Nocardia bacteremia: A single-center retrospective review and a systematic review of the literature

Journal Pre-proof Nocardia bacteremia: a single-center retrospective review and a systematic review of the literature Eloise Williams, Adam W. Jenney, Denis W. Spelman

PII:

S1201-9712(20)30013-8

DOI:

https://doi.org/10.1016/j.ijid.2020.01.011

Reference:

IJID 3902

To appear in:

International Journal of Infectious Diseases

Received Date:

14 August 2019

Revised Date:

21 December 2019

Accepted Date:

13 January 2020

Please cite this article as: Williams E, Jenney AW, Spelman DW, Nocardia bacteremia: a single-center retrospective review and a systematic review of the literature, International Journal of Infectious Diseases (2020), doi: https://doi.org/10.1016/j.ijid.2020.01.011

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier.

Title Page 1. Category: Original article 2. Title: Nocardia bacteremia: a single-center retrospective review and a systematic review of the literature.

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3. Authors:

Eloise Williams1,2*, Adam W Jenney1,2,3, Denis W Spelman1,2,3

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4. Author affiliations:

1. Microbiology Unit, Alfred Health, 55 Commercial Rd, Melbourne, Victoria, Australia.

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2. Department of Infectious Diseases, Alfred Health, 55 Commercial Rd, Melbourne, Victoria, Australia.

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5. Corresponding author

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3. Department of Infectious Diseases, Monash University, Melbourne, Victoria, Australia.

Eloise Williams

Present address: Microbiology Unit, Austin Health, 145 Studley Rd, Heidelberg, Victoria, Australia

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Email: [email protected] Phone: +613 9496 4695 or +614 0734 2680 Fax: +613 9496 6677

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Highlights    

Nocardia bacteremia is rare, with 227 cases reported in the English-language literature in the past 20 years Nocardia bacteremia is associated with high overall mortality of 40% Blood cultures represented the only positive microbiological specimen in 38% of cases Nocardia bacteremia is associated with immunocompromise and endovascular devices

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Abstract: 223 words Objectives: Nocardia bacteremia is a rare but severe disease associated with high mortality. This systematic review is the largest and most comprehensive review performed over the past 20

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years.

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Methods: A single-center retrospective review of Nocardia bacteremia was performed using hospital microbiology records from January 1st 2010 to December 31st 2017. A systematic literature

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review was also performed to identify cases of Nocardia bacteremia described in the NCBI PubMed database in English between January 1st 1999 and December 31st 2018.

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Results: Four new cases of Nocardia bacteremia are described; and systematic review identified 134 cases with sufficient information available for analysis. Of the 138 cases, median age was 58 years [interquartile range 44-69] and 70% were male. Eighty-one percent were immunocompromised (corticosteroid use (49%), hematological malignancy (20%), SOT (20%), SOM

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(19%) and HSCT (15%)) and 29% had endovascular devices. Pulmonary infection was the most common concurrent site of clinical disease (67%). Median incubation time to detection of Nocardia bacteremia was 4 days [IQR 3-6]. Blood cultures were the only positive microbiological specimen in 38% of cases. Median total duration of treatment was 75 days [IQR 25-182]. 30-day all-cause mortality was 28% and overall all-cause mortality 40%.

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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.

Key words: Nocardia

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Nocardiosis Bacteremia

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Central line-associated bloodstream infection Immunocompromise

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Manuscript: word count 3038

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1. Introduction

Nocardia species are aerobic, partially acid-fast, beaded, branching Gram-positive bacilli

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with colonies that produce aerial hyphae (Brown-Elliott et al., 2006). These ubiquitous environmental organisms can be found worldwide in components of soil, dust, decaying vegetation and other organic matter, as well as salt and fresh water (Wilson, 2012). Nocardiosis is regarded as an opportunistic infection, with the majority of infections occurring in immunocompromised

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patients, particularly those with impaired cell-mediated immunity. However, 22-39% of patients with nocardiosis have no known immunodeficiency (Beaman and Beaman, 1994, Beaman et al., 1976, Curry, 1980). Patients at increased risk include those with solid organ transplantation (SOT), hematopoietic stem cell transplantation (HSCT), hematological malignancy, solid organ malignancy (SOM), Human immunodeficiency virus (HIV) infection, those receiving long-term corticosteroid

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therapy or other medications that suppress cell-mediated immunity, diabetes and alcoholism (Beaman and Beaman, 1994, Filice, 2005, Wilson, 2012). Nocardiosis most frequently presents with pulmonary disease, followed by disseminated disease, extra-pulmonary disease (most often presenting in the central nervous system (CNS)) and primary skin and soft tissue disease (Beaman and Beaman, 1994). 32% 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, despite the

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frequency of disseminated disease and the propensity of nocardiosis to affect immunocompromised hosts, isolation of Nocardia from routine blood cultures is rare (Lerner, 1996, Wilson, 2012).

