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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
Antimicrob Agents Chemother ; 57(2): 745-50, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23165465

RESUMO

Miltefosine is an alkyl phosphocholine with good oral bioavailability and in vitro activity against Cryptococcus species that has gained interest as an additional agent for cryptococcal infections. Our objective was to further evaluate the in vivo efficacy of miltefosine in experimental in vivo models of cryptococcal meningoencephalitis and disseminated cryptococcosis. Mice were infected intracranially or intravenously with either C. neoformans USC1597 or H99. Miltefosine treatment (1.8 to 45 mg/kg of body weight orally once daily) began at either 1 h or 1 day postinoculation. Fluconazole (10 mg/kg orally twice daily) or amphotericin B deoxycholate (3 mg/kg intraperitoneally once daily) served as positive controls. In our standard models, miltefosine did not result in significant improvements in survival or reductions in fungal burden against either C. neoformans isolate. There was a trend toward improved survival with miltefosine at 7.2 mg/kg against disseminated cryptococcosis with the H99 strain but only at a low infecting inoculum. In contrast, both fluconazole and amphotericin B significantly improved survival in mice with cryptococcal meningoencephalitis and disseminated cryptococcosis due to USC1597. Amphotericin B also improved survival against both cryptococcal infections caused by H99. Combination therapy with miltefosine demonstrated neither synergy nor antagonism in both models. These results demonstrate limited efficacy of miltefosine and suggest caution with the potential use of this agent for the treatment of C. neoformans infections.


Assuntos
Antifúngicos/uso terapêutico , Criptococose/tratamento farmacológico , Cryptococcus neoformans/efeitos dos fármacos , Meningite Criptocócica/tratamento farmacológico , Meningoencefalite/tratamento farmacológico , Fosforilcolina/análogos & derivados , Anfotericina B/administração & dosagem , Animais , Criptococose/microbiologia , Cryptococcus neoformans/isolamento & purificação , Ácido Desoxicólico/administração & dosagem , Combinação de Medicamentos , Fluconazol/administração & dosagem , Meningite Criptocócica/microbiologia , Meningoencefalite/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Fosforilcolina/uso terapêutico , Sobrevida
8.
J Clin Microbiol ; 51(2): 459-65, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23175252

RESUMO

Interest in lateral-flow devices (LFDs) as potential point-of-care assays for the diagnosis of infectious diseases has increased. Our objective was to evaluate the interlaboratory and interstudy reproducibility and the effects of antifungal therapy on an LFD developed for invasive pulmonary aspergillosis (IPA) detection. An established neutropenic guinea pig model of IPA caused by Aspergillus fumigatus was used. At predetermined time points (1 h and 3, 5, and 7 days postinoculation), blood and bronchoalveolar lavage (BAL) fluid were collected from infected and uninfected animals. In a separate experiment, guinea pigs were treated with posaconazole (10 mg/kg of body weight orally [p.o.] twice a day [BID]), voriconazole (10 mg/kg p.o. BID), liposomal amphotericin B (10 mg/kg intraperitoneally [i.p.] once a day [QD]), or caspofungin (2 mg/kg i.p. QD), and samples were collected on days 7 and 11. Each laboratory independently evaluated the IgG monoclonal antibody-based LFD. Galactomannan and (1 → 3)-ß-D-glucan were also measured using commercially available kits. Good interlaboratory agreement was observed with the LFD, as the results for 97% (32/33) of the serum and 78.8% (26/33) of the BAL fluid samples from infected animals were in agreement. Good interstudy agreement was also observed. The serum sensitivity of each surrogate-marker assay was reduced in animals treated with antifungals. In contrast, these markers remained elevated within the BAL fluids of treated animals, which was consistent with the fungal burden and histopathology results. These results demonstrate that the LFD assay is reproducible between different laboratories and studies. However, the sensitivity of this assay and other markers of IPA may be reduced with serum in the presence of antifungal therapy.


