Sequential or combination antifungal therapy with voriconazole and liposomal amphotericin B in a Guinea pig model of invasive aspergillosis

We evaluated combinations of voriconazole (VRC) and liposomal amphotericin B (L-AMB) in a guinea pig invasive aspergillosis model. Simultaneous VRC and L-AMB was most effective, although VRC monotherapy was also effective. These regimens as well as sequential L-AMB followed by VRC were more effective than L-AMB alone or VRC followed by L-AMB.     

Efficacy of voriconazole in a guinea pig model of disseminated invasive aspergillosis

Voriconazole (VRC) was evaluated in an immunosuppressed-guinea pig model of invasive aspergillosis. VRC was more effective than amphotericin B or similar doses of itraconazole in the clearance of Aspergillus from tissues. VRC treatment regimens improved survival and significantly reduced tissue colony counts compared with those of controls.     

Efficacy of caspofungin and voriconazole combinations in experimental aspergillosis

Guinea pigs were infected with Aspergillus fumigatus at two challenge doses and treated for 7 days with a placebo, intraperitoneal caspofungin (1 mg/kg daily), oral voriconazole (1 mg/kg twice a day), or a combination of the caspofungin and voriconazole treatments. The combination therapy statistically significantly prolonged survival over that with the control at both challenge doses and achieved a statistically significant reduction in kidney burdens as measured by quantitative PCR. The same was true for animals given caspofungin alone at both levels of challenge and for animals treated with voriconazole alone at the lower challenge dose. However, the effects of combination therapy on prolongation of survival were greater than those of either monotherapy at both challenge doses, and the reduction in kidney burdens with combination therapy was significantly greater than that with caspofungin alone in the animals given the lower challenge dose. No synergistic interactive effects were seen for the two agents in checkerboard titration experiments in vitro. We conclude that therapy of experimental aspergillosis with caspofungin and voriconazole combined offers slight additional improvements in efficacy rather than effects of a clearly synergistic nature.     

Efficacy of voriconazole against invasive pulmonary aspergillosis in a guinea-pig model

We compared the efficacies of amphotericin B and voriconazole against invasive pulmonary aspergillosis in a guinea-pig model. A susceptible isolate of Aspergillus fumigatus was used to produce the infection. Voriconazole-treated animals had significantly better survival and decreased fungal burden in the lungs as compared with controls. Although no statistical difference was seen between the efficacies of voriconazole and amphotericin B, a trend favouring voriconazole was noted. Thus, voriconazole, with its cidal activity, may be an attractive alternative to potentially toxic amphotericin B in the treatment of invasive pulmonary aspergillosis.     

Efficacy of Abelcet and caspofungin, alone or in combination, against CNS aspergillosis in a murine model

OBJECTIVES: Currently, few options exist to treat central nervous system (CNS) aspergillosis, which is usually fatal. We tested the efficacy of Abelcet and caspofungin, alone and in combination for treatment of this disease. METHODS: Male CD-1 mice were immunosuppressed with 200 mg/kg cyclophosphamide 2 days prior to infection and every 5 days thereafter. In the first study, mice were infected intracerebrally with 2.1 x 10(6) conidia/mouse of Aspergillus fumigatus; 10 days of once daily therapy began one day later. Groups of 10 received 0.8, 4, or 8 mg/kg of Abelcet, intravenously (iv), or caspofungin, intraperitoneally, 0.8 mg/kg of conventional amphotericin B (AmB) iv, or no treatment. In a second study, mice were challenged with 6.4 x 10(6) conidia and given no treatment, 8 mg/kg of Abelcet or caspofungin, alone or in combination. On day 14, cfu were determined in survivors by plating of organ homogenates. RESULTS: In the first study, mice given any regimen of Abelcet or caspofungin had a survival rate > or =80% whereas untreated had 90% mortality. All drug regimens prolonged survival (P < or = 0.0008) and reduced cfu (P < or = 0.0001-0.003) recovered from the brains and kidneys compared with untreated. Abelcet showed an apparent dose-related reduction of cfu in the brains. Abelcet at 4 or 8 mg/kg were equivalent to AmB in reducing cfu from both organs (P > 0.05); AmB was superior to 0.8 mg/kg of Abelcet in the brain only (P < 0.02). Abelcet at 8 mg/kg or AmB at 0.8 mg/kg were superior to all regimens of caspofungin in reducing cfu (P < or = 0.05-0.001). In the second study, Abelcet alone significantly prolonged survival and reduced cfu in the organs versus the controls. Caspofungin did not significantly prolong survival or reduce cfu in comparison with the controls. In combination, Abelcet and caspofungin were equivalent to Abelcet alone. CONCLUSIONS: Abelcet proved to be efficacious, but not curative, in the treatment of CNS aspergillosis and was equivalent overall to conventional AmB. Caspofungin was not as effective against the larger inoculum, but did not enhance or interfere with the efficacy of Abelcet. Since Abelcet displayed dose-responsive efficacy, it is possible higher doses could produce superior results, yet not show toxicity.     

