Mucormycotic osteomyelitis following anterior cruciate ligament reconstruction: A case report and literature review

Abstract

We report a case of femoral osteomyelitis caused by Mucorales in a young, healthy male patient following ACL reconstruction. Fungal osteomyelitis of the extremities is a rare condition primarily caused by Aspergillus or Candida in immunocompromised patients. Diagnosis is often delayed until standard antibiotic regimens fail. Current guidelines recommend systemic amphotericin B with surgical debridement; however, the drug's clinical use is restricted by severe nephrotoxicity. To mitigate systemic toxicity, amphotericin B–loaded Polymethyl Methacrylate (PMMA) spacers have been investigated, though drug release remains short-lived. Early diagnosis—suggested by cortical and medullary bone destruction on imaging—along with timely amphotericin B therapy and surgical debridement, remains the cornerstone of effective management.

Highlights

• •Mucormycotic osteomyelitis is an uncommon but potentially fatal infection, with reported mortality rate as high as 23%.
• •Suspect fungal etiology when diffuse cortical and medullary bone lesions are disproportionately severe compared to symptoms.
• •The use of amphotericin B-loaded PMMA cement spacers is a promising method to mitigate systemic side effects.

1. Introduction

Fungal osteomyelitis is rarely documented in medical literature and presents a significant challenge for orthopedic surgeons in both diagnosis and treatment [1]. Most reported cases occur in patients with underlying conditions or immunosuppression [2]. Diagnosis is often delayed, leading to prolonged treatment difficulties, with a mortality rate of up to 23% despite antifungal therapy and multiple surgical debridement procedures [1,3].

2. Case presentation

A 21-year-old male patient had a left knee injury following a contact sport injury. He underwent anterior cruciate ligament reconstruction (ACLR) at the local hospital (day 0). After ten days, the knee became painful and swollen. He underwent arthroscopic debridement with drainage. Two weeks later, the wound did not heal well, and he underwent open debridement and received VAC therapy for both femur and tibia sites (day 24). Six days later, he underwent open debridement and received antibiotic cement beads (day 30). For further reasons, he visited our hospital on post-operative day 44. The previous culture showed that he was infected by Pseudomonas aeruginosa. His knee wound was partially healed with minimal fluid discharge; however, X-ray and CT-scan (Fig. 1, Video 1A and Video 1B) revealed diffuse cortical and intramedullary bone destruction. Throughout the treatment course at the local hospital, he was afebrile and his vital signs were stable.

Fig. 1.

The patient's left knee X-ray on date 44th after ACLR.

He underwent an operation with aggressive open debridement, aerobic and anaerobic bacterial cultures, fungal culture, PCR of Mycobacterium, bone and soft tissue histology, applying a knee-spanning external fixator (day 45). The bone lesion looked abnormal with cortical bone necrosis surrounded by periosteal bone reaction (Fig. 2). The post-op x-ray illustrated a 10-cm metaphyseal bone defect of the distal femur (Fig. 3).

Fig. 2.

Lateral-to-medial view of the distal femur shows necrosis bone surrounded by inflamed soft tissue. A: Before debridement. B: After aggressive debridement with the same view.

Fig. 3.

The post-operative X-ray of the patient illustrating approximately 10cm of metaphyseal bone defect following aggressive debridement and external fixation.

His bacterial cultures and Mycobacterium PCR results were all negative. However, the histology (day 51) showed Mucorales infection with numerous non-septate, broad, ribbon-like hyphae invading bone tissue (Fig. 4). Unfortunately, the fungal culture was negative, so that the species was not identified.

Fig. 4.

Numerous non-septate, ribbon-like hyphae (arrows) invading bone tissue. (A), (B) H&E staining (x20 and x40, respectively) illustrated bone necrosis surrounded by ribbon-like hyphae. (C) PAS staining showed reddish-purple, non-septate, ribbon-like hyphae, x40. (D) GMS staining illustrated dark, brown-black, broad, ribbon-like hyphae, x40.

He was managed with intravenous liposomal Amphotericin B using a dosage of 5mg/kg/day and underwent re-debridement with local PMMA cement spacer using a combination of Amphotericin B and Vancomycin (2 packs of Gentafix 3 cement, 4 vials of Amphotericin B 50mg, 2 vials of Vancomycin 1g - Fig. 5). The bacterial and fungal cultures in this surgery were also negative.

Fig. 5.

The antifungal cement spacer and beads intra-operative (day 53) and the post-operative X-ray following re-debridement and application of cement spacer with the combination of 2 packs of cement, 4 vials of Amphotericin B (50mg) and 2 vials of Vancomycin (1g).

One week later (day 60), he underwent re-debridement (the third surgery at our hospital) for replacement of the cement with the previous combination (Fig. 6). Intravenous liposomal amphotericin B was discontinued after the third surgery (total duration: ten days) as his wound healed well. The bacterial and fungal cultures in this third surgery were also negative, and the patient was discharged. Eight weeks after the third surgery, he underwent bone grafting using the modified Masquelet method (Fig. 7A). At six months after the fourth surgery, the X-ray (Fig. 7B) demonstrated that the bone graft has partially healed. Then the external fixator was removed, and the patients started to use the functional brace. At the latest follow-up – ten months after bone grafting – the patient could walk confidently with his functional brace, and there has been no sign of recurrent infection (Fig. 7C, Video 2).