The latest comprehensive literature review of Nocardia bacteremia by Kontoyiannis et al

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was published in 1998. It described 4 new cases and a review of the 32 previously published cases of Nocardia bacteremia identified in the literature between 1966-1997 (Kontoyiannis et al., 1998). The

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past 20 years has seen significant developments in both host and microbiological factors that may

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affect the epidemiology and laboratory identification of Nocardia bacteremia. Our single-center retrospective review and systematic literature review of cases of Nocardia bacteremia published

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over the past 20 years aims to update the current understanding of this rare but significant infection. 2. Materials and Methods

2.1 Single-center retrospective review

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The Alfred Hospital is a tertiary referral hospital with over 600 inpatient beds, located in Melbourne, Australia. It is a state center for lung and heart transplantation, HIV care and HSCT. Hospital microbiology laboratory records were used to extract all positive blood cultures for Nocardia species isolated between January 1st 2010 and December 31st 2017. From January 1st 2010 until August 2016, the BacT/ALERT® blood culture system (bioMerieux, Lyon, France) was employed for aerobic and anaerobic blood cultures. From August

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2016 (until the present), the BACTEC® (Becton Dickinson, New Jersey, US) system has been in use. The standard incubation time was 5 days, unless prolonged incubation was used, either for specific fastidious organisms or when requested by the clinician. Positive blood cultures where Gram positive rods were identified were sub-cultured to horse blood agar and incubated in 5% carbon dioxide and in anaerobic conditions at 35°C for 5 days. At the discretion of the microbiologist, a Gram stain morphology with a branching, beaded Gram-positive rod would go on to have a ZiehlNeelsen and modified Zieh-Neelsen stain performed and additional subculture to chocolate and

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Buffered Charcoal Yeast Extract (BCYE) agar. Initial identification of Nocardia species was undertaken in the Microbiology Unit at the Alfred Hospital. An isolate was deemed a presumptive Nocardia species upon identification of branching, Gram-positive bacilli, in addition to growth in aerobic

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conditions and positive staining with the modified Ziehl-Neelsen stain with the absence of staining with the standard Ziehl-Neelsen stain. Presumptive Nocardia isolates were then referred to the

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Microbiological Diagnostic Unit Public Health Laboratory for confirmation and species identification via 16S rRNA PCR and sequencing. Susceptibility testing was performed using E-tests (bioMerieux,

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Lyon, France) on Mueller-Hinton agar incubated for 72 hours. Minimum inhibitory concentration interpretations were performed using Clinical and Laboratory Institute (CLSI) breakpoints (CLSI,

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2011).

Medical records of all patients with positive blood cultures for Nocardia species during the study period were examined. Patient demographics, clinical features (particularly related to immunosuppression, disease presentation, treatment and patient outcome) and microbiology

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results were collected and summarized.

2.2 Literature review A systematic literature review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) of individual participant data guidelines (Stewart et al., 2015) was 5

performed to identify cases of Nocardia bacteremia described in the English language literature between January 1st, 1999 and December 31st, 2018 using the NCBI PubMed database with the search terms “Nocardia”, “nocardiosis”, “bacteremia” and “blood culture”. The last database search was performed on 8th March 2019. Patients referenced by the same institution in more than 1 article were analyzed as single cases in our review. A case was included in the analysis for detailed review if at least 7 of the 24 pre-defined patient demographic, clinical and microbiological components for chart review were included in the article. All published case reports with Nocardia bacteremia were

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considered to be clinically significant infections unless deemed contaminants by the authors of the reports. Significant taxonomic changes within the Nocardia genus have occurred over the past 20

years, with modern identification based on molecular methods. Nocardia asteroides and Nocardia

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asteroides complex were previously considered the most commonly encountered human pathogenic Nocardia species, however molecular analyses of these isolates have indicated that the majority of

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them belong to other species. For the purposes of this analysis, isolates identified as “Nocardia asteroides” or “Nocardia asteroides complex” based on phenotypic methods have been included as

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Nocardia species not identified to species level. Matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF MS) has been shown to have a satisfactory performance for

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identification of certain common species, including N. farcinica, N. nova, N. brasiliensis, N. cyriacigeorgica and N. otidiscavarium, however variable results have been obtained for other Nocardia species. When MALDI-TOF MS was used to identify Nocardia isolates in the cases analyzed, identification to the species level was accepted for the aforementioned species; they were

