Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 17 de 17
Filter
Add more filters










Publication year range
1.
Article in English | MEDLINE | ID: mdl-33753333

ABSTRACT

Candida auris is an emerging pathogen that has rapidly spread to many countries on multiple continents. Invasive infections caused by this species are associated with significant mortality, and treatment options are limited due to antifungal resistance. Ibrexafungerp is the first-in-class member of the triterpenoids, which inhibit the production of (1,3)-ß-d-glucan and can be administered orally. We evaluated the in vitro activity and in vivo efficacy of ibrexafungerp against C. auris Antifungal susceptibility was tested by broth microdilution against 54 C. auris isolates. Neutropenic mice were intravenously infected with a clinical isolate, and a 7-day treatment course was begun 24 h postinoculation with vehicle control, ibrexafungerp (20, 30, and 40 mg/kg orally twice daily), fluconazole (20 mg/kg orally once daily), or caspofungin (10 mg/kg intraperitoneally once daily). Fungal burden was assessed by colony counts in the kidneys on day 8 and on day 21 or as mice became moribund in the survival arm. Ibrexafungerp demonstrated consistent activity, with MICs ranging between 0.25 and 2 µg/ml against all isolates. Marked improvements in survival were observed in mice treated with the higher doses of ibrexafungerp and caspofungin. Similarly, reductions in kidney fungal burden were also observed in these groups. No improvements in survival or reductions in fungal burden were observed with fluconazole, consistent with the in vitro resistance of the isolate used to establish infection to this azole. These results demonstrate that ibrexafungerp is effective in vivo against C. auris even when the start of therapy is delayed.


Subject(s)
Candidiasis, Invasive , Fluconazole , Animals , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Candida , Candidiasis, Invasive/drug therapy , Fluconazole/pharmacology , Glycosides , Mice , Microbial Sensitivity Tests , Models, Theoretical , Triterpenes
2.
Article in English | MEDLINE | ID: mdl-31844006

ABSTRACT

The in vitro and in vivo activity of the arylamidine T-2307 against Candida auris was evaluated. T-2307 demonstrated in vitro activity (MIC ranges ≤ 0.008 to 0.015 µg/ml at 50% inhibition; 0.125 to >4 µg/ml at 100% inhibition). Treatment with T-2307 (3 mg/kg subcutaneous [SC] once daily) also significantly improved survival (70% at 21 days postinfection) and reduced kidney fungal burden (5.06 log10 CFU/g) compared to control (0% survival and 7.09 log10 CFU/g) (P < 0.01).


Subject(s)
Amidines/therapeutic use , Antifungal Agents/therapeutic use , Candida/pathogenicity , Candidiasis, Invasive/drug therapy , Animals , Candida/drug effects , Caspofungin/therapeutic use , Disease Models, Animal , Drug Resistance, Fungal , Fluconazole/therapeutic use , Male , Mice , Mice, Inbred ICR
3.
Article in English | MEDLINE | ID: mdl-31405851

ABSTRACT

We evaluated extended-interval dosing of the investigational echinocandin rezafungin (1, 4, and 16 mg/kg on days 1, 4, and 7 postinoculation) for the treatment of disseminated invasive aspergillosis caused by azole-resistant Aspergillus fumigatus Survival was significantly improved in mice treated with each dose of rezafungin and supratherapeutic posaconazole (20 mg/kg twice daily). Kidney fungal burden, as measured by quantitative real-time PCR, was also significantly reduced in mice treated with rezafungin although variability was observed.


Subject(s)
Antifungal Agents/therapeutic use , Aspergillus fumigatus/drug effects , Aspergillus fumigatus/pathogenicity , Azoles/therapeutic use , Echinocandins/therapeutic use , Animals , Aspergillosis/drug therapy , Aspergillosis/microbiology , Azoles/adverse effects , Drug Resistance, Fungal/genetics , Echinocandins/adverse effects , Fungal Proteins/genetics , Fungal Proteins/metabolism , Kidney/virology , Male , Mice , Real-Time Polymerase Chain Reaction , Triazoles/therapeutic use
4.
Article in English | MEDLINE | ID: mdl-31427304

ABSTRACT

The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole-resistant clinical isolate of C. auris Twenty-four hours postinoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg of body weight by intraperitoneal injection three times daily, or intraperitoneal 260 mg/kg twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (intraperitoneal 10 mg/kg once daily) and continued for 7 days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed.


