CASE

A 12-year-old boy, with no significant past medical history and no known drug allergies, presented to the emergency department with a deep laceration of his left knee after a fall on a ceramic plant pot in May 2013. A 10-cm long, L-shaped laceration heavily contaminated with soil and completely exposing the lateral femoral condyle was noted. He also was found to have a patella tendon avulsion (Fig. 1). The patient was oriented and comfortable with a blood pressure of 115/50 mm Hg, pulse of 68 beats/min and respiratory rate of 18 breaths/min. Blood tests showed the following mildly abnormal values: white cell count of 11.9 × 109/L (normal: 4–11 × 109/L), hemoglobin of 142 g/L (normal: 135–175 g/L), red cell distribution width of 11.9% (normal: 12%–15%), lymphocyte count of 3.87 × 109/L (normal: 1.50–3.50 × 109/L) and monocyte count of 1.27 × 109/L (normal: 0.2–0.8 × 109/L). The abnormal values from the biochemical analysis included: potassium of 3.3 mmol/L (normal: 3.5–5 mmol/L), phosphate of 0.55 mmol/L (normal: 1–2 mmol/L), alkaline aminotransferase of 74 U/L (normal: <35 U/L) and aspartate aminotransferase of 54 U/L (normal: <40 U/L). The wound was debrided and washed in the operating theater, followed by a second washout and patella tendon repair 48 hours later. Prophylactic antibiotic coverage for 10 days was provided with cephazolin. No microbial evidence of infection during the 2 surgeries was identified.

FIGURE 1.:

RX of lacerated left knee at first presentation. A patella tendon avulsion is seen.

Despite initial good recovery, the patient started noticing a painless swelling of the knee with a reduced range of motion after 6 weeks (see Figure, Supplemental Digital Content 1, https://links.lww.com/INF/F433). Treatment with doxycycline was started empirically. In July 2013, approximately 80 mL of blood-colored fluid was aspirated from his knee with no bacterial growth, thus no microbiological signs of an infection, followed by an arthroscopic washout of the knee joint. A magnetic resonance imaging was performed, which demonstrated signs of arthritis and osteomyelitis of the left knee (Fig. 2). A second arthroscopic washout was performed to remove further septic material. The culture revealed the causative pathogen.

FIGURE 2.:

Magnetic resonance imaging of left knee. Signs of severe septic arthritis and osteomyelitis of the bone sequestrum, with a rupture of the tendon and lacerated meniscus.

DENOUEMENT

Cultures of the bloody fluid aspirated from the knee grew Scedosporium prolificans, a multiresistant, fast-growing, fungal pathogen usually found in potted plants, soil, sewage and polluted waters.1 It can cause soft tissue and bone infections in immunocompromised as well as immunocompetent individuals1,2 and often leads to osteomyelitis and/or arthritis.3,4 In August 2013, the patient was diagnosed with infectious arthritis and osteomyelitis due to S. prolificans, and oral antifungal therapy with voriconazole 800 mg twice a day and terbinafine 187.5 mg once daily was initiated, as well as weekly blood tests to monitor liver and renal functions and inflammatory markers. However, the level of voriconazole was severely high at 8.1 mg/L and the patient showed visual disturbances (photophobia). Any voriconazole level between 1.1 and 5.5 mg/L is therapeutic, everything above 5.5 mg/L is toxic.5 Therefore, the oral dose was lowered to voriconazole 250 mg twice a day resulting in voriconazole levels of 1.4 mg/L.

During the first months after the start of the therapy, the left knee remained swollen and hot on palpation. The patient developed severe sunburn and photosensitivity; however, the treatment regimen was considered nonadjustable due to the lack of other acceptable medications and the need for long-term treatment of this refractory infection. Since the voriconazole level dropped below 1.1 mg/L, the voriconazole was increased several times in the hope of reaching a level of 2 mg/L or higher. The terbinafine was increased once, due to gained weight from 34.2 to 38.7 kg. The eventual oral therapy consisted of voriconazole 325 mg twice a day and terbinafine 250 mg once daily.

Five months after the start of the therapy, he continued to suffer from above severe side effects; however, concern of recurrence, intractable infection and the possible need for above-the-knee amputation precluded early discontinuation of antifungal therapy. Due to persistent swelling and limited improvement in June 2014, “out of the box” treatment options were considered, and patient underwent a joint washout with pool cleaner.

Osteomyelitis (OM) is an inflammation of bone, commonly leading to bone destruction, mostly caused by infections with bacteria or other microorganisms, such as fungi. Septic arthritis (SA), sometimes referred to as infectious arthritis, is a synovial joint infection, predominantly caused by bacteria.6 The incidence ranges from 1–5/100,000 in developed countries7–9 to 20/100,000 in developing countries.10,11 Fungal infections may underlie the cases that do not respond to bacterial treatment,11–15 often in cases of direct inoculation, as in our patient. SA can be secondary to OM. Besides affecting the joint, the epiphysial growth plate can be affected in pediatric patients. SA and/or OM can cause growth discrepancies, permanent joint destruction and/or long-term disability.16 Joint infections are a significant cause of morbidity in children.17 The causes of SA include bacteria such as Staphylococcus aureus, viruses such as alphavirus or flavivirus and fungi such as Candida albicans.