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otherwise included as Nocardia species only. 3. Results

3.1 Single-center retrospective review Four cases of Nocardia bacteremia were identified over an 8-year period at our institution. Two of these cases were included in a recent retrospective analysis of nocardiosis by Paige and

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Spelman (Paige and Spelman, 2019). A comprehensive review of these cases is presented in Table 1. These cases demonstrate important themes associated with Nocardia bacteremia, including infections associated with immunosuppression (case 2, lung transplantation; case 3, HSCT complicated by graft-versus-host disease and concurrent opportunistic infections) and intravascular devices (case 1, bioprosthetic mitral valve; case 4, Permacath for hemodialysis).

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3.2 Literature review One hundred and ten publications were identified which described 277 cases of Nocardia

bacteremia. Twenty-five of these publications involving 143 unique cases had insufficient individual patient data available regarding host factors, microbiology, clinical disease and outcomes so were

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excluded from detailed analysis. These publications are summarised in Table 2. Immunosuppression

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status for those with Nocardia bacteremia was discernible in 14/25 of these publications, with 71/79 (90%) of patients found to be immunosuppressed. Intravascular device status was available in 4/25

of their Nocardia bacteremia.

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of these publications, with 21/38 (55%) of patients having an intravascular device in situ at the time

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Eighty publications described 134 cases that had sufficient individual patient data available and were included in the analysis (Figure 1). These publications are summarized in Table 3. Including the 4 cases described at our institution, 138 cases of Nocardia bacteremia were assessed. Clinical

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factors associated with Nocardia bacteremia are presented in Table 4. Age and sex

The median age was 58 years, with an interquartile range (IQR) of 44-69 years. Patients

ranged from 3 weeks to 91 years. Seventy percent were male. Underlying conditions

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Eighty-one percent of cases were immunocompromised. The most common cause of immunosuppression was corticosteroid use (49%), followed by hematological malignancy (20%), SOT (20%), SOM (19%) and HSCT (15%). Twenty-nine percent of patients with Nocardia bacteremia had endovascular devices. The most common devices were central venous catheters (CVCs) (31/40). Only 12 out of the 138 cases (9%) either had no intravascular device or were not immunocompromised. Two of these patients were people who inject drugs (PWID).

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Clinical presentation

Pulmonary infection was the most common concurrent site of clinical disease, with 67% of

patients affected. Extra-pulmonary disease was also common, with 28% percent of patients having

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evidence of CNS disease, 17% skin or soft tissue disease and 15% pleural disease. Eleven percent of

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patients had endocarditis and urinary tract infection, respectively. In 14% of cases, no other site apart from bloodstream infection was identified. Of note, 33% of those with intravascular devices

Concurrent infection

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had no other site of infection identified, compared to 7% patients without intravascular devices.

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Seventeen percent of patients had concurrent infection with other pathogens at the time of presentation with Nocardia bacteremia, 11/23 patients had bacterial infection (Coagulase negative Staphylococcus, Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Mycobacterium

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tuberculosis, Acinetobacter baumannii and Corynebacterium species), 9/23 patients had viral infection (Cytomegalovirus and Herpes simplex virus) and 6/23 patients had fungal infection (Aspergillus species, Pneumocystis jirovecii, Zygomycetes and Candida species). Microbiology Microbiological data are presented in Table 3. In cases where the time to positivity was described (48/136), median incubation time to detection of Nocardia bacteremia was 4 days. 8

BACTEC (Becton Dickinson, New Jersey, US) was the most commonly described (27/39, 69%) blood culture system used and 16S rRNA sequencing was the most common method of identification of Nocardia species (57/91, 63%). In 38% of cases, the blood was the only site that Nocardia was identified. The most common site of isolation of Nocardia in addition to blood culture was from the respiratory tract (22%). Significant taxonomic changes within the Nocardia genus have occurred over the past 20 years, making species-level comparison over this time difficult. Despite this significant limitation,

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Nocardia farcinica made up over half of the of the eighty-three blood culture isolates identified to

species level. (46/83, 55%). AST results were reported in 77/136 cases (56%) with the AST method described in 56/136 (41%). The isolates that caused Nocardia bacteremia in this review were

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resistant to amikacin in 2% (1/44), trimethoprim-sulfamethoxazole (TMP-SMX) in 11% (5/45) and imipenem in 15% (6/40). No linezolid resistance was described in the 21 cases for which it was

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reported.

