Fungal Endophthalmitis Associated with Compounded Products

Mikosz, Christina A.; Smith, Rachel M.; Kim, Moon J.; Tyson, Clara; Lee, Ellen H.; Adams, Eleanor; Straif-Bourgeois, Susanne; Sowadsky, Rick; Arroyo, Shannon; Grant-Greene, Yoran; Duran, Julie; Vasquez, Yvonne; Robinson, Byron; Harris, Julie; Lockhart, Shawn R.; Török, Thomas J.; Mascola, Laurene; Park, Benjamin J.

doi:10.3201/eid2002.131257

Cited by 46 publications

(40 citation statements)

References 27 publications

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“…This strongly supported the epidemiological data suggesting that the source was likely not a single-source contaminated product but rather that the likely sources of the infections were environmental. In contrast, the B. hawaiiensis isolates implicated in the 2012 endophthalmitis outbreak were clonal to the extent that was shown with this typing system, which confirms the epidemiological data suggesting that the mode of transmission was likely due to contaminated triamcinolone steroid injected into the eyes of patients (5). Although fungal outbreaks are relatively uncommon, there have been a number of high-profile fungal-related outbreaks in recent years (27).…”

Section: Discussionsupporting

confidence: 70%

“…The 16 B. hawaiiensis isolates were separated into 9 different STs. All isolates from a previous Bipolaris endophthalmitis outbreak (5) had identical STs, consistent with the epidemiological conclusion of a point source from a contaminated medication. The three B. australiensis isolates were divided into three unique STs.…”

Section: Morphological and Ribosomal Dna Sequence Characteristics Ofsupporting

confidence: 53%

“…(12)(13)(14)(15)(16)(17)(18). The recent investigations of infections caused by dematiaceous fungi (5,19) have highlighted the importance of high-resolution, standardized, and archivable typing system(s) for this group of fungi.…”

mentioning

confidence: 99%

“…Here, we describe the development and implementation of a novel MLST system using six different DNA loci to differentiate B. spicifera, B. hawaiiensis, and B. australiensis isolates from case pa- tients, controls, and the environment, collected during the investigation of the cluster of fungal SSIs among POCS patients as well as from a preexisting culture collection at the CDC, including Bipolaris isolates from a previous outbreak of endophthalmitis (5).…”

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confidence: 99%

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Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

et al. 2015

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cMultilocus sequence typing (MLST) is the gold standard genotyping technique for many microorganisms. This classification approach satisfies the requirements for a high-resolution, standardized, and archivable taxonomic system. Here, we describe the development of a novel MLST system to assist with the investigation of an unusual cluster of surgical site infections caused by Bipolaris spp. in postoperative cardiothoracic surgery (POCS) patients during January 2008 to December 2013 in the southeastern United States. We also used the same MLST system to perform a retrospective analysis on isolates from a 2012 Bipolaris endophthalmitis outbreak caused by a contaminated product. This MLST system showed high intraspecies discriminatory power for Bipolaris spicifera, B. hawaiiensis, and B. australiensis. Based on the relatedness of the isolates, the MLST data supported the hypothesis that infections in the POCS cluster were from different environmental sources while confirming that the endophthalmitis outbreak resulted from a point source, which was a contaminated medication. Dematiaceous fungi belonging to the genus Bipolaris are abundant in the environment. Many species in this genus are known to cause devastating disease in plants and staple crops around the world (1). In humans, they are common etiological agents of fungal sinusitis. Surgical site infections (SSIs) and deep tissue and invasive infections by members of this genus do occur, but they are extremely rare and typically associated with immunocompromised patients (2-7). The common disease-causing Bipolaris species in humans are Bipolaris spicifera, B. hawaiiensis, and, occasionally, B. australiensis (3). A recent proposal transfers these species to the genus Curvularia (1), but this new name has not yet been widely accepted.In the clinical setting, Bipolaris infections are usually diagnosed using microscopy to distinguish the morphological characteristics of the fungus following culture. In recent years, the sequence comprising the internal transcribed spacer (ITS) regions and the 5.8S nuclear rRNA genes of the ribosomal cistron has been exploited for species assignment of dematiaceous fungi (8, 9). In most cases, ITS-based sequence identification is sufficient for determining species. However, ITS-based sequencing is limited by its dependence on the completeness and accuracy of available DNA sequence databases. A DNA typing system employing two or more loci, such as multilocus sequence typing (MLST), can be used when it is necessary to distinguish between isolates within a species (10, 11). MLST has been successfully implemented for species identification within a species complex as well as strain differentiation within a species for various fungal pathogens of humans such as Aspergillus fumigatus, Candida albicans, Candida glabrata, Candida tropicalis, Cryptococcus gattii, Cryptococcus neoformans, and Fusarium sp. (12-18). The recent investigations of infections caused by dematiaceous fungi (5, 19) have highlighted the importance of high-resolution, sta...