Subject(s)
Antifungal Agents/pharmacology , Candida/drug effects , Candidiasis, Invasive/drug therapy , Animals , Candidiasis, Invasive/microbiology , Caspofungin/pharmacology , Disease Models, Animal , Drug Resistance, Fungal/drug effects , Fluconazole/pharmacology , Mice , Microbial Sensitivity Tests
5.
Article in English | MEDLINE | ID: mdl-30530603

ABSTRACT

Candida auris is an emerging pathogen associated with significant mortality and often multidrug resistance. VT-1598, a tetrazole-based fungal CYP51-specific inhibitor, was evaluated in vitro and in vivo against C. auris Susceptibility testing was performed against 100 clinical isolates of C. auris by broth microdilution. Neutropenic mice were infected intravenously with C. auris, and treatment began 24 h postinoculation with a vehicle control, oral VT-1598 (5, 15, and 50 mg/kg of body weight once daily), oral fluconazole (20 mg/kg once daily), or intraperitoneal caspofungin (10 mg/kg once daily), which continued for 7 days. Fungal burden was assessed in the kidneys and brains on day 8 in the fungal burden arm and on the days the mice succumbed to infection or on day 21 in the survival arm. VT-1598 plasma trough concentrations were also assessed on day 8. VT-1598 demonstrated in vitro activity against C. auris, with a mode MIC of 0.25 µg/ml and MICs ranging from 0.03 to 8 µg/ml. Treatment with VT-1598 resulted in significant and dose-dependent improvements in survival (median survival, 15 and >21 days for VT-1598 at 15 and 50 mg/kg, respectively) and reductions in kidney and brain fungal burden (reductions of 1.88 to 3.61 log10 CFU/g) compared to the control (5 days). The reductions in fungal burden correlated with plasma trough concentrations. Treatment with caspofungin, but not fluconazole, also resulted in significant improvements in survival and reductions in fungal burden compared to those with the control. These results suggest that VT-1598 may be a future option for the treatment of invasive infections caused by C. auris.


Subject(s)
14-alpha Demethylase Inhibitors/therapeutic use , Antifungal Agents/therapeutic use , Candida/drug effects , Candidiasis, Invasive/drug therapy , Pyridines/therapeutic use , Tetrazoles/therapeutic use , Animals , Candidiasis, Invasive/microbiology , Caspofungin/therapeutic use , Disease Models, Animal , Fluconazole/therapeutic use , Humans , Mice , Microbial Sensitivity Tests , Sterol 14-Demethylase/metabolism
6.
Article in English | MEDLINE | ID: mdl-30104280

ABSTRACT

VT-1129 is a novel fungal enzyme-specific Cyp51 inhibitor with potent cryptococcal activity. Because of its long half-life (>6 days in mice) and our desire to quickly reach potent efficacy, we evaluated a VT-1129 loading dose-maintenance dose strategy against cryptococcal meningitis. VT-1129 plasma and brain pharmacokinetics were first studied in healthy mice, and these data were used to model loading dose-maintenance dose regimens to generate different steady-state concentrations. Mice were inoculated intracranially with Cryptococcus neoformans, and oral treatment began 1 day later. Treatment consisted of placebo or one of three VT-1129 loading dose-maintenance dose regimens, i.e., loading dose of 1, 3, or 30 mg/kg on day 1, followed by once-daily maintenance doses of 0.15, 0.5, or 5 mg/kg, respectively. In the fungal burden arm, therapy continued for 14 days and brains were collected on day 15 for fungal burden assessments. In the survival arm, treatment continued for 10 days, after which mice were monitored without therapy until day 30. VT-1129 plasma and brain concentrations were also measured. All VT-1129 doses significantly improved survival and reduced fungal burdens, compared to placebo. VT-1129 plasma and brain levels correlated with fungal burden reductions (R2 = 0.72 and R2 = 0.67, respectively), with a plasma concentration of 1 µg/ml yielding a reduction of ∼5 log10 CFU/g. With the highest loading dose-maintenance dose regimen, fungal burdens were undetectable in one-half of the mice in the fungal burden arm and in one-fourth of the mice in the survival arm, 20 days after the final dose. These data support a loading dose-maintenance dose strategy for quickly reaching highly efficacious VT-1129 concentrations for treating cryptococcal meningitis.


