scholarly journals Assessment of the Paradoxical Effect of Caspofungin in Therapy of Candidiasis

2006 ◽  
Vol 50 (4) ◽  
pp. 1293-1297 ◽  
Author(s):  
Karl V. Clemons ◽  
Marife Espiritu ◽  
Rachana Parmar ◽  
David A. Stevens
Keyword(s):  
Candida Albicans ◽  
Clinical Isolates ◽  
Paradoxical Effect ◽  
Cure Rate ◽  
Systemic Model ◽  
Paradoxical Growth ◽  
Intravenous Inoculation

ABSTRACT Paradoxical growth of some Candida albicans isolates in the presence of caspofungin (CAS) in vitro has been demonstrated previously. We sought to determine whether a similar phenomenon occurred in vivo. A systemic model of candidiasis was studied in CD-1 mice by intravenous inoculation of different isolates of C. albicans. Infected animals were treated with CAS at various dosages (0.01 to 20 mg/kg) and CFU remaining in the kidneys determined. Four clinical isolates that showed paradoxical growth in vitro and one that did not were tested. Recovery of CFU from the kidneys showed that dosages of CAS at 0.1 mg/kg and above were efficacious in the reduction of C. albicans, but were not curative. Against isolates that show paradoxical growth in vitro, CAS was efficacious, but lacked dose responsiveness above 0.5 mg/kg against three of the four. One isolate, 95-68, showed paradoxical growth in vivo with significantly higher CFU recovered from mice given CAS at 20 mg/kg than those given CAS at 5 mg/kg, but the effect was not reproducible in a subsequent experiment. When CAS was given prophylactically and therapeutically, improved efficacy and cure rate were observed. Overall, these data indicate that CAS is highly efficacious against systemic murine candidiasis and a paradoxical effect was not reproducibly demonstrated in vivo.

scholarly journals Comparative resistance of Candida albicans clinical isolates to fluconazole and itraconazole in vitro and in vivo in a murine model.

1996 ◽  
Vol 40 (6) ◽  
pp. 1342-1345 ◽  
Author(s):  
A Valentin ◽  
R Le Guennec ◽  
E Rodriguez ◽  
J Reynes ◽  
M Mallie ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Murine Model ◽  
Survival Rates ◽  
Drug Regimen ◽  
Clinical Isolates ◽  
In Vitro Susceptibility ◽  
Microdilution Method ◽  
Broth Microdilution Method

Relationships between azole susceptibility and in vivo response to antifungal therapy in a murine model of candidiasis were investigated for Candida albicans isolates sampled from human immunodeficiency virus type 1-positive patients with oropharyngeal candidiasis. The susceptibilities of seven clinical isolates and two reference strains to fluconazole (FCZ) and itraconazole (ITZ) were determined in vitro by the broth microdilution method. Four isolates were resistant to FCZ and ITZ, two were susceptible to both azoles, and three were resistant to FCZ and susceptible to ITZ (dissociated resistance). CD1 mice were inoculated with each isolate and treated with either FCZ or ITZ (drug regimen, 5 mg/kg of body weight twice daily for 5 days). Quantitative cultures of kidneys were performed at the end of the treatment. On the other hand, the survival rates of the mice were followed daily. These two parameters were clearly correlated with in vitro susceptibility. Thus, the phenomenon of a dissociation of resistance to FCZ and ITZ may be found in vivo as well as in vitro.

scholarly journals KY-62, a Polyene Analog of Amphotericin B, for Treatment of Murine Candidiasis

1998 ◽  
Vol 42 (1) ◽  
pp. 147-150 ◽  
Author(s):  
John R. Graybill ◽  
Laura K. Najvar ◽  
Annette Fothergill ◽  
Thomas Hardin ◽  
Michael Rinaldi ◽  
...  
Keyword(s):  
Body Weight ◽  
Candida Albicans ◽  
Amphotericin B ◽  
Clinical Development ◽  
Water Soluble ◽  
Clinical Isolates ◽  
In Vitro Testing ◽  
Immunocompetent Mice

ABSTRACT KY-62 is a water-soluble analog of amphotericin B. In vitro testing of five clinical isolates of Candida albicans showed KY-62 to have potency similar to that of amphotericin B. KY-62 was administered to mice infected intravenously with C. albicans. In vivo, KY-62 was effective in immunocompetent mice, with potency similar to that of amphotericin B. KY-62 was well tolerated up to 30 mg/kg of body weight per dose, an amount that would be lethal with amphotericin B. KY-62 was less effective in mice rendered neutropenic with 5-fluorouracil. The addition of flucytosine had little effect. KY-62 may have potential for clinical development.

scholarly journals Paradoxical Growth of Candida dubliniensis Does Not Preclude In Vivo Response to Echinocandin Therapy

2009 ◽  
Vol 53 (12) ◽  
pp. 5297-5299 ◽  
Author(s):  
Marçal Mariné ◽  
F. Javier Pastor ◽  
Ismail H. Sahand ◽  
José Pontón ◽  
Guillermo Quindós ◽  
...  
Keyword(s):  
Systemic Infection ◽  
Candida Dubliniensis ◽  
Clinical Isolates ◽  
Murine Models ◽  
Growth Effects ◽  
Abnormal Growth ◽  
Paradoxical Growth

ABSTRACT Candida dubliniensis commonly shows paradoxical or trailing growth effects in vitro in the presence of echinocandins. We tested the in vitro activities of anidulafungin, caspofungin, and micafungin against clinical isolates of C. dubliniensis and evaluated the efficacy of these drugs in two murine models of systemic infection. The three echinocandins were similarly effective in the treatment of experimental disseminated infections with C. dubliniensis strains showing or not showing abnormal growth in vitro.

