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.

Cryptococcosis in HIV-AIDS patients from Southern Brazil: Still a major problem.

INTRODUCTION: Cryptococcus neoformans is an opportunistic pathogen that causes ∼15% mortality in AIDS patients. Rio Grande City, Rio Grande do Sul (RS), Brazil, has the highest national rate of HIV/AIDS, considering cities with population more than 100,000 habitants. OBJECTIVE: We aimed to evaluate the clinical and epidemiological profile of cryptococcosis in a reference service for HIV-AIDS patients in the South region of Brazil, over seven years. Material and methods A retrospective study was performed including all cryptococcosis cases diagnosed at the University Hospital, Federal University of Rio Grande (UH-FURG) between January 2010 and December 2016. RESULTS: Seventy cases of cryptococcosis were diagnosis from 2010 to 2016 in the UH-FURG in the seven years of the study. These numbers were responsible for 2.1% to 8.1% of the hospitalizations/year for HIV patients. All were caused by C. neoformans infection (95% C. neoformans var. grubii VNI and 5% C. neoformans var. grubii VNII). Neurocryptococcosis was the major clinical manifestation and cryptococcosis was the HIV- defining condition in 40% of patients. The period of hospitalization was an average of 39.3 days (SD=31.3), and more than half of patients (53%; 37/70) died after a mean of 82 days. DISCUSSION: The present study showed the importance of cryptococcosis as an AIDS-defining disease in HIV-AIDS patients in a tertiary hospital from Southern Brazil. More investment is necessary to reduce the impact of this opportunistic mycosis in HIV-AIDS patients from southern Brazil.

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.

Epidemiological Effectiveness and Cost of a Fungal Meningitis Outbreak Response in New River Valley, Virginia: Local Health Department and Clinical Perspectives.

OBJECTIVE: We evaluated the effectiveness and cost of a fungal meningitis outbreak response in the New River Valley of Virginia during 2012-2013 from the perspective of the local public health department and clinical facilities. The fungal meningitis outbreak affected 23 states in the United States with 751 cases and 64 deaths in 20 states; there were 56 cases and 5 deaths in Virginia. METHODS: We conducted a partial economic evaluation of the fungal meningitis outbreak response in New River Valley. We collected costs associated with the local health department and clinical facilities in the outbreak response and estimated the epidemiological effectiveness by using disability-adjusted life years (DALYs) averted. RESULTS: We estimated the epidemiological effectiveness of this outbreak response to be 153 DALYs averted among the patients, and the costs incurred by the local health department and clinical facilities to be $30,413 and $39,580, respectively. CONCLUSIONS: We estimated the incremental cost-effectiveness ratio of $198 per DALY averted and $258 per DALY averted from the local health department and clinical perspectives, respectively, thereby assisting in impact evaluation of the outbreak response by the local health department and clinical facilities. (Disaster Med Public Health Preparedness. 2018;12:38-46).

Prevalence, healthcare resource utilization and overall burden of fungal meningitis in the United States.

PURPOSE: Previous epidemiological and cost studies of fungal meningitis have largely focused on single pathogens, leading to a poor understanding of the disease in general. We studied the largest and most diverse group of fungal meningitis patients to date, over the longest follow-up period, to examine the broad impact on resource utilization within the United States. METHODOLOGY: The Truven Health Analytics MarketScan database was used to identify patients with a fungal meningitis diagnosis in the United States between 2000 and 2012. Patients with a primary diagnosis of cryptococcal, Coccidioides, Histoplasma, or Candida meningitis were included in the analysis. Data concerning healthcare resource utilization, prevalence and length of stay were collected for up to 5 years following the original diagnosis. RESULTS: Cryptococcal meningitis was the most prevalent type of fungal meningitis (70.1 % of cases over the duration of the study), followed by coccidioidomycosis (16.4 %), histoplasmosis (6.0 %) and candidiasis (7.6 %). Cryptococcal meningitis and candidiasis patients accrued the largest average charges ($103 236 and $103 803, respectively) and spent the most time in the hospital on average (70.6 and 79 days). Coccidioidomycosis and histoplasmosis patients also accrued substantial charges and time in the hospital ($82 439, 48.1 days; $78 609, 49.8 days, respectively). CONCLUSION: Our study characterizes the largest longitudinal cohort of fungal meningitis in the United States. Importantly, the health economic impact and long-term morbidity from these infections are quantified and reviewed. The healthcare resource utilization of fungal meningitis patients in the United States is substantial.

Clinical Response, Outbreak Investigation, and Epidemiology of the Fungal Meningitis Epidemic in the United States: Systematic Review.

We conducted a systematic review of the 2012-2013 multistate fungal meningitis epidemic in the United States from the perspectives of clinical response, outbreak investigation, and epidemiology. Articles focused on clinical response, outbreak investigation, and epidemiology were included, whereas articles focused on compounding pharmacies, legislation and litigation, diagnostics, microbiology, and pathogenesis were excluded. We reviewed 19 articles by use of the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework. The source of the fungal meningitis outbreak was traced to the New England Compounding Center in Massachusetts, where injectable methylprednisolone acetate products were contaminated with the predominant pathogen, Exserohilum rostratum. As of October 23, 2013, the final case count stood at 751 patients and 64 deaths, and no additional cases are anticipated. The multisectoral public health response to the fungal meningitis epidemic from the hospitals, clinics, pharmacies, and the public health system at the local, state, and federal levels led to an efficient epidemiological investigation to trace the outbreak source and rapid implementation of multiple response plans. This systematic review reaffirms the effective execution of a multisectoral public health response and efficient delivery of the core functions of public health assessment, policy development, and service assurances to improve population health.

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.

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.

Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.

The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19-275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.

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.

Sterile compounding: clinical, legal, and regulatory implications for patient safety.

BACKGROUND: Poor compounding practices by the New England Compounding Center resulted in the 2012-2013 fungal infections outbreak. Contaminated injectable methylprednisolone led to the diagnosis of fungal infections in 751 patients and 64 deaths. In the United States, pharmacy compounding has traditionally been regulated by state boards of pharmacy rather than the FDA. To minimize safety risks related to pharmacy compounding, the Drug Quality and Security Act (DQSA) was signed into law November 27, 2013, to improve regulation of compounding pharmacies. OBJECTIVES: To (a) review the literature regarding clinical, legal, and regulatory implications of pharmacy compounding for patient safety during the 2012-2013 fungal infections outbreak and (b) discuss strategies that managed care organizations (MCOs) can use to promote safe compounding practices.  METHODS: A literature search was conducted via PubMed for original articles on fungal infections related to drug compounding published October 2012 to March 2014. Specific search terms included "drug compounding and fungal infection" and "fungal meningitis outbreak." The FDA website was also utilized for material related to the Food, Drug, and Cosmetic Act and the DQSA.  RESULTS: Four articles met inclusion criteria. The 2012-2013 fungal infections outbreak was attributed to 3 lots of preservative-free methylprednisolone acetate, which comprised 17,675 vials distributed to 76 facilities across 23 states. Median incubation period (from time of last injection to initial diagnosis) was 47 days, ranging from 0 to 249 days. According to the FDA, a total of 30 recalls regarding compounded products were issued by pharmacies during March through December 2013. CONCLUSIONS: Pharmacy compounding has the potential for significant safety risks. The purpose of the DQSA is to improve regulation of compounding pharmacies. Since registration as an outsourcing facility is voluntary, uncertainty still remains regarding advancement in safe compounding practices. MCOs can employ multiple strategies to ensure patient safety and promote appropriate drug therapy.

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.