Subject(s)
Antifungal Agents/pharmacology , Meningitis, Cryptococcal/drug therapy , Pyridines/pharmacology , Tetrazoles/pharmacology , Animals , Brain/microbiology , Cryptococcus neoformans/drug effects , Male , Meningitis, Cryptococcal/microbiology , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests/methods
7.
Article in English | MEDLINE | ID: mdl-29987152

ABSTRACT

Cryptococcal meningitis is a significant cause of morbidity and mortality in immunocompromised patients. VT-1129 is a novel fungus-specific Cyp51 inhibitor with potent in vitro activity against Cryptococcus species. Our objective was to evaluate the in vivo efficacy of VT-1129 against cryptococcal meningitis. Mice were inoculated intracranially with Cryptococcus neoformans Oral treatment with VT-1129, fluconazole, or placebo began 1 day later and continued for either 7 or 14 days, and brains and plasma were collected on day 8 or 15, 1 day after therapy ended, and the fungal burden was assessed. In the survival study, treatment continued until day 10 or day 28, after which mice were monitored off therapy until day 30 or day 60, respectively, to assess survival. The fungal burden was also assessed in the survival arm. VT-1129 plasma and brain concentrations were also measured. VT-1129 reached a significant maximal survival benefit (100%) at a dose of 20 mg/kg of body weight once daily. VT-1129 at doses of ≥0.3 mg/kg/day and each dose of fluconazole significantly reduced the brain tissue fungal burden compared to that in the control after both 7 and 14 days of dosing. The fungal burden was also undetectable in most mice treated with a dose of ≥3 mg/kg/day, even ≥20 days after dosing had stopped, in the survival arm. In contrast, rebounds in fungal burden were observed with fluconazole. These results are consistent with the VT-1129 concentrations, which remained elevated long after dosing had stopped. These data demonstrate the potential utility of VT-1129 to have a marked impact in the treatment of cryptococcal meningitis.


Subject(s)
14-alpha Demethylase Inhibitors/pharmacology , Cryptococcus neoformans/drug effects , Meningitis, Cryptococcal/drug therapy , Pyridines/pharmacology , Sterol 14-Demethylase/metabolism , Tetrazoles/pharmacology , Animals , Antifungal Agents/pharmacology , Cryptococcosis/drug therapy , Fluconazole/pharmacology , Mice , Microbial Sensitivity Tests/methods , Models, Theoretical
8.
Article in English | MEDLINE | ID: mdl-29941638

ABSTRACT

Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activities of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infections were established in mice via intracranial inoculation with Coccidioides immitis arthroconidia. Oral therapy began 48 h postinoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg three times daily or 10 mg/kg twice daily) or 40 mg/kg (13.3 mg/kg three times daily or 20 mg/kg twice daily), or fluconazole (25 mg/kg twice daily). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burdens were assessed by CFU counts in brains. Olorofim demonstrated potent in vitro activity (MIC range, ≤0.008 to 0.06 µg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burdens were also observed on day 9 in the olorofim-treated groups. Improvements in survival and reductions in fungal burdens also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burdens. In the group treated with 13.3 mg/kg olorofim three times daily, fungal burdens remained low on day 30 (15 days after treatment was stopped), with undetectable levels in 7 of 10 mice. In contrast, fungal burdens rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.


Subject(s)
Acetamides/pharmacology , Antifungal Agents/pharmacology , Central Nervous System/microbiology , Coccidioides/drug effects , Coccidioidomycosis/drug therapy , Piperazines/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Animals , Disease Models, Animal , Fluconazole/pharmacology , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests/methods
9.
Article in English | MEDLINE | ID: mdl-29437615

