Lomentospora prolificans osteomyelitis and septic arthritis in an immunocompromised patient, requiring transhumeral amputation and use of the novel antifungal olorofim

Introduction

Lomentospora prolificans (L. prolificans) is an emerging fungal pathogen with the potential to cause invasive osteoarticular infections, particularly in immunocompromised hosts. L. prolificans has traditionally been a treatment resistant organism; however, new antifungal therapies are providing some efficacy. Here, we present a unique case of invasive L. prolificans osteomyelitis and septic arthritis in an immunocompromised patient who receives management with the novel drug olorofim and undergoes a trans-humeral amputation. This case reports highlights the surgical importance of early identification and treatment for an invasive, resistant, and emerging organism.

Case study

A 65-year-old male presented to a regional referral orthopedic center with pain and swelling of the right elbow two weeks following a fall. He had a history of rheumatoid arthritis managed with upadacitinib and prednisolone, smoked 20-25 cigarettes per day, and lived in rural Victoria, Australia. A former right-hand dominant boilermaker, he was no longer working. Elbow joint aspirate initially cultured methicillin-susceptible Staphylococcus aureus from purulent fluid. He was treated with 2 surgical débridements followed by six weeks of antibiotics while his immunosuppression was withheld.

Four weeks later, he developed worsening pain and discharge from the elbow. On this occasion, bacterial cultures were negative; however, fungal studies were also requested. The tissue sample was set up on Sabouraud's dextrose agar plates with (CG agar) and without (SAB agar) chloramphenicol/gentamycin. SAB and CG agar are routinely used for fungal culture in diagnostic microbiology laboratories typically with incubation in air (O₂) at 28 °C and 37 °C for up to 4 weeks and performed upon request for fungal investigation. After 5 days incubation, an olive-gray to black fungus with a dark reverse grew, typical of a dematiaceous fungus (Fig. 1). Micromorphological examination using lactophenol cotton blue stain demonstrated vegetative hyphae with small groups of oval-shaped conidia produced from basally swollen conidiophores (Fig. 2). An identification of L. prolificans was made based on the characteristic microscopic and macroscopic morphology.¹⁶

Figure 1.

Lomentospora prolificans colonies on Sabouraud's dextrose agar.

Figure 2.

Lomentospora prolificans microscopic morphology under light microscopy at x100 magnification using lactophenol cotton blue stain. Arrow indicating the flask-shaped conidiophore.

Antifungal susceptibility testing using the Sensititre YO10 panel (Thermo Fisher Scientific), with modifications to inoculum preparation, incubation, and endpoint reading was performed according to the Clinical & Laboratory Standards Institute (CLSI) guidelines for broth microdilution of filamentous fungi (CLSI M38M51).⁴ This demonstrated high minimum inhibitory concentration values to all conventional antifungals, including the azoles and amphotericin B, which is well known and expected of this organism^6,18,20 (Table I). Antifungal treatment was initiated with a combination of voriconazole and terbinafine, recommended first line treatment against this organism¹ despite resistance.²²

Table I.

Minimum inhibitory concentrations of antifungals against the L. prolificans isolate.

Antifungal agent	MIC (μg/mL)
Amphotericin B	>8
Anidulafungin	>8
Micafungin	>8
Itraconazole	>16
Posaconazole	>8
Fluconazole	>256
Voriconazole	>8
Olorofim	0.25

MIC, minimum inhibitory concentration.

The patient underwent a total of 8 washouts and débridements over a period of five weeks. Intraoperative findings were significant for ongoing purulent fluid and synovitis. L prolificans was reisolated on 4 separate occasions. No other organisms were isolated from bacterial or mycobacterial culture, and no bacterial DNA was detected by 16S ribosomal RNA polymerase chain reaction. After five weeks of conventional treatment, compassionate access to olorofim, a novel antifungal with activity against L prolificans,²² was obtained. Susceptibility testing to olorofim using the CLSI method⁴ demonstrated a minimum inhibitory concentration of 0.25 mg/L. The patient was commenced on olorofim 90 mg twice daily and continued for a period of 12 weeks with ongoing withholding of immunosuppression.

