Endpoint Assessment in Rabbit Models of Invasive Pulmonary Aspergillosis and Mucormycosis

Petraitis, Vidmantas; Petraitienė, Rūta; Hope, William; Walsh, Thomas J.

doi:10.1007/978-1-4939-7104-6_18

Cited by 4 publications

(3 citation statements)

References 32 publications

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“…The study of combination antifungal therapy in experimental model systems of invasive aspergillosis is essential for understanding the basic pharmacology of the combination, as well for designing, implementing, and derisking clinical protocols for the treatment of invasive fungal infections. The model system described here investigated a series of endpoints that individually and collectively allowed a detailed understanding of the efficacies of the antifungals in relation to the distinctive properties of invasive pulmonary aspergillosis (7). Determination of the values of markers of organism-mediated pulmonary injury (lung weights and pulmonary infarct scores) is essential to understand the impact of an echinocandin-based regimen, in which the quantitative results for cultures may, paradoxically, be elevated.…”

Section: Discussionmentioning

confidence: 99%

Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis

Petraitis

Petraitienė

McCarthy

et al. 2017

Antimicrob Agents Chemother

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Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-β-d-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole (ISA) and the echinocandin micafungin (MFG) may result in improved outcomes in experimental IPA in persistently neutropenic rabbits. Treatments included ISA at 20 mg/kg of body weight/day (ISA20), 40 mg/kg/day (ISA40), and 60 mg/kg/day (ISA60); MFG at 2 mg/kg/day (MFG2); combinations of ISA20 and MFG2, ISA40 and MFG2, and ISA60 and MFG2; and no treatment (untreated controls [UC]). The galactomannan index (GMI) and (1→3)-β-d-glucan levels in serum were measured. The residual fungal burden (number of CFU per gram) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20-MFG2-, ISA40-MFG2-, and ISA60-MFG2-treated rabbits compared with that in MFG2-treated or UC rabbits ( < 0.01). Measures of organism-mediated pulmonary injury, lung weights, and pulmonary infarct score were lower in ISA40-MFG2-treated rabbits than in rabbits treated with ISA40 or MFG2 alone ( < 0.01). Survival was prolonged in ISA40-MFG2-treated rabbits in comparison to those treated with ISA40 or MFG2 alone ( < 0.01). These outcome variables correlated directly with significant declines in GMI and serum (1→3)-β-d-glucan levels during therapy. The GMI correlated with measures of organism-mediated pulmonary injury, lung weights ( = 0.764; < 0.001), and pulmonary infarct score ( = 0.911; < 0.001). In summary, rabbits receiving combination therapy with isavuconazole and micafungin demonstrated a significant dose-dependent reduction in the residual fungal burden, decreased pulmonary injury, prolonged survival, a lower GMI, and lower serum (1→3)-β-d-glucan levels in comparison to rabbits receiving isavuconazole or micafungin as a single agent.

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Section: Discussionmentioning

confidence: 99%

Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis

Petraitis

Petraitienė

McCarthy

et al. 2017

Antimicrob Agents Chemother

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“…Some examples include the development of a sinusitis infection model 209 , a rat model to study asthma 275 and a guinea pig endophthalmitis model 228 . In addition to Cryptococcus and Aspergillus , model systems for other environmental fungi have also been developed such as a fusariosis model system 276 , a sporotrichosis model system 277 , a mucorales model system 278 279 and a model system for Scedosporium 280 (see Table 1). Efficacy of treatment of these fungal infections is often performed by non-culture based methods, such as qPCR to determine organ fungal burden 281 .…”

Section: Methods For Monitoring In Vivo Performancmentioning

confidence: 99%

Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms

Dijck¹,

Sjollema²,

Cammue³

et al. 2018

Microb Cell

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Unlike superficial fungal infections of the skin and nails, which are the most common fungal diseases in humans, invasive fungal infections carry high morbidity and mortality, particularly those associated with biofilm formation on indwelling medical devices. Therapeutic management of these complex diseases is often complicated by the rise in resistance to the commonly used antifungal agents. Therefore, the availability of accurate susceptibility testing methods for determining antifungal resistance, as well as discovery of novel antifungal and antibiofilm agents, are key priorities in medical mycology research. To direct advancements in this field, here we present an overview of the methods currently available for determining (i) the susceptibility or resistance of fungal isolates or biofilms to antifungal or antibiofilm compounds and compound combinations; (ii) the in vivo efficacy of antifungal and antibiofilm compounds and compound combinations; and (iii) the in vitro and in vivo performance of anti-infective coatings and materials to prevent fungal biofilm-based infections.