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Treatment

Duration of treatment was described in 97/136 patients. Median total duration of treatment

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was 75 days [IQR 25-182 days]. Five patients received no antibiotics (4%); limited information is available for these cases as they were reported as part of retrospective analyses, however Nocardia bacteremia was considered clinically significant in each of these cases (Garg et al. 2015; Tuo et al., 2008). Two of these patients died. Four had intravascular devices, including the 3 patients who

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survived; device management was not described. Thirty-three patients received single agent antibiotic therapy (24%); of these, 30-day all-cause mortality was 36%. The remaining 97 patients received 2 or more concurrent antimicrobial agents (71%); 30-day all-cause mortality in these patients was 20%.

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Sulfonamide-containing antibiotics were used in 74% of patients, mostly in the form of TMPSMX; amongst these patients, 30-day all-cause mortality was 21%. Carbapenems were used in 49% of cases, in whom 30-day all-cause mortality was also 21%. Where intravascular device management was described, 21/26 (81%) of patients had the device removed as part of management of their Nocardia bacteremia; 30-day all-cause mortality in this group was 5%. Device management was not described for 14/40 patients (35%).

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Outcome In the 127/138 patients where 30-day all-cause mortality was described, 28% of patients

died. When Nocardia bacteremia was associated with central nervous system or pulmonary disease, 30-day all-cause mortality was 32% and 30%, respectively. When associated with endocarditis or an

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intravascular device, 30-day all-cause mortality was 13 and 8%, respectively. Treatment outcomes

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were described in 132/138 patients, however the follow up-period varied between the cases. Follow-up period was described in 98/136 patients, with a median of 120 days [IQR 30-180 days].

4. Discussion

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Overall all-cause mortality of Nocardia bacteremia was 40%, with microbiological relapse in 5%.

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This systematic review represents the largest and most extensive review of Nocardia bacteremia to date. Although rare, Nocardia bacteremia is an important diagnosis due to the specific antimicrobial and supportive management strategies required for treatment and high overall all-

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cause mortality. In this review, blood cultures were the only positive microbiological specimen in 38% of cases, thus serving as an important non-invasive diagnostic test for nocardiosis. Immunosuppression and intravascular devices were most commonly associated with Nocardia bacteremia in this review, with 91% of cases having one of these factors present. Compared to the previous review of the literature incorporating Nocardia bacteremia cases published between 1966-1997 (Kontoyiannis et al., 1998), the more recent cases had an older

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median age (57 vs 47 years), were more likely to have an intravascular device (29% vs 14%), and were somewhat more likely to be immunosuppressed (81% vs 70%). HSCT (15% vs 3%) and SOM (19% vs 3%) were more commonly seen, however people living with HIV (3% vs 14%) were less prevalent in our study compared with the earlier review. Potential risk factors found to be similar in both reviews included male predominance (70% vs 72%), corticosteroid use (49% vs 44%), hematological malignancy (20% vs 19%), SOT (20% vs 22%) and PWID (2% vs 8%). Clinical presentation was similar between the Nocardia bacteremia reviews, with pulmonary

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involvement the most common concomitant site of Nocardia infection (67% vs 64%); CNS

involvement (28% vs 19%) and endocarditis were seen in similar proportions (11%, respectively).

Concurrent infections were also common, affecting 17% of the more recent cases and 29% of cases

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in the earlier review. Despite significant advancements in medical care over the past 20 years, overall mortality was also similar between the reviews (40% vs 50%). This likely reflects the

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significant immunosuppression and comorbid status of the population affected by Nocardia

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bacteremia.

The proportion of immunosuppressed patients with nocardiosis reported in the literature

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ranges between 61-78% (Beaman and Beaman, 1994, Beaman et al., 1976, Curry, 1980), somewhat lower than in the bacteremic group analyzed in this review. However, it remains difficult to explain overall low rates of Nocardia bacteremia described in patients with nocardiosis, despite up to one third having clinically disseminated disease (Beaman and Beaman, 1994). Even in single-center

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studies of patients with nocardiosis in the context of malignancy or SOT, reported rates of Nocardia bacteremia are just 9-12% (Peleg et al., 2007, Torres et al., 2002, Wang et al., 2014). Single-center studies of nocardiosis in HSCT recipients have demonstrated higher proportions of patients with Nocardia bacteremia (27-33%), however this is still significantly less than the 47-83% reported to have clinically disseminated disease (Daly et al., 2003, Shannon et al., 2016).

