Candida tropicalis arthritis of the knee in a child on chemotherapy treated with intra-articular amphotericin B

Xin Yang Tan; Natalie Woon-Hui Tan; Rina Yue Ling Ong; Michaela Su-Fern Seng; Kenneth Pak Leung Wong

doi:10.1016/j.jorep.2024.100361

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Case Report

2025

:4;

100361

doi:

10.1016/j.jorep.2024.100361

Candida tropicalis arthritis of the knee in a child on chemotherapy treated with intra-articular amphotericin B

Xin Yang Tan^a,, Natalie Woon-Hui Tan^c,e,f, Rina Yue Ling Ong^b, Michaela Su-Fern Seng^d,e, Kenneth Pak Leung Wong^a,e,f

a Department of Orthopaedic Surgery, KK Women's and Children's Hospital, Singapore

b Department of Pharmacy, KK Women's and Children's Hospital, Singapore

c Infectious Disease Service, Department of Paediatrics, KK Women's and Children's Hospital, Singapore

d Department of Haematology/Oncology, KK Women's and Children's Hospital, Singapore

e Duke-NUS Medical School, Singapore

f Yong Loo Lin School of Medicine, National University of Singapore, Singapore

⁎Corresponding author: Xin Yang Tan. research@xinyangtan.com

Received: 2023-12-31, Accepted: 2024-5-12, Published: 2024-5-18

The Authors

Disclaimer:
This article was originally published by Reed Elsevier India Pvt. Ltd. and was migrated to Scientific Scholar after the change of Publisher.

Abstract

Fungal osteoarticular infections are rare but severe life-threatening infections, commonly in patients with risk factors such as in the setting of immunosuppression, indwelling prosthesis or intravenous substance abuse. Marked improvement in diagnostic techniques have also contributed to their early detection. Candida species remains the most common cause of fungal osteoarticular infections. While systemic antifungal therapy and surgical drainage remain the mainstay of therapy, intra-articular instillation of antifungals may present a useful adjunct therapy to achieve articular antifungal concentrations. Herein we report a case of a 9-year-old male child with a case of Candida tropicalis septic arthritis of the knee, and our subsequent treatment regimen. This paper also aims to summarise the available evidence surrounding the use of intra-articular instillation of antifungals as adjunct for the treatment of fungal arthritis and highlights the need to further evaluate and develop a standardised treatment regimen.

1 Introduction

Fungal infections of the joint are rarely encountered in routine clinical practice, more commonly appearing in the setting of prosthetic joint infections, intravenous substance abuse, or in an immunocompromised host.¹ The presentation varies widely, ranging from indolent to aggressive.²^,³

In those with indolent presentation, clinical features largely parallel that of degenerative or inflammatory arthritis.⁴ Lacking pathognomonic features that aid rapid diagnosis, all the while being less symptomatic than bacterial infections,^5–7 the diagnosis of fungal arthritis can often be delayed. The treatment course is often protracted due to factors including poor antifungal bone penetration, as well as the high recurrence rates from the stubborn nature of fungal infections.³

While systemic antifungal therapy and adequate source control remain the mainstay of therapy,³ intra-articular instillation of antifungals may present a useful adjunct therapy to achieve high articular antifungal concentrations. Given the rarity of such infections however, as well as the paucity of available data, there is no clear consensus on the recommended dose of intra-articular antifungals instilled. The systematic review, as well as our case report, seek to establish the safe upper bounds of intra-articular administration of antifungals.

2 Case report

A male child with a background of pre-B acute lymphoblastic leukaemia was referred to the orthopaedic surgery team for an acute onset fever with right knee arthralgia and effusion. He had last received a fifth cycle of induction chemotherapy two weeks prior consisting of intravenous cyclophosphamide, intravenous cytarabine and intrathecal methotrexate.

The chemotherapy regimen was complicated by an episode of neutropenic fever four months prior with Candida tropicalis fungemia, for which he was treated with 14 days of intravenous micafungin with clinical and microbiological resolution. A magnetic resonance imaging (MRI) of the calves performed for nonspecific calf pain in that admission revealed nonspecific bone marrow signal changes in the right tibial shaft, for which bone biopsy was performed revealing focal bone necrosis, and a diagnosis of focal bone infarcts secondary to leukaemia was made.

