Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet®) in combination with caspofungin in experimental systemic aspergillosis

Sivak, Olena; Bartlett, Karen H.; Risovic, Verica; Choo, Eugene; Marra, Fawziah; Batty, D. Scotty; Wasan, Kishor M.

doi:10.1002/jps.20080

Cited by 29 publications

(22 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the combination of CAS and ABLC was not more efficient than ABLC alone in reducing the tissue fungal burden. These findings suggest that combination of CAS plus ABLC is not antagonistic in vivo, although ABLC alone (5 mg/kg once daily for 4 days) appears to be the best therapeutic choice in this animal model (205). patients with refractory IA and administered MICAF alone or in combination with azoles.…”

Section: Newer Antifungals In Combination Against Aspergillosismentioning

confidence: 75%

Combination Treatment of Invasive Fungal Infections

et al. 2005

View full text Add to dashboard Cite

The persistence of high morbidity and mortality from systemic fungal infections despite the availability of novel antifungals points to the need for effective treatment strategies. Treatment of invasive fungal infections is often hampered by drug toxicity, tolerability, and specificity issues, and added complications often arise due to the lack of diagnostic tests and to treatment complexities. Combination therapy has been suggested as a possible approach to improve treatment outcome. In this article, we undertake a historical review of studies of combination therapy and also focus on recent studies involving newly approved antifungal agents. The limitations surrounding antifungal combinations include nonuniform interpretation criteria, inability to predict the likelihood of clinical success, strain variability, and variations in pharmacodynamic/pharmacokinetic properties of antifungals used in combination. The issue of antagonism between polyenes and azoles is beginning to be addressed, but data regarding other drug combinations are not adequate for us to draw definite conclusions. However, recent data have identified potentially useful combinations. Standardization of assay methods and adoption of common interpretive criteria are essential to avoid discrepancies between different in vitro studies. Larger clinical trials are needed to assess whether combination therapy improves survival and treatment outcome in the most seriously debilitated patients afflicted with life-threatening fungal infections

show abstract

Section: Newer Antifungals In Combination Against Aspergillosismentioning

confidence: 75%

Combination Treatment of Invasive Fungal Infections

et al. 2005

View full text Add to dashboard Cite

show abstract

“…Treatment of experimental invasive aspergillosis with caspofungin (0.5 or 1 mg/kg) and amphotericin B reduced fungal burden and prolonged survival compared to monotherapy (5,36). When higher dosages of caspofungin (3 mg/kg) were combined with amphotericin B lipid complex, the beneficial effects were reduced or reversed (37). In addition, combination therapy with caspofungin plus amphotericin B against murine aspergillosis reduced the fungal burden in the spleen and lung, whereas in kidneys there was no significant reduction compared to monotherapy (36).…”

Section: Discussionmentioning

confidence: 99%

Concentration-Dependent Synergy and Antagonism within a Triple Antifungal Drug Combination againstAspergillusSpecies: Analysis by a New Response Surface Model

Meletiadis

Stergiopoulou

O’Shaughnessy

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E max -based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E max model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients (20). New therapeutic approaches are needed to improve outcome (30). The introduction of newer antifungal agents with different mechanisms of action has made combination therapy a possibility and an area of compelling investigational interest (38). Because of their different mechanisms of action, triazoles, echinocandins, and polyenes are likely candidates for combination therapy. Echinocandins inhibit the synthesis of 1,3-␤-D-glucan, a key component of the cell walls of most fungi; triazoles inhibit the synthesis of ergosterol by inhibiting the enzyme lanosterol C-14 demethylase; and polyenes act directly at the fungal cell membrane to alter its integrity (10).Triple combination therapy using all three classes of antifungal agents may be used in refractory aspergillosis (8,35,39). However, this practice has not been well studied, and the in vitro pharmacodynamic interactions are unknown. Preclinical studies are therefore required to understand the pharmacodynamic interactions and appropriately adjust in vivo dosing regimens in order to maximize synergistic effects and minimize the antagonistic ones. In vitro pharmacodynamic interactions within a triple combination can be complex (24); powerful analytical tools are required to accurately describe the effects of the triple combination in a wide range of drug concentrations and to determine the nature and intensity of antifungal pharmacodynamic interactions. Response surface methodologies provide the necessary tools to capture the information present in the full concentration-effect data set for two or more agents and to quantify synergy and antagonism (9).A new nonlinear mixture-amount response surface model for analyzing three-drug combinations was recently described (40). By contrast with other fully parametric response surface models, the new model is flexible enough to describe complicated response surfaces and to determine complex patterns of synergy and antagonism. With this model, response surfaces are modeled using the sigmoid E max concentration-effect relationship, and pharmacodynamic interactions are assessed based o...