Assuntos
Aspergilose Pulmonar Invasiva/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Aspergillus/imunologia , Aspergillus/isolamento & purificação , Líquido da Lavagem Broncoalveolar/imunologia , Líquido da Lavagem Broncoalveolar/microbiologia , Contagem de Colônia Microbiana , Modelos Animais de Doenças , Glucanos/metabolismo , Cobaias , Humanos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Aspergilose Pulmonar Invasiva/microbiologia , Masculino , Mananas/metabolismo , Sistemas Automatizados de Assistência Junto ao Leito/normas , Reprodutibilidade dos Testes , Fatores de Tempo
9.
J Antimicrob Chemother ; 67(6): 1432-8, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22378683

RESUMO

OBJECTIVES: Meningoencephalitis caused by Cryptococcus gattii is associated with significant morbidity and the need for aggressive therapy, and often necessitates neurosurgical intervention. We adapted a previously described murine model of cryptococcal meningoencephalitis due to Cryptococcus neoformans to that caused by C. gattii. METHODS: Mice were inoculated intracranially with either C. gattii (genotype VGIIa) or C. neoformans. In virulence studies, different C. gattii infecting inocula were compared with a fixed inoculum of C. neoformans, and differences were assessed by survival, brain tissue fungal burden, serum antigen titres and histopathological changes within brain tissue. For treatment, fluconazole or posaconazole (10 mg/kg orally twice daily) was initiated 24 h post-inoculation. RESULTS: C. gattii was more virulent than C. neoformans, as evident by shorter median survival, earlier histopathological changes and higher serum antigen titres. However, no differences in fungal burden or dissemination to other organs were observed among the various groups. In treatment studies, both fluconazole and posaconazole improved the median survival of mice infected with either species. However, neither regimen improved the percentage of animals surviving to the predetermined study endpoint. CONCLUSIONS: These results demonstrate the virulence of C. gattii meningoencephalitis and the potential of this model for the assessment of new treatment strategies.


Assuntos
Criptococose/microbiologia , Criptococose/patologia , Cryptococcus gattii/patogenicidade , Modelos Animais de Doenças , Meningoencefalite/microbiologia , Meningoencefalite/patologia , Animais , Antifúngicos/administração & dosagem , Antígenos de Fungos/sangue , Encéfalo/microbiologia , Contagem de Colônia Microbiana , Criptococose/tratamento farmacológico , Cryptococcus neoformans/patogenicidade , Fluconazol/administração & dosagem , Histocitoquímica , Meningoencefalite/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Análise de Sobrevida , Triazóis/administração & dosagem
10.
J Antimicrob Chemother ; 67(4): 970-6, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22240402

RESUMO

OBJECTIVES: Amphotericin B inhalation powder (ABIP) is a novel dry-powder amphotericin B formulation that is directly delivered to the lung, resulting in elevated lung tissue drug concentrations of this polyene. We evaluated the prophylactic efficacy of single dose administration of ABIP in a guinea pig model of invasive pulmonary aspergillosis. METHODS: Guinea pigs were immunosuppressed with cyclophosphamide and cortisone acetate and challenged with Aspergillus fumigatus conidia in an aerosol chamber. Guinea pigs received prophylaxis with a single inhaled dose of ABIP at 0.05, 0.5, 4 or 10 mg/kg administered 24 h prior to infection. Treatment with oral voriconazole at doses of 5 or 10 mg/kg twice daily beginning 24 h post-challenge served as the positive control. RESULTS: Improvements in survival were observed with ABIP prophylaxis. A single inhaled dose of 4 mg/kg ABIP and treatment with 5 mg/kg voriconazole both improved median and percentage survival compared with untreated controls. In addition, pulmonary fungal burden, as assessed by cfu, quantitative PCR and galactomannan, was also reduced in a dose-dependent fashion with ABIP prophylaxis as well as with both doses of voriconazole treatment. CONCLUSIONS: Single-dose prophylaxis with inhaled ABIP as prophylaxis demonstrated a significant survival advantage and reductions in pulmonary fungal burden in this model of invasive pulmonary aspergillosis. Optimization of the dose and dosing frequency of ABIP dose may help to further enhance the anti-Aspergillus activity of this novel amphotericin B formulation.


