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1.
J Clin Microbiol ; 54(3): 734-8, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26763959

ABSTRACT

Significant interlaboratory variability is observed in testing the caspofungin susceptibility of Candida species by both the CLSI and EUCAST broth microdilution methodologies. We evaluated the influence of treated versus untreated polystyrene microtiter trays on caspofungin MICs using 209 isolates of four Candida species, including 16 C. albicans and 11 C. glabrata isolates with defined FKS mutations. Caspofungin MICs were also determined using the commercially available YeastOne and Etest assays and 102 isolates. All C. glabrata isolates had caspofungin MICs of ≥0.5 µg/ml, the clinical breakpoint for caspofungin resistance in this species, measured using trays made of treated polystyrene, regardless of the FKS status. In contrast, susceptible isolates could readily be distinguished from resistant/non-wild-type isolates when caspofungin MICs were measured using untreated polystyrene trays and both the YeastOne and Etest assays. Similar results were also observed for C. krusei isolates, as all isolates had caspofungin MICs above the threshold for resistance measured using treated polystyrene trays. In contrast, C. albicans isolates could be correctly identified as susceptible or resistant when caspofungin MICs were measured with treated or untreated trays and with the YeastOne and Etest assays. MICs falsely elevated above the resistance breakpoint were also not observed for C. tropicalis isolates. These results demonstrated that the use of treated polystyrene may be one factor that leads to falsely elevated caspofungin in vitro susceptibility results and that this may also be a greater issue for some Candida species than for others.


Subject(s)
Antifungal Agents/pharmacology , Candida/drug effects , Echinocandins/pharmacology , Lipopeptides/pharmacology , Polystyrenes , Candida/isolation & purification , Caspofungin , Humans , Microbial Sensitivity Tests , Reproducibility of Results
2.
J Clin Microbiol ; 54(1): 168-71, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26491179

ABSTRACT

Azole resistance in Aspergillus fumigatus is an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmed A. fumigatus isolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here.


Subject(s)
Antifungal Agents/pharmacology , Aspergillus fumigatus/enzymology , Aspergillus fumigatus/genetics , Azoles/pharmacology , Drug Resistance, Fungal , Mutation, Missense , Sterol 14-Demethylase/genetics , Aspergillosis/microbiology , Aspergillus fumigatus/drug effects , Aspergillus fumigatus/isolation & purification , Humans , Microbial Sensitivity Tests , United States
3.
J Antimicrob Chemother ; 71(3): 692-5, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26620102

ABSTRACT

OBJECTIVES: Candida species are major causes of invasive mycoses in immunocompetent and immunocompromised hosts. Treatment options are limited in the setting of antifungal resistance and increased rates of echinocandin-resistant Candida glabrata have been reported. The novel arylamidine T-2307 demonstrates potent in vitro antifungal activity against Candida species. Our objective was to evaluate the in vitro and in vivo activity of T-2307 against resistant C. glabrata. METHODS: In vitro activity was determined against 42 clinical C. glabrata isolates, including 17 echinocandin-resistant strains. Neutropenic ICR mice were inoculated intravenously with an echinocandin-resistant C. glabrata isolate (T-2307; caspofungin MICs ≤0.008 and 0.5 mg/L, respectively). Therapy with vehicle control, T-2307 (0.75, 1.5, 3 or 6 mg/kg subcutaneously once daily) or caspofungin (1 or 10 mg/kg intraperitoneally once daily) began 1 day post-challenge. Kidneys were collected on day 8 and fungal burden was assessed by counting cfu. RESULTS: T-2307 demonstrated potent in vitro activity against C. glabrata (geometric mean MIC 0.0135 mg/L), which was maintained against echinocandin-resistant isolates (geometric mean MIC 0.0083 mg/L). T-2307 also demonstrated in vivo efficacy in mice infected with echinocandin-resistant C. glabrata. Significant reductions in fungal burden were observed at each dosage level of T-2307 compared with control. Reductions in fungal burden were also observed with high-dose caspofungin. CONCLUSIONS: T-2307 demonstrated potent in vitro activity against C. glabrata, including echinocandin-resistant isolates, which translated into in vivo efficacy against invasive candidiasis caused by an echinocandin-resistant C. glabrata strain. These results demonstrate the potential for T-2307 as therapy against echinocandin-resistant Candida.


Subject(s)
Amidines/administration & dosage , Amidines/pharmacology , Antifungal Agents/administration & dosage , Antifungal Agents/pharmacology , Candida glabrata/drug effects , Candidiasis/drug therapy , Candidiasis/microbiology , Animals , Candida glabrata/isolation & purification , Colony Count, Microbial , Disease Models, Animal , Humans , Kidney/microbiology , Male , Mice, Inbred ICR , Microbial Sensitivity Tests , Treatment Outcome
4.
Antimicrob Agents Chemother ; 59(2): 1341-3, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25451054

ABSTRACT

We evaluated the in vitro and in vivo activities of the investigational arylamidine T-2307 against echinocandin-resistant Candida albicans. T-2307 demonstrated potent in vitro activity, and daily subcutaneous doses between 0.75 and 6 mg/kg of body weight significantly improved survival and reduced fungal burden compared to placebo control and caspofungin (10 mg/kg/day) in mice with invasive candidiasis caused by an echinocandin-resistant strain. Thus, T-2307 may have potential use in the treatment of echinocandin-resistant C. albicans infections.