show abstract

“…Other studies showed no significant enhanced benefit of combination antifungal regimens in experimental aspergillosis (8,11,29). Indeed, the lack of consistent results between studies is not surprising considering the variability in the type of animal model tested, the immunosuppression used, the route of fungal challenge, and the timing and dosing of antifungal regimens.…”

Section: Discussionmentioning

confidence: 99%

Effect of Amphotericin B and Micafungin Combination on Survival, Histopathology, and Fungal Burden in Experimental Aspergillosis in the p47 ^phox ⁻ ^/ ⁻ Mouse Model of Chronic Granulomatous Disease

Dennis¹,

Greco

Brun

et al. 2006

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase characterized by recurrent life-threatening bacterial and fungal infections. We characterized the effects of single and combination antifungal therapy on survival, histopathology, and laboratory markers of fungal burden in experimental aspergillosis in the p47 phox؊/؊ knockout mouse model of CGD. CGD mice were highly susceptible to intratracheal Aspergillus fumigatus challenge, whereas wild-type mice were resistant. CGD mice were challenged intratracheally with a lethal inoculum ( Invasive aspergillosis is a major cause of morbidity and mortality in highly immunocompromised persons. Chronic granulomatous disease (CGD) is an inherited disorder of the NADPH oxidase complex in which phagocytes are defective in generating the reactive oxidant superoxide anion and its metabolites, hydrogen peroxide, hydroxyl anion, and hypohalous acid. Activation of preformed granular proteases is likely to be principally responsible for NADPH oxidase-mediated destruction of pathogens (25, 31). As a result of the defect in this key host defense pathway, CGD patients suffer from recurrent life-threatening bacterial and fungal infections. CGD patients are susceptible to a broad spectrum of opportunistic filamentous fungi, but Aspergillus infection is by far the most common. Invasive aspergillosis is the most important cause of mortality in CGD (10,(26)(27)(28). Genetically engineered CGD mice (Xlinked and p47 phoxϪ/Ϫ ) recapitulate the human disease and are highly susceptible to Aspergillus infection (5, 9, 24). p47phoxϪ/Ϫ mice were used in experimental pulmonary aspergillosis to evaluate single and combination antifungal regimens on the basis of survival, histopathology, and fungal burden in lungs. The following four treatment groups were evaluated: (i) vehicle, (ii) amphotericin B, (iii) micafungin, and (iv) amphotericin B plus micafungin. The combination of amphotericin B and micafungin was more effective than either agent alone in prolonging survival after Aspergillus fumigatus challenge. Our study also demonstrated unique features of the CGD mouse model that are distinct from other immunocompromised animal models of experimental aspergillosis.(Material in this paper was presented in abstract form at the 44th Interscience Conference on Antimicrobial Agents and Chemotherapy, Washington, D.C., October 2004 [abstr. M-232].) MATERIALS AND METHODS Mice. Mice with a targeted disruption of the p47phox gene have a defective NADPH oxidase, rendering phagocytes incapable of generating measurable superoxide (12). CGD mice were derived from C57BL/6 and 129 intercrosses, and mice used were backcrossed either 5 (N5) or 14 (N14) generations in the C57BL/6 background. In all experiments, treatment groups were matched with respect to age (16 to 24 weeks) and generation of backcrossing. Mice were bred

show abstract

Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet®) in combination with caspofungin in experimental systemic aspergillosis

Cited by 29 publications

References 34 publications

Combination Treatment of Invasive Fungal Infections

Combination Treatment of Invasive Fungal Infections

Concentration-Dependent Synergy and Antagonism within a Triple Antifungal Drug Combination againstAspergillusSpecies: Analysis by a New Response Surface Model

Effect of Amphotericin B and Micafungin Combination on Survival, Histopathology, and Fungal Burden in Experimental Aspergillosis in the p47 ^phox ⁻ ^/ ⁻ Mouse Model of Chronic Granulomatous Disease

Contact Info

Product

Resources

About

Assessing the antifungal activity and toxicity profile of amphotericin B lipid complex (ABLC; Abelcet®) in combination with caspofungin in experimental systemic aspergillosis

Cited by 29 publications

References 34 publications

Combination Treatment of Invasive Fungal Infections

Combination Treatment of Invasive Fungal Infections

Concentration-Dependent Synergy and Antagonism within a Triple Antifungal Drug Combination againstAspergillusSpecies: Analysis by a New Response Surface Model

Effect of Amphotericin B and Micafungin Combination on Survival, Histopathology, and Fungal Burden in Experimental Aspergillosis in the p47 phox − / − Mouse Model of Chronic Granulomatous Disease

Contact Info

Product

Resources

About

Effect of Amphotericin B and Micafungin Combination on Survival, Histopathology, and Fungal Burden in Experimental Aspergillosis in the p47 ^phox ⁻ ^/ ⁻ Mouse Model of Chronic Granulomatous Disease