Development of Candidemia on Caspofungin Therapy: a Case Report

Cheung, C. N.; Guo, Yi; Gialanella, Philip; Feldmesser, Marta

doi:10.1007/s15010-006-5613-7

Cited by 50 publications

(41 citation statements)

References 31 publications

(33 reference statements)

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“…Most infections due to C. parapsilosis respond to primary echinocandin therapy (3,32), although resistance to CSF resulting in clinical failure has been reported (5). In this context, there is a concern that as echinocandin therapy expands to countries in Latin America, where C. parapsilosis is a common cause of fungal bloodstream infection (24,29), the elevated baseline drug susceptibility could represent an initial step toward clinical resistance or a new factor contributing to an even higher prevalence.…”

Section: Discussionmentioning

confidence: 99%

A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis , Candida orthopsilosis , and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility

García‐Effrón¹,

Katiyar

Park³

et al. 2008

Antimicrob Agents Chemother

278

250

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Candida parapsilosis has emerged as a common cause of invasive fungal infection, especially in Latin America and in the neonatal setting. C. parapsilosis is part of a closely related group of organisms that includes the species Candida orthopsilosis and Candida metapsilosis. All three species show elevated MICs for the new echinocandin class drugs caspofungin, micafungin, and anidulafungin relative to other Candida species. Despite potential impacts on therapy, the mechanism behind this reduced echinocandin susceptibility has not been determined. In this report, we investigated the role of a naturally occurring Pro-to-Ala substitution at amino acid position 660 (P660A), immediately distal to the highly conserved hot spot 1 region of Fks1p, in the reduced-echinocandin-susceptibility phenotype. Kinetic inhibition studies demonstrated that glucan synthase from the C. parapsilosis group was 1 to 2 logs less sensitive to echinocandin drugs than the reference enzyme from C. albicans. Furthermore, clinical isolates of C. albicans and C. glabrata which harbor mutations at this equivalent position also showed comparable 2-log decreases in target enzyme sensitivity, which correlated with increased MICs. These mutations also resulted in 2.4- to 18.8-fold-reduced V max values relative to those for the wild-type enzyme, consistent with kinetic parameters obtained for C. parapsilosis group enzymes. Finally, the importance of the P660A substitution for intrinsic resistance was confirmed by engineering an equivalent P647A mutation into Fks1p of Saccharomyces cerevisiae. The mutant glucan synthase displayed characteristic 2-log decreases in sensitivity to the echinocandin drugs. Overall, these data firmly indicate that a naturally occurring P660A substitution in Fks1p from the C. parapsilosis group accounts for the reduced susceptibility phenotype.

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Section: Discussionmentioning

confidence: 99%

A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis , Candida orthopsilosis , and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility

García‐Effrón¹,

Katiyar

Park³

et al. 2008

Antimicrob Agents Chemother

278

250

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“…Nonetheless, echinocandins demonstrate reduced in vitro activity against C. parapsilosis (1,(12)(13)(14)(15), and failures of echinocandin treatment have been reported in C. parapsilosis IC (16,17). In particular, clinical failure due to CAS-resistant (CAS-R) isolates has been recently reported in patients receiving CAS (18,19). Furthermore, a rise in the incidence of C. parapsilosis infections, which has been partially attributed to the increased use of CAS, has been noted in some cancer centers and the ICU setting (17)(18)(19).…”

mentioning

confidence: 99%

Anidulafungin versus Caspofungin in a Mouse Model of Candidiasis Caused by Anidulafungin-Susceptible Candida parapsilosis Isolates with Different Degrees of Caspofungin Susceptibility

Dimopoulou

Hamilos

Tzardi

et al. 2014

Antimicrob Agents Chemother

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. We analyzed tissue fungal burden, histopathology, and weight loss patterns. Increasing CAS resistance was associated with reduced virulence of C. parapsilosis isolates (mortality rates for CAS-S versus CAS-I versus CAS-R, 100% versus 11.1% versus 0%, respectively; P < 0.001). High doses of either echinocandin were active against infection with the CAS-I isolate when assessed by fungal burden reduction and weight gain. In contrast to CAS-S and CAS-I isolates, there was no reduction in fungal burden in mice infected with the CAS-R isolate following treatment with either echinocandin, each given at a high or low dose. Nevertheless, mice infected with the CAS-R isolate had reduced disease severity following echinocandin treatment, suggesting that echinocandins have activity in vivo, even against echinocandin-resistant strains. A complex interplay of residual echinocandin activity, decreased virulence, and/or fitness of isolates with altered cell wall and possible immunomodulatory effects can be encountered in vivo during infection with CASresistant C. parapsilosis isolates.