ABSTRACT

Coccidioidal meningitis can cause significant morbidity, and lifelong antifungal therapy is often required. VT-1598 is a fungus-specific Cyp51 inhibitor that has potent in vitro activity against Coccidioides species. We evaluated the in vivo efficacy of VT-1598 in murine models of central nervous system coccidioidomycosis caused by C. posadasii and C. immitis Infection was introduced via intracranial inoculation, and therapy began 48 h postinoculation. Oral treatments consisted of vehicle control, VT-1598, and positive controls of fluconazole in the C. immitis study and VT-1161 in the C. posadasii study. Treatment continued for 7 and 14 days in the fungal-burden and survival studies, respectively. Fungal burden was assessed in brain tissue collected 24 to 48 h posttreatment in the fungal-burden studies, on the days the mice succumbed to infection, or at prespecified endpoints in the survival studies. VT-1598 plasma concentrations were also measured in the C. posadasii study. VT-1598 resulted in significant improvements in survival in mice infected with either species. In addition, the fungal burden was significantly reduced in the fungal-burden studies. Plasma concentrations 48 h after dosing stopped remained above the VT-1598 MIC against the C. posadasii isolate, although levels were undetectable in the survival study after a 4-week washout. Whereas fungal burden remained suppressed after a 2-week washout in the C. immitis model, a higher fungal burden was observed in the survival arm of the C. posadasii model. This in vivo efficacy supports human studies to establish the utility of VT-1598 for the treatment of coccidioidomycosis.


Subject(s)
14-alpha Demethylase Inhibitors/therapeutic use , Coccidioides/drug effects , Coccidioides/pathogenicity , Coccidioidomycosis/drug therapy , Animals , Fluconazole/therapeutic use , Male , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests , Models, Theoretical
10.
J Antimicrob Chemother ; 73(2): 448-451, 2018 02 01.
Article in English | MEDLINE | ID: mdl-29177447

ABSTRACT

Background: Echinocandins are recommended as first-line therapy against Candida glabrata infections, although increased resistance to this class has been reported worldwide and they are currently only available for parenteral administration. SCY-078 is an investigational glucan synthase inhibitor that is orally available. Objectives: To evaluate the in vivo efficacy of SCY-078 in an experimental model of invasive candidiasis due to WT and echinocandin-resistant C. glabrata isolates. Methods: Neutropenic ICR mice were inoculated intravenously with a WT isolate (SCY-078 and caspofungin MICs 0.25 and 0.125 mg/L, respectively) or an echinocandin-resistant isolate (SCY-078 and caspofungin MICs 1 and 0.5 mg/L, respectively). Treatment with placebo, SCY-078 (8, 30 or 40 mg/kg orally every 12 h) or caspofungin (1 mg/kg by intraperitoneal injection once daily) began 24 h later. Kidney fungal burden was measured on day 8 post-inoculation. Results: Significant reductions in kidney fungal burden were observed with 30 mg/kg SCY-078 against both isolates and with the 40 mg/kg dose against the echinocandin-resistant isolate. These results were supported by SCY-078 plasma concentration data at the higher doses, where levels above the MICs for both isolates were observed 12 h after the last oral dose. Reductions in fungal burden were also observed with caspofungin against the WT isolate, but not against the resistant isolate. Conclusions: SCY-078 demonstrated in vivo efficacy against infections caused by both WT and echinocandin-resistant C. glabrata isolates in this experimental model. This orally available glucan synthase inhibitor has potential as a therapy against echinocandin-resistant C. glabrata infections.


Subject(s)
Antifungal Agents/administration & dosage , Candida glabrata/drug effects , Candidiasis, Invasive/drug therapy , Glycosides/administration & dosage , Triterpenes/administration & dosage , Administration, Oral , Animals , Caspofungin/administration & dosage , Colony Count, Microbial , Disease Models, Animal , Injections, Intraperitoneal , Kidney/microbiology , Male , Mice, Inbred ICR , Placebos/administration & dosage , Treatment Outcome
11.
Antimicrob Agents Chemother ; 60(11): 6703-6708, 2016 11.
Article in English | MEDLINE | ID: mdl-27572393

ABSTRACT

Candida albicans, normally found as a commensal in the gut, is a major human fungal pathogen responsible for both mucosal and systemic infections in a wide variety of immunocompromised individuals, including cancer patients and organ transplant recipients. The gastrointestinal tract represents a major portal of entry for the establishment of disseminated candidiasis in many of these individuals. Here we report the development of a diet-based mouse model for disseminated candidiasis acquired via the gastrointestinal tract. Using this model, as well as an appropriate immunosuppression regimen, we demonstrate that dissemination of C. albicans from the gastrointestinal tract can result in mortality within 30 days postinfection. We also show a significant increase in fungal burden in systemic organs, but not gastrointestinal tract organs, upon immunosuppression. Importantly, we demonstrate that the administration of two widely used antifungals, fluconazole and caspofungin, either pre- or postimmunosuppression, significantly reduces fungal burdens. This model should prove to be of significant value for testing the ability of both established and experimental therapeutics to inhibit C. albicans dissemination from the gastrointestinal tract in an immunocompromised host as well as the subsequent mortality that can result from disseminated candidiasis.