Despite this treatment, the patient continued to experience severe pain, purulent discharge, and loss of function from his elbow. After 12 weeks, his symptoms were unchanged. Imaging, including radiographs (Fig. 3), computed tomography (Fig. 4), magnetic resonance imaging (Fig. 5), and bone scan (Fig. 6), demonstrated osteomyelitis of distal humerus, proximal ulna, and radius with no other dissemination of infection. His C-reactive protein remained elevated at 52 mg/L. He also developed worsening symptoms of rheumatoid arthritis in other joints due to withholding of immunosuppression. He experienced subjective fevers, loss of appetite, and 17 kg (37.5 pounds) of weight loss and was therefore referred to a tertiary orthopedic center for further management.

Figure 3.

Oblique and lateral right elbow x-rays demonstrating severe joint destruction.

Figure 4.

Sagittal and coronal right elbow CT slices compatible with elbow joint chronic septic arthritis and osteomyelitis. CT, computed tomography.

Figure 5.

Sagittal and coronal T2 MRI slices of right elbow joint demonstrating elbow joint effusion and prominent surrounding soft tissue edema consistent with the given history of septic arthritis. Bone marrow edema in the adjacent distal humerus, proximal ulna, and proximal radius suggesting early osteomyelitis. MRI, magnetic resonance imaging.

Figure 6.

Axial and coronal bone scan (IV 815 MBq TC-99 M HDP) slices of right elbow joint demonstrating increase blood pool activity suspicious for infection.

Multidisciplinary meetings between orthopedics and infectious diseases were undertaken. Due to the severity of joint destruction and chronic osteomyelitis, no further débridement for source control was possible and functional outcomes with ongoing conservative management were deemed to be futile. With a shared decision-making approach, the patient consented to a transhumeral amputation. The infected elbow joint was thoroughly débrided, and necrotic bone in the distal humerus was removed. A transhumeral amputation was performed with clear macroscopic margins distal to deltoid insertion. Major vessels and nerves were ligated and transected appropriately. A biceps–triceps sling tenodesis was created to cover the bony stump and skin closure was achieved (Fig. 7).

Figure 7.

Post-operative photos demonstrating right transhumeral amputation.

Olorofim was continued for 12 weeks post-operatively, then ceased. At 12-month follow-up, the patient showed no signs of recurrent infection. A distal humerus prosthesis has been fitted to assist dexterity of the right upper limb; however, the patient chooses not to wear it. Chronic pain consultation is ongoing, immunosuppression for rheumatoid arthritis has been reinitiated, and the patients' systemic symptoms have resolved. The patient has returned to baseline weight and reports no systemic or local infective symptoms. On recent review, the patient reports their quality of life has been restored despite the ongoing challenges with phantom pain.

Discussion

L. prolificans (formerly Scedosporium prolificans) was first described as a human pathogen in 1988 by Salkin et al.²⁵ They described a new species of Scedosporium, which was isolated from a bone biopsy obtained from a 6-year-old boy with a deep subcutaneous lesion on the foot²⁵ and is now a well-described human pathogen. Compared to infections with Scedosporium species, patients with L prolificans have poorer outcomes, including reduced survival times and higher mortality.²⁸ This is due to the organism's ability to rapidly disseminate into the bloodstream,^23,24 with higher rates of invasive infection in immunocompromised individuals⁵ and antimicrobial resistance.²²

We present a novel case of L prolificans osteoarticular infection in a 65-year-old immunocompromised smoker with rheumatoid arthritis who required transhumeral amputation. Osteoarticular infections caused by L prolificans are uncommon overall and are more commonly seen in immunocompetent patients, including in the setting of trauma.^2,8,14,15

Due to L. prolificans' invasive nature, rapid and accurate diagnosis of L prolificans infections is essential in improving patient outcomes before dissemination occurs. Detection of L. prolificans from clinical specimens hinges on direct microscopy and culture using dedicated routine SAB and CG media for fungal pathogens, which are formulated to enhance fungal growth while inhibiting bacterial growth using standard procedures.¹² Routine bacteriology media may fail to reveal its presence, as exemplified in our case and supported by the literature; therefore, clinical awareness or suspicion of fungal infection is essential. For instance, a recent report described a pediatric patient with elbow septic arthritis in whom L prolificans was not recovered on standard bacterial culture but eventually identified through targeted fungal isolation and advanced microscopy.¹⁴ This case also illustrated dramatic joint destruction by the time of diagnosis, reinforcing that early suspicion and use of specific fungal investigation can be life- and limb-saving. Furthermore, distinguishing fungal pathogens from other etiologies often requires histopathology in combination with culture, as microscopic features of hyphae, branching patterns, and sporulation are characteristic of L prolificans infection.^15,16 The complexities of isolating rare fungal pathogens such as L prolificans can be challenging in the laboratory; thus, clinicians must maintain a high index of suspicion and promptly request appropriate fungal diagnostic modalities in cases of unexplained, persistent, or treatment-resistant osteoarticular infection to ensure optimal management and reduce the high morbidity and mortality rate associated with fungal disease.

