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EQUINE VETERINARY EDUCATION / AE / NOVEMBER 2020


Pulmonary cryptococcosis has also been successfully treated with oral fluconazole for 7–18 months, with declines in cryptococcal antigen titres corresponding to disease resolution (Secombe et al. 2017). The pharmacokinetically determined dose of fluconazole, that is a loading dose of 14 mg/kg bwt followed by 5 mg/kg bwt every 24 h (Latimer et al. 2001), has resulted in successful treatment of equine cryptococcus over the last decade. The duration of therapy for each case is likely dependent on the extensiveness of the lesions and can be monitored endoscopically and by reduction in cryptococcal antigen titres. The horse in the case described by Daniel et al. (2020) was treated for 11 weeks, with the mare returning to endurance racing. Recurrence is possible and follow-up annual endoscopic re- evaluation, and antigen titre measurement is recommended. One of the first reported successful treatments of nasopharyngeal Cryptococcus was a mare with a 9-month history of bilateral mucopurulent nasal discharge and


intermittent epistaxis. She was initially treated with oral fluconazole for 6 weeks, sodium iodine for 3 weeks and adjunctive intralesional therapy. After a 2.5-year period of remission, the mare redeveloped stertorous breathing and nasal discharge. In the second episode, the lesions were more extensive and treatment was more aggressive. Extensive surgical debulking was performed with administration of amphotericin B (93 lg/kg q. 8 h i.v. for 7 days then 156 lg/kg q. 8 h i.v. for 7 days) and oral fluconazole (at recommended dosages) for 8 months. Susceptibility testing indicated intermediate sensitivity to fluconazole and susceptibility to clotrimazole, miconazole, ketoconazole, amphotericin B and itraconazole. Fluconazole had already been administered for 5 months and was continued because the alternative medications were not feasible. A cryptococcal antigen titre had reduced from 1:40 to 1:4 after 7 months of fluconazole. Fifteen months after discontinuation of therapy, the horse was re-evaluated and the cryptococcal antigen titre was 1:2 (Stewart et al. 2009). Despite the intermediate sensitivity of the cryptococcal organism to fluconazole, it was still considered the treatment of choice. Results of fungal susceptibility testing often do not correlate well with clinical response to treatment in humans (Rex et al. 2001). Fluconazole is known for its in vivo effectiveness despite low in vitro activity, which may be attributable to its excellent tissue solubility (Latimer et al. 2001; Rex et al. 2001). Other options for long-term treatment of equine


cryptococcal infections are limited. Ketoconazole must be administered by nasogastric intubation with acidification using 0.2N hydrochloric acid for dissolution and gastrointestinal absorption (Prades et al. 1989). Amphotericin B is administered intravenously, ideally with premedication with oral table salt to promote water intake to reduce nephrotoxicity (Anderson 1995; Stewart et al. 2009). As amphotericin B is nephrotoxic, frequent monitoring for changes in urine specific gravity, presence of casts and elevations in serum creatinine is recommended. The commercially available itraconazole solution (Sporonox)1 is prohibitively expensive, and the drug is unstable as a


compounded formulation (Davis et al. 2004). The cost of fluconazole is reasonable since the availability of generic


products. In contrast to itraconazole, compounded fluconazole formulations are stable. Orally administered fluconazole is well absorbed in horses with a bioavailability of 100% (Latimer et al. 2001). It has a wide margin of safety, is


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minimally protein bound, water soluble and distributes well in body tissues and fluids including urine, synovial fluid, CSF and aqueous humour (Latimer et al. 2001). A case report describes a one-hour soak of the nasal


passages and sinuses using a mixture of fluconazole and dimethylsulfoxide on just two occasions under general anaesthesia for treatment of Cryptococcus uniguttulatus and Rhodotorula minuta rhinitis. Although the lesions were extensive, superficial plaques were described which may have allowed adequate penetration of the topical medication, with high local concentrations of fluconazole resulting in rapid killing of organisms (Lean and Ahern 2018). Cryptococcosis spp. can also be treated with voriconazole, but this drug is usually cost prohibitive (Passler et al. 2010). In humans, 2 weeks of intravenous amphotericin B either alone or in combination with oral 5-flucytosine, followed by approximately 10 weeks of either oral fluconazole or oral itraconazole, is a long-standing recommended treatment protocol for cryptococcosis (Saag et al. 2000; Lewis and Kontoyiannis 2001; Gubbins 2005).


Alternative treatments include amphotericin B and 5- flucytosine administered for 6–10 weeks (Gubbins 2005). Although iodides have historically been used to treat


equine fungal disease, and a handful of successful cases are reported when used as primary or adjunctive therapy (Steiger and Williams 2000), the overall efficacy of iodides is considered limited (Stewart 2019a). Although the exact mode of action of iodides is unknown, they inhibit the granulomatous inflammatory process. However, iodides have very little, if any in vitro antifungal activity (Plumb 2002). Iodide treatment is inexpensive but toxicity can occur and is characterised by increased respiratory secretions, nonproductive cough, excessive lacrimation and dermatitis (Steiger and Williams 2000; Plumb 2002). Administration of iodine to pregnant mares may cause congenital hypothyroidism in foals and is contraindicated. Of the equine cases of cryptococcosis reported in the


literature, no underlying immunodeficiency has been identified, but immune function testing is still recommended, especially if concurrent disease is identified. Cell-mediated immunity is important in preventing cryptococcosis. In humans, HIV infection is a predisposing factor in 80-90% of cryptococcal infections (Levitz 1991). Additionally, lymphoma, chronic leukaemia, other cancers, sarcoidosis, collagen vascular disease, diabetes mellitus and immunosuppressive drug treatments are often identified as underlying conditions associated with cryptococcosis in human patients (Pappas et al. 2001; Vilchez et al. 2001).


Author's declaration of interests No conflicts of interest have been declared.


Ethical animal research None.


Source of funding None.


Manufacturer's address 1Janssen Pharmaceutica Products NV, Beerse, Belgium.


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