Background: Cryptococcus spp. is an opportunistic fungal pathogen rarely infecting immunocompetent individuals. Cryptococcal osteomyelitis is an uncommon disease characterized by the invasion of bone tissue by Cryptococcus. It typically arises in disseminated infection, while isolated cryptococcal osteomyelitis is scarcely diagnosed. This study seeks to review all published Cryptococcus spp. osteomyelitis cases in humans, focusing on epidemiology, microbiology, clinical complications, treatment, and clinical outcomes.

Methods: A systematic review was conducted through a literature search of PubMed and Scopus databases. The protocol was registered in Prospero (ID: CRD42024627780).

Results: In total, 106 studies provided data on 118 patients with Cryptococcus spp. osteomyelitis. The mean age of patients was 41.83 years and 56.41% were male. Immunosuppression constituted the most common predisposing risk factor (17.8%), followed by history of tuberculosis (15.25%) or diabetes mellitus (12.71%). The most frequently infected bone structures included the thorax (24.58%), vertebrae, and upper extremities (15.25% respectively), while in 16.1%, multiple bones were involved. Cryptococcus neoformans was the identified pathogen in most cases (97.22%). Fluconazole (72.41%), amphotericin B (62.93%), and flucytosine (34.48%) were the most commonly used antifungals. In 47.41%, a combination of antifungals was administered. Overall mortality was relatively low (7.63%), while only 4.24% of deaths were attributed to the infection.

Conclusions: Given the potential of Cryptococcus spp. to cause severe bone infection, clinicians should include this disease in the differential when encountering yeast microorganisms in microbiological specimens, especially in patients with significant comorbidities or immunodeficiency. This is essential for ensuring accurate diagnosis and appropriate treatment.