3 Clinical findings

3.1

3.1 Diagnostic assessment

Ultrasound of the knee revealed anechoic fluid with a depth of 1.0cm in the suprapatellar pouch. A right proximal tibial diaphyseal lucency and cortical irregularity, corresponding to the previous biopsy site, was noted on X-rays which were otherwise unremarkable. Arthrocentesis was attempted but no aspirate was obtained. An MRI of the knee joint was performed, which demonstrated diffuse synovial thickening with intramuscular T2-weighted hyperintensity highly suspicious of septic arthritis.

Laboratory studies revealed a white blood count of 1.57 × 10⁹/L with 71.3% neutrophils, C-reactive protein (CRP) of 85.5 mg/L and erythrocyte sedimentation rate (ESR) of 74 mm/hour. Multiple blood cultures were negative after 5 days of incubation in both aerobic and anaerobic culture media.

Arthroscopic right knee washout and biopsy was performed in view of the clinical suspicion of fungal septic arthritis. Apart from mild synovitis and scarring, no significant abnormalities were noted within the knee joint. Fungal cultures from the right knee joint fluid returned positive for Candida tropicalis. FilmArray® Blood Culture Identification (BCID) polymerase-chain reaction (PCR) test (BioFire® Diagnostics, Inc.) performed on the right knee joint fluid also returned positive for Candida tropicalis. Antifungal susceptibility testing performed on the isolated Candida tropicalis was reported to be susceptible to anidulafungin (minimum inhibitory concentration (MIC): 0.12 mcg/mL), micafungin (MIC: 0.03 mcg/mL),⁸ and fluconazole (MIC: 4 mcg/ml) and intermediate to voriconazole (MIC: 0.25 mcg/mL).⁹ Amphotericin B was reported as wild-type with an MIC of 1 mcg/mL,¹⁰ which meant that the reported MIC remains below or at the epidemiological cut-off value.¹¹ Histopathology of the right knee joint tissue revealed granulation tissue with acute-on-chronic inflammation.

4 Therapeutic intervention

The patient was initiated on empiric broad-spectrum systemic antimicrobial therapy (meropenem and amikacin) for fever in an immunocompromised patient with a recent stool colonization with an extended-spectrum beta-lactamase (ESBL) producing Klebsiella aerogenes. When the right knee joint fluid cultures from the first arthroscopic right knee washout returned positive for growth of yeast on post-operative day 3, intravenous micafungin 150 mg once daily (5 mg/kg/day) was added on. In view of the clinical suspicion of a concurrent central nervous system (CNS) involvement with presentation of right eye ptosis, micafungin was empirically switched to intravenous liposomal amphotericin B (Ambisome®) 150 mg once daily (5 mg/kg/day) for better CNS penetration on post-operative day (POD) 5.

The fever returned on POD 7 with significant worsening of the arthralgia, with CRP increasing to 178.7mg/L, and the patient underwent a second arthroscopic washout of the knee joint on POD 8. Generalised synovitis was again noted with old blood clots, but with no frank purulent material. Repeat fungal cultures from the right knee joint fluid were negative. In view of the persistent fever and worsening arthralgia despite appropriate systemic antifungal therapy, the clinical decision was made to initiate adjunct therapy with intra-articular antifungal instillation during the second arthroscopic washout of the knee joint. Joint lavage was performed with 9 L of Normal Saline (0.9% NaCl) solution between washes with Hydrogen Peroxide 3%, Povidone Iodine 10%, and Chlorhexidine Gluconate 0.05% in order. Following a final lavage with Normal Saline 0.9%, the knee was drained. An intra-articular dose of 10 mg of liposomal amphotericin B (AmBisome®) diluted to a concentration of 5 mg/mL with sterile Water for Injection USP was given, which was anticipated to result in an articular concentration well above the MIC of C. tropicalis (1 mcg/mL). Pain improved post-operatively with improvement in CRP from an initial post-operative level of 306.1 mg/L to 90.2 mg/L by POD 4.

