Neurovascular Complications of Iatrogenic Fusarium solani Meningitis.

A multinational outbreak of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone surgery with epidural anesthesia in Mexico. The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury. Effective treatment options remain limited; in vitro susceptibility testing of the organism suggested that it is resistant to all currently approved antifungal medications in the United States. To highlight the severe complications associated with fusarium infection acquired in this manner, we report data, clinical courses, and outcomes from 13 patients in the outbreak who presented with symptoms after a median delay of 39 days.

Cerebrovascular Complications Associated With Iatrogenic Fungal Meningitis Following Surgical Procedures in Mexico.

BACKGROUND: The current fungal meningitis outbreak caused by contaminated epidural anesthesia with Fusarium solani among patients who underwent surgical procedures in Matamoros, Mexico remains a cause of concern. Its association with an increased susceptibility for cerebrovascular complications (CVC) has not been reported. This single-center study describes 3 patients with a unique pattern of CVC attributed to fungal meningitis. METHODS: A retrospective case series of patients diagnosed with fungal meningitis following surgical procedures under contaminated epidural anesthesia who developed a unique pattern of CVC during their hospitalization. RESULTS: Three female patients (mean age, 35 years) with CVC due to iatrogenic fungal meningitis were included. Positive Fungitell ß-D-glucan assay in cerebrospinal fluid was documented in all cases, and F. solani was confirmed by polymerase chain reaction in case 3. All cases were complicated by severe vertebrobasilar circulation vasculopathy and arterial dissections with resultant subarachnoid hemorrhage and intraventricular hemorrhage, ultimately leading to patients' death. CONCLUSIONS: The death toll from the ongoing fungal meningitis outbreak keeps rising, underscoring the need for early recognition and aggressive treatment. We highlight the risk for vertebrobasilar circulation CVC among these patients. The angioinvasive nature of F. solani is yet to be clarified; however, a clear pattern has been observed. Public health awareness should be raised and a strong response should be pursued.

Fungal Diseases Caused by Serious Contamination of Pharmaceuticals and Medical Devices, and Rapid Fungal Detection Using Nano-Diagnostic Tools: A Critical Review.

Fungal-contaminated compounded pharmaceuticals and medical devices pose a public health problem. This review aimed to provide an organized overview of the literature on that critical issue. Firstly, it was found that compounding pharmacies can produce drugs that are contaminated with fungi, leading to outbreaks of severe fungal diseases. Secondly, inadequate sterile compounding techniques or storage conditions, or exceeding the limit of a fungal count, can result in fungal contamination. Lastly, nanotools can be used to rapidly detect fungi, thus improving fungal diagnostic procedures. To achieve this goal, we have reviewed the published data on PubMed, the CDC, and FDA Web sites, and a literature search was undertaken to identify severe fungal infections associated with compounding pharmacies outside of hospitals, limited by the dates 2003 to 2021. The "Preferred Reporting Items for Critical Reviews" were followed in searching, including, and excluding papers. Fungal outbreaks have been documented due to contaminated pharmaceuticals and medical devices. In 2013, 55 people died from fungal meningitis caused by contaminated steroid injections containing methylprednisolone acetate. Additionally, in 2021, Aspergillus penicillioides contamination was reported in ChloraPrep drugs, which was attributed to the storage conditions that were conducive to the growth of this fungus. These incidents have resulted in severe infectious diseases, such as invasive mycoses, cornea infections, Endophthalmitis, and intestinal and gastric mycosis. By implementing preventive measures and policies, it is possible to avoid these outbreaks. Creating Nano-diagnostics presents a major challenge, where promptly diagnosing fungal infections is required to determine the proper corrective and preventive measures.

Coccidioidal Meningitis in New York Traced to Texas by Fungal Genomic Analysis.

A child developed hydrocephalus. Sixteen months later, it was discovered to be a complication of coccidioidal meningitis. The infection's source was uncertain until genomic analysis of the fungal isolate identified its origin to be a visit to Beeville, Texas. Improved national reporting of cases of coccidioidomycosis might reduce diagnostic delays.

Epidemiology of fungaemia in Sweden: A nationwide retrospective observational survey.