Fig. 6.

Post-operative x-ray of the patient following replacement of antifungal cement spacer and beads (after the third surgery).

Fig. 7.

The post-operative of the patient following bone grafting procedure using the modified Masquelet method. A. One day post-op. B. 6 months post-op. C. 10 months post-op.

3. Discussion

Fungal osteomyelitis remains a challenge not only to orthopaedic surgeons but also to internal medicine doctors. A review conducted by Asperges and colleagues highlighted a rising incidence of fungal osteomyelitis, with the United States reporting the highest number of cases [2]. The most commonly implicated pathogens were Aspergillus, Candida, and members of the order Mucorales. Infections caused by Aspergillus and Candida predominantly involved the permeative marrow lucency with a low incidence of periosteal reaction [2,[4], [5], [6], [7]].

Regarding mucormycosis-related osteomyelitis, Saad and colleagues, on behalf of the International Society for Human and Animal Mycology, analyzed 34 cases [1]. Their findings showed a mortality rate of 23% and a median diagnostic delay of 60 days (range: 10–180 days). The species were identified in 74% of cases (26/34 cases) [1] and in 85% of cases (18/21 cases) [8]. In our case, the fungal culture sample was collected from the necrosis cortical bone, while in the report of Costa-Paz [8], the fungal cultures were collected from joint fluid, synovial lining, ACL graft, and bone. Therefore, the fungal cultures of Costa-Paz and colleagues were negative in only 3 cases.

In the report of Saad [1], antifungal therapy in these cases extended for up to 570 days. Current treatment guidelines recommend systemic antifungal therapy with amphotericin B in combination with surgical debridement. The systemic use of amphotericin B remains limited due to its severe adverse effects, particularly acute renal failure, which poses significant therapeutic challenges [9,10].

Mucormycosis following anterior cruciate ligament reconstruction (ACLR) has rarely been reported. The first documented case by Burke and colleagues involved radical debridement and six weeks of intravenous amphotericin B, resulting in residual knee stiffness at follow-up [11]. Similarly, Muscolo and colleagues reported a case series of six patients treated with extensive surgical debridement and prolonged amphotericin B therapy [12]. Most patients ultimately required mega-prosthetic reconstruction to address large segmental bone loss; however, all experienced nephrotoxicity associated with long-term amphotericin B use.

To mitigate amphotericin B–related renal toxicity, several reports have explored the use of amphotericin B–loaded PMMA cement spacers [[13], [14], [15]]. Recent experimental studies have investigated optimal methods for incorporating amphotericin B into PMMA; however, even with advanced techniques, drug elution is limited to only a few days [[16], [17], [18]]. Consequently, the management of mucormycosis osteomyelitis remains a substantial clinical challenge.

The report by Costa-Paz and colleagues [8] found that the initial bone compromises were at the tibial or femoral tunnels, suggesting a potential contamination through drilling cannulated devices. In our case, the distal femur showed medial and lateral cortical bone destruction while the knee cartilage looked normal, suggesting that the fungal infection could be due to wound care after open debridement from previous surgery at the local hospital. Sundermann and colleagues showed that healthcare linens could be the cause with Mucorales contamination rate of 47% upon arrival at transplant and cancer hospital [19]. However, in our country, there have been no studies on finding the cleanliness of healthcare linens. Another study by Sundermann and colleagues showed that environmental remediation at the laundry facility could reduce the Mucorales culture positivity rate of healthcare linens from 20% to 0.3% [20]. However, to our knowledge, this was the first report of mucormycotic osteomyelitis after knee surgery in our country. If it was caused by healthcare linens, it would have led to cluster case reports.

Mucormycotic osteomyelitis is an uncommon but potentially fatal infection, and clinical outcomes are closely linked to timely diagnosis and treatment. Early recognition requires consideration of fungal etiology when diffuse cortical and medullary bone lesions are observed on imaging that do not correspond to the clinical picture. In addition, the prompt initiation of antifungal therapy, even before definitive pathogen identification, is a key factor in improving prognosis.

CRediT authorship contribution statement

Phu Nguyen Hoang: Writing – review & editing, Writing – original draft, Visualization, Validation, Investigation, Formal analysis. Dong Phan Ba Vu: Visualization, Formal analysis. Tinh Pham Van: Visualization, Investigation. Thong Pham Quang: Visualization, Investigation. Hung Do Phuoc: Writing – review & editing, Supervision, Conceptualization.

Ethical approval

This report was conducted in accordance with the World Medical Association Declaration of Helsinki.

Consent

Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

This report did not receive any specific grant from any funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

“The authors declare that they have no competing interests”.

Appendix A. Supplementary data

The following are the supplementary data related to this article: