In vitro susceptibilities of Malassezia species to a new triazole,albaconazole (UR-9825), and other antifungal compounds

The in vitro activity of the new triazole albaconazole (UR-9825) in comparison with those of flucytosine, fluconazole, ketoconazole, itraconazole, and voriconazole against 70 strains of Malassezia spp. was determined by a microdilution method using a colorimetric indicator for metabolic activity. Albaconazole showed an in vitro profile similar to those of the different antifungals tested (MIC 相似文献   

Antifungal activities of posaconazole and granulocyte-macrophage colony-stimulating factor ex vivo and in mice with disseminated infection due to Scedosporium prolificans

Invasive infection due to Scedosporium prolificans is characterized by drug resistance and a high rate of mortality. The effects of posaconazole (POS), an investigational antifungal triazole, murine granulocyte-macrophage colony-stimulating factor (GM-CSF), and their combination against S. prolificans were evaluated ex vivo and in a newly developed murine model of disseminated infection due to this organism. When POS was combined with polymorphonuclear leukocytes from untreated or GM-CSF-treated mice (P < 0.01) ex vivo, it had increased activity in terms of the percentage of hyphal damage. Immunocompetent BALB/c mice were infected with 4 x 10(4) conidia of S. prolificans via the lateral tail vein. At 24 h postinfection the mice were treated with GM-CSF (5 microg/kg of body weight/day subcutaneously), POS (50 mg/kg/day by gavage), both agents, or saline only. Half of the brain, lung, liver, and kidney from each animal were cultured; and the other half of each organ was processed for histopathology. The mean survival times were 7.0 +/- 0.3 days for the controls, 7.4 +/- 0.4 days for POS-treated mice, 8.0 +/- 0.3 days for GM-CSF-treated mice (P = 0.08 compared with the results for the controls), and 7.3 +/- 0.3 days for POS-GM-CSF-treated mice. Fungal burdens (determined as the numbers of CFU per gram of tissue) were found in descending orders of magnitude in the kidneys, brains, livers, and lungs. The burdens were significantly reduced in the brains of GM-CSF-treated mice (P < 0.05) and the livers of POS-treated mice (P < 0.05). The numbers of lesions in the organs closely corresponded to the fungal burdens. GM-CSF tended to prolong survival (P = 0.08 compared with the results for the controls). While the combination of POS and GM-CSF showed enhanced activity ex vivo, it did not increase the activities of the two agents against this highly refractory filamentous fungus in mice.     

Comparative in-vitro activity of voriconazole (UK-109,496) and six other antifungal agents against clinical isolates of Scedosporium prolificans and Scedosporium apiospermum.

We report the in-vitro susceptibility of 27 clinical isolates of Scedosporium apiospermum and 43 of Scedosporium prolificans. S. apiospermum was resistant to fluconazole and flucytosine, with variable susceptibility to amphotericin B, itraconazole, ketoconazole and susceptible to miconazole. Voriconazole was much more active than fluconazole and flucytosine, more active than amphotericin B, itraconazole and ketoconazole and was as active as miconazole against S. apiospermum isolates. Voriconazole and the other six antifungal agents showed low activity against S. prolificans isolates.     

Liposomal amphotericin B and granulocyte colony-stimulating factor therapy in a murine model of invasive infection by Scedosporium prolificans

We established a reproducible lethal disseminated infection by the opportunistic fungus Scedosporium prolificans in an immunosuppressed murine model. We compared the effectiveness of the combined administration of liposomal amphotericin B (LAMB) and granulocyte colony-stimulating factor (G-CSF) with that of either agent alone and with that of amphotericin B deoxycholate (AMB). LAMB + G-CSF and LAMB treatments improved survival significantly with respect to the untreated control. The mean survival times of these three groups were 13.2, 9.1 and 7.9 days, respectively. Culture results in terms of colony counts for samples of deep organs were lower in mice treated with the combined therapy, although differences were not significant. Combined LAMB + G-CSF therapy could be a promising approach for the treatment of disseminated infections of S. prolificans, although further studies are required to determine the most appropriate doses.     