Efficacy of voriconazole in a guinea pig model of invasive trichosporonosis

We have evaluated the efficacy of voriconazole (VRC) in a systemic infection by Trichosporon asahii in immunosuppressed guinea pigs. VRC was more effective than amphotericin B in prolonging survival and reducing tissue burden. The best results were obtained with VRC at 10 mg/kg of body weight/day.     

Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis

Background and objective: Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune‐compromised patients such as organ‐transplant recipients. Recently, voriconazole has been approved for first‐line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung‐transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter’s tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without. Methods: Lung‐transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student’s t‐test. Statistical significance was defined by P‐value <0·05. Results: Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12·3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14·9 days vs. 8·3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole. Conclusion: This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung‐transplant recipients a median of 12·3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.     

米卡芬净单药及联合两性霉素B对小鼠侵袭性肺曲霉病的治疗作用

目的评价米卡芬净单药及联合两性霉素B对小鼠侵袭性肺曲霉病(IPA)的治疗作用。方法采用环磷酰胺骨髓抑制、烟曲霉孢子滴鼻接种构建中性粒细胞减少小鼠IPA模型。实验动物随机分为为4组:模型对照组(NS+5%GS,A组)、米卡芬净治疗组[5 mg/(kg.d),B组]、两性霉素B治疗组[1 mg/(kg.d),C组]和米卡芬净[5 mg/(kg.d)]加两性霉素B[1mg/(kg.d)]治疗组(D组),治疗从接种第2天开始,每天1次,共7 d。①动物生存期观察:每组15~16只小鼠,接种后每天观察1次至第21天。共进行2批次实验,分别给予2×105和6×106个孢子/小鼠。②肺的真菌负荷:每组9只小鼠,给予1.5×104个孢子/小鼠。治疗结束后取肺,匀浆后梯度稀释培养,记取菌落数并计算肺的真菌负荷量。结果①生存分析:第1批次,米卡芬净、两性霉素B单药及联合用药治疗均能延长小鼠生存期,但3种治疗方案在延长生存期方面差异无显著性(B组、C组分别与A组比较均有P<0.05,D组与A组比较P<0.01)。第2批次,联合用药组生存期长于其它各组,米卡芬净及两性霉素B单药治疗组与模型组比较差异无显著性(D组与A组比较P<0.01;D组分别与B组及C组比较均有P<0.05)。②肺的真菌负荷:两性霉素B单药及联合用药均能降低肺的真菌负荷,米卡芬净单药不降低肺的真菌负荷(C组与A组比较P<0.01;D组与A组比较P<0.05;B组与C组比较P<0.05;B组与D组比较P<0.01)。结论单独应用米卡芬净或两性霉素B及联合用药均能够延长中性粒细胞减少IPA小鼠生存期,当孢子接种量为6×106/小鼠时,联合用药优于单独应用米卡芬净或两性霉素B。单独应用米卡芬净不降低肺的真菌负荷,联合用药或两性霉素B单药在降低肺的真菌负荷方面均优于对照组及米卡芬净组。     