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The association between intravascular devices and Nocardia bacteremia has been described in single-center studies, with Al Ahkrass et al reporting 17 cases of Nocardia bacteremia in patients with cancer between 1998-2010 that had CVCs at the time of bacteremia (Al Akhrass et al., 2011). Ten (59%) of these had definite or probable central line-associated bloodstream infections (CLABSIs) according to the Center for Disease Control and Prevention (Atlanta, USA) guidelines (Centers for Disease Control and Prevention, 2019) and the remaining 7 had disseminated nocardiosis with pulmonary disease. Those with CLABSIs had shorter hospital stays (median 5 vs 24 days) and

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improved 90-day mortality rates (10% vs 43%) compared to those with disseminated bacteremia (Al Akhrass et al., 2011). Our review also describes improved outcomes in patients with Nocardia

bacteremia associated with intravascular devices, with a low 30-day mortality observed in this

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patient group (8%). It was not possible to assess most cases included in this review against CLABSI criteria due to the insufficient clinical and microbiological data provided. However, 33% of those

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with intravascular devices had no other site of infection described, compared to only 7% in those without intravascular devices. This suggests that intravascular devices may play an important role in

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inoculation and early Nocardia infection in these patients.

Despite relatively low rates of Nocardia bacteremia even in disseminated nocardiosis and

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immunosuppressed patients, blood cultures were an important diagnostic method in this review, with blood cultures representing the only positive microbiological specimen in 38% of cases. The BACTEC and BacT/ALERT automated blood culture systems appear efficient at recovering Nocardia species. In some cases, negative blood cultures may be due to empiric treatment of patients with

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antimicrobials with Nocardia activity, concomitant bacteremia with less fastidious organisms, insufficient blood culture sampling in immunocompromised patients presenting with pulmonary infection or inadequate duration of incubation, with up 14 days required to identify visible colonies of Nocardia on solid media. Importantly, there may also be an underrepresentation of Nocardia bacteremia in this analysis, with ascertainment bias due to blood cultures being more frequently performed in patients with severe illness or high temperature. Strategies to optimize the isolation of 12

Nocardia from blood cultures include prolonged blood culture incubation up to 21 days duration and blood culture collection in patients with clinical features suggestive of nocardiosis prior to empiric antimicrobial therapy. Particularly those that present with a pulmonary or central nervous system focus in the context of immunosuppression or fever with an intravascular device in situ. Due to variable host factors, clinical syndromes, antimicrobial agents, duration of antimicrobials and intravascular device management strategies used, conclusions regarding treatment regimens is limited. However, it is clear that combination sulfonamide-based

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antimicrobial therapy remains the cornerstone of treatment. Intravascular device removal is also

commonly employed. These treatment principles are supported by the results demonstrated in this review, with improved 30-day mortality in those treated with TMP-SMX and when 2 or more

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antimicrobial agents were used.

In conclusion, both immunosuppression and intravascular devices are associated with

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Nocardia bacteremia. The rarity of Nocardia bacteremia, despite nocardiosis frequently presenting

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as clinically disseminated disease, is not well explained. However, blood cultures remain an important diagnostic test in those at risk for nocardiosis, with modern automated blood culture

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systems efficiently supporting the isolation of Nocardia in these cases. Adequate blood culture sampling prior to empiric antimicrobials and prolonged incubation may improve the yield of blood cultures in the setting of disseminated nocardiosis. Despite advances in medical therapy, Nocardia bacteremia still portends a poor overall prognosis. We recommend an extended course of

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combination sulfonamide-based antimicrobial therapy, intravascular device removal and meticulous supportive care including reduction of immunosuppression, as well as vigilance for coinfection with opportunistic pathogens in affected patients.

Acknowledgements

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The authors thank the Microbiology Unit, Alfred Health for culture and presumptive identification of Nocardia species, the Medical Diagnostics Unit Public Health Laboratory for 16S rRNA PCR and sequencing and the Infectious Diseases Unit, Alfred Health for their clinical management of the patients described. The authors also thank Anton Peleg, Sarah McGuinness and Xiang Y. Han for generously providing the authors with further information regarding patients described in their studies with Nocardia

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bacteremia, thus allowing detailed review and inclusion in this analysis.

Funding and Conflicts of Interest

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This research did not receive any specific grant from funding agencies in the public, commercial, or

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not-for-profit sectors. There are no conflicts of interest to declare.