Subject(s)
Antifungal Agents/pharmacology , Candida albicans/drug effects , Candidiasis/drug therapy , Diet/adverse effects , Echinocandins/pharmacology , Fluconazole/pharmacology , Immunocompromised Host , Lipopeptides/pharmacology , Animals , Candida albicans/growth & development , Candida albicans/pathogenicity , Candidiasis/etiology , Candidiasis/immunology , Candidiasis/mortality , Caspofungin , Colony Count, Microbial , Cyclophosphamide/adverse effects , Disease Models, Animal , Gastrointestinal Tract/drug effects , Gastrointestinal Tract/immunology , Gastrointestinal Tract/microbiology , Humans , Immunosuppressive Agents/adverse effects , Male , Mice , Mice, Inbred BALB C , Prednisolone/adverse effects , Prednisolone/analogs & derivatives , Survival Analysis
12.
Antimicrob Agents Chemother ; 60(9): 5600-3, 2016 09.
Article in English | MEDLINE | ID: mdl-27324761

ABSTRACT

We evaluated the efficacy of isavuconazole against cryptococcal meningitis. Treatment with either oral isavuconazole (120 mg/kg and 240 mg/kg twice a day [BID]) or fluconazole as the positive control significantly improved survival in mice infected intracranially with either Cryptococcus neoformans USC1597 or H99 and significantly reduced brain fungal burdens for both isolates. Concentrations of isavuconazole in plasma and brain tissue also demonstrated that the greatest improvements in survival and fungal burden were associated with elevated exposures.


Subject(s)
Antifungal Agents/pharmacology , Meningitis, Cryptococcal/drug therapy , Nitriles/pharmacology , Pyridines/pharmacology , Triazoles/pharmacology , Animals , Brain/microbiology , Cryptococcus neoformans/drug effects , Disease Models, Animal , Meningitis, Cryptococcal/microbiology , Mice , Microbial Sensitivity Tests
13.
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
14.
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
15.
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
17.
Antimicrob Agents Chemother ; 51(5): 1616-20, 2007 May.
Article in English | MEDLINE | ID: mdl-17307976

ABSTRACT

In vitro studies have demonstrated that anidulafungin has greater potency than caspofungin against Candida glabrata. However, data from in vivo studies demonstrating that it has superior efficacy are lacking. The objective of this study was to compare the activities of anidulafungin and caspofungin against C. glabrata in a murine model of disseminated candidiasis. Two clinical C. glabrata isolates were used, including one with reduced caspofungin susceptibility. MICs were determined by broth microdilution in the presence and absence of sera. For the animal studies, mice were immunosuppressed with 5-fluorouracil one day prior to intravenous inoculation. Treatment with anidulafungin and caspofungin (0, 0.5, 1, 5, and 10 mg/kg of body weight per day) was begun 24 h later and was continued through day 7 postinoculation. The CFU were enumerated from kidney tissue. According to the standard microdilution methodology, anidulafungin had superior in vitro activity. However, this enhanced potency was attenuated by the addition of mouse and human sera. Caspofungin reduced the kidney fungal burden at lower doses compared to that achieved with anidulafungin in mice infected with the isolate with the lower MIC. Against the strain with the elevated caspofungin MIC, both anidulafungin and caspofungin were effective in reducing the kidney fungal burden at the higher doses studied. Despite the greater in vitro activity of anidulafungin in the absence of sera, both echinocandins were similarly effective in reducing the fungal burden in kidney tissue. The superior in vitro activity of anidulafungin did not confer enhanced in vivo efficacy against C. glabrata.


Subject(s)
Antifungal Agents/pharmacology , Candida glabrata/drug effects , Peptides, Cyclic/pharmacology , Serum/physiology , Anidulafungin , Animals , Candidiasis/drug therapy , Caspofungin , Echinocandins , Lipopeptides , Mice , Mice, Inbred ICR , Microbial Sensitivity Tests
SELECTION OF CITATIONS
SEARCH DETAIL
...