A third relook arthroscopy and washout of the right knee joint was subsequently performed on POD 9 due to a recurrence of high-grade fever and knee pain. Upon entry to the joint, there was minimal bloody aspirate and copious adhesions but otherwise no pus found. Notably, the cartilage was intact (Outerbridge 0) with no softening, fissures or fibrillations noted following the intra-articular instillation of liposomal amphotericin B in a previous arthroscopy. The joint was thoroughly washed with the same procedure as previously described, and an intra-articular dose of 25 mg of conventional amphotericin B (Fungizone®) diluted to a concentration of 5 mg/mL with sterile Water for Injection USP was instilled, in combination with 25 mg of hydrocortisone sodium succinate (diluted to 50 mg/mL) and 50 mg of preservative-free lignocaine (1%). The fever lysed 2 days post-operatively with a significant resolution of the right knee pain.

5 Follow-up and outcomes

Following the third arthroscopy and washout of the right knee joint, the patient's knee remained asymptomatic for the rest of the hospital admission. With continuous physiotherapy he was able to ambulate 5 m with a walking frame, and he was subsequently discharged 2 weeks postoperatively. His systemic antifungal therapy was subsequently switched to oral high-dose fluconazole (400 mg once daily, 12 mg/kg/day) on discharge as the fluconazole was susceptible-dose dependent with an MIC of 4 mcg/mL, after a total of 26 days of intravenous liposomal amphotericin B therapy.

The patient was seen in clinic a month after the third arthroscopy where he was found to have a right knee range of motion from 30 to 80°. Manipulation under anaesthesia with an indwelling nerve block catheter was offered and performed with a satisfactory range of motion from 0 to 140° while under anaesthesia.

As of three months post-operatively, the patient remained well, and the right knee had an active range of motion from 10 to 110°.

He has since completed a total of 6 months of systemic antifungal therapy, inclusive of 26 days of liposomal amphotericin B, followed by 5 months of oral high-dose fluconazole with no recurrence of infection. He is now able to stand and do sports with assistance and is less dependent on his walking frame. He continues to do well to date.

6 Discussion

Fungal arthritis is notoriously difficult to diagnose,³ in part because of the indolent nature of the infections, as well as the turnaround time required in confirmatory testing. Common risk factors include immunocompromising conditions (including malignancy, human immunodeficiency virus infection, organ transplantation, haematopoietic stem cell transplantation), presence of external devices, use of broad-spectrum antibiotics, and parenteral nutrition.² Fungal osteoarticular infections may occur because of haematogeneous dissemination, direct inoculation during surgical procedures, implantation of prosthesis or instrumentation, trauma, or even the use of intra-articular corticosteroid injection.^1–3 The most common fungal pathogen remains Candida species, but other fungi including Aspergillus spp., Cryptococcus spp., Coccidioides spp., and Trichosporon spp. have also been reported.²^,³

Fungal arthritis largely affects the large joints of the knee and the hip,¹² although other joints such as the shoulder, elbow and wrist have been reported.¹³ Physical examination may parallel those of arthritis with pain, erythema, swelling, decreased range of motion and effusion. Nevertheless, the most common complaint remains that of pain, and yet many fungal arthritides tend to be less symptomatic than their bacterial counterparts, often lacking systemic signs such as fever.^5–7 Additional delays in diagnosis may arise from the fact that synovial fluid obtained via arthrocentesis typically reflect counts that mimic inflammatory arthritides.⁴ Because of the nature of the difficulty in diagnosis and uncertainty of usual culture-based methods of diagnosis, there is now an increased focus on rapid molecular diagnostic techniques. PCR-based tests, such as the newly developed Biofire® Joint Infection (JI) panel (BioFire® Diagnostics, Inc), may potentially allow for rapid microbiological identification in the near future.¹⁴

The cornerstone of septic arthritis management remains source control, in the form of drainage of the closed abscess and irrigation, followed by susceptibility testing-guided systemic antimicrobial therapy.²^,³ Systemic antifungal therapy is guided by the identification and antifungal susceptibilities of the pathogen. Historically, the clinical experience of treating fungal arthritis has been with systemic antifungal therapy such as amphotericin B (with or without flucytosine) or with fluconazole.³ The clinical practice guideline for the management of osteoarticular candidiasis updated by the Infectious Diseases Society of America (IDSA) in 2016 recommends fluconazole or echinocandins as first line therapies given the good efficacy and safety profile.¹⁵ Liposomal amphotericin B has been recommended as an alternative. On the other hand, voriconazole is the preferred antifungal agent as recommended by IDSA for the management of Aspergillus spp. osteoarticular infections.¹⁶