Assuntos
Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Aspergillus fumigatus/patogenicidade , Quimioprevenção/métodos , Aspergilose Pulmonar Invasiva/prevenção & controle , Administração por Inalação , Animais , Aspergillus fumigatus/efeitos dos fármacos , Contagem de Colônia Microbiana , Cortisona/administração & dosagem , Cortisona/análogos & derivados , Ciclofosfamida/administração & dosagem , Modelos Animais de Doenças , Cobaias , Imunossupressores/administração & dosagem , Pulmão/microbiologia , Masculino , Pirimidinas/administração & dosagem , Análise de Sobrevida , Triazóis/administração & dosagem , Voriconazol
11.
Antimicrob Agents Chemother ; 55(7): 3254-60, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21502632

RESUMO

Previous in vivo studies have reported caspofungin dose escalation to be effective against Candida glabrata with reduced susceptibility. We hypothesized that higher doses of caspofungin would be effective against invasive candidiasis caused by the more virulent species Candida albicans, including isolates resistant to this echinocandin. Immunocompetent mice were inoculated with one of three C. albicans isolates, including one susceptible and two resistant isolates with different FKS1 hot spot 1 point mutations. Mice received daily caspofungin treatment for 7 days and were then followed off therapy for 2 weeks to assess survival. Kidney tissue and blood were collected, and fungal burden and serum (1 → 3)-ß-D-glucan were measured. Significant differences in virulence were observed among the three C. albicans isolates, which translated into differences in responses to caspofungin. The most virulent of the resistant isolates studied (isolate 43001; Fks1p F641S) did not respond to caspofungin doses of up to 10 mg/kg of body weight, as there were no differences in survival (survival range, 0 to 12% with treatment), tissue burden, or (1 → 3)-ß-D-glucan concentration compared to those for untreated controls. Higher doses of caspofungin did improve survival against the second resistant isolate (53264; Fks1p S645P) that demonstrated reduced virulence (5 and 10 mg/kg; 80% survival). In contrast, caspofungin doses as low as 1 mg/kg improved survival (85 to 95%) and reduced tissue burden and (1 → 3)-ß-D-glucan concentration against the susceptible isolate (ATCC 90028). These data suggest that caspofungin dose escalation for invasive candidiasis may not be consistently effective against resistant C. albicans isolates, and this may be associated with the virulence of the strain.


Assuntos
Antifúngicos/uso terapêutico , Candida albicans/efeitos dos fármacos , Candida albicans/patogenicidade , Candidíase Invasiva/tratamento farmacológico , Equinocandinas/uso terapêutico , Animais , Antifúngicos/farmacologia , Candidíase Invasiva/microbiologia , Caspofungina , Farmacorresistência Fúngica/genética , Equinocandinas/farmacologia , Proteínas Fúngicas/genética , Lipopeptídeos , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Mutação
12.
Antimicrob Agents Chemother ; 54(3): 1055-9, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20065054

RESUMO

Invasive fusariosis is a highly aggressive fungal infection associated with high mortality in heavily immunocompromised patients. Although posaconazole is efficacious as salvage therapy against infections caused by Fusarium species, concerns remain regarding this agent in the setting of reduced potency. To evaluate the efficacy of posaconazole as treatment or prophylaxis against invasive fusariosis caused by Fusarium solani, we utilized a neutropenic murine model of disseminated disease. ICR mice were administered escalating doses of posaconazole (6.25, 12.5, 25, or 50 mg/kg of body weight twice daily [BID]) by oral gavage beginning 2 days prior to inoculation in the prophylaxis studies or beginning 12 h after inoculation as treatment. Therapy was continued until day 9 postinoculation, and animals were monitored off therapy until day 15 for survival. Fungal burden was assessed as CFU in the kidneys. A clear dose-response relationship was observed, as the highest dose of posaconazole (50 mg/kg) was the most effective in prolonging survival and reducing tissue fungal burden both as prophylaxis and as treatment. This dose response was associated with high posaconazole serum concentrations as measured by bioassay. However, the extent of efficacy was also dependent on the infecting inoculum, as greater increases in survival and reductions in fungal burden were observed with the lower inocula tested. In this model high dosages of posaconazole were effective as treatment and prophylaxis against disseminated fusariosis caused by F. solani.