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Ethical Approval

The authors have read and complied with the journal's ethical consent policy. No specific ethical

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Hemar V, Danjean MP, Imbert Y, Rispal P. Retrospective analysis of nocardiosis in a general hospital from 1998 to 2017. Med Mal Infect 2018;48(8):516-25. Hemmersbach-Miller M, Stout JE, Woodworth MH, Cox GM, Saullo JL. Nocardia infections in the

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transplanted host. Transpl Infect Dis 2018;20(4):e12902. Heo ST, Ko KS, Kwon KT, Ryu SY, Bae IG, Oh WS, et al. The first case of catheter-related bloodstream infection caused by Nocardia farcinica. J Korean Med Sci 2010;25(11):1665-8. Hitti W, Wolff M. Two cases of multidrug-resistant Nocardia farcinica infection in immunosuppressed patients and implications for empiric therapy. Eur J Clin Microbiol Infect Dis 2005;24(2):142-4.

18

Hopler W, Laferl H, Szell M, Pongratz P, Brandl I, Tucek G, et al. Blood culture positive Nocardia asteroides infection: a case report. Wien Med Wochenschr 2013;163(1-2):37-9. Hu Y, Zheng D, Takizawa K, Mikami Y, Dai L, Yazawa K, et al. Systemic nocardiosis caused by Nocardia concava in China. Med Mycol 2011;49(6):662-6. Hui CH, Au VW, Rowland K, Slavotinek JP, Gordon DL. Pulmonary nocardiosis re-visited: experience of 35 patients at diagnosis. Respir Med 2003;97(6):709-17.

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endophthalmitis. Jpn J Opthalmol 2010;54(2):164-6.

Kontoyiannis DP, Jacobson KL, Whimbey EE, Rolston KV, Raad, II. Central venous catheter-associated

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Kontoyiannis DP, Ruoff K, Hooper DC. Nocardia bacteremia. Report of 4 cases and review of the literature. Medicine 1998;77(4):255-67.

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Kouppari G, Zaphiropoulou A, Skandami V, Stamos HG, Papadatos J, Sinaniotis C, et al. Disseminated Nocardia asteroides complex infection in an immunocompromised child. Clin MIcrobiol Infect 2000;6(5):287-8.

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Liu WL, Lai CC, Hsiao CH, Hung CC, Huang YT, Liao CH, et al. Bacteremic pneumonia caused by Nocardia veterana in an HIV-infected patient. Int J Infect Dis 2011;15(6):e430-2.

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Lui WY, Lee AC, Que TL. Central venous catheter-associated Nocardia bacteremia. Clin Infect Dis

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2001;33(9):1613-4.

Majeed A, Beatty N, Iftikhar A, Mushtaq A, Fisher J, Gaynor P, et al. A 20-year experience with

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20

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21

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Transpl Infect Dis 2003;5(2):94-7.

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Quinn MP, Courtney AE, McCarron MO, McCluskey M, Hedderwick S. Breathless and dizzy!--

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22

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Severo CB, Oliveira Fde M, Cunha L, Cantarelli V, Severo LC. Disseminated nocardiosis due to

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Shannon K, Pasikhova Y, Ibekweh Q, Ludlow S, Baluch A. Nocardiosis following hematopoietic stem

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Wang HL, Seo YH, LaSala PR, Tarrand JJ, Han XY. Nocardiosis in 132 patients with cancer:

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microbiological and clinical analyses. Am J Clin Pathol 2014;142(4):513-23. Watson A, French P, Wilson M. Nocardia asteroides native valve endocarditis. Clin Infect Dis 2001;32(4):660-1. Watson ME, Jr., Estabrook MM, Burnham CA. Catheter-associated Nocardia higoensis bacteremia in a child with acute lymphocytic leukemia. J Clin Microbiol 2011;49(1):469-71.

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Wilson JW. Nocardiosis: updates and clinical overview. Mayo Clinic proceedings 2012;87(4):403-7. Yang M, Xu M, Wei W, Gao H, Zhang X, Zhao H, et al. Clinical findings of 40 patients with nocardiosis: A retrospective analysis in a tertiary hospital. Exp Ther Med 2014;8(1):25-30. Yu HX, Liu M, Pu ZH, Liu Y, Zhao MM. Microbiological and clinical data analysis of 32 patients with Nocardia infections in Yantai. Turk J Med Sci 2018;48(2):366-71. Yu X, Han F, Wu J, He Q, Peng W, Wang Y, et al. Nocardia infection in kidney transplant recipients:

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case report and analysis of 66 published cases. Transpl Infect Dis 2011;13(4):385-91.

