In Vivo Fluconazole Pharmacodynamics and Resistance Development in a Previously Susceptible<i>Candida albicans</i>Population Examined by Microbiologic and Transcriptional Profiling

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Multiple in vivo studies have characterized the pharmacodynamics of drugs from the triazole and polyene antifungal drug classes. Fewer studies have investigated these pharmacodynamic relationships for the echinocandin drug class. We used a neutropenic murine model of disseminated Candida albicans, Candida tropicalis, and Candida glabrata infection to characterize the time course of activity of the new echinocandin anidulafungin. The pharmacokinetic-pharmacodynamic (PK-PD) indices (the percentage of time that the drug concentration was above the MIC, the ratio of the area under the concentration-time curve from 0 to 24 h [AUC 0-24 ] to the MIC, and the ratio of the maximum serum drug concentration [C max ] to the MIC) were correlated with in vivo efficacy, as measured by organism numbers in kidney cultures after 96 h of therapy. The kinetics following intraperitoneal anidulafungin dosing in neutropenic infected mice were monitored. Peak levels and AUCs were linear over the 16-fold dose range studied. The drug elimination half-life in serum ranged from 14 to 24 h. Single-dose postantifungal-effect studies demonstrated prolonged suppression of organism regrowth after serum anidulafungin levels had fallen below the MIC. Of the four dosing intervals studied, treatment with the more widely spaced dosing regimens was most efficacious, suggesting the C max /MIC ratio as the PK-PD index most predictive of efficacy. Nonlinear regression analysis suggested that both the C max /MIC and AUC/ MIC ratios were strongly predictive of treatment success. Studies were then conducted with 13 additional C. albicans, C. tropicalis, and C. glabrata isolates with various anidulafungin susceptibilities (MICs of anidulafungin for these strains, 0.015 to 2.0 g/ml) to determine if similar C max /MIC and AUC 0-24 /MIC ratios for these isolates were associated with efficacy. The anidulafungin exposures associated with efficacy were similar among Candida species.The incidence of invasive fungal infections continues to rise (36,42). Despite advances in antifungal therapy, morbidity and mortality associated with these infections remain high. The echinocandins constitute the most recently Food and Drug Administration-approved antifungal drug class (10, 14, 50). The three available drugs from this class include anidulafungin, caspofungin, and micafungin. These compounds exhibit broad-spectrum activity against Candida and Aspergillus species, including emerging non-albicans Candida species (10,14,20,40,41,54). The present studies were designed to determine the in vivo pharmacodynamic (PD) characteristics of a new compound against Candida albicans, C. tropicalis, and C. glabrata. We first examined the impact of the anidulafungin concentration on in vivo antimicrobial killing activity over time. Studies were then performed to determine (i) which pharmacokinetic (PK) index (the maximum concentration of the drug in serum [C max ], the area under the concentration-time curve [AUC], or the duration of time that levels in serum exceed the MIC [TϾMIC]) bes...

Section: Vol 52 2008 Anidulafungin Pharmacodynamics In Murine Candisupporting

confidence: 69%

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confidence: 99%

In Vivo Pharmacodynamic Characterization of Anidulafungin in a Neutropenic Murine Candidiasis Model

Andes

Diekema

Pfaller

et al. 2008

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“…Ergosterol is a major and essential lipid constituent of the fungal cell membrane (1). The acquisition of azole resistance, particularly after prolonged exposure, as happens with prophylactic overuse, is a well-known phenomenon in fungi (5,6,29). The widespread use of azole antifungals, especially fluconazole (FLC), resulted in a growing incidence of Candida species in which resistance is easily induced, such as Candida glabrata (75), or species that show intrinsic resistance, such as C. krusei (74).…”

