandin retains activity against clinical Candida isolates with documented resistance to either the azoles or the polyenes (4,14,17,29). In several phase II/III trials, caspofungin has exhibited efficacy outcomes comparable to those of amphotericin B deoxycholate or fluconazole for the treatment of esophageal candidiasis (3,30,31). Similarly, in a large multicenter study, caspofungin was as effective as amphotericin B deoxycholate in the primary treatment of invasive candidiasis (candidemia and other Candida infections) (12,15). In all of these studies, caspofungin has demonstrated an excellent safety profile with few serious drug-related adverse events and few therapy discontinuations resulting from toxicity (3,12,15,30,31).Despite its favorable clinical profile against Candida infections, the utility of in vitro susceptibility testing for caspofungin has not been fully established. Recent work has focused on the development of a standard, reproducible method of susceptibility testing for caspofungin. This study, involving 17 different microbiology laboratories, assessed the interlaboratory reproducib...

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mentioning

confidence: 99%

Caspofungin Susceptibility Testing of Isolates from Patients with Esophageal Candidiasis or Invasive Candidiasis: Relationship of MIC to Treatment Outcome

Kartsonis

Killar

Mixson

et al. 2005

Antimicrob Agents Chemother

131

View full text Add to dashboard Cite

show abstract

“…The use of conventional amphotericin B preparations is complicated by its significant toxicity. Newer lipid formulations of amphotericin have reduced, but not eliminated, some of these adverse effects (15).Caspofungin possesses activity in vitro (6,17,23,30,31,42) and in vivo (1, 2, 11, 13) against a variety of fungal pathogens, including Candida and Aspergillus species. Echinocandins noncompetitively inhibit 1,3-␤-D-glucan synthesis, interfering with the normal formation of the fungal cell wall (3).…”

mentioning

confidence: 99%

Randomized, Double-Blind, Multicenter Study of Caspofungin versus Amphotericin B for Treatment of Oropharyngeal and Esophageal Candidiases

Arathoon

Gotuzzo

Noriega

et al. 2002

Antimicrob Agents Chemother

247

156

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Caspofungin is an antifungal agent of the novel echinocandin class. We investigated its efficacy, safety, and tolerability as therapy for oropharyngeal and/or esophageal candidiasis in a phase II dose-ranging study. Patients were randomized in a double-blind manner to receive either caspofungin acetate (35, 50, or 70 mg) or amphotericin B (0.5 mg/kg of body weight) intravenously once daily for 7 to 14 days. A favorable response required both complete resolution of symptoms and quantifiable improvement of mucosal lesions 3 to 4 days after discontinuation of study drug. Efficacy was assessed using a modified intent-to-treat analysis. No hypothesis testing of efficacy was planned or performed. Of 140 enrolled patients, 63% had esophageal involvement and 98% were infected with the human immunodeficiency virus (HIV) (median CD4 count, 30/mm 3 ). A modestly higher proportion of patients in each of the caspofungin groups (74 to 91%) achieved favorable responses compared to amphotericin B recipients (63%), but there was considerable overlap in the 95% confidence intervals surrounding these point estimates. Similar trends were found in the subgroups with esophageal involvement, a history of fluconazole failure, and CD4 counts of <50/mm 3 . A smaller proportion of patients receiving any dose of caspofungin experienced drug-related adverse events compared to patients given standard doses of conventional amphotericin B (P < 0.01). Caspofungin provided a generally well-tolerated parenteral therapeutic option for HIV-infected patients with oropharyngeal and/or esophageal candidiasis in this study.Mucosal candidiasis, although not life-threatening, causes significant morbidity in patients infected with the human immunodeficiency virus (HIV) (16). The development of drug resistance in the causative strain or the selection of intrinsically more resistant species may complicate therapy of recurrent candidal infections (19,20,28,34,36,40,43). This study describes the use of a new echinocandin, caspofungin (Cancidas; formerly MK-0991), as treatment for oropharyngeal and esophageal candidiasis in an immunocompromised patient population.Oral fluconazole is widely regarded as the treatment of choice for mucosal candidiasis under most circumstances (36). Amphotericin B deoxycholate has been the standard recourse for patients infected with Candida sp. unresponsive to azole therapy (5,10,24,36). The use of conventional amphotericin B preparations is complicated by its significant toxicity. Newer lipid formulations of amphotericin have reduced, but not eliminated, some of these adverse effects (15).Caspofungin possesses activity in vitro (6,17,23,30,31,42) and in vivo (1, 2, 11, 13) against a variety of fungal pathogens, including Candida and Aspergillus species. Echinocandins noncompetitively inhibit 1,3-␤-D-glucan synthesis, interfering with the normal formation of the fungal cell wall (3). Since glucans are not present in mammalian cells, it is hoped that echinocandins will have a relatively high therapeutic index. Crossresistance with...

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“…However, multidrug efflux pumps display affinity for a wide variety of compounds (including different types of antifungals), and thus the possibility exists that their overexpression may affect susceptibility to caspofungin. Previous studies have demonstrated that caspofungin is highly active against Candida species, including some azole-resistant isolates (1,3,11), but the molecular mechanisms responsible for azole resistance in these isolates were not known.…”

mentioning

confidence: 99%

In Vitro Activity of Caspofungin (MK-0991) against Candida albicans Clinical Isolates Displaying Different Mechanisms of Azole Resistance

2002

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Caspofungin inhibits the synthesis of 1,3-␤-D-glucan, a key step in fungal cell wall biosynthesis. Here we report on its potent in vitro activity (MIC at which 90% of the isolates tested are inhibited ‫؍‬ 1 g per ml of RPMI medium) against 32 Candida albicans fluconazole-susceptible and -resistant clinical isolates irrespective of the underlying resistance mechanism (alterations in ERG11 and/or upregulation of MDR and CDR genes encoding efflux pumps) and provide further evidence that caspofungin is not a substrate for multidrug transporters.

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In Vitro Activity of the New Echinocandin Antifungal, MK-0991, against Common and Uncommon Clinical Isolates of Candida Species

Cited by 43 publications

References 13 publications

Caspofungin Susceptibility Testing of Isolates from Patients with Esophageal Candidiasis or Invasive Candidiasis: Relationship of MIC to Treatment Outcome

Caspofungin Susceptibility Testing of Isolates from Patients with Esophageal Candidiasis or Invasive Candidiasis: Relationship of MIC to Treatment Outcome

Randomized, Double-Blind, Multicenter Study of Caspofungin versus Amphotericin B for Treatment of Oropharyngeal and Esophageal Candidiases

In Vitro Activity of Caspofungin (MK-0991) against Candida albicans Clinical Isolates Displaying Different Mechanisms of Azole Resistance

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