In vitro antiproliferative effects and mechanism of action of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi

We describe the in vitro antiproliferative effects of the new triazole derivative UR-9825 against the protozoan parasite Trypanosoma (Schizotrypanum) cruzi, the causative agent of Chagas' disease in Latin America. The compound was found to be extremely active against the cultured (epimastigote) form of the parasite, equivalent to that present in the reduviid vector, with a MIC of 30 nM, a concentration 33-fold lower than that required with the reference compound ketoconazole. At that MIC, growth arrest coincided with depletion of the parasite's 4,14-desmethyl endogenous sterols (ergosterol, 24-ethylcholesta-5,7,22-trien-3b-ol, and precursors) and their replacement by methylated sterols (lanosterol, 24-methylenedihydrolanosterol, and obtusifoliol), as revealed by high-resolution gas chromatography coupled with mass spectrometry. This indicated that the primary mechanism of action of UR-9825 was inhibition of the parasite's sterol C14alpha demethylase, as seen with other azole derivatives. The phospholipid composition of growth-arrested epimastigotes was also altered, when compared to controls, with a significant increase in the content of phosphatidylethanolamine and phosphatidylserine and a concomitant reduction of the content of phosphatidylcholine. The clinically relevant intracellular amastigote form, grown in cultured Vero cells at 37 degrees C, was even more sensitive to UR-9825, with a MIC of 10 nM, comparable to that for ketoconazole. The results showed that UR-9825 is among the most potent azole derivatives tested against this parasite and support in vivo studies with this compound.     

The in vitro susceptibility of Scedosporium prolificans to ajoene,allitridium and a raw extract of garlic (Allium sativum)

The in vitro susceptibility of 20 medical isolates of Scedosporium prolificans to ajoene, allitridium and raw garlic extract derived from cloves of garlic (Allium sativum) was tested using the NCCLS reference method (with minor modifications) for broth microdilution. The results demonstrate that both garlic derivatives and raw garlic extract appear to have in vitro activity against S. prolificans.     

Infective endocarditis and meningitis due to Scedosporium prolificans in a renal transplant recipient

Scedosporium prolificans is a ubiquitous filamentous fungi that may cause disseminated diseases in neutropenic patients with hematological malignancies. We report a fatal case of renal transplant recipient who developed both infective endocarditis and meningitis due to S. prolificans during treatment with micafungin and itraconazole for chronic necrotizing aspergillosis. Breakthrough Scedosporium infection should be considered among differential diagnosis of invasive fungal diseases in patients with renal transplant recipients receiving antifungal agents.     

Efficacy of FK463, a (1,3)-beta-D-glucan synthase inhibitor, in disseminated azole-resistant candida albicans infection in mice

The efficacy of FK463, a new (1,3)-beta-D-glucan synthase inhibitor, against azole-resistant Candida albicans strains has been studied. The MIC of FK463 was lower than those of azoles and amphotericin B against CDR1-expressing C26 and CaMDR-expressing C40 strains. All mice treated with FK463 (1 mg/kg) survived disseminated murine candidiasis. The fungal burden in the kidney after 6 days was markedly reduced after therapy with FK463 and amphotericin B sodium deoxycholate, and plasma (1,3)-beta-D-glucan concentration was found to be lower in FK463-treated mice. In our study, FK463 was found to be a potent antifungal agent against disseminated infection with azole-resistant C. albicans.     

Effects of Double and Triple Combinations of Antifungal Drugs in a Murine Model of Disseminated Infection by Scedosporium prolificans

We have evaluated the efficacies of micafungin, amphotericin B, and voriconazole, alone and in double and triple combinations, in a murine model of systemic infection by Scedosporium prolificans. Micafungin combined with voriconazole or amphotericin B was the most effective, these being the only treatments able to prolong survival and to reduce the fungal load in the kidneys and brain. Triple combinations of these drugs did not improve the results obtained with double combinations.Invasive infections by Scedosporium species are difficult to treat and cause high mortality (7). The outcome of these infections is generally worse when they are caused by Scedosporium prolificans (3, 7), which is refractory to antifungal therapy (18).Up to now, the only drugs that have shown any beneficial effect in infection of animals by S. prolificans have been liposomal amphotericin B (AMB) at high doses (1, 16), albaconazole (2), and caspofungin (1). However, in the clinical setting, the usefulness of these drugs is questionable (8, 9, 12). It seems reasonable, therefore, to explore the use of new approaches, testing two and even three drugs with different action mechanisms. The in vitro combinations of AMB with different echinocandins or triazoles have shown some degree of synergy against S. prolificans (4, 23). Combinations of more than two drugs have been poorly explored.We have evaluated the efficacies of micafungin (MFG), AMB, and voriconazole (VRC), alone and in double and triple combinations, in a murine model of disseminated scedosporiosis caused by S. prolificans. Although none of these drugs is active in vitro against this fungus (14, 23), it is not known if the combination of these drugs could be effective in vivo.A clinical isolate of S. prolificans, FMR 6719, was used. On the day of infection, it was suspended in sterile saline and filtered through sterile gauze to remove clumps of cells or hyphae (17). The resulting suspension, containing ≥95% of viable conidia, was adjusted to the desired inoculum based on the hemocytometer counts and confirmed by culture on potato dextrose agar.In vitro susceptibilities of the isolate to MFG, AMB, and VRC determined by a reference method (15) are shown in Table ​Table1.1. Drug interactions were assessed using a checkerboard method (5, 6, 10). All double combinations resulted in indifferent interactions, while the triple combination of MFG plus AMB and VRC was synergistic.