Assuntos
Antifúngicos , Fusarium/efeitos dos fármacos , Micoses/tratamento farmacológico , Triazóis , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Quimioprevenção , Modelos Animais de Doenças , Farmacorresistência Fúngica , Fusarium/classificação , Humanos , Rim/microbiologia , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Micoses/microbiologia , Micoses/mortalidade , Micoses/prevenção & controle , Neutropenia/complicações , Resultado do Tratamento , Triazóis/administração & dosagem , Triazóis/farmacologia , Triazóis/uso terapêutico
13.
14.
Antimicrob Agents Chemother ; 53(6): 2613-5, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19289523

RESUMO

Targeted airway delivery of antifungals as prophylaxis against invasive aspergillosis may lead to high lung drug concentrations while avoiding toxicities associated with systemically administered agents. We evaluated the effectiveness of aerosolizing the intravenous formulation of voriconazole as prophylaxis against invasive pulmonary aspergillosis caused by Aspergillus fumigatus in an established murine model. Inhaled voriconazole significantly improved survival and limited the extent of invasive disease, as assessed by histopathology, compared to control and amphotericin B treatments.


Assuntos
Antifúngicos/administração & dosagem , Aspergilose Pulmonar Invasiva/prevenção & controle , Pirimidinas/administração & dosagem , Triazóis/administração & dosagem , Administração por Inalação , Anfotericina B/uso terapêutico , Animais , Camundongos , Camundongos Endogâmicos ICR , Voriconazol
15.
J Antimicrob Chemother ; 62(5): 1094-100, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18658194

RESUMO

BACKGROUND: Aminocandin is an investigational echinocandin with excellent activity against Candida species, including Candida albicans and Candida tropicalis. However, few data are available for this agent versus Candida glabrata. We compared the in vitro potency and in vivo efficacy of aminocandin and caspofungin against clinical isolates of C. glabrata including those with reduced caspofungin susceptibility (MIC > 2 mg/L). METHODS: In vitro activity was assessed using microdilution broth susceptibility testing. Three isolates, one with a low and two with elevated caspofungin MICs, were chosen and mice were infected with C. glabrata followed by a single dose of aminocandin or caspofungin (0.5-100 mg/kg), or daily doses of caspofungin (0.07-14.3 mg/kg) begun 1 day after inoculation. Reduction in fungal burden, assessed in kidney tissue on day 8 post-inoculation, was the marker of antifungal response. RESULTS: Aminocandin was more potent than caspofungin against each isolate with reduced caspofungin susceptibility. Mice infected with the caspofungin-susceptible isolate had significant decreases in tissue burden with low doses of either drug. Higher single doses of aminocandin (> or = 10 mg/kg) were required to reduce fungal burden against the two isolates with elevated caspofungin MICs. Single dose administration of caspofungin was ineffective against one of these isolates, and higher daily doses were required to reduce fungal burden. CONCLUSIONS: These studies suggest that aminocandin has the potential for extended interval dosing in the treatment of C. glabrata infections caused by susceptible isolates. However, higher doses may be required against isolates with reduced caspofungin susceptibility.


Assuntos
Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida glabrata/efeitos dos fármacos , Candidíase/tratamento farmacológico , Farmacorresistência Fúngica , Equinocandinas/farmacologia , Equinocandinas/uso terapêutico , Lipopeptídeos/farmacologia , Lipopeptídeos/uso terapêutico , Animais , Antifúngicos/administração & dosagem , Caspofungina , Contagem de Colônia Microbiana , Equinocandinas/administração & dosagem , Rim/microbiologia , Lipopeptídeos/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
16.
Antimicrob Agents Chemother ; 52(7): 2593-8, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18474582

