cancidas and posaconazole

The in vivo efficacy of posaconazole against 4 clinical Aspergillus fumigatus isolates with posaconazole MICs ranging from 0.03 to 16 mg/liter, as determined by CLSI method M38A, was assessed in a nonneutropenic murine model of disseminated aspergillosis. The underlying resistance mechanisms of the isolates included substitutions in the cyp51A gene at codon 220 (M220I), codon 54 (G54W), and codon 98 (L98H). The latter was combined with a 34-bp tandem repeat in the gene promoter region (TR L98H). The control isolate exhibited a wild-type phenotype without any known resistance mechanism. Oral posaconazole therapy was started 24 h after infection and was given once daily for 14 consecutive days. Mice were treated with four different doses (1 to 64 mg/kg of body weight), and survival was used as the end point. Survival was dependent both on the dose and on the MIC. The Hill equation with a variable slope fitted the relationship between the dose/MIC ratio and 14-day survival well (R2, 0.92), with a 50% effective dose (ED50) of 29.0 mg/kg (95% confidence interval [CI], 15.6 to 53.6 mg/kg). This also applied to the relationship between the area under the plasma concentration-time curve (AUC)/MIC ratio and 14-day survival (50% effective pharmacodynamic index [EI50], 321.3 [95% CI, 222.7 to 463.4]). Near-maximum survival was reached at an AUC/MIC ratio of nearly 1,000. These results indicate that treatment of infections with A. fumigatus strains for which MICs are 0.5 mg/liter requires doses exceeding the present licensed doses. Increasing the standard dosing regimen may have some effect and may be clinically useful if no alternatives are available.

Topics: Administration, Oral; Animals; Antifungal Agents; Area Under Curve; Aspergillosis; Aspergillus fumigatus; Cytochrome P-450 Enzyme System; Disease Models, Animal; Drug Administration Schedule; Female; Fungal Proteins; Mice; Microbial Sensitivity Tests; Mutation; Triazoles

The in vitro activities of eight antifungal drugs against clinical isolates of Fonsecaea pedrosoi (n = 21), Fonsecaea monophora (n = 25), and Fonsecaea nubica (n = 9) were tested. The resulting MIC(90)s for all strains (n = 55) were as follows, in increasing order: posaconazole, 0.063 microg/ml; itraconazole, 0.125 microg/ml; isavuconazole, 0.25 microg/ml; voriconazole, 0.5 microg/ml; amphotericin B, 2 microg/ml; caspofungin, 2 microg/ml; anidulafungin, 2 microg/ml; and fluconazole, 32 microg/ml.

Topics: Amphotericin B; Anidulafungin; Antifungal Agents; Ascomycota; Caspofungin; Chromoblastomycosis; Drug Resistance, Fungal; Echinocandins; Fluconazole; Humans; In Vitro Techniques; Itraconazole; Lipopeptides; Microbial Sensitivity Tests; Nitriles; Pyridines; Pyrimidines; Triazoles; Voriconazole

Forty-four isolates belonging to human pathogenic species of Lichtheimia were tested against nine antifungal agents by using the EUCAST methodology. No remarkable differences were found between the clinical species, although L. ramosa showed slightly higher MICs for all drugs. Amphotericin B was the most active drug. Among azole drugs, posaconazole had the best activity in vitro and voriconazole was inactive. Echinocandins showed activity for some isolates, suggesting a potential role in combination therapy.

Topics: Amphotericin B; Antifungal Agents; Humans; Microbial Sensitivity Tests; Mucorales; Pyrimidines; Triazoles; Voriconazole

