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1.
J Fungi (Basel) ; 7(4)2021 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-33919611

RESUMO

There is increased concern that the quality, generalizability and reproducibility of biomedical research can be influenced by the sex of animals used. We studied the differences between male and female mice in response to invasive pulmonary mucormycosis including susceptibility to infection, host immune reaction and responses to antifungal therapy. We used diabetic ketoacidotic (DKA) or neutropenic mice infected with either Rhizopus delemar or Mucor circinelloides. The only difference detected was that when DKA mice were infected with M. circinelloides, female mice were more resistant to infection than male mice (median survival time of 5 vs. 2 days for female and male mice, respectively). However, a 100% lethality was detected among infected animals of both sexes. Treatment with either liposomal amphotericin B (L-AMB) or posaconazole (POSA) protected mice from infection and eliminated the difference seen between infected but untreated female and male mice. Treatment with L-AMB consistently outperformed POSA in prolonging survival and reducing tissue fungal burden of DKA and neutropenic mice infected with R. delemar or M. circinelloides, in both mouse sexes. While little difference was detected in cytokine levels among both sexes, mucormycosis infection in the DKA mouse model induced more inflammatory cytokines/chemokines involved in neutrophil (CXCL1) and macrophage (CXCL2) recruitment vs. uninfected mice. As expected, this inflammatory response was reduced in the neutropenic mouse model. Our studies show that there are few differences between female and male DKA or neutropenic mice infected with mucormycosis with no effect on the outcome of treatment or host immune response.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33753333

RESUMO

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.


Assuntos
Candidíase Invasiva , Fluconazol , Animais , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida , Candidíase Invasiva/tratamento farmacológico , Fluconazol/farmacologia , Glicosídeos , Camundongos , Testes de Sensibilidade Microbiana , Modelos Teóricos , Triterpenos
3.
Artigo em Inglês | MEDLINE | ID: mdl-31844006

RESUMO

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).


Assuntos
Amidinas/uso terapêutico , Antifúngicos/uso terapêutico , Candida/patogenicidade , Candidíase Invasiva/tratamento farmacológico , Animais , Candida/efeitos dos fármacos , Caspofungina/uso terapêutico , Modelos Animais de Doenças , Farmacorresistência Fúngica , Fluconazol/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR
4.
Artigo em Inglês | MEDLINE | ID: mdl-31405851

RESUMO

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.


Assuntos
Antifúngicos/uso terapêutico , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/patogenicidade , Azóis/uso terapêutico , Equinocandinas/uso terapêutico , Animais , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Azóis/efeitos adversos , Farmacorresistência Fúngica/genética , Equinocandinas/efeitos adversos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo , Rim/virologia , Masculino , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Triazóis/uso terapêutico
5.
Artigo em Inglês | MEDLINE | ID: mdl-31427304

RESUMO

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.


Assuntos
Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Animais , Candidíase Invasiva/microbiologia , Caspofungina/farmacologia , Modelos Animais de Doenças , Farmacorresistência Fúngica/efeitos dos fármacos , Fluconazol/farmacologia , Camundongos , Testes de Sensibilidade Microbiana
6.
Artigo em Inglês | MEDLINE | ID: mdl-30530603

RESUMO

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.


Assuntos
Inibidores de 14-alfa Desmetilase/uso terapêutico , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Piridinas/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Candidíase Invasiva/microbiologia , Caspofungina/uso terapêutico , Modelos Animais de Doenças , Fluconazol/uso terapêutico , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Esterol 14-Desmetilase/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-30104280

RESUMO

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 (R 2 = 0.72 and R 2 = 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.


Assuntos
Antifúngicos/farmacologia , Meningite Criptocócica/tratamento farmacológico , Piridinas/farmacologia , Tetrazóis/farmacologia , Animais , Encéfalo/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Masculino , Meningite Criptocócica/microbiologia , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana/métodos
8.
Artigo em Inglês | MEDLINE | ID: mdl-29987152

RESUMO

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.


Assuntos
Inibidores de 14-alfa Desmetilase/farmacologia , Cryptococcus neoformans/efeitos dos fármacos , Meningite Criptocócica/tratamento farmacológico , Piridinas/farmacologia , Esterol 14-Desmetilase/metabolismo , Tetrazóis/farmacologia , Animais , Antifúngicos/farmacologia , Criptococose/tratamento farmacológico , Fluconazol/farmacologia , Camundongos , Testes de Sensibilidade Microbiana/métodos , Modelos Teóricos
9.
Artigo em Inglês | MEDLINE | ID: mdl-29941638

RESUMO

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.


Assuntos
Acetamidas/farmacologia , Antifúngicos/farmacologia , Sistema Nervoso Central/microbiologia , Coccidioides/efeitos dos fármacos , Coccidioidomicose/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Animais , Modelos Animais de Doenças , Fluconazol/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana/métodos
10.
Artigo em Inglês | MEDLINE | ID: mdl-29437615

RESUMO

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.