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

2011 ◽  
Vol 55 (6) ◽  
pp. 2641-2647 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Chen Du ◽  
Ellen Press ◽  
Shaoji Cheng ◽  
...  
Keyword(s):  
Human Serum ◽  
Stress Responses ◽  
Wall Stress ◽  
Paradoxical Effect ◽  
Content Type ◽  
Paradoxical Effects ◽  
Paradoxical Growth ◽  
Synthase Inhibitor

ABSTRACTParadoxical growth ofCandida in vitroat echinocandin concentrations exceeding the MIC is well described, but the clinical relevance is unknown. We assessed echinocandin paradoxical effects againstCandidabloodstream 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) ofCandida albicansBSI exposed to caspofungin, anidulafungin, and micafungin, respectively, at achievable human serum concentrations (≤8 μg/ml). A paradoxical effect was not evident among 34C. glabrataBSI and was observed only for caspofungin againstC. parapsilosis(4%, 1/23). As determined in time-kill studies, a caspofungin paradoxical effect was demonstrated byC. albicans(2/3),C. glabrata(1/3), andC. 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 μg/ml for 100% (8/8) of theC. albicansBSI. 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) ofC. albicans, respectively, and exerted their own paradoxical effects. Finally, paradoxical growth was eliminated inC. albicans irs4- andinp51-null mutants, which lack phosphatidylinositol-(4,5)-bisphosphate 5′-phosphatase. Our findings suggest that the paradoxical effect is unlikely to be importantin vivobut 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.

scholarly journals A variant ECE1 allele contributes to reduced pathogenicity of Candida albicans during vulvovaginal candidiasis via altered secretion of candidalysin

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Junyan Liu ◽  
Emily Sansevere ◽  
Katherine Barker ◽  
Hubertine Willems ◽  
David Lowes ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Amino Acid Sequences ◽  
Vulvovaginal Candidiasis ◽  
Clinical Isolates ◽  
Disease States ◽  
Peptide Toxin ◽  
Future Work

Background: Candida albicans is the primary etiological agent of vulvovaginal candidiasis (VVC) and exerts its pathogenicity through secretion of the peptide toxin candidalysin encoded by the ECE1 gene. A highly conserved variant ECE1 sequence exists across a diverse set of clinical isolates. Thus, we sought to determine the relative pathogenicity and mechanism(s) associated with this alternative ECE1 allele. Methods: Isogenic strains harboring WT or variant ECE1 sequences were engineered in an Δ/Δece1 background. After confirmation of equivalent expression by qPCR, pathogenicity of strains were tested using in vitro epithelial cell and in vivo VVC models of infection and LDH, IL-1β, neutrophil levels monitored. Follow up studies using synthetic candidalysin peptide were also performed. Lastly, a panel of ECE1 chimeras were constructed to assess potential processing defects and detected by a novel HiBiT-tagging approach. Results: Strains transformed with either the variant full length ECE1 or candidalysin allele, as compared to the WT sequence, demonstrated significantly reduced immunopathogenicity during in vitro or in vivo infection despite equivalent fungal burden. Interestingly, epithelial challenge with WT or variant synthetic peptide revealed similar capacity to elicit damage and IL-1β. Allele profiling and ECE1 chimera experiments demonstrated that defects in pathogenicity are at least partly due to inefficient ECE1 processing at the peptide 2-peptide 3 junction. Discussion: The ECE1 gene displays conserved polymorphisms that alter candidalysin secretion and strain pathogenicity. Future work is focused on determining specific amino acid sequences that contribute to these affects across clinical isolates and disease states.

scholarly journals Eap1p, an Adhesin That Mediates Candida albicans Biofilm Formation In Vitro and In Vivo

2007 ◽  
Vol 6 (6) ◽  
pp. 931-939 ◽  
Author(s):  
Fang Li ◽  
Michael J. Svarovsky ◽  
Amy J. Karlsson ◽  
Joel P. Wagner ◽  
Karen Marchillo ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Cell Adhesion ◽  
Biofilm Formation ◽  
Fungal Infections ◽  
Gene Dosage ◽  
Venous Catheter ◽  
Flow Chamber ◽  
Dependent Manner

ABSTRACT Candida albicans is the leading cause of systemic fungal infections in immunocompromised humans. The ability to form biofilms on surfaces in the host or on implanted medical devices enhances C. albicans virulence, leading to antimicrobial resistance and providing a reservoir for infection. Biofilm formation is a complex multicellular process consisting of cell adhesion, cell growth, morphogenic switching between yeast form and filamentous states, and quorum sensing. Here we describe the role of the C. albicans EAP1 gene, which encodes a glycosylphosphatidylinositol-anchored, glucan-cross-linked cell wall protein, in adhesion and biofilm formation in vitro and in vivo. Deleting EAP1 reduced cell adhesion to polystyrene and epithelial cells in a gene dosage-dependent manner. Furthermore, EAP1 expression was required for C. albicans biofilm formation in an in vitro parallel plate flow chamber model and in an in vivo rat central venous catheter model. EAP1 expression was upregulated in biofilm-associated cells in vitro and in vivo. Our results illustrate an association between Eap1p-mediated adhesion and biofilm formation in vitro and in vivo.

Virulence of “white-gray-opaque” tri-stable transformation in clinical Candida albicans in vitro and in vivo

2021 ◽  
Vol 154 ◽  
pp. 104825
Author(s):  
Jing Yang ◽  
Wenli Feng ◽  
Zhiqin Xi ◽  
Lu Yang ◽  
Xiaoxia Zhao ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Stable Transformation
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