Little data is available about the pharmacokinetics of antifungal agents in synovial fluid and tissue, and it remains unclear if their concentrations exceed the MIC of the fungal pathogens. In human synovial fluid, it has been reported that the measured amphotericin B synovial fluid: plasma concentration ratio is approximately 0.4–1.4.¹⁷ Good synovial fluid or bone concentrations from human and animal studies have been reported for the azole antifungals (fluconazole, itraconazole and voriconazole), whereas limited data exists for echinocandin antifungals (caspofungin, micafungin, anidulafugin), though they have been used successfully to treat patients with osteoarticular infections.¹⁷ In our patient, we chose liposomal amphotericin B as the initial empiric systemic antifungal therapy given the need for CNS penetration, the susceptibility of Candida tropicalis to amphotericin B with a MIC of 1 mcg/mL, and possible synovial penetration.

6.1

6.1 Intra-articular antifungal instillation

The use of intra-articular antifungals is generally not recommended in view of the paucity of data.¹⁵ However, given the persistent symptoms of fever and worsening arthralgia despite systemic antifungal therapy and surgical drainage, as well as concerns with lower concentrations of antifungals to the synovial fluid and joints, the clinical decision for intra-articular instillation of antifungal therapy was made to increase the antifungal concentration at the site of the infection. The local instillation of antifungals into the joint space is potentially useful as it provides targeted drug delivery with high antifungal concentrations, especially if synovial penetration of the systemic antifungals is uncertain. To the best of our knowledge, there have only been 15 reports, including a total of 17 patients, describing the use of intra-articular amphotericin B, one report of intra-articular micafungin 18 and one report of intra-articular voriconazole.¹⁹ None have been reported for caspofungin, anidulafungin or fluconazole. Table 1 summarizes the clinical features, treatment, and outcomes of the 19 patients who received intra-articular antifungals for the treatment of fungal arthritis.

Table 1 Clinical features of patients treated with intra-articular antifungals.^a