TABLE 1.

In vitro antifungal activities and interactions among antifungal drugs against S. prolificans FMR 6719

Efficacy of parenteral itraconazole against disseminated Candida albicans infection in two mouse strains

The efficacy of a new cyclodextrin intravenous formulation of itraconazole was evaluated by intraperitoneal treatment of experimental disseminated Candida albicans infections in BALB/c and DBA/2 mice. Mice were treated with doses of 5 or 20 mg/kg for 14 days and observation was continued for 28 days. Mice were randomly assigned to groups given either water or grapefruit juice as drinking fluid, since components of grapefruit juice that inhibit cytochrome P450 enzymes might influence the pharmacokinetic behaviour of itraconazole. The experiments showed that the itraconazole/cyclodextrin solution unequivocally prolonged survival and reduced weight loss over the first 4 days post-challenge, relative to placebo-treated control animals, in both mouse strains. However, the antifungal treatments did not reduce burdens of C. albicans in kidneys or brain. Placebo-treated DBA/2 mice given grapefruit juice to drink had a significantly shorter mean survival time than the equivalent group given water. In BALB/c mice the placebo-treated animals given grapefruit juice survived longer, though not significantly longer, than placebo-treated animals given water. These results give a preliminary hint that grapefruit juice alters the susceptibility of some mouse strains to C. albicans infection, regardless of any effects or non-effects it may have on itraconazole pharmacokinetics in the animals.     

Efficacy of aztreonam in treatment of experimental syphilis in rabbits

The efficacy of aztreonam (SQ 26,776) in the therapy of active syphilis infection was evaluated in the rabbit model. Aztreonam was effective in treating active syphilis at a dose of 25 mg/kg given intramuscularly twice daily for 10 days; doses of 2.5 and 0.25 mg/kg were not effective.     

Efficacy of cilofungin therapy administered by continuous intravenous infusion for experimental disseminated candidiasis in rabbits.

Cilofungin has potent in vitro activity against Candida albicans, but previous in vivo models using twice daily intermittent dosing regimens have not consistently demonstrated in vivo efficacy. Because of the pharmacokinetics of cilofungin in rabbits, it has been suggested that administration by continuous intravenous infusion might be more effective. We compared the in vivo efficacy of continuous intravenous infusion of cilofungin with that of amphotericin B in a rabbit model of disseminated candidiasis. Cilofungin prepared as previously described in phosphate-buffered 33% polyethylene glycol was lethal to infected rabbits in this model, as was phosphate-buffered 33% polyethylene glycol alone. In contrast, cilofungin in 26% polyethylene glycol and sterile water administered by continuous intravenous infusion was tolerated by rabbits, was significantly more effective than amphotericin therapy in reducing candida colony counts in kidney tissue, and was as effective as amphotericin therapy in lung and spleen tissue and in cardiac valvular vegetations. The dosage regimen and diluent used in some previous studies may have adversely affected outcome of treatment with cilofungin.     