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“…As echinocandin use has escalated, cases of echinocandin breakthrough IC have been described (6,7,13,25,39,50), and nonsusceptible isolates (MIC Ͼ 2 g/ml) have been recovered from patients who demonstrated treatment failure (9). Moreover, several of these nonsusceptible isolates possess nonsynonymous point mutations in genes encoding the ␤-1,3-glucan synthase enzyme complex (Fksp) (4,13,39,47).…”

mentioning

confidence: 99%

Breakthrough Invasive Candidiasis in Patients on Micafungin

et al. 2010

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For Candida species, a bimodal wild-type MIC distribution for echinocandins exists, but resistance to echinocandins is rare. We characterized isolates from patients with invasive candidiasis (IC) breaking through >3 doses of micafungin therapy during the first 28 months of its use at our center: MICs were determined and hot-spot regions within FKS genes were sequenced. Eleven of 12 breakthrough IC cases identified were in transplant recipients. The median duration of micafungin exposure prior to breakthrough was 33 days (range, 5 to 165). Seventeen breakthrough isolates were recovered: FKS hot-spot mutations were found in 5 C. glabrata and 2 C. tropicalis isolates; of these, 5 (including all C. glabrata isolates) had micafungin MICs of >2 g/ml, but all demonstrated caspofungin MICs of >2 g/ml. Five C. parapsilosis isolates had wild-type FKS sequences and caspofungin MICs of 0.5 to 1 g/ml, but 4/5 had micafungin MICs of >2 g/ml. The remaining isolates retained echinocandin MICs of <2 g/ml and wild-type FKS gene sequences. Breakthrough IC on micafungin treatment occurred predominantly in severely immunosuppressed patients with heavy prior micafungin exposure. The majority of cases were due to C. glabrata with an FKS mutation or wild-type C. parapsilosis with elevated micafungin MICs. MIC testing with caspofungin identified all mutant strains. Whether the naturally occurring polymorphism within the C. parapsilosis FKS1 gene responsible for the bimodal wild-type MIC distribution is also responsible for micafungin MICs of >2 g/ml and clinical breakthrough or an alternative mechanism contributes to the nonsusceptible echinocandin MICs in C. parapsilosis requires further study.Invasive candidiasis (IC) is an important, life-threatening infection in hospitalized patients. The echinocandins (micafungin, caspofungin, and anidulafungin) are the newest class of medications approved for the prophylaxis and treatment of IC. They act via noncompetitive inhibition of ␤-1,3-glucan synthase, the enzyme responsible for producing ␤-1,3-D-glucan in the fungal cell wall (41). These drugs have low toxicity and few drug-drug interactions and possess a broad spectrum of antifungal activity against Candida species, including those resistant to fluconazole. In clinical trials, the echinocandins have demonstrated noninferiority for the treatment of IC versus amphotericin B deoxycholate, liposomal amphotericin B, and fluconazole (25,32,44). The echinocandins are considered interchangeable for clinical use, and a recent study comparing micafungin to caspofungin for IC supports this notion (38). Based on the accumulated experience, echinocandins are now considered a first-line therapeutic choice for IC (37).The echinocandins exhibit a bimodal MIC distribution among Candida species. MICs of C. parapsilosis, C. guilliermondii, and C. famata MICs (MIC 90 , 0.25 to 2 g/ml) are up to 133 times higher than those of C. albicans, C. glabrata, C. tropicalis, C. krusei, and C. kefyr (MIC 90 , 0.015 to 0.25 g/ml) (42). However, this difference has not...

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Development of Candidemia on Caspofungin Therapy: a Case Report

Cited by 50 publications

References 31 publications

A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis , Candida orthopsilosis , and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility

A Naturally Occurring Proline-to-Alanine Amino Acid Change in Fks1p in Candida parapsilosis , Candida orthopsilosis , and Candida metapsilosis Accounts for Reduced Echinocandin Susceptibility

Anidulafungin versus Caspofungin in a Mouse Model of Candidiasis Caused by Anidulafungin-Susceptible Candida parapsilosis Isolates with Different Degrees of Caspofungin Susceptibility

Breakthrough Invasive Candidiasis in Patients on Micafungin

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