米卡芬净单药及联合两性霉素B对小鼠侵袭性肺曲霉病的治疗作用

目的 评价米卡芬净单药及联合两性霉素B对小鼠侵袭性肺曲霉病(IPA)的治疗作用.方法 采用环磷酰胺骨髓抑制、烟曲霉孢子滴鼻接种构建中性粒细胞减少小鼠IPA模型.实验动物随机分为为4组:模型对照组(NS+5%Gs,A组)、米卡芬净治疗组[5 mg/(kg·d),B组]、两性霉素B治疗组[1 mg/(kg·d),C组]和米卡芬净[5 mg/(kg·d)]加两性霉素B[1mg/(kg·d)]治疗组(D组),治疗从接种第2天开始,每天1次,共7 d.①动物生存期观察:每组15～16只小鼠,接种后每天观察1次至第21天.共进行2批次实验.分别给予2×105和6×106个孢子/小鼠.②肺的真菌负荷:每组9只小鼠,给予1.5×104个孢子/小鼠.治疗结束后取肺,匀浆后梯度稀释培养,记取菌落数并计算肺的真菌负荷量.结果 ①生存分析:第1批次,米卡芬净、两性霉素B单药及联合用药治疗均能延长小鼠生存期.但3种治疗方案在延长生存期方面差异无显著性(B组、C组分别与A组比较均有P<0.05.D组与A组比较P<0.01).第2批次,联合用药组生存期长于其它各组.米卡芬净及两性霉素B单药治疗组与模型组比较差异无显著性(D组与A组比较P<0.01:D组分别与B组及C组比较均有P<0.05).②肺的真菌负荷:两性霉素B单药及联合用药均能降低肺的真菌负荷,米卡芬净单药不降低肺的真菌负荷(C组与A组比较P<0.01;D组与A组比较P<0.05;B组与C组比较P<0.05;B组与D组比较P<0.01).结论 单独应用米卡芬净或两性霉素B及联合用药均能够延长中性粒细胞减少IPA小鼠生存期,当孢子接种量为6×106/小鼠时,联合用药优于单独应用米卡芬净或两性霉素B.单独应用米卡芬净不降低肺的真菌负荷,联合用药或两性霉素B单药在降低肺的真菌负荷方面均优于对照组及米卡芬净组.     

Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis.

Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.     

Efficacy of micafungin alone or in combination against systemic murine aspergillosis

We tested the efficacy of micafungin (FK) alone or in combination with other antifungals against systemic murine aspergillosis. FK alone at 10 mg/kg of body weight/dose prolonged survival (P = 0.01) and reduced CFU in the brain and kidney. Combination therapy that used suboptimal FK with amphotericin B or itraconazole prolonged survival. Although no survivors were free of infection, no antagonism was seen. Nikkomycin Z with FK showed significantly greater potency (P < 0.01) than either alone.     

卡泊芬净联合伏立康唑治疗恶性血液病患者合并侵袭性真菌感染12例疗效分析

我们对2007年11月至2011年1月收治的12例恶性血液病合并侵袭性真菌感染(IFI)应用伏立康唑疗效不佳患者,改用伏立康唑联合卡泊芬净治疗,取得了较好的疗效,现报道如下.     

Efficacy of SCH56592 in a rabbit model of invasive aspergillosis

SCH56592 (SCH) was evaluated in an immunosuppressed rabbit model of invasive aspergillosis. SCH was more effective than similar doses of itraconazole and as effective as amphotericin B in the clearance of Aspergillus spp. from tissues. Compared with controls, SCH regimens reduced mortality, improved survival, and significantly reduced tissue colony counts.     

Therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate for coccidioidomycosis in a mouse model

OBJECTIVES: The therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate was evaluated in treatment of murine coccidioidomycosis. METHODS: Survival and tissue burdens of the spleens and livers were used as antifungal response markers. In a monotherapy study, caspofungin was injected intraperitoneally at 0.1, 0.2, 0.5, 1 and 5 mg/kg per day on days 2 through 15. Amphotericin B deoxycholate was given at 0.1, 0.2 and 0.5 mg/kg intravenously and 1 and 5 mg/kg intraperitoneally three times per week for 2 weeks. In a combination therapy study, amphotericin B deoxycholate at 0.1 mg/kg was administered intravenously three times per week for 2 weeks, respectively, with and without caspofungin intraperitoneally given at 0.1, 0.5 and 5 mg/kg daily on days 2 through 15 post-infection. RESULTS: The study shows that caspofungin and amphotericin B deoxycholate at > or =0.5 and > or =0.1 mg/kg, respectively, were significant in both prolongation of survival and reduction of the tissue fungal burdens of mice compared with controls. No sterilization of either organ was observed with caspofungin doses. In combination therapy, any combination of caspofungin (0.1, 0.5 and 5 mg/kg) with amphotericin B deoxycholate (0.1 mg/kg) improved the period of survival and significantly reduced spleen and liver counts compared with controls. CONCLUSIONS: This study indicates that caspofungin has efficacy against systemic coccidioidomycosis in a murine model given in combination with amphotericin B deoxycholate.     

卡泊芬净治疗肺黄曲霉病失败1例

随着肿瘤化疗强度的不断增加、免疫抑制剂大量使用以及艾滋病患者的增多,曲霉感染明显上升。侵袭性曲霉感染的首选药物为伏立康唑,棘白菌素类常被作为二线药物使用。三唑类耐药的曲霉感染报道很多,但原发或继发性棘白菌素类耐药的曲霉感染报道极少。我们收治1例卡泊芬净治疗无效的侵袭性肺曲霉感染患者,现报道如下。     

Efficacy of ambruticin analogs in a murine model of invasive pulmonary aspergillosis

Ambruticins are a family of polyketides. The antifungal activity of an ambruticin, KOSN-2079, was tested in the mouse model of invasive aspergillosis. KOSN-2079 significantly reduced pulmonary fungal burdens and improved survival over that with the vehicle control. These results support the continued development of ambruticins as antifungal agents.     

Comparative efficacies of conventional amphotericin b, liposomal amphotericin B (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis

Central nervous system (CNS) aspergillosis is a severe disease that responds poorly to current therapies. The current studies examined the efficacies of several antifungal agents alone or in combination with a murine model of CNS aspergillosis. Immunosuppressed mice were infected intracerebrally with Aspergillus fumigatus and treated with an amphotericin B preparation, an echinocandin, or voriconazole (VCZ) given alone or in combination. Monotherapy studies showed that micafungin (MICA), caspofungin (CAS), VCZ, conventional amphotericin B (AMB), Abelcet (ABLC) (a lipid-carried AMB formulation; Enzon Pharmaceuticals, Inc.), and AmBisome (AmBi) (liposomal AMB; Gilead Sciences, Inc.) were efficacious. However, doses of AmBi above 15 mg/kg of body weight showed reduced efficacy. Neither MICA nor CAS showed dose responsiveness at the doses tested (1, 5, or 10 mg/kg). Only the 40-mg/kg dose of VCZ was effective. AmBi and ABLC showed dose responsiveness, with 10-mg/kg doses causing a significant reduction in fungal burden; they had equivalent activities at the 10-mg/kg dose. Suboptimal dosages of AmBi in combination with MICA, CAS, or VCZ were effective in prolonging survival. However, significantly enhanced activity was demonstrated only with AmBi and VCZ in combination. AmBi in combination with MICA or CAS showed a trend toward enhanced activity, but the combination was not significantly superior to monotherapy. The use of AmBi with CAS or VCZ at optimal doses did not improve efficacy. Cure was not attained with any dosage combinations. These results indicate that AmBi in combination with VCZ may be superior for treatment of CNS aspergillosis; combinations of AmBi and MICA or CAS were not antagonistic and may have a slight benefit.     