Subject(s)
Amidines/pharmacology , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida albicans/pathogenicity , Echinocandins/pharmacology , Echinocandins/therapeutic use , Animals , Candida albicans/drug effects , Candidiasis/drug therapy , Drug Resistance, Fungal , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests
5.
Antimicrob Agents Chemother ; 59(1): 690-2, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25331706

ABSTRACT

The in vitro and in vivo activity of the inositol acyltransferase inhibitor E1210 was evaluated against echinocandin-resistant Candida albicans. E1210 demonstrated potent in vitro activity, and in mice with invasive candidiasis caused by echinocandin-resistant C. albicans, oral doses of 10 and 40 mg E1210/kg of body weight twice daily significantly improved survival and reduced fungal burden compared to those of controls and mice treated with caspofungin (10 mg/kg/day). These results demonstrate the potential use of E1210 against resistant C. albicans infections.


Subject(s)
Aminopyridines/pharmacology , Antifungal Agents/pharmacology , Candida albicans/drug effects , Candidiasis, Invasive/drug therapy , Isoxazoles/pharmacology , Aminopyridines/therapeutic use , Animals , Antifungal Agents/therapeutic use , Caspofungin , Dose-Response Relationship, Drug , Drug Resistance, Fungal , Echinocandins/pharmacology , Echinocandins/therapeutic use , Fluconazole/pharmacology , Fluconazole/therapeutic use , Isoxazoles/therapeutic use , Lipopeptides , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests
6.
Antimicrob Agents Chemother ; 58(6): 3553-5, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24709260

ABSTRACT

The in vitro activities of luliconazole, amorolfine, ciclopirox, and terbinafine were determined against 320 dermatophyte isolates from large toenails of onychomycosis patients enrolled into an ongoing phase 2b/3 clinical study. The geometric mean MIC for luliconazole was 0.00022 µg/ml against all isolates, compared to 0.0194 to 0.3107 µg/ml for the three other agents. The in vitro potency of luliconazole was maintained regardless of the dermatophyte species.


Subject(s)
Antifungal Agents/pharmacology , Arthrodermataceae/drug effects , Dermatomycoses/drug therapy , Imidazoles/pharmacology , Onychomycosis/microbiology , Ciclopirox , Dermatomycoses/complications , Humans , Microbial Sensitivity Tests , Morpholines/pharmacology , Naphthalenes/pharmacology , Onychomycosis/complications , Pyridones/pharmacology , Terbinafine
7.
J Clin Microbiol ; 52(3): 994-7, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24403302

ABSTRACT

We reviewed our antifungal susceptibility data for micafungin, anidulafungin, fluconazole, and voriconazole against Candida species and compared resistance rates determined by the previous and recently revised CLSI antifungal breakpoints. With the new breakpoints, resistance was significantly increased for micafungin (from 0.8% to 7.6%), anidulafungin (from 0.9% to 7.3%), and voriconazole (from 6.1% to 18.4%) against Candida glabrata. Resistance was also increased for fluconazole against Candida albicans (from 2.1% to 5.7%).


Subject(s)
Antifungal Agents/pharmacology , Candida/drug effects , Candidiasis/microbiology , Drug Resistance, Fungal , Antifungal Agents/therapeutic use , Candida/isolation & purification , Candidiasis/drug therapy , Humans , Microbial Sensitivity Tests/methods , Microbial Sensitivity Tests/standards
8.
Med Mycol ; 48(6): 807-16, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20109095

ABSTRACT

We examined the utility of agar dilution to screen yeasts for reduced susceptibility to several newer antifungal drugs including echinocandins and azoles. We compared agar dilution susceptibility screening with the Clinical and Laboratory Standards Institute (CLSI) method for Candida isolates. We added echinocandins and azoles to CHROMagar Candida medium prior to its solidification. Assessment of resistance was based on growth characteristics, wherein decreased colony size in the presence of antifungal drugs was used as an indicator of susceptibility. Clinical Candida isolates of C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. guilliermondii, C. lusitaniae, C. rugosa and C. dubliniensis were screened for drug susceptibility. Overall, antifungal susceptibility of the yeasts to anidulafungin, caspofungin, micafungin, posaconazole and voriconazole, determined using CHROMagar agar dilution, were shown to be 96, 80, 94, 90 and 97% as accurate, respectively, as those determined by the CLSI method, i.e., within one tube dilution of CLSI MICs. Categorical errors by percentage had a broader range. Major errors noted with anidulafungin, caspofungin and micafungin were 3, 6 and 0%, respectively, while very major errors were 15, 55 and 38%, respectively. Major errors with posaconazole and voriconazole were 12 and 0%, respectively, while very major errors were 0 and 22%, respectively, compared to CLSI standards. Most of the assessment errors were found with C. glabrata and C. parapsilosis. Agar dilution screening for drug susceptibility with the current panel of antifungal drugs is rapid, accurate and effective. However, the determination of resistance or non-susceptibility in yeasts may be more problematic, and may be species dependent.