OBJECTIVES: To identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates to identify the epidemiology and antifungal susceptibilities of Candida spp. among blood culture isolates in Sweden. METHODS: The study was a retrospective, observational nationwide laboratory-based surveillance for fungaemia and fungal meningitis and was conducted from September 2015 to August 2016. RESULTS: In total, 488 Candida blood culture isolates were obtained from 471 patients (58% males). Compared to our previous study, the incidence of candidaemia has increased from 4.2/100 000 (2005-2006) to 4.7/100 000 population/year (2015-2016). The three most common Candida spp. isolated from blood cultures were Candida albicans (54.7%), Candida glabrata (19.7%) and species in the Candida parapsilosis complex (9.4%). Candida resistance to fluconazole was 2% in C. albicans and between 0% and 100%, in non-albicans species other than C. glabrata and C. krusei. Resistance to voriconazole was rare, except for C. glabrata, C. krusei and C. tropicalis. Resistance to anidulafungin was 3.8% while no Candida isolate was resistant to amphotericin B. CONCLUSIONS: We report an overall increase in candidaemia but a minor decrease of C. albicans while C. glabrata and C. parapsilosis remain constant over this 10-year period.

Fungal infections associated with contaminated methylprednisolone injections.

BACKGROUND: Fungal infections are rare complications of injections for treatment of chronic pain. In September 2012, we initiated an investigation into fungal infections associated with injections of preservative-free methylprednisolone acetate that was purchased from a single compounding pharmacy. METHODS: Three lots of methylprednisolone acetate were recalled by the pharmacy; examination of unopened vials later revealed fungus. Notification of all persons potentially exposed to implicated methylprednisolone acetate was conducted by federal, state, and local public health officials and by staff at clinical facilities that administered the drug. We collected clinical data on standardized case-report forms, and we tested for the presence of fungi in isolates and specimens by examining cultures and performing polymerase-chain-reaction assays and histopathological and immunohistochemical testing. RESULTS: By October 19, 2012, more than 99% of 13,534 potentially exposed persons had been contacted. As of July 1, 2013, there were 749 reported cases of infection in 20 states, with 61 deaths (8%). Laboratory evidence of Exserohilum rostratum was present in specimens from 153 case patients (20%). Additional data were available for 728 case patients (97%); 229 of these patients (31%) had meningitis with no other documented infection. Case patients had received a median of 1 injection (range, 1 to 6) of implicated methylprednisolone acetate. The median age of the patients was 64 years (range, 15 to 97), and the median incubation period (the number of days from the last injection to the date of the first diagnosis) was 47 days (range, 0 to 249); 40 patients (5%) had a stroke. CONCLUSIONS: Analysis of data from a large, multistate outbreak of fungal infections showed substantial morbidity and mortality. The infections were associated with injection of a contaminated glucocorticoid medication from a single compounding pharmacy. Rapid public health actions included prompt recall of the implicated product, notification of exposed persons, and early outreach to clinicians.

Clinical findings for fungal infections caused by methylprednisolone injections.

BACKGROUND: Since September 18, 2012, public health officials have been investigating a large outbreak of fungal meningitis and other infections in patients who received epidural, paraspinal, or joint injections with contaminated lots of methylprednisolone acetate. Little is known about infections caused by Exserohilum rostratum, the predominant outbreak-associated pathogen. We describe the early clinical course of outbreak-associated infections. METHODS: We reviewed medical records for outbreak cases reported to the Centers for Disease Control and Prevention before November 19, 2012, from the six states with the most reported cases (Florida, Indiana, Michigan, New Jersey, Tennessee, and Virginia). Polymerase-chain-reaction assays and immunohistochemical testing were performed on clinical isolates and tissue specimens for pathogen identification. RESULTS: Of 328 patients without peripheral-joint infection who were included in this investigation, 265 (81%) had central nervous system (CNS) infection and 63 (19%) had non-CNS infections only. Laboratory evidence of E. rostratum was found in 96 of 268 patients (36%) for whom samples were available. Among patients with CNS infections, strokes were associated with an increased severity of abnormalities in cerebrospinal fluid (P<0.001). Non-CNS infections were more frequent later in the course of the outbreak (median interval from last injection to diagnosis, 39 days for epidural abscess and 21 days for stroke; P<0.001), and such infections developed in patients with and in those without meningitis. CONCLUSIONS: The initial clinical findings from this outbreak suggest that fungal infections caused by epidural and paraspinal injection of a contaminated glucocorticoid product can result in a broad spectrum of clinical disease, reflecting possible variations in the pathogenic mechanism and in host and exposure risk factors. (Funded by the Centers for Disease Control and Prevention.).

Estimated deaths and illnesses averted during fungal meningitis outbreak associated with contaminated steroid injections, United States, 2012-2013.