S. prolificans is resistant to almost all antifungal therapies and it is difficult to distinguish whether patients are colonized or have an active infection by this organism.18,19 Despite the washouts aimed to eradicate the fungus, nonetheless, it continued to grow within the respective knee. The isolated S. prolificans was sensitive to voriconazole. Review of the literature shows combination of voriconazole with other antifungal therapies, such as caspofungin, terbinafine or even surgery, to control infection with the S. prolificans.4,20,21 However, amputation or even death are still common outcomes. Voriconazole in combination with terbinafine has shown synergistic effect in treating the SA, indicating its potential as the best treatment option.22 However, more research is needed to determine the extent of sensitivity and this synergism in vivo, as it may not align with the results obtained in vitro.23 To the best of the authors’ knowledge, there is no literature to specify the best regimen and best length of treatment. At the initiation of the treatment, it was decided to start with a year of voriconazole and terbinafine, depending on the side effects along with weekly evaluation of liver and renal functions as well as the inflammatory markers.

Unfortunately, voriconazole can cause many severe side effects, where extreme photosensitivity and sunburns were most prominent in this patient. Photosensitivity is a well-known side effect of the voriconazole.24 Additionally, our patient was suffering from brittle nails, left thigh proximal myopathy, anorexia, anemia, decreased muscle bulk and osteoporosis. The side effects had a significant impact on our patient’s well-being.

Due to insufficient improvement and the impact of the side effects of the treatment, the case was discussed during an International Scientific Meeting of Infectious Diseases. The recommendation was to perform a washout with 0.2% polyhexamethylene biguanide (pool cleaner) via open arthroscopy in June 2014. Afterwards the antifungal therapy was continued until September 2014 to eradicate the fungus completely. Our patient was treated with voriconazole and terbinafine for 13 months, from August 2013 to September 2014.

A case report by Steinbach et al4 describes the use of voriconazole with caspofungin in combination with 0.2% polyhexamethylene biguanide for local irrigation and soaking during surgical debridement against a foot infection caused by S. prolificans. The infection was successfully cleared. Pool cleaner is a promising antiseptic that has been used in medicine for a variety of indications, such as presurgery antimicrobial scrub and wound dressing.25 Even though there is limited evidence on the treatment of pediatric infections caused by S. prolificans, this published case reported successful treatment with pool cleaner.

The washout with pool cleaner was carried out in June 2014, 13 months after the initial injury. Extensive cartilage damage, especially to the lateral femoral condyle was observed during this procedure. It was decided to stop the voriconazole and terbinafine 3 months after the washout due to continued severe side effects and their impact on the physical and mental well-being of the patient.

In January 2015, the patient had a relatively minor fall that resulted in a distal femoral fracture on the same left side. This was suspected to be due to osteoporosis, potentially caused by an extended period of inactivity and prolonged use of voriconazole.13 Following an open reduction and internal fixation, the femur fracture healed uneventfully. Then, during follow-up in June 2015, 2 years after the initial injury, the patient was still struggling with a significant limp and a limited range of motion and knee function (extension deficit of 30° and maximum flexion of 60°). He has continued with physiotherapy, learning to cope with his restrictions and refusing any further surgical treatment. Almost 10 years following the incident (December 2022), our patient visited our clinic for a review. During the 10-year follow-up, the patient showed signs of joint destruction and a limited left knee function. The Knee Injury and Osteoarthritis Outcome questionnaire showed: 40.0/100 (pain), 67.5/100 (symptoms), 66.75/100 (activities of daily living), 10.0/100 (sports/recreation) and 12.5/100 (quality of life).26 Furthermore, he presented with a leg length difference of 3 cm, with the affected left leg being shorter. Active and passive flexion were both 70°. His apparent left knee extension is full, but overestimated due to 20° proximal tibial recurvatum (see Figure, Supplemental Digital Content 2, https://links.lww.com/INF/F434). Radiographs reveal a deformity of the lateral femur condyle, together with an anterior slope of the tibial plateau (see Figure, Supplemental Digital Content 3, https://links.lww.com/INF/F435), likely caused by an early closure of the anterior side of the proximal tibial epiphysis. He has accepted his situation, made adjusted career choices and is doing relatively well.

Even though the infection was successfully cleared with voriconazole and terbinafine and a washout with pool cleaner, damage to the articular cartilage and growth plate could not be prevented. This infection caused growth arrest and physeal injury, explaining the leg length discrepancy, angular deformity and his limited knee function. These are uncommon complications in typical SA in children.27,28 This shows that SA caused by S. prolificans can have severe consequences in pediatric patients.

We presented a pediatric patient with a SA of the knee, caused by S. prolificans, after a fall on a ceramic plant pot with a 10-year follow-up. Despite the damage done to the knee joint, it was successfully eradicated with voriconazole and terbinafine and a washout with 0.2% polyhexamethylene biguanide. This case demonstrates the destructive nature of the S. prolificans as a cause of SA of the knee, where aggressive antifungal treatment and a washout with 0.2% polyhexamethylene biguanide should be considered.

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