Subject(s)
Antifungal Agents/pharmacology , Candida/drug effects , Culture Media/chemistry , Agar , Candida/isolation & purification , Candidiasis/microbiology , Humans , Microbial Sensitivity Tests
9.
Antimicrob Agents Chemother ; 49(12): 5139-41, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16304187

ABSTRACT

Immunosuppressed mice were infected intravenously with conidia of Scedosporium prolificans. Treatment was begun 1 day later with liposomal amphotericin B, caspofungin, or both drugs initiated concurrently. Amphotericin B and caspofungin were each effective, but combined therapy did not appear to offer advantages over liposomal amphotericin B alone.


Subject(s)
Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Mycetoma/drug therapy , Peptides, Cyclic/therapeutic use , Scedosporium , Amphotericin B/administration & dosage , Animals , Antifungal Agents/administration & dosage , Caspofungin , Dose-Response Relationship, Drug , Drug Interactions , Drug Therapy, Combination , Echinocandins , Lipopeptides , Mice
10.
J Antimicrob Chemother ; 54(2): 477-80, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15215225

ABSTRACT

OBJECTIVE: Amphotericin B failure is frequently seen in patients with candidaemia caused by Candida rugosa. We evaluated amphotericin B, fluconazole, posaconazole and voriconazole as alternative treatments against infection in mice with two isolates of C. rugosa. METHODS: Neutropenic mice were inoculated intravenously with C. rugosa. Amphotericin B, fluconazole, posaconazole and voriconazole were administered for 7 days after infection. Efficacy of the antifungal treatment was assessed by survival and tissue burden of C. rugosa. RESULTS: All of the four drugs significantly prolonged survival over controls. With both isolates, kidney counts were reduced significantly below controls for amphotericin B, fluconazole and posaconazole. However, voriconazole was less effective than the other antifungals. CONCLUSION: Despite poor clinical response to amphotericin B, in vivo data indicate that amphotericin B increases organ clearance and survival over untreated controls. However, although voriconazole improved survival over controls, increased tissue clearance was not seen. This discrepancy may be caused by rapid clearance of voriconazole in mice. These studies suggest fluconazole, posaconazole or voriconazole may be useful alternatives to amphotericin B in therapy of C. rugosa infection.


Subject(s)
Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Candidiasis/drug therapy , Animals , Candidiasis/microbiology , Colony Count, Microbial , Fluconazole/therapeutic use , Kidney/microbiology , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Neutropenia/microbiology , Organ Size , Pyrimidines/therapeutic use , Spleen/microbiology , Survival Analysis , Triazoles/therapeutic use , Voriconazole
11.
Antimicrob Agents Chemother ; 48(4): 1382-3, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15047549

ABSTRACT

A patient with azole-refractory thrush-esophagitis responded initially to caspofungin, but the treatment eventually failed. In a murine model, caspofungin was effective against two early isolates for which the MICs of caspofungin were low, but it was less effective against a late isolate for which the MIC of caspofungin was greater. We concluded that there is a correlation between in vivo failure and rising in vitro caspofungin MICs.


Subject(s)
Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida albicans/drug effects , Candidiasis/drug therapy , Esophagitis/drug therapy , Peptides, Cyclic , Peptides/pharmacology , Peptides/therapeutic use , Acquired Immunodeficiency Syndrome/complications , Adult , Animals , Candidiasis/microbiology , Caspofungin , Drug Resistance, Fungal , Echinocandins , Esophagitis/microbiology , Humans , Lipopeptides , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Treatment Failure
12.
Antimicrob Agents Chemother ; 46(5): 1581-2, 2002 May.
Article in English | MEDLINE | ID: mdl-11959605

ABSTRACT

In vitro antifungal susceptibility testing results of a new antifungal triazole, posaconazole (POS), were compared to results with amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC), and fluconazole (FLC) against clinical agents of zygomycosis. The MICs of POS at which 50% and 90% of the isolates were inhibited were 0.25 and 4 microg/ml, respectively. POS was significantly more active than VRC and FLC and slightly more active than ITC. The results suggest that POS has significant potential for clinical development against the zygomycetes.


Subject(s)
Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Fungi/drug effects , Triazoles/pharmacology , Humans , Microbial Sensitivity Tests , Mycoses/microbiology
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