During 2012-2013, the US Centers for Disease Control and Prevention and partners responded to a multistate outbreak of fungal infections linked to methylprednisolone acetate (MPA) injections produced by a compounding pharmacy. We evaluated the effects of public health actions on the scope of this outbreak. A comparison of 60-day case-fatality rates and clinical characteristics of patients given a diagnosis on or before October 4, the date the outbreak was widely publicized, with those of patients given a diagnosis after October 4 showed that an estimated 3,150 MPA injections, 153 cases of meningitis or stroke, and 124 deaths were averted. Compared with diagnosis after October 4, diagnosis on or before October 4 was significantly associated with a higher 60-day case-fatality rate (28% vs. 5%; p<0.0001). Aggressive public health action resulted in a substantially reduced estimated number of persons affected by this outbreak and improved survival of affected patients.

Fungal infections associated with contaminated methylprednisolone in Tennessee.

BACKGROUND: We investigated an outbreak of fungal infections of the central nervous system that occurred among patients who received epidural or paraspinal glucocorticoid injections of preservative-free methylprednisolone acetate prepared by a single compounding pharmacy. METHODS: Case patients were defined as patients with fungal meningitis, posterior circulation stroke, spinal osteomyelitis, or epidural abscess that developed after epidural or paraspinal glucocorticoid injections. Clinical and procedure data were abstracted. A cohort analysis was performed. RESULTS: The median age of the 66 case patients was 69 years (range, 23 to 91). The median time from the last epidural glucocorticoid injection to symptom onset was 18 days (range, 0 to 56). Patients presented with meningitis alone (73%), the cauda equina syndrome or focal infection (15%), or posterior circulation stroke with or without meningitis (12%). Symptoms and signs included headache (in 73% of the patients), new or worsening back pain (in 50%), neurologic symptoms (in 48%), nausea (in 39%), and stiff neck (in 29%). The median cerebrospinal fluid white-cell count on the first lumbar puncture among patients who presented with meningitis, with or without stroke or focal infection, was 648 per cubic millimeter (range, 6 to 10,140), with 78% granulocytes (range, 0 to 97); the protein level was 114 mg per deciliter (range, 29 to 440); and the glucose concentration was 44 mg per deciliter (range, 12 to 121) (2.5 mmol per liter [range, 0.7 to 6.7]). A total of 22 patients had laboratory confirmation of Exserohilum rostratum infection (21 patients) or Aspergillus fumigatus infection (1 patient). The risk of infection increased with exposure to lot 06292012@26, older vials, higher doses, multiple procedures, and translaminar approach to epidural glucocorticoid injection. Voriconazole was used to treat 61 patients (92%); 35 patients (53%) were also treated with liposomal amphotericin B. Eight patients (12%) died, seven of whom had stroke. CONCLUSIONS: We describe an outbreak of fungal meningitis after epidural or paraspinal glucocorticoid injection with methylprednisolone from a single compounding pharmacy. Rapid recognition of illness and prompt initiation of therapy are important to prevent complications. (Funded by the Tennessee Department of Health and the Centers for Disease Control and Prevention.).

The index case for the fungal meningitis outbreak in the United States.

Persistent neutrophilic meningitis presents a diagnostic challenge, because the differential diagnosis is broad and includes atypical infectious causes. We describe a case of persistent neutrophilic meningitis due to Aspergillus fumigatus in an immunocompetent man who had no evidence of sinopulmonary or cutaneous disease. An epidural glucocorticoid injection was identified as a potential route of entry for this organism into the central nervous system, and the case was reported to the state health department.

Utility of real-time PCR for detection of Exserohilum rostratum in body and tissue fluids during the multistate outbreak of fungal meningitis and other infections.

Exserohilum rostratum was the major cause of the multistate outbreak of fungal meningitis linked to contaminated injections of methylprednisolone acetate produced by the New England Compounding Center. Previously, we developed a fungal DNA extraction procedure and broad-range and E. rostratum-specific PCR assays and confirmed the presence of fungal DNA in 28% of the case patients. Here, we report the development and validation of a TaqMan real-time PCR assay for the detection of E. rostratum in body fluids, which we used to confirm infections in 57 additional case patients, bringing the total number of case patients with PCR results positive for E. rostratum to 171 (37% of the 461 case patients with available specimens). Compared to fungal culture and the previous PCR assays, this real-time PCR assay was more sensitive. Of the 139 identical specimens from case patients tested by all three methods, 19 (14%) were positive by culture, 41 (29%) were positive by the conventional PCR assay, and 65 (47%) were positive by the real-time PCR assay. We also compared the utility of the real-time PCR assay with that of the previously described beta-d-glucan (BDG) detection assay for monitoring response to treatment in case patients with serially collected CSF. Only the incident CSF specimens from most of the case patients were positive by real-time PCR, while most of the subsequently collected specimens were negative, confirming our previous observations that the BDG assay was more appropriate than the real-time PCR assay for monitoring the response to treatment. Our results also demonstrate that the real-time PCR assay is extremely susceptible to contamination and its results should be used only in conjunction with clinical and epidemiological data.