Efficacy of ravuconazole (BMS-207147) in a guinea pig model of disseminated aspergillosis

Ravuconazole (BMS-207147, ER-30346), an oral triazole, was evaluated in an immunosuppressed temporarily neutropenic guinea pig model of invasive aspergillosis. In this model, guinea pigs were immunosuppressed with triamcinolone 20 mg/kg sc od beginning 4 days before challenge and made neutropenic with cyclophosphamide 300 mg/kg ip 1 day before challenge. Treatments of ravuconazole 5, 10 and 25 mg/kg po od were compared with itraconazole 2.5 and 5.0 mg/kg po bd and amphotericin B 1.25 mg/kg ip od. Treatment began 24 h after lethal intravenous challenge with Aspergillus fumigatus and continued for 5 days. Mortality occurred in eight of eight untreated control animals versus none of eight treated with ravuconazole 5 or 10 mg/kg/day or itraconazole 10 mg/kg/day. Mortality occurred in one of eight animals treated with ravuconazole 25 mg/kg/day, one of eight with amphotericin B and two of eight treated with itraconazole 5 mg/kg/day. Compared with controls, each of the antifungals examined significantly reduced the tissue burden in liver and brain, although only the highest doses of the azole drugs and amphotericin B significantly reduced tissue burden in the kidney. All three doses of ravuconazole improved survival and also reduced the tissue burden of ASPERGILLUS: In this model of invasive aspergillosis, ravuconazole showed significant activity and may be a useful compound in human disease.     

SCH-39304 in prevention and treatment of disseminated candidiasis in persistently granulocytopenic rabbits.

To investigate the potential use of SCH-39304 for the prevention and treatment of disseminated candidiasis in granulocytopenic patients, we studied its in vivo antifungal activity as preventive, early, and late treatments in three models (acute, subacute, and chronic) of disseminated candidiasis in persistently granulocytopenic rabbits. SCH-39304 was an effective as amphotericin B alone and fluconazole alone for the prevention of disseminated candidiasis. SCH-39304 alone and fluconazole alone were as effective as amphotericin B plus flucytosine for early treatment of subacute disseminated candidiasis. When treatment was delayed for 5 days to establish chronic disseminated candidiasis, SCH-39304 was less effective than amphotericin B plus flucytosine. In comparison with different treatment regimens, SCH-39304 was more effective in early and preventive treatment. Thus, SCH-39304 was comparable to treatment control regimens in prevention and early treatment of subacute disseminated candidiasis. SCH-39304 also was most effective in granulocytopenic rabbits with disseminated candidiasis when used for prevention or early treatment.     

Efficacy of intravenous liposomal amphotericin B (AmBisome) against coccidioidal meningitis in rabbits

The efficacy of intravenously administered liposomal amphotericin B (AmBisome [AmBi]) for the treatment of experimental coccidioidal meningitis was compared with those of oral fluconazole (FLC) and intravenously administered conventional amphotericin B (AMB). Male New Zealand White rabbits were infected by intracisternal inoculation of arthroconidia of Coccidioides immitis. Starting 5 days postinfection, animals received one of the following: 5% dextrose water diluent; AMB given at 1 mg/kg of body weight; AmBi given at 7.5, 15, or 22.5 mg/kg intravenously three times per week for 3 weeks; or oral FLC given at 80 mg/kg for 19 days. One week after the cessation of therapy, all survivors were euthanatized, the numbers of CFU remaining in the spinal cord and brain were determined, and histological analyses were performed. All AmBi-, FLC-, or AMB-treated animals survived and had prolonged lengths of survival compared with those for the controls (P < 0.0001). Treated groups had significantly lower numbers of white blood cells and significantly lower protein concentrations in the cerebrospinal fluid compared with those for the controls (P < 0.01 to 0.0005) and had fewer clinical signs of infection (e.g., weight loss, elevated temperature, and neurological abnormalities including motor abnormalities). The mean histological scores for AmBi-treated rabbits were lower than those for FLC-treated and control rabbits (P < 0.016 and 0.0005, respectively); the scores for AMB-treated animals were lower than those for the controls (P < 0.0005) but were similar to those for FLC-treated rabbits. All regimens reduced the numbers of CFU in the brain and spinal cord compared with those for the controls (P < or =0.0005). AmBi-treated animals had 3- to 11-fold lower numbers of CFU than FLC-treated rabbits and 6- to 35-fold lower numbers of CFU than AmB-treated rabbits. Three of eight animals given 15 mg of AmBi per kg had no detectable infection in either tissue, whereas other doses of AmBi or FLC cleared either the brain or the spinal cord of infection in fewer rabbits. In addition, clearance of the infection from both tissues was achieved in none of the rabbits, and neither tissue was cleared of infection in AMB-treated animals. Overall, these data indicate that intravenously administered AmBi is superior to oral FLC or intravenous AMB and that FLC is better than AMB against experimental coccidioidal meningitis. These data indicate that AmBi may offer an improvement in the treatment of coccidioidal meningitis. Additional studies are warranted.     

