Finally terbinafine is generally associated with a low index
Finally, terbinafine is generally associated with a low index of toxicity and few adverse effects. In humans, only mild GI toxicity and hepatobiliary dysfunction are reported. In red-tailed hawks, oral administration of a high dose of terbinafine (120 mg/kg BW) was furthermore demonstrated to induce regurgitation. Anecdotally, some mild GI toxicity and hepatobiliary dysfunction were observed in some psittacine Losartan australia including an African gray parrot, a blue-fronted Amazon parrot (Amazona aestiva), and a Senegal parrot (Poicephalus senegalus) after long-term administration of terbinafine (10–15 mg/kg BW, twice a day) alone or in combination with itraconazole or voriconazole (van Zeeland, personal communication, 2017).
Drug resistance Antifungal susceptibility testing is a useful tool to provide information to clinicians to help guide therapy. The European Committee on Antimicrobial Susceptibility Testing and the Clinical and Laboratory Standards Institute have developed a standardized in vitro antifungal susceptibility testing method for yeasts and molds, whereby the minimum inhibitory concentration (MIC) is measured and referenced to a clinical breakpoint. However, in birds, the interpretation of the MICs of different antifungal agents remains uncertain, because of lack of correlation of in vitro resistance with clinical outcome. Although information on antifungal resistance in avian medicine is very limited, human medicine shows that antifungal resistance is increasing and is an emerging threat to patient management and clinical success. Beernaert and colleagues reported an acquired resistance of Aspergillus fumigatus strains, isolated from companion and wild birds, to both itraconazole and voriconazole. However, current in vitro antifungal susceptibility tests do not (yet) take the impact of drug formulation into account. Consequently, interpretation of MICs of amphotericin B against Aspergillus spp remains uncertain because of lack of correlation of in vitro resistance with clinical outcome. For example, differences in PK characteristics (eg, tissue concentration of free drug in the site of infection) or immunomodulating properties between, for example, amphotericin B deoxycholate and liposomal amphotericin B, might be more important determinants of outcome of amphotericin B-based therapy than the MIC. In a murine model of disseminated invasive aspergillosis, treatment with liposomal amphotericin B resulted in a better outcome than treatment with amphotericin B deoxycholate, despite no differences in the MIC being observed between the drug formulations.
Drug formulation Several antifungal drugs are characterized by their insolubility in water at physiologic pH, poor oral bioavailability, and limited formulation approaches. In addition, a narrow therapeutic–toxic range and drug–drug interactions of systemic antifungal agents are other major problems that compromise optimal treatment. Therefore, there is a strong need to develop innovative drug formulations to address these issues. In an attempt to decrease the intrinsic toxicity and enhance the efficacy of amphotericin B, 3 lipid-associated formulations were developed and approved for use in human medicine in the 1990s, that is, amphotericin B lipid complex, liposomal amphotericin B, and amphotericin B colloidal dispersion. Amphotericin B lipid complex (Abelcet, Cephalon, Inc., Fraser, PA) forms ribbonlike particles of dimyristoyl phosphatidyl choline and dimyristoyl phosphatidyl glycerol with amphotericin B; liposomal amphotericin B (AmBisome, Gilead Sciences International Ltd., Cambridge, UK; and Fungisome, Lifecare Innovations Pvt Ltd, Gurgaon, India) is a true unilamellar liposome composed of a mixture of phosphatidyl choline:distearoyl:phosphatidylglycerol:cholesterol; and amphotericin B colloidal dispersion (Amphotec of Amphocil, Sequus Pharmaceuticals, Menlo Park, CA) is a formulation in which amphotericin B is complexed to cholesterol sulfate resulting in the formation of disclike structures. Knowledge based on in vitro and in vivo studies in rodents, dogs, and humans suggest that these lipid formulations of amphotericin B generally have a slower onset of action, because of the required dissociation of free amphotericin B from the lipid vehicle. Moreover, incorporation of amphotericin B into the lipid vesicle will enhance drug uptake by the liver and spleen, and cause accumulation of the drug by the mononuclear phagocyte system and at sites of capillary damage and inflammation. Consequently, the PK characteristics of lipid-based amphotericin is strongly determined by its physicochemical properties. Amphotericin B lipid complex is the largest compound of the lipid preparations (diameter of 1600–11,000 nm), resulting in a fast recognition in the blood by activated monocytes/macrophages, which subsequently transport the drug to the site of infection, where phospholipases release the free drug. In addition, this compound is sequestered to a high extent in the tissues of the mononuclear phagocyte system (liver and spleen), including the lungs. This rapid and extensive distribution, predominantly to the liver, spleen, and lungs, is reflected in the PK characteristics by a very large volume of distribution and a low area under the plasma concentration time curve. Lung levels are considerably higher than those achieved with other lipid-associated preparations and amphotericin B deoxycholate. The small size of liposomal amphotericin B (diameter of 60–80 nm) and negative charge tend to result in a prolonged circulation in plasma, because these compounds are not readily recognized and taken up by the mononuclear phagocyte system. However, the clinical relevance of these PK differences between liposomal amphotericin B and amphotericin B lipid complex remains unknown. After IV infusion, amphotericin B colloidal dispersion (disks of 122 nm diameter and 4 nm thickness) is rapidly removed from the circulation by the mononuclear phagocyte system, predominantly by Kupffer cells of the liver, and to a lesser extent in the spleen and bone marrow. These differences in PK and pharmacodynamic characteristics are reflected in the dose recommendations in human medicine: amphotericin B deoxycholate 0.25 to 1.5 mg/kg once a day, amphotericin B lipid complex 5 mg/kg BW once a day, liposomal amphotericin B 1 to 5 mg/kg BW once a day, and amphotericin B colloidal dispersion 3 to 5 mg/kg once a day. However, the impact of these differences in PK/pharmacodynamics on clinical efficacy in birds is still unclear. Comparatively, amphotericin B deoxycholate is administered at a dose of 1 to 1.5 mg/kg BW 3 times a day to birds.