International Journal of Infectious Diseases 92 (2020) 197–207 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal homepage: www.elsevier.com/locate/ijid Nocardia bacteremia: A single-center retrospective review and a systematic review of the literature a,b, a,b,c a,b,c Eloise Williams *, Adam W. Jenney , Denis W. Spelman a Microbiology Unit, Alfred Health, 55 Commercial Rd, Melbourne, Victoria, Australia b Department of Infectious Diseases, Alfred Health, 55 Commercial Rd, Melbourne, Victoria, Australia c Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia A R T I C L E I N F O A B S T R A C T Article history: Objectives: Nocardia bacteremia is a rare but severe disease associated with high mortality. This Received 14 August 2019 systematic review is the largest and most comprehensive review performed over the past 20 years. Received in revised form 21 December 2019 Methods: A single-center retrospective review of Nocardia bacteremia was performed using hospital Accepted 13 January 2020 microbiology records from January 1, 2010 to December 31, 2017. A systematic literature review was also performed to identify cases of Nocardia bacteremia described in the NCBI PubMed database in English Keywords: between January 1, 1999 and December 31, 2018. Nocardia Results: Four new cases of Nocardia bacteremia are described. The systematic review identified 134 cases Nocardiosis with sufficient information available for analysis. Of the total 138 cases, the median age was 58 years Bacteremia (interquartile range (IQR) 44–69 years) and 70% were male. Eighty-one percent were immunocom- Central line-associated bloodstream infection promised (corticosteroid use (49%), hematological malignancy (20%), solid organ transplant (20%), Immunocompromise solid organ malignancy (19%), and hematopoietic stem cell transplantation (15%)) and 29% had endovascular devices. Pulmonary infection was the most common concurrent site of clinical disease (67%). The median incubation time to the detection of Nocardia bacteremia was 4 days (IQR 3–6 days). Blood cultures were the only positive microbiological specimen in 38% of cases. The median total duration of treatment was 75 days (IQR 25–182 days). Thirty-day all-cause mortality was 28% and overall all-cause mortality was 40%. Conclusions: Nocardia bacteremia is most frequently identified in immunocompromised patients and those with intravascular devices. Although rare, it represents a serious infection with high associated overall mortality. © 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by- nc-nd/4.0/). Introduction Beaman, 1994; Beaman et al., 1976; Curry, 1980). Patients at increased risk include those with solid organ transplantation Nocardia species are aerobic, partially acid-fast, beaded, (SOT), hematopoietic stem cell transplantation (HSCT), hemato- branching gram-positive bacilli with colonies that produce aerial logical malignancy, solid organ malignancy (SOM), Human hyphae (Brown-Elliott et al., 2006). These ubiquitous environ- immunodeficiency virus (HIV) infection, those receiving long- mental organisms can be found worldwide in components of soil, term corticosteroid therapy or other medications that suppress dust, decaying vegetation, and other organic matter, as well as salt cell-mediated immunity, diabetes, and alcoholism (Beaman and and fresh water (Wilson, 2012). Nocardiosis is regarded as an Beaman, 1994; Filice, 2005; Wilson, 2012). opportunistic infection, with the majority of infections occurring Nocardiosis most frequently presents with pulmonary disease, in immunocompromised patients, particularly those with im- followed by disseminated disease, extrapulmonary disease (most paired cell-mediated immunity. However, 22–39% of patients with often presenting in the central nervous system (CNS)), and primary nocardiosis have no known immunodeficiency (Beaman and skin and soft tissue disease (Beaman and Beaman,1994). Thirty-two percent of patients will have disseminated disease at presentation (Beaman and Beaman, 1994), presumably due to hematogenous spread from pulmonary or cutaneous sites of inoculation. However, * Corresponding author at: Microbiology Unit, Austin Health, 145 Studley Rd, despite the frequency of disseminated disease and the propensity of Heidelberg, Victoria, Australia. E-mail address: [email protected] (E. Williams). nocardiosis to affect immunocompromised hosts, the isolation of https://doi.org/10.1016/j.ijid.2020.01.011 1201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 198 E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207 Nocardia