The antifungal resistance of L. prolificans presents a challenge in clinical management. Until recently, therapeutic options for L. prolificans were very limited, with intrinsic resistance to all available antifungals.^13,23 This difficulty to treat has been noted by recent registration on the World Health Organization fungal priority pathogens list.^3,29 Furthermore, with the extended time required to identify fungal pathogens from specimens and the high levels of resistance that is seen to most therapeutic antifungals,²¹ this could reduce the possibility of successful recovery for those diagnosed with this infection.¹⁵ Consistent with the literature, the L prolificans isolate from this study was resistant to all licensed antifungal agents (Table I). Meletiadis et al²¹ has shown the synergistic effect of a combination therapy of voriconazole with terbinafine could be beneficial for the management of L prolificans infections and other sources have recommended it as standard of care^7,15; however, outcomes with this treatment have been very poor.

The novel antifungal olorofim is a promising agent with activity against L prolificans and emerging clinical data describing improving outcomes.^14,26 Olorofim is a first-in-class orotomide compound that targets dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines and fungus production.²⁷ A recent phase 2b trial of olorofim for invasive fungal diseases showed encouraged encouraging results in treating patients with limited or no treatment options.¹⁹ The study included 26 patients with L prolificans infection, including 16 receiving moderate or severe immunosuppression and 12 with bone and joint infections. However, global treatment success was under 50% for patients with moderate or severe immunosuppression and those with bone and joint infections. A recent case report described curative olorofim treatment of septic arthritis in a patient with Scedosporium apiospermum.⁹ In our case, the patient was changed to olorofim as soon as the agent could be accessed through compassionate means as institutional funding is restricted. In the setting of established osteomyelitis and extensive bone and soft tissue destruction, neither clinical stability nor cure was possible. Olorofim treatment may have contributed to clearance of infection post amputation, but this is difficult to assess. Due to the difficulty in treating patients that are diagnosed with L prolificans and its high potential to cause invasive fungal disease, emerging classes of antifungals, including olorofim, could help improve clinical outcomes.

L.prolificans septic arthritis and osteomyelitis remains rare in the literature, with most documented cases occurring in immunocompetent individuals following traumatic injury.¹⁵ This case study highlights the unique and formidable challenge presented by osteoarticular infection in the context of ongoing immunosuppression, where additional risk factors such as smoking further complicate disease course and management. The pathobiology of L prolificans is characterized by its predilection for immunocompromised hosts, its ability to form treatment-resistant biofilms,¹⁵ and its intrinsic resistance to most antifungal agents, leading to high rates of morbidity and mortality—up to 80% in immunocompromised patients with disseminated infection.²⁴ Effective management hinges on prompt recognition, early aggressive surgical débridement, and, when possible, tailored antifungal therapy; novel agents like olorofim may show promise. However, close follow-up is mandatory, given the propensity of Lomentospora and Scedosporium infections to recur and their capacity for causing limb-threatening complications, occasionally requiring amputation for cure and symptom management^10,11,17 regardless of novel therapies. Curing infection demands optimal source control, support for host immune function, and enhancement of quality of life and function, making a multidisciplinary approach essential in guiding difficult treatment decisions in these complex cases.

Conclusion

This case highlights the morbidity caused by the uncommon and opportunistic fungal pathogen L prolificans in an immunocompromised 65-year-old patient. Management of L. prolificans septic arthritis and osteomyelitis requires a multidisciplinary approach, aggressive surgical clearance, systemic antifungal treatment, and a reduction in immunosuppression. New classes of antifungals such as olorofim could help improve the clinical outcomes of infections caused by this more resistant species. Despite this, limb salvage may remain difficult.