Fusarium Meningitis

By Stan Deresinski, MD, FACP, FIDSA

Clinical Professor of Medicine, Stanford University

SYNOPSIS: The presentation, management, and course of 13 patients in Texas with meningitis due to Fusarium solani occurring after spinal epidural anesthesia in Mexico are presented. At least nine have died despite multiple interventions.

SOURCE: Strong N, Meeks G, Sheth SA, et al. Neurovascular complications of iatrogenic Fusarium solani meningitis. N Engl J Med 2024;390:522-529.

An outbreak of fungal meningitis due to Fusarium solani in patients who underwent surgical procedures involving spinal epidural anesthesia occurred at two clinics in Matamaros, Mexico, just across the Rio Grande from Brownsville, TX. Thirty-three of the affected patients were from the United States, including nine suspected cases, 14 probable cases, and 10 confirmed cases, with 12 deaths among the probable and confirmed cases. Strong and colleagues reported the experience with 13 patients hospitalized in southeastern Texas.

Hospital admission was delayed by a median of 39 days after the onset of symptoms. Two symptomatic patients were notified by a health department to seek emergency care, and both were discharged from the emergency department without having undergone lumbar puncture — only to return with worsening symptoms. Cerebrospinal fluid (CSF) opening pressure was elevated in 8/10 patients, and pleocytosis, hypoglycorrhachia, and increased protein concentration, as well as elevated 1,3-beta-d-glucan concentrations occurred in all 13 patients.

“Yeast-like” forms were reported on Gram stain in two cases, but all cultures were negative. Panfungal polymerase chain reaction (PCR) was positive in 5/10 cases, with one detecting Ascomycota (the phylum in which Fusarium belongs), and in four, 28S ribosomal ribonucleic acid (rRNA) sequencing identified F. solani. Post-mortem tissue culture yielded F. solani in a single patient. The organism was found to be resistant to anidulafungin, caspofungin, micafungin, rezafungin, ibrexafungerp, itraconazole, posaconazole, voriconazole, isavuconazole, olorofim, and terbinafine, while it was highly susceptible to manogepix, with a minimal inhibitory concentration (MIC) of ≤ 0.008 mg/L.

Among imaging findings, significant abnormalities were prominent at the skull base, including the cranial subarachnoid space, the prepontine cistern, and the fourth ventricle, with vascular abnormalities due to fungal invasion of the vertebrobasilar arterial system. Resulting arterial complications included stenoses and occlusions with brain stem and cerebellar infarction, as well as subarachnoid and parenchymal hemorrhage.

Glucocorticoids were administered to 10/13 patients, often in response to the detection of vascular abnormalities. Twelve patients initially received voriconazole and intravenous liposomal amphotericin B (LAB). Nine patients were given intrathecal LAB in response to disease progression. A variety of interventions were implemented as appeared to be indicated, such as CSF diversion (e.g., drains, shunting) as well as vascular interventions. Patients often initially improved before deteriorating, often in association with vascular complications.

At the time of this report, only 4/13 patients were still alive, three of whom had been discharged from the hospital. All four received voriconazole and intravenous LAB, three of the four received intrathecal LAB, and three of the four received fosmanogepix (a manogepix prodrug), which was obtained upon learning the results of susceptibility testing of the single fungal isolate. Three of the four survivors had no neurological sequelae.

COMMENTARY

This outbreak is not the first of its kind. A 2012 U.S. outbreak of meningitis and intradural abscess formations due to Exserohilum rostratum contamination of methylprednisolone used in epidural injections affected 753 patients, 61 of whom died.¹ Another outbreak associated with epidural anesthesia in 2022 in Durango, Mexico, involved 80 cases with 41 deaths.² The vascular complications of infection with Fusarium, which appears to be angioinvasive, are a key component in its virulence in this setting.

The authors indicated that the optimal responses were seen in the small number of patients given fosmanogepix, a phosphonooxymethylene prodrug of manogepix for which the MIC of the single available isolate was ≤ 0.008 mg/L, while it was resistant to all other antifungals tested. The target of manogepix is a highly conserved fungal enzyme, Gwt1, which is required for acylation of inositol in the glycosylphosphatidylinositol biosynthesis pathway, which is necessary for anchoring of mannoproteins to the fungal cell wall. Its disruption compromises fungal cell wall integrity.³

As of this time, fosmanogepix remains an investigative agent, and acquisition is through an expanded access program.⁴

REFERENCES

1. Renfrow JJ, Frenkel MB, Hsu W. Fungal contamination of methylprednisolone causing recurrent lumbosacral intradural abscess. Emerg Infect Dis 2017;23:552-553.
2. Secretaría de Salud. Comunicado técnico semanal — meningitis, Durango. Nov. 28, 2023. https://www.gob.mx/cms/uploads/attachment/file/874853/COMUNICADO_TECNICO_SEMANAL_28NOVIEMBRE2023.pdf
3. Shaw KJ, Ibrahim AS. Fosmanogepix: A review of the first-in-class broad spectrum agent for the treatment of invasive fungal infections. J Fungi (Basel) 2020;6:239.
4. Pfizer. Expanded Access and Compassionate Use. https://www.pfizer.com/science/clinical-trials/expanded-access