Assuntos
Inibidores de 14-alfa Desmetilase/uso terapêutico , Coccidioides/efeitos dos fármacos , Coccidioides/patogenicidade , Coccidioidomicose/tratamento farmacológico , Animais , Fluconazol/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Modelos Teóricos
11.
J Antimicrob Chemother ; 73(2): 448-451, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29177447

RESUMO

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.


Assuntos
Antifúngicos/administração & dosagem , Candida glabrata/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Glicosídeos/administração & dosagem , Triterpenos/administração & dosagem , Administração Oral , Animais , Caspofungina/administração & dosagem , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Injeções Intraperitoneais , Rim/microbiologia , Masculino , Camundongos Endogâmicos ICR , Placebos/administração & dosagem , Resultado do Tratamento
12.
Drug Dev Ind Pharm ; 43(2): 264-274, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27645428

RESUMO

Previously, modified release itraconazole in the form of a melt-extruded amorphous solid dispersion based on a pH dependent enteric polymer combined with hydrophilic additives (HME-ITZ), exhibited improved in vitro dissolution properties. These properties agreed with pharmacokinetic results in rats showing high and sustained itraconazole (ITZ) systemic levels. The objective of the present study was to better understand the best choice of rodent model for evaluating the pharmacokinetic and efficacy of this orally administered modified release ITZ dosage form against invasive Aspergillus fumigatus. A mouse model and a guinea pig model were investigated and compared to results previously published. In the mouse model, despite similar levels as previously reported values, plasma and lung levels were variable and fungal burden was not statistically different for placebo controls, HME-ITZ and Sporanox® (ITZ oral solution). This study demonstrated that the mouse model is a poor choice for studying modified release ITZ dosage forms based on pH dependent enteric polymers due to low fluid volume available for dissolution and low intestinal pH. To the contrary, guinea pig was a suitable model to evaluate modified release ITZ dosage forms. Indeed, a significant decrease in lung fungal burden as a result of high and sustained ITZ tissue levels was measured. Sufficiently high intestinal pH and fluids available for dissolution likely facilitated the dissolution process. Despite high ITZ tissue level, the primary therapeutic agent voriconazole exhibited an even more pronounced decrease in fungal burden due to its reported higher clinical efficacy specifically against Aspergillus fumigatus.


Assuntos
Antifúngicos/administração & dosagem , Aspergillus fumigatus/efeitos dos fármacos , Itraconazol/química , Itraconazol/farmacologia , Administração Oral , Animais , Antifúngicos/química , Antifúngicos/farmacologia , Aspergillus fumigatus/química , Varredura Diferencial de Calorimetria , Modelos Animais de Doenças , Cobaias , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Itraconazol/farmacocinética , Camundongos , Ratos , Solubilidade
13.
Antimicrob Agents Chemother ; 60(11): 6703-6708, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27572393

RESUMO

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.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Dieta/efeitos adversos , Equinocandinas/farmacologia , Fluconazol/farmacologia , Hospedeiro Imunocomprometido , Lipopeptídeos/farmacologia , Animais , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Candidíase/etiologia , Candidíase/imunologia , Candidíase/mortalidade , Caspofungina , Contagem de Colônia Microbiana , Ciclofosfamida/efeitos adversos , Modelos Animais de Doenças , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Humanos , Imunossupressores/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Prednisolona/efeitos adversos , Prednisolona/análogos & derivados , Análise de Sobrevida
14.
Antimicrob Agents Chemother ; 60(9): 5600-3, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27324761

RESUMO

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.


Assuntos
Antifúngicos/farmacologia , Meningite Criptocócica/tratamento farmacológico , Nitrilas/farmacologia , Piridinas/farmacologia , Triazóis/farmacologia , Animais , Encéfalo/microbiologia , Cryptococcus neoformans/efeitos dos fármacos , Modelos Animais de Doenças , Meningite Criptocócica/microbiologia , Camundongos , Testes de Sensibilidade Microbiana
15.
J Clin Microbiol ; 54(4): 960-6, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26791366

RESUMO

The EuropeanAspergillusPCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and ß-d-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and ß-d-glucan were 73%, 65%, 68%, and 46%, respectively. The corresponding specificities were 92%, 79%, 80%, and 100%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and ß-d-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and ß-d-glucan proved optimal (area under the curve [AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests.


Assuntos
Testes Diagnósticos de Rotina/métodos , Aspergilose Pulmonar Invasiva/diagnóstico , Mananas/análise , Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase/métodos , beta-Glucanas/análise , Animais , Sangue/microbiologia , Modelos Animais de Doenças , Cobaias , Masculino , Sensibilidade e Especificidade , Fatores de Tempo
16.
J Antimicrob Chemother ; 71(3): 692-5, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26620102

RESUMO

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.


