scholarly journals Modeling Invasive Aspergillosis: How Close Are Predicted Antifungal Targets?

2020 ◽  
Vol 6 (4) ◽  
pp. 198
Author(s):  
Thomas J. Walsh ◽  
Ruta Petraitiene ◽  
Vidmantas Petraitis
Keyword(s):  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Antifungal Agents ◽  
Therapeutic Response ◽  
Rabbit Model ◽  
Colloidal Dispersion ◽  
Model Systems ◽  
Lipid Complex ◽  
Treatment And Prevention ◽  
Amphotericin B Lipid Complex

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.

Apparent lack of cross-reactivity for infusion-related reactions between two forms of lipid-based amphotericin B

2013 ◽  
Vol 70 (12) ◽  
pp. 1047-1051 ◽  
Author(s):  
Mitchell S. Buckley ◽  
Clint S. Anderson ◽  
Shardool A. Patel ◽  
Melanie J. Yerondopoulos ◽  
Laura M. Wicks ◽  
...  
Keyword(s):  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Adverse Reactions ◽  
Cross Reactivity ◽  
Alternative Formulation ◽  
Lipid Complex ◽  
Apparent Lack ◽  
Course Of Action ◽  
Amphotericin B Lipid Complex ◽  
Alternative Lipid

Abstract Purpose The case of a patient who experienced probable infusion-related reactions to amphotericin B lipid complex (ABLC) but tolerated continued amphotericin B therapy after a switch to an alternative lipid-based formulation is reported. Summary A 28-year-old immunocompromised man with pneumonia, respiratory failure, and neutropenic fever was initiated on ABLC and other antibiotics for suspected invasive aspergillosis. Due to the patient’s deteriorating renal function, the use of amphotericin B was deemed preferable to the standard therapy for invasive aspergillosis (voriconazole) even though he had experienced likely infusion-related reactions to ABLC on two prior occasions. During the infusion of ABLC, significant increases in the man’s temperature, respiratory rate, systolic blood pressure, and heart rate were observed. Although those symptoms were suspected to be infusion related, it was decided that continuing amphotericin B therapy with an alternative lipid-based form of the drug was the best course of action. After the patient was switched to liposomal amphotericin B one day later, no further infusion-related adverse reactions were noted for the duration of therapy. While this case suggests that adverse reactions to one type of amphotericin B might not occur with the use of an alternative formulation, further research is needed to better define the potential for cross-reactivity among various forms of amphotericin B and related safe-infusion practices. Conclusion A patient with invasive aspergillosis who experienced likely infusion- related reactions to ABLC was able to tolerate continued amphotericin B therapy after a switch to the liposomal formulation.

scholarly journals Comparison of In Vitro Activity of Liposomal Nystatin againstAspergillus Species with Those of Nystatin, Amphotericin B (AB) Deoxycholate, AB Colloidal Dispersion, Liposomal AB, AB Lipid Complex, and Itraconazole

1999 ◽  
Vol 43 (5) ◽  
pp. 1264-1266 ◽  
Author(s):  
Karen L. Oakley ◽  
Caroline B. Moore ◽  
David W. Denning
Keyword(s):  
Amphotericin B ◽  
Aspergillus Terreus ◽  
Antifungal Agents ◽  
Geometric Mean ◽  
Colloidal Dispersion ◽  
Vitro Activity ◽  
In Vitro Activity ◽  
Lipid Complex

ABSTRACT We compared the in vitro activity of liposomal nystatin (Nyotran) with those of other antifungal agents against 60Aspergillus isolates. Twelve isolates were itraconazole resistant. For all isolates, geometric mean (GM) MICs (micrograms per milliliter) were 2.30 for liposomal nystatin, 0.58 for itraconazole, 0.86 for amphotericin B (AB) deoxycholate, 9.51 for nystatin, 2.07 for liposomal AB, 2.57 for AB lipid complex, and 0.86 for AB colloidal dispersion. Aspergillus terreus (GM, 8.72 μg/ml; range, 8 to 16 μg/ml) was significantly less susceptible to all of the polyene drugs than all other species (P = 0.0001).

scholarly journals Invasive aspergillosis a complication severe respiratory viral infections (influenza and COVID-19)

2021 ◽  
Vol 13 (4) ◽  
pp. 14-24
Author(s):  
N. N. Klimko ◽  
O. V. Shadrivova
Keyword(s):  
Risk Factors ◽  
Invasive Aspergillosis ◽  
Amphotericin B ◽  
Viral Infections ◽  
Underlying Disease ◽  
Lipid Complex ◽  
Sabouraud Agar ◽  
Severe Influenza ◽  
Life Threatening ◽  
Amphotericin B Lipid Complex

Invasive aspergillosis is a life-threatening complication in patients with severe influenza and COVID-19 in intensive care units. Risk factors for the invasive aspergillosis development are transitory immunosuppression associated with severe influenza and COVID-19, as well as the use of glucocorticosteroids and immunosuppressive therapy. In the presence of risk factors, suspected clinical and radiological signs of invasive aspergillosis, bronchoscopy and examination of material from the lower respiratory tract are necessary: test for galactomannan, microscopy with white calcofluor staining and inoculation on Sabouraud agar medium. Voriconazole or are recommended as first-line treatment for invasive aspergillosis in patients with severe influenza and COVID-19. Amphotericin B Liposomal, Amphotericin B Lipid Complex, and Caspofungin are the alternative options for the invasive aspergillosis treatment. Combination therapy is possible. It is necessary to control the underlying disease with eliminate or reduce the severity of risk factors. 

