Antifungal exposure in Scedosporium septic arthritis: synovial penetration of voriconazole and terbinafine and plasma concentrations of olorofim

S cedosporium ellipsoideum, phylogenetically close to Scedosporium boydii, is a rare cause of invasive fungal disease with osteoarticular tropism (1).Current expert recommendations support the use of systemic antifungal therapy combined with surgical debridement when feasible (2); however, data on antifungal penetration into inflammatory synovial fluid remain scarce.We report a 73-year-old immunocompromised man with profound acquired B-cell and CD4+ T-cell lymphopenia and severe IgG hypogammaglobulinemia, who developed S. ellipsoideum fungemia complicated by multiple articular localizations, including septic arthritis of the native left knee joint.Diagnosis was confirmed by positron emission tomography-computed tomography (PET-CT) imaging and joint aspiration.S. ellipsoi deum was repeatedly isolated from blood cultures, synovial fluid, and bone biopsy.MICs (EUCAST) were as follows: amphotericin B 2.0 mg/L, voriconazole 0.5 mg/L, micafungin 0.25 mg/L, terbinafine >8 mg/L, and olorofim 0.015 mg/L.The patient had normal serum albumin and a CYP2C19 *2/*17 genotype (intermediate metabolizer for voriconazole).Initial therapy with voriconazole (200 mg twice daily, increased to 300 mg) was followed by arthrotomy after 3 months due to progressive knee disease.Ongoing infection and difficulty achieving therapeutic plasma concentrations (2-5.5 mg/L) prompted a switch to olorofim (90 mg twice daily) as salvage therapy.Nine months later, persistent arthritis and hypermetabolic PET activity led to repeat arthrotomy and synovectomy, after which therapy was switched back to high-dose voriconazole (400 mg twice daily).Despite trough concentrations >2 mg/L, septic arthritis persisted, and terbinafine (250 mg once daily) was added.Given persistent infection despite multiple therapies, antifungal concentrations in synovial fluid were further investigated.Plasma and synovial fluid samples were collected to evaluate voriconazole and terbinafine penetration.Voriconazole, terbinafine, and its inactive metabolite N-desmethyl-terbinafine were quantified by liquid chromatography and mass spectrometry.A linear response from synovial fluid serially diluted in drug-free plasma confirmed the suitability of plasma-based calibration for quantification in both matrices.Sampling occurred 15 days after voriconazole monotherapy and 2 days after combination therapy (Table 1).Four months after initiation, combination therapy led to marked clinical and radiological improvement.Voriconazole showed substantial synovial penetration (30-80%), with concentrations 3.7-6.5 fold above the MIC, consistent with published human clinical and animal data (3,4).Synovial concentrations varied despite stable inflammatory markers and albumin.Terbinafine plasma concentrations were higher, whereas