26

Identification

Figure: Literature Review Flowchart

Records identified through database searching (n = 5688)

Records after duplicates removed (n = 2763)

 

re

Eligibility

-p

Records screened (n = 2763)

Full-text articles excluded, with reasons (n = 39)  

No original Nocardia bacteremia case (n = 14) Insufficient information (n= 25)

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lP

Full-text articles assessed for eligibility (n = 124)

Non-English language (n = 311) No original Nocardia bacteraemia case (n = 2321)

Studies included in analysis (n = 85)

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Included

Records excluded (n = 2566)

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Screening

(n = 218)

27

Age/

Medical Comorbidities

Device

Clinical Disease

Positive Microbiology/ Incubation Time

ro

Case

Gender 70/M

T2DM, Colorectal cancer, IHD, CKD Stage 3, MVR

Bio-prosthetic MVR

Endocarditis, central nervous system

2/8 Blood cultures (BACTEC)/4 days;

Nocardia Species

Nocardia veterana

Mitral valve tissue/3 days

63/M

al P Nil

Pulmonary, pleural

Pulmonary, pleural

ESKD due to membranoproliferative GN, hemodialysis, IVDU, COPD, HCV

Pulmonary

Multiple myeloma, allogeneic HSCT 6 months prior, CMV colitis & pneumonitis, gastrointestinal & cutaneous GVHD

PICC line

Permacath

3/17 Blood cultures (BACTEC)/

Outcome/

Repeat MVR;

Survived/

TMP-SMX & Meropenem/12 days;

12 months

Linezolid & Ertapenem/23 days;

re 4

63/F

Lung transplant 10 months prior, Osteoporosis, Gastroparesis

ur n

3

63/M

Jo

2

Treatment/Duration

Follow-up

-p

1

of

Table 1. Nocardia bacteremia cases: single-center retrospective review, 2010-2017

Clarithromycin & Ertapenem/12 days; Clarithromycin & TMP-SMX/10 months Nocardia farcinca/ Nocardia kroppensteddii*

3 days;

TMP-SMX & Meropenem/28 days;

Survived/ 12 months

TMP-SMX/36 days

Lung tissue & BAL/ 3 days 2/4 Blood cultures/4 days (bacT/ALERT); BAL/3 days

Nocardia farcinica

2/3 Blood cultures/3 days (bacT/ALERT); 3/3 urine cultures/ 2 days

Nocardia nova

PICC line removal;

Died day 38 VRE bacteremia

TMP-SMX & Meropenem/38 days

Permacath removal;

Survived/

TMP-SMX & Imipenem/30 days;

12 months

TMP-SMX/5 months

BAL: bronchoalveolar lavage. COPD: chronic obstructive pulmonary disease. CKD: chronic kidney disease. CMV: Cytomegalovirus. ESKD: end-stage kidney disease. F: female. GN: glomerulonephritis. GVHD: graft versus host disease. HCV: Hepatitis C virus. HSCT: hematopoietic stem cell transplant. IHD: ischemic heart disease. IVDU: intravenous drug use. M: male. MVR:

28

al P

re

-p

ro

of

mitral valve replacement. PICC: peripherally inserted central catheter. T2DM: Type 2 diabetes mellitus. TMP-SMX: trimethoprim-sulfamethoxazole. VRE: Vancomycin resistant Enterococcus.*16S rRNA sequencing failed to resolve identification between N. farcinica and N. kroppensteddii

Table 2. Literature review of publications with cases of Nocardia bacteremia 1999-2018: studies excluded from further analysis due to insufficient individual patient data

Period of study

HemmersbachMiller et al., 2018

19962013

Country

Study type

Number of patients with bacteremia

Number of patients in study

Immunosuppression

Intravascular device

Identification method

AST method

Mortality

Single-center retrospective review

12

51

12/12

ND

16S rRNA

BMD

ND

USA

Single-center retrospective review

2

54

2/2

ND

16S rRNA

BMD

ND

Italy

Single-center retrospective review

1

14

ND

ND

16S rRNA

BMD

Survived

ur n

Publication

Jo

USA

Majeed et al., 2018

19972016

Mazaferri et al., 2018

20112015

29

10

112

China

Single-center retrospective review

4

32

19952015

Japan

Single-center retrospective review

1

Coussement et al., 2016

20002014

Europe (Belgium, France, Spain, Switzerland, the Netherlands)