Study	Patient Characteristics					Treatment							Safety	Efficacy	Outcome
	Age (yrs)	Sex	Joint	Pathogen	Risk factor(s)	Systemic Antifungal	Intra-articular antifungal regimen					Surgical intervention
	Age (yrs)	Sex	Joint	Pathogen	Risk factor(s)	Systemic Antifungal	Antifungal	Cumulative Dose	Max. dose	Frequency	Duration	Surgical intervention
Amphotericin B
Bayer²⁵	12	M	Right Knee	C. albicans	ALL	5-FC	AmpB	40mg	5mg	Every other day	3 weeks	None	Not reported	Synovial fluid cultures became negative, knee effusion and joint tenderness improved at 3 weeks.	Died (gram-negative bacteremia. disseminated candidiasis)
Bayer²⁵	0.06	F	Both Knees	C. albicans	Low birth weight	AmpB	AmpB	5mg	5mg	Once	Once	No	Not reported	Synovial fluid cultures became negative at 6 weeks	Recovered
Cevik²⁰	35	M	Right Knee	C. albicans	Injection	AmBi	AmBi	50mg	50mg	Once	Once	Arthroscopic debridement	Not reported	Synovial fluid cultures became negative, improvement of arthritis.	Recovered
Christenssen²⁹	32	M	Right Knee	C. albicans	Injection	Flucon, then AmpB + 5-FC	AmpB	40mg	25mg	Every 5 days	5 days	Arthrectomy and total synovectomy	Not reported	Synovial fluid culture became negative.	Recovered (No recurrence at 18 months)
Downs³⁰	59	M	Left Knee	S. schenckii	Not stated	Not reported	AmpB	5.2mg	0.25mg	Twice weekly	19 weeks	No	No evidence of chemical synovitis	Synovial fluid cultures became negative.	Recovered (No recurrence at 24 months)
Fainstein 32	62	F	Left Knee	C. albicans	CML	AmpB	AmpB	50mg	10mg	Every 3 days	2 weeks	Not reported	Not reported	Not reported	Died (disseminated candidiasis)
	68	M	Right Knee	C. albicans	Smoldering leukaemia	Micon, then AmpB	AmpB	50mg	10mg	Every other day	10 days	Not reported	Not reported	Not reported.	Recovered
Hayden²¹	6	M	Right Knee	S. apiospermum	Trauma	None	AmpB	42.5mg (joint space), 15.5mg (prepatellar bursa)	Not reported	Not reported	4 weeks	No	Presented with 2–3 days of fever, anorexia, lethargy, and local tenderness after every instillation. Joint size increased by 3cm.	Joint aspirate cultures became negative. Knee size decreased, and mobility increased at 1 month.	Recovered (No recurrence at 24 months)
Imbeau²²	75	F	Left Knee	C. parapsilosis	Injection	5-FC	AmpB	Not reported	Not reported	Not reported	Not reported	No	Acute synovitis	Stopped IA antifungal, continued on 5-FC with clinical improvement.	Recurrence (at 3 month)
Jeragh²⁴	29	M	Right Knee	C. lusitaniae	Intravenous drug abuse	AmpB + Flucon	AmpB	Not reported	Not reported	Not reported	17 days (3 doses)	Synovectomy	Worsening knee pain	Stopped IA antifungal, decision made for surgery. Synovial fluid cultures became negative with clinical improvement.	Recovered
Katzenstein 26	63	M	Left Knee	C. parapsilosis	Injection	Ketocon, then AmpB + 5-FC	AmpB	5mg	5mg	Once	Once	Synovectomy	Not reported	Synovial fluid cultures became negative, decreased swelling and discomfort with improved function.	Recovered
Mandel⁴	57	M	Left Knee	C. parapsilosis	Injection	AmpB	AmpB (with hydro-cortisone premed-ication)	8mg	2mg	Every 2 days	12 days	Arthroscopy	Presented with fever to 38^OC after every instillation, but no change to blood count or creatinine.	Minimal clinical improvement, started on IV AmpB. Knee remains swollen and tender. Repeat X-ray with slight narrowing of medial compartment of knee.	Defaulted treatment
Marmor²³	75	M	Right Knee	C. spp	Aspiration	5-FC	AmpB	Not reported	Not reported	Not reported	Once	Arthrotomy	Presented with fever after IA instillation.	Minimal clinical improvement, with pain and effusions in knee joint, declined treatment	Recovered
Meberg²⁷	21 m	M	Left Knee	C. spp	Wilms	Micon	AmpB	5mg	3mg	Every 2 weeks	6 weeks	No	Presented with local erythema and short fever after every IA instillation.	Clinical and radiological improvement 1 week after 1st IA instillation.	Recovered (No recurrence at 8-months)
Poplack²⁸	11	F	Left Knee	C. tropicalis	ALL	AmpB	AmpB	9mg	5mg	Every 2 weeks	6 weeks	No	Presented with 3 days of increased joint swelling, tenderness, fever, nausea and vomiting after every IA instillation	Clinical improvement, became asymptomatic 2 weeks after last IA instillation.	Recovered
Wall³¹	48	M	Left Knee	C. tropicalis	Lymphoma	AmpB then Ketocon	AmpB (with hydro-cortisone)	890mg	40mg	Daily	5 months	Arthrotomy irrigation and debridement; Posterior calf dissection and arthrodesis	Not reported	Infection did not respond	Recovered (after definitive surgery)
Zuo (36)	73	F	Both Knees	T. asahii	TKR	AmpB, then Voricon	AmpB	425mg	25mg	Daily	17 days	Joint debridement and lavage, synovectomy	Not reported	Clinical improvement, temperature stabilized with improved range of motion to 0–90^o.	Recovered (No recurrence at 26-months)
Micafungin
Van Egmond¹⁸	49	M	Left Knee	C. krusei	AML	Mica + AmBi	Mica	25mg	3mg	Daily	11 days	Arthroscopic debridement and synovectomy	Not reported	Clinical improvement, blood cultures became negative. Left knee with good recovery and function, with minimal pain at 6-month after.	Recovered
Voriconazole
Kawashima¹⁹	18	M	Both Knees	F. solani	ALL	Voricon + AmBi	Voricon	Not reported	200mg	Twice weekly	Not reported	Synovial irrigation	No adverse effects to synovial tissue under endoscopic observation	Clinical improvement in pain and swelling, synovial fluid cultures became negative.	Died (leukaemia relapse with multi-organ failure)