Update on Multistate Outbreak of Fungal Infections Associated with Contaminated Methylprednisolone Injections, 2012-2014.

During September 2012, CDC, in collaboration with state and local health departments and the Food and Drug Administration (FDA), investigated a multistate outbreak of fungal meningitis and other infections caused by injections of contaminated methylprednisolone acetate solution (MPA). After this unprecedented outbreak, scientists in the CDC Mycotic Diseases Branch, along with infectious diseases specialists who cared for patients from the outbreak, clinical experts, and public health officials from affected states, have continued to monitor the recovery of affected patients. A long-term follow-up study involving these patients was initiated and is being conducted by the Mycoses Study Group Education and Research Consortium (MSGERC). This update summarizes subsequent information about the current state of the outbreak.

Utility of (1-3)-ß-D-glucan testing for diagnostics and monitoring response to treatment during the multistate outbreak of fungal meningitis and other infections.

BACKGROUND: The 2012 outbreak of fungal meningitis associated with contaminated methylprednisolone produced by a compounding pharmacy has resulted in >750 infections. An important question facing patients and clinicians is the duration of antifungal therapy. We evaluated (1-3)-ß-d-glucan (BDG) as a marker for monitoring response to treatment. METHODS: We determined sensitivity and specificity of BDG testing using the Fungitell assay, by testing 41 cerebrospinal fluid (CSF) specimens from confirmed cases of fungal meningitis and 66 negative control CSF specimens. We also assessed whether BDG levels correlate with clinical status by using incident samples from 108 case patients with meningitis and 20 patients with serially collected CSF. RESULTS: A cutoff value of 138 pg/mL provided 100% sensitivity and 98% specificity for diagnosis of fungal meningitis in this outbreak. Patients with serially collected CSF were divided into 2 groups: those in whom BDG levels declined with treatment and those in whom BDG remained elevated. Whereas most patients with a decline in CSF BDG had clinical improvement, all 3 patients with continually elevated BDG had poor clinical outcomes (stroke, meningitis relapse, or development of new disease). CONCLUSIONS: Our data suggest that measuring BDG in CSF is a highly sensitive test for diagnosis of fungal meningitis in this outbreak. Analysis of BDG levels in serially collected CSF demonstrated that BDG may correlate with clinical response. Routine measurement of BDG in CSF may provide useful adjunctive data for the clinical management of patients with outbreak-associated meningitis.

Whole-genome analysis of Exserohilum rostratum from an outbreak of fungal meningitis and other infections.

Exserohilum rostratum was the cause of most cases of fungal meningitis and other infections associated with the injection of contaminated methylprednisolone acetate produced by the New England Compounding Center (NECC). Until this outbreak, very few human cases of Exserohilum infection had been reported, and very little was known about this dematiaceous fungus, which usually infects plants. Here, we report using whole-genome sequencing (WGS) for the detection of single nucleotide polymorphisms (SNPs) and phylogenetic analysis to investigate the molecular origin of the outbreak using 22 isolates of E. rostratum retrieved from 19 case patients with meningitis or epidural/spinal abscesses, 6 isolates from contaminated NECC vials, and 7 isolates unrelated to the outbreak. Our analysis indicates that all 28 isolates associated with the outbreak had nearly identical genomes of 33.8 Mb. A total of 8 SNPs were detected among the outbreak genomes, with no more than 2 SNPs separating any 2 of the 28 genomes. The outbreak genomes were separated from the next most closely related control strain by ∼136,000 SNPs. We also observed significant genomic variability among strains unrelated to the outbreak, which may suggest the possibility of cryptic speciation in E. rostratum.

Detection of fungal DNA in human body fluids and tissues during a multistate outbreak of fungal meningitis and other infections.

Exserohilum rostratum was the major cause of an outbreak of fungal infections linked to injections of contaminated methylprednisolone acetate. Because almost 14,000 persons were exposed to product that was possibly contaminated with multiple fungal pathogens, there was unprecedented need for a rapid throughput diagnostic test that could detect both E. rostratum and other unusual agents of fungal infection. Here we report development of a novel PCR test that allowed for rapid and specific detection of fungal DNA in cerebrospinal fluid (CSF), other body fluids and tissues of infected individuals. The test relied on direct purification of free-circulating fungal DNA from fluids and subsequent PCR amplification and sequencing. Using this method, we detected Exserohilum rostratum DNA in 123 samples from 114 case-patients (28% of 413 case-patients for whom 627 samples were available), and Cladosporium DNA in one sample from one case-patient. PCR with novel Exserohilum-specific ITS-2 region primers detected 25 case-patients with samples that were negative using broad-range ITS primers. Compared to fungal culture, this molecular test was more sensitive: of 139 case-patients with an identical specimen tested by culture and PCR, E. rostratum was recovered in culture from 19 (14%), but detected by PCR in 41 (29%), showing a diagnostic sensitivity of 29% for PCR compared to 14% for culture in this patient group. The ability to rapidly confirm the etiologic role of E. rostratum in these infections provided an important contribution in the public health response to this outbreak.

Early clinical observations in prospectively followed patients with fungal meningitis related to contaminated epidural steroid injections.

UNLABELLED: Chinese translation BACKGROUND: Administration of epidural steroid injections (ESIs) with contaminated methylprednisolone resulted in an outbreak of fungal meningitis in many locations in the United States. OBJECTIVE: To characterize early clinical findings and initial response to treatment. DESIGN: Case series with standardized observation studied from 4 October to 31 October 2012. SETTING: An 800-bed hospital in Virginia. PATIENTS: 172 patients who presented to the hospital with exposure to contaminated ESI. INTERVENTION: Standardized approach to screening, case definition, treatment, and data collection. MEASUREMENTS: Clinical findings, cerebrospinal fluid (CSF) values, magnetic resonance imaging (MRI), serum and CSF voriconazole concentrations, and clinician assessment of response to therapy. RESULTS: Of 172 patients presenting to the hospital who had had ESI, 131 had lumbar puncture because of symptoms or signs consistent with central nervous system disease. Twenty-five (19%) had neutrophilic meningitis. All were started on voriconazole therapy alone. Three patients developed stroke during treatment. Ten patients had arachnoiditis, another had an epidural abscess, and 9 had urine retention. Fifteen continued to receive voriconazole, and 10 were switched to amphotericin B. Cerebrospinal fluid leukocyte counts began to decrease by day 13 of treatment. Findings on MRI included ventriculitis, leptomeningeal enhancement, infarction, hemorrhage, and arachnoiditis. Serum voriconazole levels varied, and CSF concentrations of voriconazole were approximately 50% those of serum. Exserohilum rostratum and Cladosporium species have been cultured. LIMITATIONS: This is an observational study of an evolving outbreak. Not all exposed patients presented for evaluation. Follow-up is too short to determine final outcomes. CONCLUSION: Meningitis after receipt of contaminated ESI has been diagnosed in many exposed patients presenting to 1 hospital. Most patients have improved on receipt of empirical voriconazole therapy. The full natural history and long-term sequelae of this infection are currently unknown. PRIMARY FUNDING SOURCE: None.

What can we learn and what do we need to know amidst the iatrogenic outbreak of Exserohilum rostratum meningitis?

The tragedy of the ongoing epidemic of meningitis caused by Exserohilum rostratum brings into focus the epidemiology, risk factors, pathogenesis, diagnosis, and treatment of a multitude of opportunistic mold infections of the central nervous system. Herein we provide our perspective regarding the translational research objectives of this infection that are needed to make an impact on this important healthcare crisis.

Insights into fungal pathogenesis from the iatrogenic epidemic of Exserohilum rostratum fungal meningitis.

In 2012 the medical community in the United States faced an unprecedented outbreak of fungal meningitis caused by Exserohilum rostratum associated with injections of contaminated lots of methyprednilsone acetate. Rapid response by public health authorities led to the identification of the cause of the outbreak and the epidemic quickly abated, even though new cases were still being reported many months later. Although the cause of the outbreak is known there are many uncertainties regarding the management of infected individuals and the long term risk for those who were exposed to this organism. The epidemic of E. rostratum infections illustrates how an organism that normally has low pathogenic potential for humans can transform into a very dangerous pathogen when conditions are changed such that skin barriers are breached while it is simultaneously delivered with an immunosuppressive drug. Furthermore, this epidemic highlights the potential threats to human and animal health from the fungal kingdom.