We have determined the in vitro activities of amphotericin B (AMB), voriconazole, posaconazole (PSC), itraconazole (ITC), ravuconazole, terbinafine, and caspofungin against five strains of Cunninghamella bertholletiae and four of Cunninghamella echinulata. The best activity was shown by terbinafine against both species (MIC range = 0.3 to 0.6 μg/ml) and PSC against Cunninghamella bertholletiae (MIC = 0.5 μg/ml). We have also evaluated the efficacies of PSC, ITC, and AMB in neutropenic and diabetic murine models of disseminated infection by Cunninghamella bertholletiae. PSC at 40, 60, or 80 mg/kg of body weight/day was as effective as AMB at 0.8 mg/kg/day in prolonging survival and reducing the fungal tissue burden in neutropenic mice. PSC at 80 mg/kg/day was more effective than AMB at 0.8 mg/kg/day in reducing the fungal load in brain and lung of diabetic mice. Histological studies revealed an absence of fungal elements in organs of mice treated with either AMB at 0.8 mg/kg/day or PSC at 60 or 80 mg/kg/day in both models. ITC showed limited efficacy in both models. PSC could be a therapeutic option for the treatment of systemic infections caused by Cunninghamella bertholletiae.

Topics: Amphotericin B; Animals; Antifungal Agents; Caspofungin; Cunninghamella; Diabetes Mellitus, Experimental; Echinocandins; Itraconazole; Lipopeptides; Male; Mice; Microbial Sensitivity Tests; Mucormycosis; Pyrimidines; Thiazoles; Triazoles; Voriconazole

We evaluated the effects of sequential therapy with caspofungin (CAS) or amphotericin B (AMB) followed by posaconazole (POS) against Candida glabrata. The susceptibilities to POS of yeast cells pre-exposed to CAS or AMB were identical to those of untreated cells as shown by standard Clinical and Laboratory Standards Institute broth dilution, cell viability, and disk diffusion methods. We then investigated the activity of sequential regimens in an experimental model of disseminated candidiasis. CAS given at 1 mg/kg/day for 2 days followed by POS at either 15 or 30 mg/kg/day significantly reduced the counts compared to the controls, but this treatment was not superior to the use of CAS alone. Also, sequential regimens with AMB given at 1 mg/kg/day for 2 days followed by POS (AMB/POS) were effective at reducing the fungal burden against the controls. In addition, AMB/POS with both doses of the triazole were significantly more effective than AMB alone. Overall, our data showed that there is no therapeutic advantage in using CAS followed by POS, whereas an induction therapy with AMB followed by a maintenance regimen with POS might be a suitable strategy in managing C. glabrata infections.

Topics: Amphotericin B; Animals; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Colony Count, Microbial; Drug Administration Schedule; Echinocandins; Humans; Kidney; Lipopeptides; Male; Mice; Microbial Sensitivity Tests; Treatment Outcome; Triazoles

We investigated the in vitro activities of posaconazole (POS), fluconazole (FLC), amphotericin B (AMB), and caspofungin (CAS) against four clinical isolates of Candida glabrata with various susceptibilities to FLC (FLC MICs ranging from 1.0 to >64 microg/ml). POS MICs ranged from < or =0.03 to 0.5 microg/ml; AMB MICs ranged from 0.25 to 2.0 microg/ml, while CAS MICs ranged from 0.03 to 0.25 microg/ml. When FLC MICs increased, so did POS MICs, although we did not observe any isolate with a POS MIC greater than 0.5 mug/ml. Time-kill experiments showed that POS, FLC, and CAS were fungistatic against all isolates, while AMB at eight times the MIC was fungicidal against three out of four isolates of C. glabrata tested. Then, we investigated the activity of POS in an experimental model of disseminated candidiasis using three different isolates of C. glabrata: one susceptible to FLC (S; FLC MICs ranging from 1.0 to 4.0 microg/ml; POS MIC of < or =0.03 microg/ml), one susceptible in a dose-dependent manner (SDD; FLC MICs ranging from 32 to 64 microg/ml; POS MICs ranging from 0.125 to 0.25 microg/ml), and another one resistant to FLC (R; FLC MIC of >64 microg/ml; POS MIC of 0.5 microg/ml). FLC significantly reduced the kidney burden of mice infected with the S strain (P = 0.0070) but not of those infected with the S-DD and R strains. POS was significantly effective against all three isolates at reducing the kidney fungal burden with respect to the controls (P ranging from 0.0003 to 0.029). In conclusion, our data suggest that POS may be a useful option in the management of systemic infections caused by C. glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC.