a M: Male; F: Female; ALL: acute lymphoblastic leukemia; CML: chronic myeloid leukemia; TKR: total knee replacement; AML: acute myeloid leukemia; AmpB: conventional amphotericin B; AmBi: liposomal amphotericin B; 5-FC: flucytosine; Flucon: fluconazole; Micon: miconazole; Ketocon: ketoconazole; Voricon: voriconazole; Mica: micafungin.

6.1.1

6.1.1 Demographics and diagnosis

Nineteen patients (13 adults and 6 paediatric patients) with fungal arthritis were included. Median age of the adult patients was 59 years (IQR: 48–68) and paediatric patients was 8.5 years (IQR: 2.8–11.8). There were 14 males (74%), and all patients had fungal arthritis involving the knee joint(s). The most common isolated fungal pathogens in these patients was Candida species, with six C. albicans, three C. parapsilosis, two C. tropicalis, one C. lusitaniae, one C. krusei. Other fungal pathogens isolated also included one Trichosporon asahii, one Scedosporium apiospermum, one Sporothrix schenckii and one Fusarium solani.

All but one study reported predisposing risk factors with presence of an immunocompromising condition (n = 8) and direct inoculation (n = 7) being the two major causes. In the patients with immunocompromising conditions, seven were diagnosed with a hematological malignancy while one had a background of Wilms’ tumour. In the patients with direct inoculations as a potential risk factor, five had recent receipt of intra-articular injections, one had undergone a total knee replacement for bilateral arthritis, and one sustained a traumatic inoculation.

6.1.2

6.1.2 Therapeutic dosage

In the 15 reports detailing the use of intra-articular amphotericin B, only Çevik et al.²⁰ described the use of intra-articular liposomal amphotericin B (Ambisome®), while the rest utilized conventional amphotericin B. Treatment regimens vary widely with varying dosages, instillation frequency, and treatment duration. With the exception of 1 study which utilized intra-articular amphotericin B in isolation,²¹ all the other studies utilized intra-articular antifungal instillation, in combination with systemic antifungal therapy.

In the five paediatric patients who received intra-articular conventional amphotericin B, the maximum dose per instillation was 5 mg, with cumulative dosages ranging from 5 mg to 58 mg. In the adult patients, the maximum dose per instillation was 40mg, with cumulative dosages ranging from 5 mg to 890 mg. Three studies^22–24 in the adult population did not report the doses administered. Among the patients who were able to tolerate intra-articular conventional amphotericin B, three received single doses,²⁰^,²⁵^,²⁶ while the rest received daily to fortnightly doses. The median total duration of treatment was 19 days (IQR: 13.5–42).

6.1.3

6.1.3 Safety

Local toxicity of the joint is one of the main concerns after local instillation of high concentrations of antifungals into the joint space. From our review, the most reported systemic and local adverse events included fever, local joint swelling and tenderness, anorexia, nausea, vomiting and lethargy in five patients (26.3%) after the intra-articular instillation of antifungals, which typically resolved within two to three days.⁴^,²¹^,²³^,²⁷^,²⁸ There was also one patient (5.3%) who developed an acute synovitis.²² However, in half of these patients, the safety outcomes were not reported. Two patients also stopped the administration of intra-articular antifungals due to adverse events.²²^,²⁴

6.1.4

6.1.4 Efficacy

Of the 19 patients who were administered intra-articular antifungals, there was clinical improvement in 13 patients (68.4%) with microbiological culture clearance in nine (47.4%).⁴^,¹⁸^,²⁰^,²¹^,^23–30 In four patients, there was minimal clinical improvement requiring further surgical intervention in two patients (10.5%)²⁴^,³¹ and initiation of systemic antifungal therapy in one (5.3%).⁴ The fourth patient eventually died of disseminated candidiasis.³²

