Abstract

Fusarium is a large genus of hyphomycete filamentous fungi that are ubiquitous in the water and soil environments, and are best known as plant pathogens. However, a group of morphologically similar species, collectively referred to as Fusarium solani, or F. solani  Species Complex, is emerging as a highly pathogenic disease of both humans and animals.¹⁰ The invasive mycoses can cause dermal and ocular lesions or become disseminated in immunocompromised patients leading to very high morbidity and mortality.⁸ Hammerhead sharks (Family Sphyrnidae) seem to be highly susceptible to Fusarium with confirmed cases in bonnethead (Sphyrna tiburo) and scalloped hammerhead (S. lewini) sharks in multiple aquaria, including Adventure Aquarium.^3,5,6,9 Histopathologically, the fungal infections cause chronic, necrotizing, pyogranulomatous dermatitis, cellulitis, and vasculitis centered around the lateral line canals and ampullae of Lorenzini, with hematogenous dissemination through multiple organ systems in advanced cases. There are minimal published and anecdotal reports of successful management of this disease in sharks.⁴ Treatment success is based around water temperature elevation above 29.5°C and antifungal therapy. Different antifungals have been used, but voriconazole appears to be the treatment of choice. Based on fungal mean inhibitory concentration (MIC), voriconazole produces superior MICs compared to other antifungals, however, most Fusarium isolates are still resistant in vitro (MIC >16 µg/ml). Yet one study determined an MIC₉₀ for voriconazole against F. solani of 2 µg/ml.² The voriconazole therapeutic range for fusariosis is unknown, but anecdotal evidence suggests that clinical outcome does not correlate with F. solani  MICs. Nevertheless, treatment success has been reported in belugas with plasma voriconazole concentrations maintained above 2 µg/ml.^1,7 Fusariosis has been diagnosed at Adventure Aquarium in five bonnetheads and three scalloped hammerheads with 88% mortality rate. There has only been one successful managed case in a scalloped hammerhead. Compared to the previous cases quick and aggressive management has been key. Treatment failures occurred when sharks were left on exhibit too long with suboptimal water temperature, an inability to reliably medicate and subtherapeutic dosing of voriconazole. Therapeutic drug monitoring is paramount. Through subsequent dosing across the cases, it was determined that sphyrnidae sharks require a much higher voriconazole dose to achieve measurable plasma voriconazole concentrations. Dosing regimens from 5 mg/kg p.o. e.o.d. to 50 mg/kg p.o. b.i.d. were evaluated. The highest trough plasma voriconazole concentrations were achieved in a bonnethead with a dose of 30 mg/kg p.o. s.i.d. (1.65 µg/ml), and a scalloped hammerhead with a dose of 50 mg/kg p.o. b.i.d. (1.2 µg/ml). Currently, the scalloped hammerhead is doing well under continued treatment. Based on this treatment success, we recommend as soon as lesions are observed, immediately moving the shark to where the water temperature can be increased to 29.5°C, reliably be fed at least twice daily and administer voriconazole >50 mg/kg p.o. b.i.d. with therapeutic drug monitoring. Species-specific voriconazole pharmacokinetics in sharks is needed.

Acknowledgements

The author thanks the Adventure Aquarium Fish and Invertebrate husbandry team for their dedicated care of these sharks. The author is greatly appreciative for a generous donation of voriconazole.

* Presenting author

Literature Cited

1.  Clauss TM, Walsh MT, Camus AC, Dove ADM. 2008. Resolution of cutaneous Fusarium solani infection in a beluga whale (Delphinapterus leucas) following aggressive wound management and oral voriconazole therapy. IAAAM 39th Annual Conference Proceedings; Pomezia, Italy; Pp. 129.

2.  Consigny S, Dhedin N, Datry A, Choquet S, Leblond V, Chosidow O. 2003. Successful voriconazole treatment of disseminated Fusarium infection in an immunocompromised patient. Clin Infect Dis. 37:311–313.

3.  Crow GL, Brock JA, Kaiser S. 1995. Fusarium solani fungal infection of the lateral line canal system in captive scalloped hammerhead sharks (Sphyrna lewini) in Hawaii. J Wildl Dis. 31(4):562–565.

4.  Davis MR, Poll C, Van Bonn W, Curtis E, Sattler M. 2007. Successful resolution of "bonnethead shark disease", presumptive disseminated Fusarium infection, with anti-fungal therapy and environmental manipulation. IAAAM 38th Annual Conference Proceedings; Lake Buena Vista, FL; Pp. 128.

5.  Fernando N, Hui S-W, Tsang C-C, Leung S-Y, Ngan AHY, Leung RWW, Groff JM, Lau SKP, Woo PCY. 2015. Fatal Fusarium solani species complex infections in elasmobranchs: the first case report for black spotted stingray (Taeniura melanopsila) and a literature review. Mycoses. 58:422–431.

6.  Muhvich AG, Reimschuessel R, Lipsky MM, Bennett RO. 1989. Fusarium solani isolated from newborn bonnethead sharks, Sphyrna tiburo (L.). J Fish Dis. 12(1):57–62.

7.  Naples LM, Poll CP, Berzins IK. 2012. Successful treatment of a severe case of fusariomycosis in a beluga whale (Delphinapterus leucas leucas). J Zoo Wildl Med. 43(3):596–602.

8.  O'Donnell K, Sutton DA, Fothergill A, McCarthy D, Rinaldi MG, Brandt ME, Zhang N, Geiser DM. 2008. Molecular phylogenetic diversity, multilocus haplotype nomenclature, and in vitro antifungal resistance within the Fusarium solani species complex. J Clin Microbiol. 46(8):2477–2490.

9.  Pirarat N, Sahatrakul K, Lombardini E, Chansue N, Techangamsuwan S. 2016. Molecular and pathological characterization of Fusarium solani species complex infection in the head and lateral line system of Sphyrna lewini. Dis Aquat Organ. 120:15–204.

10. Zhang N, O'Donnell K, Sutton DA, Ameena Nalim F, Summerbell RC, Padhye AA. 2006. Members of the Fusarium solani species complex that cause infections in both humans and plants are common in the environment. J Clin Microbiol. 44(6):2186–2190.