scholarly journals Compartmentalized Intrapulmonary Pharmacokinetics of Amphotericin B and Its Lipid Formulations

2006 ◽  
Vol 50 (10) ◽  
pp. 3418-3423 ◽  
Author(s):  
Andreas H. Groll ◽  
Caron A. Lyman ◽  
Vidmantas Petraitis ◽  
Ruta Petraitiene ◽  
Derek Armstrong ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Lung Tissue ◽  
Colloidal Dispersion ◽  
Pharmacokinetic Parameters ◽  
Dilution Method ◽  
Lipid Complex ◽  
Drug Concentrations ◽  
Amphotericin B Deoxycholate ◽  
Amphotericin B Lipid Complex ◽  
Lipid Formulations

ABSTRACT We investigated the compartmentalized intrapulmonary pharmacokinetics of amphotericin B and its lipid formulations in healthy rabbits. Cohorts of three to seven noninfected, catheterized rabbits received 1 mg of amphotericin B deoxycholate (DAMB) per kg of body weight or 5 mg of either amphotericin B colloidal dispersion (ABCD), amphotericin B lipid complex (ABLC), or liposomal amphotericin B (LAMB) per kg once daily for a total of 8 days. Following sparse serial plasma sampling, rabbits were sacrificed 24 h after the last dose, and epithelial lining fluid (ELF), pulmonary alveolar macrophages (PAM), and lung tissue were obtained. Pharmacokinetic parameters in plasma were derived by model-independent techniques, and concentrations in ELF and PAM were calculated based on the urea dilution method and macrophage cell volume, respectively. Mean amphotericin B concentrations ± standard deviations (SD) in lung tissue and PAM were highest in ABLC-treated animals, exceeding concurrent plasma levels by 70- and 375-fold, respectively (in lung tissue, 16.24 ± 1.62 versus 2.71 ± 1.22, 6.29 ± 1.17, and 6.32 ± 0.57 μg/g for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0029]; in PAM, 89.1 ± 37.0 versus 8.92 ± 2.89, 5.43 ± 1.75, and 7.52 ± 2.50 μg/ml for DAMB-, ABCD-, and LAMB-treated animals, respectively [P = 0.0246]). By comparison, drug concentrations in ELF were much lower than those achieved in lung tissue and PAM. Among the different cohorts, the highest ELF concentrations were found in LAMB-treated animals (2.28 ± 1.43 versus 0.44 ± 0.13, 0.68 ± 0.27, and 0.90 ± 0.28 μg/ml in DAMB-, ABCD-, and ABLC-treated animals, respectively [P = 0.0070]). In conclusion, amphotericin B and its lipid formulations displayed strikingly different patterns of disposition in lungs 24 h after dosing. Whereas the disposition of ABCD was overall not fundamentally different from that of DAMB, ABLC showed prominent accumulation in lung tissue and PAM, while LAMB achieved the highest concentrations in ELF.

scholarly journals Dose-Dependent Pharmacokinetics of Amphotericin B Lipid Complex in Rabbits

2000 ◽  
Vol 44 (8) ◽  
pp. 2068-2076 ◽  
Author(s):  
Thomas J. Walsh ◽  
Andre J. Jackson ◽  
James W. Lee ◽  
Michael Amantea ◽  
Tin Sein ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Fungal Infections ◽  
Rabbit Model ◽  
Time Dependent ◽  
Antifungal Compound ◽  
Lipid Complex ◽  
Detailed Model ◽  
Amphotericin B Lipid Complex ◽  
Cellular Components

ABSTRACT Amphotericin B lipid complex (ABLC) was recently approved by the Food and Drug Administration for treatment of patients with invasive fungal infections who are intolerant of or refractory to conventional amphotericin B therapy. Little is known, however, about the pharmacokinetics of this new antifungal compound. We therefore investigated the pharmacokinetics of ABLC in comparison with those of conventional desoxycholate amphotericin B (DAmB) in rabbits. The pharmacokinetics of DAmB in a rabbit model were similar to those previously reported in humans. The pharmacokinetics of ABLC differed substantially from those of DAmB. Plasma amphotericin B levels following ABLC administration were 10 times lower than those following administration of an equal dosage of DAmB. The levels of ABLC in whole blood were approximately 40 times greater than those in plasma. The ABLC model differed from the DAmB model by (i) a dose- and time-dependent uptake and return between the plasma compartment and apparent cellular components of the blood-sediment compartment and (ii) time-dependent tissue uptake and return to plasma from serially connected compartments. Following infusion of ABLC, there was a nonlinear uptake into the apparent cellular components of the blood-sediment compartment. This uptake was related to the reciprocal of the integral of the total amount of drug infused (i.e., the more drug infused the greater the fractional uptake between 0.5 and 5 mg/kg of body weight for ABLC). The transfer of drug from plasma to the cellular components of the blood-sediment compartment resulted in initial uptake followed by rapid redistribution back to the plasma. The study describes a detailed model of the pharmacokinetics of ABLC and characterizes a potential role of the cellular components of the blood-sediment compartment in the distribution of this new antifungal compound in tissue.

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