Thus far, only amphotericin B, micafungin and voriconazole have been instilled intra-articularly as adjunct therapy for fungal arthritis. Amphotericin B (both conventional and liposomal amphotericin B formulations) has been used in most cases with encouraging results.³ In our patient, the use of amphotericin B for intra-articular instillation was selected in view of the availability of safety and efficacy data in paediatric patients and the reported antifungal susceptibility of the C. tropicalis to amphotericin B at a MIC of 1 mcg/ml. Significant variability in the therapeutic regimen, varying dosages, instillation frequency, and treatment duration exists for intra-articular amphotericin B. However, none have explained the rationale behind the selected treatment regimens. Consequently, one may deduce that the reported doses and instillation frequencies represent the upper bounds of safe doses for administration. Given that the maximum reported conventional amphotericin B dose in paediatric patients was 5 mg and that in adult patients was 40mg, we eventually decided on a dose of 25 mg (diluted to a concentration of 5 mg/mL) during the second intra-articular instillation in our patient to account for the estimated knee joint space for instillation in a 30 kg child. In our patient, as the C. tropicalis isolated was also susceptible to micafungin and intermediate to voriconazole, alternative intra-articular instillation of micafungin or voriconazole could be considered,¹⁸^,¹⁹ though data remains limited.

Although most patients generally tolerate the intra-articular instillation of antifungals, an important safety consideration is that of local toxicity of the joint, such as synovitis. Prior to intra-articular instillation of antifungals as adjunct therapy, clinicians should be mindful of, and patients should be counselled on, the possible systemic and local adverse events. In our patient, he reported right knee tightness and pain post-instillation, which significantly improved with analgesia. The relook arthroscopy however did not demonstrate any evidence of cartilage change resulting from the first instillation. Defervescence was also reported two days post-instillation. Notably, and in keeping with our findings, no studies have reported the presence of cartilage toxicity following instillation.

Besides the direct instillation of antifungals into the joint space, operative techniques have also been described such as utilizing intraoperative irrigation with diluted amphotericin B while applying continuous suction.³³ There have also been other novel formulations for the delivery of antifungals to the required site of infection for the treatment of osteoarticular fungal infections. Data on the elution characteristics of antifungals have been limited but promising.¹^,²^,³⁴ Depot delivery of antifungals, in the form of delivery vehicles with non-bioactive polymers such as impregnated polymethyl methacrylate (PMMA) bone cement or bioactive osteoconductive materials such as calcium sulphate beads have been described,² typically utilized in the setting of periprosthetic infections. Use of amphotericin B suspension in a novel glyceryl monooleate gel³⁵ has also been developed to allow sustained drug release while minimising the frequency of repeated intra-articular injections. With advances in novel drug delivery systems in recent years, this is a promising field to look forward to in the near future.

In conclusion, fungal osteoarticular infections continue to present a therapeutic surgical and medical dilemma. Although the mainstay of treatment remains surgical intervention with systemic antifungal therapy, the local instillation of antifungals into the joint space remains an attractive therapeutic option by providing targeted drug delivery with high antifungal concentrations, especially in the setting of unknown synovial antifungal penetration. There is, however, an urgent need to further evaluate and develop a standardised treatment regimen utilizing antifungals for intra-articular instillation. Recognition of the possible systemic and local adverse events associated with the intra-articular instillation of antifungals is also important. It is the hope of the authors that this review, and the presented case report, will add to the body of knowledge surrounding this therapeutic dilemma.

Financial support and sponsorship

No authors received financial support for the conduct of the research and/or preparation of the article.

Informed consent

Informed consent was obtained from the legal guardian (mother) of the patient for publication, as the patient was a minor at the time of treatment.

Ethical statement

All procedures were performed in compliance with relevant laws and institutional guidelines and have been approved by the appropriate institutional committees. Informed consent was obtained from the legal guardian of the patient described in the case report, and with acknowledgement from the patient himself.

The authors declare that no funding was received for the work reported in this paper.

CRediT authorship contribution statement

Xin Yang Tan: Writing – original draft, Writing – review & editing, Visualization. Natalie Woon-Hui Tan: Writing – review & editing. Rina Yue Ling Ong: Writing – original draft, Writing – review & editing, Visualization. Michaela Su-Fern Seng: Supervision. Kenneth Pak Leung Wong: Conceptualization, Supervision.

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