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confidence: 99%

Transcriptional Profiling of Azole-Resistant Candida parapsilosis Strains

Silva

Miranda

Guida

et al. 2011

Herein we describe the changes in the gene expression profile of Candida parapsilosis associated with the acquisition of experimentally induced resistance to azole antifungal drugs. Three resistant strains of C. parapsilosis were obtained following prolonged in vitro exposure of a susceptible clinical isolate to constant concentrations of fluconazole, voriconazole, or posaconazole. We found that after incubation with fluconazole or voriconazole, strains became resistant to both azoles but not to posaconazole, although susceptibility to this azole decreased, whereas the strain incubated with posaconazole displayed resistance to the three azoles. The resistant strains obtained after exposure to fluconazole and to voriconazole have increased expression of the transcription factor MRR1, the major facilitator transporter MDR1, and several reductases and oxidoreductases. Interestingly, and similarly to what has been described in C. albicans, upregulation of MRR1 and MDR1 is correlated with point mutations in MRR1 in the resistant strains. The resistant strain obtained after exposure to posaconazole shows upregulation of two transcription factors (UPC2 and NDT80) and increased expression of 13 genes involved in ergosterol biosynthesis. This is the first study addressing global molecular mechanisms underlying azole resistance in C. parapsilosis; the results suggest that similarly to C. albicans, tolerance to azoles involves the activation of efflux pumps and/or increased ergosterol synthesis.Candida parapsilosis is the second most common Candida species isolated from patients with bloodstream infections in Latin America and Asia (46, 60), and it is also commonly found in European surveys (4,17,43,67). It is responsible for a broad variety of clinical manifestations that generally occur in individuals with impaired immune systems, in neutropenic or burn patients, as well as in patients admitted to medical or surgical intensive care units (43), especially pediatric units (26,48).Azoles are the most commonly used drugs for the treatment of Candida infections (13). They target lanosterol 14␣-demethylase, a member of the cytochrome P450 enzymes, which is required for the synthesis of ergosterol (1, 76). Ergosterol is a major and essential lipid constituent of the fungal cell membrane (1). The acquisition of azole resistance, particularly after prolonged exposure, as happens with prophylactic overuse, is a well-known phenomenon in fungi (5,6,29). The widespread use of azole antifungals, especially fluconazole (FLC), resulted in a growing incidence of Candida species in which resistance is easily induced, such as Candida glabrata (75), or species that show intrinsic resistance, such as C. krusei (74). Previous studies with C. albicans (38), C. dubliniensis (59), and C. tropicalis (9) demonstrated that resistance to fluconazole can be promoted following repeated in vitro exposure to the drug. The ability of a drug to induce in vitro resistance suggests that similar mechanisms may also occur in vivo, which may thus became proble...

“…The single-dose pharmacokinetics of micafungin were determined in infected neutropenic ICR/Swiss mice after intraperitoneal administration of 80, 20, and 5 mg/kg administered in 0.2-ml volumes. Blood from groups of three isofluorane-anesthetized mice (nine mice for each dose level) was collected at each of eight time points (1,2,4,6,8,12,24, and 48 h). Serum was collected by centrifugation, and samples were stored at Ϫ80°C until drug assay.…”

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confidence: 99%

In Vivo Pharmacodynamic Target Investigation for Micafungin against Candida albicans and C. glabrata in a Neutropenic Murine Candidiasis Model

Andes

Diekema

Pfaller

et al. 2008

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111

Previous studies using in vivo candidiasis models have demonstrated that the concentration-associated pharmacodynamic indices, the maximum concentration of a drug in serum/MIC and 24-h area under the curve (AUC)/MIC, are associated with echinocandin treatment efficacy. The current investigations used a neutropenic murine model of disseminated Candida albicans and C. glabrata infection to identify the 24-h AUC/MIC index target associated with a stasis and killing endpoint for the echinocandin, micafungin. The kinetics after intraperitoneal micafungin dosing were determined in neutropenic infected mice. Peak levels and AUC values were linear over the 16-fold dose range studied. The serum drug elimination half-life ranged from 7.5 to 16 h. Treatment studies were conducted with 4 C. albicans and 10 C. glabrata isolates with micafungin MICs varying from 0.008 to 0.25 g/ml to determine whether similar 24-h AUC/MIC ratios were associated with efficacy. The free drug AUC/MICs associated with stasis and killing (1-log) endpoints were near 10 and 20, respectively. The micafungin exposures associated with efficacy were similar for the two Candida species. Furthermore, the free drug micafungin exposures required to produce stasis and killing endpoints were similar to those recently reported for another echinocandin, anidulafungin, against the identical Candida isolates in this model. Antifungal pharmacodynamic studies have been helpful to optimize dosing regimen design and provide a rationale for the development of susceptibility breakpoints for several antifungal drugs including the triazoles, amphotericin B, and flucytosine. Recent studies have begun to apply these pharmacodynamic principles to understand the exposure and response relationship for drugs from the echinocandin class (10,15,46,50). These compounds exhibit broad-spectrum activity against Candida and Aspergillus species, including emerging Candida species such as C. glabrata (13,20,41,42). Previous investigations with other echinocandins, including micafungin (D. Andes, unpublished observations) have demonstrated that the concentration-associated pharmacodynamic indices, the maximum concentration of a drug in serum (C max )/MIC and the area under the curve (AUC)/MIC, drive treatment efficacy for this drug class in candidiasis models (2, 9, 21, 26). The present study was performed to determine whether the magnitude of the pharmacokinetic/pharmacodynamic index required for efficacy is similar for C. albicans and C. glabrata strains, including several previously characterized caspofungin-resistant organisms. These study observations were also compared to recently published data with the echinocandin anidulafungin in this model with the same strains (9). The results from these studies provide a pharmacodynamic rationale in support of the current clinical dosing regimens. Furthermore, the data provide information useful regarding the susceptibility breakpoints for this new compound. MATERIALS AND METHODSOrganisms. Fourteen clinical Candida isolates were used: four ...