Topics: Animals; Antifungal Agents; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Fluconazole; Humans; Kidney; Male; Mice; Microbial Sensitivity Tests; Treatment Outcome; Triazoles

Voriconazole, posaconazole, caspofungin, micafungin, and anidulafungin demonstrated potent in vitro activities against 286 invasive Candida isolates. Analysis of the fluconazole susceptibilities of 204 bloodstream Candida glabrata isolates revealed a rapid shift from susceptible (64% in 1999 to 2001 to 19% in 2007) to susceptible-dose dependent (27% in 1999 to 2001 and 75% in 2007).

Topics: Anidulafungin; Antifungal Agents; Candida; Candida glabrata; Caspofungin; Echinocandins; Fluconazole; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Pyrimidines; Triazoles; Voriconazole

We compared the activities of antifungal agents against a wide range of yeasts and filamentous fungi. The methodology of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for yeasts and spore-forming molds was applied; and a total of 349 clinical isolates of Candida spp., other yeast species, Aspergillus spp., and nondermatophyte non-Aspergillus spp. were investigated. The average geometric mean (GM) of the MICs of the various drugs for Candida spp. were as follows: amphotericin B (AMB), 0.55 microg/ml; liposomal amphotericin B (l-AMB); 0.35 microg/ml; itraconazole (ITC), 0.56 microg/ml; voriconazole (VRC), 0.45 microg/ml; posaconazole (POS), 0.44 microg/ml; and caspofungin (CPF), 0.45 microg/ml. The data indicated that the majority of Candida spp. were susceptible to the traditional and new antifungal drugs. For Aspergillus spp., the average GM MICs of AMB, l-AMB, ITC, VRC, POS, and CPF were 1.49 microg/ml, 1.44 microg/ml, 0.65 microg/ml, 0.34 microg/ml, 0.25 microg/ml, and 0.32 microg/ml, respectively. For the various zygomycetes, the average GM MICs of AMB, l-AMB, ITC, and POS were 1.36 microg/ml, 1.42 microg/ml, 4.37 microg/ml, and 1.65 microg/ml, respectively. Other yeastlike fungi and molds displayed various patterns of susceptibility. In general, the minimal fungicidal concentrations were 1 to 3 dilutions higher than the corresponding MICs. POS, AMB, and l-AMB showed activities against a broader range of fungi than ITC, VRC, and CPF did. Emerging pathogens such as Saccharomyces cerevisiae and Fusarium solani were not killed by any drug. In summary, the EUCAST data showed that the in vitro susceptibilities of yeasts and filamentous fungi are variable, that susceptibility occurs among and within various genera and species, and that susceptibility depends on the antifungal drug tested. AMB, l-AMB, and POS were active against the majority of pathogens, including species that cause rare and difficult-to-treat infections.

Topics: Amphotericin B; Antifungal Agents; Aspergillus; Candida; Drug Resistance, Fungal; Europe; Fungi; Guidelines as Topic; Humans; Microbial Sensitivity Tests; Mycoses; Opportunistic Infections; Triazoles; Yeasts

We evaluated the in vitro susceptibilities of 217 zygomycetes to amphotericin B, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, caspofungin, and flucytosine. The significant in vitro activity of posaconazole against several species appears to support its reported clinical efficacy. Decreased susceptibility to amphotericin B was noted with Cunninghamella bertholletiae.

Topics: Amphotericin B; Antifungal Agents; Caspofungin; Echinocandins; Fluconazole; Flucytosine; Humans; In Vitro Techniques; Itraconazole; Ketoconazole; Lipopeptides; Microbial Sensitivity Tests; Mucormycosis; Peptides, Cyclic; Pyrimidines; Triazoles; Voriconazole

Topics: Antifungal Agents; Caspofungin; Drug Synergism; Echinocandins; Fungi; Lipopeptides; Microbial Sensitivity Tests; Triazoles