Efficacy of aminocandin in the treatment of immunocompetent mice with haematogenously disseminated fluconazole-resistant candidiasis

OBJECTIVES: The objective of this study was to compare the activity of aminocandin, a new echinocandin with broad-spectrum activity against Candida spp., with that of amphotericin B, caspofungin and fluconazole, in an immunocompetent murine model of haematogenously disseminated candidiasis caused by a fluconazole-resistant Candida albicans. METHODS: Mice were infected with a fluconazole-resistant strain of C. albicans and treated with aminocandin 5 and 10 mg/kg intravenously (iv) once and twice weekly, amphotericin B 0.5 mg/kg iv every other day for 5 days, fluconazole 20 mg/kg orally (po) once a day for 5 days and caspofungin 0.5 mg/kg intraperitoneally (ip) once daily for 5 days. RESULTS: Treatment with aminocandin, given iv twice a week, resulted in 100% survival. Further, the tissue fungal burden of the aminocandin group was equivalent to that of amphotericin B (administered every other day) and caspofungin (administered daily). CONCLUSIONS: Aminocandin may be an effective addition to the arsenal of antifungal compounds for the treatment of candidiasis caused by fluconazole-resistant C. albicans.     

外伤导致膝关节尖端赛多孢子菌感染一例

患者女,7岁.1月前因不慎摔伤,右膝局部皮肤挫伤、出血,未做特殊处理,数天后出现关节肿胀、疼痛并发烧后入当地医院治疗,未明显好转后转入我院,入院体检:体温38.4℃,白细胞:11.37×10~9／L,红细胞:4.35×10~(12)／L,血红蛋白:123 g／L,血小板:354×10~9／L,红细胞沉降率:60mm／1 h,肝肾功能均正常,查体右膝肿胀明显,右膝及右胫骨上段压痛、叩击痛,经抗感染治疗未见缓解后行右胫骨钻孔减压,切开冲洗引流术,术中取病变组织送检,术后又取引流液送检,均检出丝状真菌,经鉴定为尖端赛多孢菌.     

Need for early antifungal treatment confirmed in experimental disseminated Candida albicans infection

Groups of mice infected intravenously with Candida albicans were treated intraperitoneally with amphotericin B, caspofungin, or fluconazole, starting at intervals before and after challenge. Survival was longest and tissue burdens were most reduced with early treatment, and survival times fell proportionately as treatment was delayed, reinforcing clinical recommendations for the earliest possible initiation of antifungal therapy.     

Comparison of fluconazole and amphotericin B for treatment of disseminated candidiasis and endophthalmitis in rabbits.

We compared the efficacy of intravenous fluconazole (80 mg/kg of body weight per day) with that of amphotericin B (1 mg/kg/day) for the long-term treatment of endophthalmitis in rabbits with disseminated candidiasis. After 17 days of therapy, fluconazole decreased the fungal colony counts of the choroid-retinas significantly more than did the saline control (P less than 0.05); however, after 24 days of fluconazole therapy, this treatment effect was lost and fluconazole was no more effective than saline. In contrast, treatment for 24 days with amphotericin B reduced the vitreous and choroid-retina fungal colony counts significantly more than either fluconazole or saline (P less than 0.05 for both treatment groups). After 17 days of therapy, indirect ophthalmoscopy revealed less severe eye involvement in both antifungal treatment groups than in saline controls; however, this difference reached statistical significance only for the amphotericin B-treated rabbits (P less than 0.05). Also, there was a trend towards worsening eye lesions, as seen by indirect ophthalmoscopy, in the fluconazole-treated rabbits after 24 days of therapy, which roughly paralleled the quantitative culture results. Despite the presence of negative choroid-retina cultures, some rabbits in all treatment groups had persistently visible eye lesions, indicating that ophthalmoscopic resolution of Candida endophthalmitis may lag behind lesion sterilization. Amphotericin B was superior to fluconazole in the treatment of Candida endophthalmitis in this model.