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Section: Discussionsupporting

confidence: 70%

Section: Morphological and Ribosomal Dna Sequence Characteristics Ofsupporting

confidence: 53%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

et al. 2015

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“…This is especially important for outbreaks of fungal infections where rapid laboratory methods to establish the relatedness of different strains may be the critical factor in determining whether a cluster of rare mold infections represent a true outbreak or a just an unusual coincidence. In the past 18 months, the CDC has investigated several potential outbreaks of rare molds that did not have established DNA typing methods, including an outbreak of Bipolaris hawaiiensis associated with compounded triamcinolone for intraocular administration (37), Curvularia (Bipolaris) spicifera in cardiac surgical site infections (CDC unpublished data), and Apophysomyces trapeziformis soft tissue infections occurring after a natural disaster (21). The determination of whether these isolates were related relied on painstaking epidemiologic studies, as typing methods were not initially available.…”

Section: Discussionmentioning

confidence: 99%

Whole-Genome Analysis of Exserohilum rostratum from an Outbreak of Fungal Meningitis and Other Infections

et al. 2014

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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 ϳ136,000 SNPs. We also observed significant genomic variability among strains unrelated to the outbreak, which may suggest the possibility of cryptic speciation in E. rostratum. Beginning in September, 2012, the United States experienced one of the largest outbreaks of health care-associated infections ever reported. More than 13,000 people were exposed to three lots of contaminated methylprednisolone acetate (MPA) produced by a single compounding pharmacy, and Ͼ750 developed fungal infections following their MPA injections (1-3). Infections included meningitis, as well as localized epidural, paraspinal, and peripheral joint infections, complicated by arachnoiditis and abscess formation (4, 5). Although several fungal species were implicated in the outbreak, the vast majority of infections were caused by Exserohilum rostratum, a saprobic mold found in soil and plant debris worldwide (2, 6-10). Most species of Exserohilum are plant pathogens. Exserohilum rostratum and the species formerly known as Exserohilum longirostratum and Exserohilum mcginnisii are morphologically similar and are the only species known to cause human infections; however, their taxonomic status remains under investigation (11-13).DNA fingerprinting has been used as an epidemiological tool to answer questions pertaining to strain relatedness (14, 15). However, no methodologies for DNA fingerprinting of E. rostratum existed at the time of the outbreak. While whole-genome sequencing (WGS) is a relatively new tool of molecular epidemiology, it has quickly been embraced as a mechanism for inferring phylogenetic relationships among organisms. This has translated to the recent use of whole-genome single nucleotide polymorphism (SNP) typing (whole-genome sequence typing [WGST]) as a mechanism for inferring relatedness of both bacteria (16)(17)(18)(19) and fungi (20, 21) during outbreak investigations. One of the benefits of WGST is that prior knowledge of the genome i...

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Utility of Ophthalmologic Screening for Patients With Candida Bloodstream Infections

et al. 2019

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Fungal Endophthalmitis Associated with Compounded Products

Cited by 46 publications

References 27 publications

Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

Development of a Multilocus Sequence Typing System for Medically Relevant Bipolaris Species

Whole-Genome Analysis of Exserohilum rostratum from an Outbreak of Fungal Meningitis and Other Infections

Utility of Ophthalmologic Screening for Patients With Candida Bloodstream Infections

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