Pathogenic Nocardia: A diverse genus of emerging pathogens or just poorly recognized?

Introduction to pathogenic Nocardia, a clinically relevant non-ESKAPE pathogenThe clear and present danger posed by the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species) and their ability to evade antimicrobials is generally well appreciated [1].There are, however, a multitude of pathogens, some more rare than others, that can be clinically challenging to diagnose and treat.Nocardia, a genus of aerobic actinomycetes found ubiquitously in soil and water, harbors one such group of pathogens with unique attributes and often complicated properties.Opportunistic infections caused by Nocardia often afflict immunocompromised individuals like cancer patients receiving chemotherapy, individuals with AIDS, and organ transplant recipients.Although commonly considered opportunistic, among 1,000 cases of Nocardia infection published between 1950 and 1991, about one-third occurred in patients with no identifiable underlying predisposing conditions [2], implying that immune status is not the only factor affecting infectivity.Skin and lung are the primary infection sites for these rod shaped, gram-positive bacteria.Nocardia also have the ability to survive as facultative intracellular parasites within macrophages [3,4] and escape killing by human neutrophils and monocytes [5].Infections can sometimes be largely asymptomatic, which, when coupled with the slow growth rate of Nocardia, makes them difficult to identify in clinical specimens [6].Dissemination, particularly to the central nervous system (CNS), is relatively common and can be life threatening, with mortality rates as high as 85% in immunocompromised individuals [6][7][8].To date, 119 species of Nocardia have been documented (http://www.bacterio.net/ nocardia.html),with more than 40 of them being considered clinically relevant (https://www. cdc.gov/nocardiosis/health-care-workers/index.html). Nocardia infections: Difficult to identify and difficult to treatThe ability of this organism to cause infection was first recognized in 1888 [9].However, to date, Nocardia has received relatively little attention as a human pathogen.The Centers for Disease Control and Prevention (CDC) estimates approximately 500 to 1000 new cases of nocardiosis infections occur every year in the United States (https://www.cdc.gov/nocardiosis/ infection/index.html).This statistic is based on a study conducted in 1976 [9] but is likely to be a significant underestimate given the paucity of molecular diagnostics in that era.Nocardia isolates can take up to two weeks to grow on routine culture media used in clinical labs, and mixed bacterial infections can further obscure identification [3,10].Concomitant infections in immunocompromised individuals are common and can include Nocardia co-infecting with

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