RESUMO

Early diagnosis of invasive pulmonary aspergillosis is problematic in some patient groups due to the lack of rapid, sensitive, specific, and reliable diagnostic tests. Fungal burden and therapeutic efficacy were assessed by survival, quantitative culture (CFU counts), galactomannan enzyme immunoassay (GM-EIA), and quantitative PCR (qPCR) in a new guinea pig model of invasive pulmonary aspergillosis using an aerosol challenge. At 1 day postinfection, qPCR determined that the pulmonary fungal burden was 2 log(10) higher than that determined by CFU counting and increased significantly (P < 0.03) over time. In contrast, the tissue burden assessed by CFU counting did not rise over the course of the study. Therapy with the antifungal drug voriconazole produced statistically significant decreases in pulmonary fungal burden, as detected by CFU counting (P < 0.02), qPCR, and GM-EIA (both P < 0.0002). Daily assessment of the progression of fungal infection in serum was performed by qPCR and GM-EIA. GM-EIA demonstrated a statistically significant reduction in the fungal load on days 6 and 7 in voriconazole-treated animals compared to time-matched controls (P < 0.02). Confirmation of fungal tissue burden by two or more methods should provide a more precise account of the burden, allowing improved assessment of diagnostic and therapeutic strategies in invasive pulmonary aspergillosis.


Assuntos
Aspergilose/diagnóstico , Aspergillus fumigatus/isolamento & purificação , Pneumopatias Fúngicas/diagnóstico , Animais , Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Aspergillus fumigatus/química , Aspergillus fumigatus/genética , Sequência de Bases , Contagem de Colônia Microbiana , Primers do DNA/genética , DNA Fúngico/genética , Modelos Animais de Doenças , Cobaias , Humanos , Técnicas Imunoenzimáticas/métodos , Pulmão/microbiologia , Pulmão/patologia , Pneumopatias Fúngicas/tratamento farmacológico , Pneumopatias Fúngicas/microbiologia , Masculino , Mananas/análise , Micologia/métodos , Reação em Cadeia da Polimerase/métodos , Pirimidinas/uso terapêutico , Triazóis/uso terapêutico , Voriconazol
18.
19.
J Infect ; 55(1): 68-74, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17360039

RESUMO

OBJECTIVE: Prophylactic strategies against invasive pulmonary aspergillosis are often limited by drug interactions and toxicities. Targeted airway delivery of antifungals to the lungs may avoid these pitfalls. We evaluated the effectiveness of an aerosolized nanostructured formulation of itraconazole produced by spray freezing into liquid (SFL) as prophylaxis against invasive pulmonary aspergillosis caused by A. fumigatus. METHODS: Immunocompromised Balb/C mice received either itraconazole by oral gavage (Sporanox Oral Liquid [SOL] 30 mg/kg TID) or by aerosolization (SFL 30 mg/kg via 20 min aerosolizations, or control, BID). Dosing began 2 days prior to pulmonary inoculation with A. fumigatus and continued for 7 days post-inoculation. Changes in lung histopathology were also assessed. In the survival arm, mice were monitored over a 5 day period following discontinuation of therapy and survival was assessed by Kaplan-Meier analysis. RESULTS: SFL survival (35%) was greater compared to control (10%; p=0.03) and SOL (0%; p=0.02). Histopathology demonstrated severe invasive disease involving vessels and small airways in control and SOL animals. SFL animals demonstrated colonization with some invasion predominately of large airways. CONCLUSIONS: Prophylactic aerosolization of nanostructured SFL significantly improved survival and limited invasive disease of small airways due to A. fumigatus.


Assuntos
Antifúngicos , Aspergilose/prevenção & controle , Aspergillus fumigatus/efeitos dos fármacos , Itraconazol , Pneumopatias Fúngicas/prevenção & controle , Aerossóis , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Aspergilose/microbiologia , Aspergilose/mortalidade , Aspergilose/patologia , Modelos Animais de Doenças , Feminino , Humanos , Hospedeiro Imunocomprometido , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Itraconazol/uso terapêutico , Pulmão/microbiologia , Pulmão/patologia , Pneumopatias Fúngicas/microbiologia , Pneumopatias Fúngicas/mortalidade , Pneumopatias Fúngicas/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanoestruturas , Resultado do Tratamento
20.
Antimicrob Agents Chemother ; 51(5): 1616-20, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17307976

RESUMO

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.


Assuntos
Antifúngicos/farmacologia , Candida glabrata/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Soro/fisiologia , Anidulafungina , Animais , Candidíase/tratamento farmacológico , Caspofungina , Equinocandinas , Lipopeptídeos , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana
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