Efficacy and pharmacodynamics of flucytosine monotherapy in a nonneutropenic murine model of invasive aspergillosis

The therapeutic efficacy of flucytosine (5FC) monotherapy and the pharmacodynamic index predictive of efficacy were evaluated in a nonneutropenic mouse model of acute invasive aspergillosis. Mice were infected intravenously with an Aspergillus fumigatus isolate (the median MICs of 5FC were 128 mug/ml under the standard condition, 0.5 microg/ml at pH 6.0, and 0.031 microg/ml at pH 5.0) 2 h prior to the start of therapy and were treated for 7 days with different 5FC dosing regimens. The total doses ranged from 50 to 800 mg/kg of body weight/day and were administered at 6-, 12-, and 24-h intervals. The efficacy was assessed by means of survival. The survival rates of the treatment groups ranged from 40 to 90%, while the survival rate of the control group was 20%. The efficacy found depended primarily on the total daily dose. However, the power of our sample size may have been too low to exclude an effect of dose fractionation. The pharmacodynamic index that most strongly correlated with the efficacy was the area under the serum concentration-time curve and MIC ratio (R(2) = 0.86). We conclude that 5FC monotherapy is efficacious in a murine Aspergillus fumigatus infection model.     

Therapeutic drug monitoring of voriconazole and posaconazole for invasive aspergillosis

Voriconazole and posaconazole are extended-spectrum triazoles recommended for treatment, prophylaxis and salvage therapy of Aspergillus diseases. Over the past decade many papers have emerged supporting the use of therapeutic drug monitoring (TDM) for azole antifungals. TDM is used to tailor the exposure of a specific drug to the individuals to optimize treatment response and minimize side effects. We reviewed the pharmacokinetics and pharmacodynamics (PK-PD) characteristics of voriconazole and posaconazole. We present the available evidence on target concentrations defining maximal efficacy and minimal toxicity. Finally we provide some practical recommendations how to best perform TDM in clinical practice.     

Experimental systemic murine aspergillosis: treatment with polyene and caspofungin combination and G-CSF

OBJECTIVES: In view of the poor therapy outcomes of invasive aspergillosis, the objective of this study was to evaluate the efficacy of combination treatment consisting of the polyene amphotericin-B-intralipid, the echinocandin caspofungin and granulocyte-colony stimulating factor (G-CSF) in experimental murine systemic aspergillosis. With inhibition of synthesis of 1,3-beta-d-glucan in the fungal cell wall by caspofungin and an effect on the cell membrane by amphotericin-B-intralipid, this treatment may result in a synergic effect against Aspergillus fumigatus. Addition of G-CSF may further contribute to therapy of aspergillosis. METHODS: ICR mice were immunosuppressed by intraperitoneal administration of cyclophosphamide. Three days later, the mice were inoculated intravenously (iv) with A. fumigatus conidia. Infection and treatment were evaluated during an observation period of 30 days in terms of mortality (survival rate and mean survival time) and morbidity (quantitative determination of fungal burden, histopathology, and detection of serum galactomannan). RESULTS: Combination of caspofungin + G-CSF or addition of G-CSF to the combination of caspofungin + amphotericin-B-intralipid increased the survival rate of infected mice up to 78.9% and prolonged their mean survival time to 25 days. These combinations also resulted in a reduction in fungal burden in organs, and a decrease in serum galactomannan. CONCLUSIONS: The successful results obtained in the experimental model may possibly open the way to more effective management of aspergillosis in humans.