from routine blood cultures is rare (Lerner, 1996; Wilson, the English language literature between January 1, 1999 and 2012). December 31, 2018 using the NCBI PubMed database with the The latest comprehensive literature review of Nocardia search terms “Nocardia”, “nocardiosis”, “bacteremia”, and “blood bacteremia by Kontoyiannis et al. was published in 1998. It culture”. The last database search was performed on March 8, 2019. described four new cases and a review of the 32 previously Patients referenced by the same institution in more than one published cases of Nocardia bacteremia identified in the literature article were analyzed as single cases in this review. A case was between 1966 and 1997 (Kontoyiannis et al., 1998). The past 20 included in the analysis for detailed review if at least seven of the years has seen significant developments in both host and 24 predefined patient demographic, clinical, and microbiological microbiological factors that may affect the epidemiology and components for chart review were included in the article. All laboratory identification of Nocardia bacteremia. The aim of this published case reports with Nocardia bacteremia were considered single-center retrospective review and systematic literature to be clinically significant infections unless deemed contaminants review of cases of Nocardia bacteremia published over the past by the authors of the reports. 20 years was to update the current understanding of this rare but Significant taxonomic changes within the Nocardia genus have significant infection. occurred over the past 20 years, with modern identification based on molecular methods. Nocardia asteroides and Nocardia asteroides Materials and methods complex were previously considered the most commonly encoun- tered human pathogenic Nocardia species; however molecular Single-center retrospective review analyses of these isolates have indicated that the majority of them belong to other species. For the purposes of this analysis, isolates The Alfred Hospital is a tertiary referral hospital with over 600 identified as ‘Nocardia asteroides’ or ‘Nocardia asteroides complex’ inpatient beds, located in Melbourne, Australia. It is a state center based on phenotypic methods have been included as Nocardia for lung and heart transplantation, HIV care, and HSCT. Hospital species not identified to the species level. Matrix-assisted laser microbiology laboratory records were used to extract all positive desorption ionization time-of flight mass spectrometry (MALDI- blood cultures for Nocardia species isolated between January 1, TOF MS) has been shown to have a satisfactory performance for the 2010 and December 31, 2017. identification of certain common species, including N. farcinica, N. From January 1, 2010 until August 2016, the BacT/ALERT blood nova, N. brasiliensis, N. cyriacigeorgica, and N. otitidiscaviarum; culture system (bioMérieux, Lyon, France) was employed for however variable results have been obtained for other Nocardia aerobic and anaerobic blood cultures. From August 2016 (until the species. When MALDI-TOF MS was used to identify Nocardia present), the BACTEC (Becton Dickinson, New Jersey, USA) system isolates in the cases analyzed, identification to the species level was in use. The standard incubation time was 5 days, unless was accepted for the aforementioned species; they were otherwise prolonged incubation was used, either for specific fastidious included as Nocardia species only. organisms or when requested by the clinician. Positive blood cultures where gram-positive rods were identified were subcul- Results tured on horse blood agar and incubated in 5% carbon dioxide and in anaerobic conditions at 35 C for 5 days. At the discretion of the Single-center retrospective review microbiologist, a Gram stain morphology with a branching, beaded gram-positive rod would go on to have a Ziehl–Neelsen and Four cases of Nocardia bacteremia were identified over the 8- modified Ziehl–Neelsen stain performed and additional subculture year period at our institution. Two of these cases were included in to chocolate and buffered charcoal yeast extract (BCYE) agar. Initial a recent retrospective analysis of nocardiosis by Paige and identification of Nocardia species was undertaken in the Microbi- Spelman (Paige and Spelman, 2019). A comprehensive review of ology Unit at the Alfred Hospital. An isolate was deemed a these cases is presented in Table 1. These cases demonstrate presumptive Nocardia species upon identification of branching, important themes associated with Nocardia bacteremia,