Assuntos
Amidinas/administração & dosagem , Amidinas/farmacologia , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Candida glabrata/efeitos dos fármacos , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Animais , Candida glabrata/isolamento & purificação , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Humanos , Rim/microbiologia , Masculino , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Resultado do Tratamento
17.
Antimicrob Agents Chemother ; 59(5): 2875-81, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25753643

RESUMO

ASP9726 is an investigational echinocandin with in vitro activity against Aspergillus species. We evaluated the pharmacokinetics and efficacy of this agent in an established guinea pig model of invasive pulmonary aspergillosis. ASP9726 plasma concentrations were measured in guinea pigs administered either a single dose or multiple doses of this agent at 2.5, 5, and 10 mg/kg of body weight/day by subcutaneous injection. Immunosuppressed guinea pigs were inoculated with A. fumigatus AF293, and ASP9726 (2.5, 5, and 10 mg/kg/day), voriconazole (10 mg/kg by oral gavage twice daily), or caspofungin (3 mg/kg/day by intraperitoneal injection) was administered for 8 days. Changes in fungal burden were measured by enumerating CFU and by quantitative PCR of specimens from within the lungs, as well as by analysis of serum (1 → 3)-ß-D-glucan and galactomannan. Lung histopathology was also evaluated. ASP9726 plasma concentrations increased in a dose-proportional manner, and the drug was well tolerated at each dose. Each dose of ASP9726, voriconazole, and caspofungin significantly reduced pulmonary fungal burden as measured by quantitative PCR and by determining (1 → 3)-ß-D-glucan and galactomannan levels, but only voriconazole significantly reduced numbers of CFU. ASP9726 at 5 mg/kg also significantly improved survival. Histopathology demonstrated morphological changes in hyphae in animals exposed to ASP9726 and caspofungin, consistent with the activities of the echinocandins. These results suggest that ASP9726 may be efficacious for the treatment of invasive pulmonary aspergillosis.


Assuntos
Equinocandinas/uso terapêutico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Animais , Modelos Animais de Doenças , Equinocandinas/farmacocinética , Cobaias , Pulmão/microbiologia , Masculino
18.
Antimicrob Agents Chemother ; 59(1): 690-2, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25331706

RESUMO

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.


Assuntos
Aminopiridinas/farmacologia , Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Isoxazóis/farmacologia , Aminopiridinas/uso terapêutico , Animais , Antifúngicos/uso terapêutico , Caspofungina , Relação Dose-Resposta a Droga , Farmacorresistência Fúngica , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Isoxazóis/uso terapêutico , Lipopeptídeos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
19.
Antimicrob Agents Chemother ; 59(2): 1341-3, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25451054

RESUMO

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.


Assuntos
Amidinas/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida albicans/patogenicidade , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Animais , Candida albicans/efeitos dos fármacos , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
20.
Med Mycol ; 51(6): 592-602, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23356446

RESUMO

Improved diagnostics are needed to detect invasive pulmonary aspergillosis, a life-threatening infection caused by the pathogenic fungus Aspergillus fumigatus. We are investigating secreted fungal proteases as novel biomarkers for the diagnosis of this disease. Although the A. fumigatus genome encodes a multitude of secreted proteases, few have been experimentally characterized. Here, we employed an unbiased combinatorial library of internally quenched fluorogenic probes to detect infection-associated proteolysis in the lungs of guinea pigs experimentally infected with A. fumigatus. Comparative protease activity profiling revealed a prolyl endopeptidase activity that is reproducibly induced during infection but is not observed in healthy animals. This proteolytic activity was found in four independent animal experiments involving two A. fumigatus isolates. We synthesized a small, focused fluorogenic probe library to define the substrate specificity of the prolyl endopeptidase substrate motif and to identify optimal Probe sequences. These efforts resulted in the identification of a panel of six individual substrate-based fluorescent probes capable of detecting infection in guinea pigs with high statistical significance (P<0.005 in most cases). Receiver operating characteristic analyses demonstrated that this fluorogenic assay could detect A. fumigatus infection-associated proteolysis with comparable sensitivity and specificity as existing diagnostic procedures, suggesting that further optimization of the methodology may lead to improved diagnostics options for invasive pulmonary aspergillosis.


Assuntos
Aspergillus fumigatus/enzimologia , Biomarcadores/análise , Líquido da Lavagem Broncoalveolar/química , Aspergilose Pulmonar Invasiva/diagnóstico , Serina Endopeptidases/análise , Animais , Modelos Animais de Doenças , Corantes Fluorescentes/metabolismo , Cobaias , Prolil Oligopeptidases , Curva ROC , Sensibilidade e Especificidade
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