Resistance Issues Pose Treatment Challenges for This Invasive Fungal Infection

Opportunistic infections pose a constant threat to patients who are immunocompromised.

When it comes to opportunistic fungal infections, we often think of aspergillus, the most common cause of fungal invasive infection in this patient population.¹ Another fungal pathogen that is not as common, but just as life-threatening is Scedosporium.

Throughout the years invasive infections caused by Scedosporium have increased. Common sites of infection include the lungs, sinuses, bones, joints, eyes, and brain.² Most of the infections connected with Scedosporium occur in the thorax/lungs region, according to research from the Fungus Testing Laboratory at the University of Texas Health Science System at San Antonio collected from January 2000 to May 2007.²

Two species of Scedosporium have been identified as causative pathogens in humans, Scedosporium apiospermum and Scedosporium prolificans. These pathogens are usually present in soil, sewage, and polluted waters.² Some complications of invasive Scedosporium spp. infection include septic arthritis, osteomyelitis, pneumonia, endocarditis, and meningitis.² These pathogens also are capable of causing cutaneous and subcutaneous tissue infections.

Resistance

Scedosporium is resistant to many antifungal agents. Classification of the specific Scedosporium spp. and susceptibility results could take days until finalized. Initiating appropriate therapy is very important especially when dealing with immunocompromised patients. In vitro studies have shown that voriconazole has the best activity against the species among the available azoles.² Monotherapy with other antifungal agents such as amphotericin B, terbinafine, and 5-flucytosine have not shown to be efficacious due to high minimum inhibitory concentrations (MIC).

Although monotherapy with these agents may not be efficacious, combination therapy with voriconazole could be an option. The combination of terbinafine with voriconazole resulted in synergy for more than 85% isolates of S. prolificans, which tends to be the more resistant of the 2 species.² The different mechanism of action of these drugs in the fungal ergosterol biosynthesis allowed for the synergistic activity. In vitro studies of other antifungal combinations are available and treatment regimens may need to be adjusted based on patient characteristics.

Voriconazole seems to be main drug involved in the treatment of Scedosporium. Patients are going to be started on intravenous therapy (IV) of voriconazole unless there is some contraindication. The recommended initial dosing regimen is 6mg/kg IV every 12 hours on day 1 followed by maintenance regimen of 4 mg/kg IV every 12 hours after day 1 therapy.¹ Oral therapy is another option when the patient is capable of taking oral medications. Voriconazole 200mg every 12 hours is the recommended oral therapy.^1,3 Patients that are less than 40kg should receive half of the recommended oral dose.³ A major monitoring parameter with voriconazole and mostly all azoles in general would be liver function tests to assess for hepatotoxicity. Serum trough levels of voriconazole need to be obtained in patients that are receiving oral or IV therapy for Scedosporium infections.

The trough level should be between 2-5.5 mcg/ml for appropriate efficacy without toxicity.¹ The duration of therapy is currently unknown. Immunocompromised patients will likely receive antifungal therapy for months depending on the time it takes for all signs and symptoms to resolve.¹ Long term IV voriconazole therapy could potentially be toxic in patients that have renal insufficiencies. The IV formulation of voriconazole contains cyclodextrins. In patients with creatinine clearance (CrCl) of less than 50ml/min, accumulation of cyclodextrins can occur.³ Accumulation of cyclodextrins is believed to cause further kidney impairment. A recent study by Kim SH, Kwon JC, Park C et al. looked into use of IV voriconzole in critically ill patients with renal impairment and found that no additional nephrotoxicity occurred in patients with CrCl less than 50 ml/min.⁴

Scedosporium invasive infections can cause many complications including fatality. Infections by this fungal pathogen are likely to occur in immunocompromised patients. Once diagnosed with this type of infection, patients are likely going to be on long-term antifungal therapy that will require appropriate monitoring.

References

1. Costa SF, Alexander BD. Treatment of Scedosporium infection. UpToDate. Updated October 20, 2015.

2. Cortez KJ, Roilides E, Quiroz-Telles F, et al. Infections caused by Scedosporium spp. Clin Microbiol Rev. 2008;21(1):157-197. doi:10.1128/CMR.00039-07.

3. Voriconazole tablet. DailyMed. Available at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=bda70104-d84b-4d3f-9ca0-5f4f1ca816ad

4. Kim SH, Kwon JC, Park C et al. Therapeutic drug monitoring and safety of intravenous voriconazole formulated with sulfobutylether β-cyclodextrin in haematological patients with renal impairment. Mycoses. 2016;59(10):644-651.