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“…The efficacy of liposomal amphotericin B in primary treatment of invasive pulmonary aspergillosis was established in a randomized trial comparing a high loading dose regimen with a standard dose (AmBiLoad trial) [70]. In this double-blind trial, patients with proven or probable invasive aspergillosis or other mold infection were randomized to receive liposomal amphotericin B at either 3 or 10 mg/kg per day for fourteen days, followed by 3 mg/kg per day.…”

Section: Lipid Formulations Of Amphotericin Bmentioning

confidence: 99%

Modeling Invasive Aspergillosis: How Close Are Predicted Antifungal Targets?

Walsh

Petraitienė

Petraitis

2020

JoF

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Animal model systems are a critical component of the process of discovery and development of new antifungal agents for treatment and prevention of invasive aspergillosis. The persistently neutropenic rabbit model of invasive pulmonary aspergillosis (IPA) has been a highly predictive system in identifying new antifungal agents for treatment and prevention of this frequently lethal infection. Since its initial development, the persistently neutropenic rabbit model of IPA has established a strong preclinical foundation for dosages, drug disposition, pharmacokinetics, safety, tolerability, and efficacy for deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, amphotericin B colloidal dispersion, caspofungin, micafungin, anidulafungin, voriconazole, posaconazole, isavuconazole, and ibrexafungerp in treatment of patients with invasive aspergillosis. The findings of combination therapy with a mould-active triazole and an echinocandin in this rabbit model also predicted the outcome of the clinical trial for voriconazole plus anidulafungin for treatment of IPA. The plasma pharmacokinetic parameters and tissue disposition for most antifungal agents approximate those of humans in persistently neutropenic rabbits. Safety, particularly nephrotoxicity, has also been highly predictive in the rabbit model, as exemplified by the differential glomerular filtration rates observed in animals treated with deoxycholate amphotericin B, liposomal amphotericin B, amphotericin B lipid complex, and amphotericin B colloidal dispersion. A panel of validated outcome variables measures therapeutic outcome in the rabbit model: residual fungal burden, markers of organism-mediated pulmonary injury (lung weights and infarct scores), survival, and serum biomarkers. In selected antifungal studies, thoracic computerized tomography (CT) is also used with diagnostic imaging algorithms to measure therapeutic response of pulmonary infiltrates, which exhibit characteristic radiographic patterns, including nodules and halo signs. Further strengthening the predictive properties of the model, therapeutic response to successfully developed antifungal agents for treatment of IPA has been demonstrated over the past two decades by biomarkers of serum galactomannan and (1→3)-β-D-glucan with patterns of resolution, that closely mirror those documented responses in patients with IPA. The decision to move from laboratory to clinical trials should be predicated upon a portfolio of complementary and mutually validating preclinical laboratory animal models studies. Other model systems, including those in mice, rats, and guinea pigs, are also valuable tools in developing clinical protocols. Meticulous preclinical investigation of a candidate antifungal compound in a robust series of complementary laboratory animal models will optimize study design, de-risk clinical trials, and ensure tangible benefit to our most vulnerable immunocompromised patients with invasive aspergillosis.

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Endpoint Assessment in Rabbit Models of Invasive Pulmonary Aspergillosis and Mucormycosis

Cited by 4 publications

References 32 publications

Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis

Combination Therapy with Isavuconazole and Micafungin for Treatment of Experimental Invasive Pulmonary Aspergillosis

Methodologies for in vitro and in vivo evaluation of efficacy of antifungal and antibiofilm agents and surface coatings against fungal biofilms

Modeling Invasive Aspergillosis: How Close Are Predicted Antifungal Targets?

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