Background: Macrophomina phaseolina is an important phytopathogenic fungus affecting over 500 plant species worldwide. However, this fungus rarely causes disease in humans. Methods: We reported the first case of endophthalmitis due to M. phaseolina, describing microbiological diagnostic approaches. Also, we performed a systematic review of human infections by this plant pathogen in literature. We searched PubMed, Scopus, and Web of Science databases from inception to 31 December 2024. Results: Our case involved a male patient who presented with photophobia and pain in his right eye. His recent medical history revealed a superficial corneal injury caused by a metal burr three months prior, managed unsuccessfully by topical treatment and subsequent conjunctival flap surgery two months later. Ophthalmological and microbiological investigations, including microscopic examination, cultures, and DNA sequencing of ocular specimens, revealed M. phaseolina endophthalmitis. Despite intravenous and intravitreal antifungal therapy, the patient’s condition continued to worsen, eventually leading to enucleation. Regarding the literature review, we identified 12 additional cases of M. phaseolina human infections previously reported in literature. Overall, M. phaseolina was primarily associated with ocular infections (76.9% of cases), followed by skin infections and combined skin–joint infections. The majority of patients with M. phaseolina infection (63.6%) had no known immunosuppressive factors. Clinical outcomes were unfavorable in 46.15% of cases. Conclusions: M. phaseolina is an emerging cause of human infections, even in immunocompetent hosts, with a predilection for ocular infections. Further research is warranted to elucidate the pathogenesis of fungal infections caused by plant pathogens in humans.
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