Multicenter casecontrol study

9

Chen et al., 2014

20092013

Yang et al., 2014

20002013

Rosman et al., 2013

19962011

Wang et al., 2014

19882006

Al Akhrass et al., 2011

19982010

ND

7/10 Survived

ND

16S rRNA

BMD

1/4 Survived

ND

ND

16S rRNA

BMD

ND

117

9/9

ND

16S rRNA

ND

ND

4/4

-p 30

3/10

ro

7/10

Single-center retrospective review

3

17

ND

ND

Phenotypic

ND

ND

Single-center retrospective review

5

40

3/5

ND

Phenotypic

ND

ND

Israel

Single-center retrospective review

8

39

ND

ND

Phenotypic

Etest

ND

Taiwan

Single-center retrospective review

1

81

ND

ND

Phenotypic

DD

ND

Israel

Single-center retrospective review

6

53

6/6

5/6

Phenotypic/16S rRNA

Etest

5/6 Survived

USA

Single-center retrospective review

17

17

17/17

10/17

Phenotypic/16S rRNA

BMD

13/17 Survived

China

China

Jo

Hardak et al., 2012

19962000

MALDI-TOF MS

re

Takiguchi et al., 2017

al P

Yu et al., 2018

20102016

ur n

19942015

of

USA

Single-center retrospective review

Steinbrink et al., 2018

30

Castro and Espinoza, 2007

19992004

Martinez Tomas et all, 2007

19892001

Mootsikapun et al., 2004

19962001

Matulionyte et al., 2004

19892003

Hui et al., 2003

19952000

718

Switzerland

Single-center retrospective review

1

Spain

Single-center retrospective review

2

USA

Single-center retrospective review

1

19982002

Torres et al., 2002

19982001

Phenotypic

DD

ND

ND

ND

Phenotypic/16S rRNA

BMD

ND

28

Yes

ND

ND

ND

Died

37

2/2

ND

16S rRNA

BMD

ND

25

Yes

ND

ND

ND

ND

Single-center retrospective review

2

31

ND

ND

Phenotypic

DD

ND

Single-center retrospective review

4

70

1/4

ND

ND

DD

ND

Switzerland

Single-center retrospective review

1

20

Yes

ND

Phenotypic/16S rRNA

Etest

Survived

Australia

Single-center retrospective review

1

35

ND

ND

16S rRNA

DD

ND

USA

Single-center retrospective review

23

470

ND

ND

16S rRNA

BMD

ND

USA

Single-center retrospective review

5

42

5/5

3/5

Phenotypic

BMD

ND

Spain

Thailand

Jo

Saubolle and Sussland, 2003l

of

Minero et al., 2009

19952006

18

ND

ro

19892009

Canada

Multi-center retrospective review

ND

-p

Ambrosioni et al., 2011

120

re

19982008

4

al P

Tremblay et al., 2011

Pakistan

Single-center retrospective review

ur n

Bibi et al., 2011

19902005

31

19941997

USA

Single-center retrospective review

2

12

ND

of

Dominguez and Antony, 1999

ND

Phenotypic

DD

ND

ro

16S rRNA: 16S ribosomal RNA sequencing. BMD: broth microdilution. DD: disc diffusion. MALDI-TOF MS: matrix-assisted laser desorption ionization time of flight mass spectrometry. ND: not described, USA: United States of America.

Country

Okimoto et al., 2019

2019

Japan

Hazim and Mansoor, 2018

2018

USA

Hemar et al., 2018

19982017

France

Jackson and Shorman, 2018

2018

Garner et al., 2017

2017

Haussaire et al., 2017

20042014

Jackson et al., 2017 Majeed et al., 2017

Study type

Number of patients with bacteremia

al P

Period of study

Number of patients in study

Immunosuppression

Intravascular device

Identification method

AST method

Mortality

1

1

Yes

No

ND

ND

Died

Case report

1

1

Yes

No

ND

ND

Survived

Single-center retrospective review

1

9

Yes

ND

16S rRNA

Etest

Died

USA

Case report

1

1

No

No

ND

NP

Survived

USA

Case report

1

1

Yes

No

ND

ND

Survived

France

Multicenter retrospective review

9

41

9/9

ND

16S rRNA

DD

5/9 Survived

2017

USA

Case report

1

1

No

No

ND

ND

Survived

2017

USA

Case report

1

1

Yes

No

16S rRNA

ND

Died

ur n

Case report

Jo

Publication

re

-p

Table 3. Literature review of publications with cases of Nocardia bacteremia 1999-2018: studies with sufficient individual patient data to be included in the summary of the literature

32

12

1/2

2016

USA

Case report

1

1

No

Lim et al., 2016

2016

USA

Case report

1

1

McGuinness et al., 2016

19972014

Australia

Single-center retrospective review

1

Piukavics et al., 2016

2016

Hungary

Case series

1

Scoreyand Daniel, 2016

2016

Australia

Case report

Shannon et al., 2016

20032013

USA

Single-center retrospective review

De la Cruz et al., 2015

20062012

Garg et al., 2015

11 year period

Piau et al., 2015

Yes

-p

Kuretski et al., 2016

of

2

20102015

1/2

Phenotypic

ND

1/2 Survived

No

ND

ND

Survived

Yes

16S rRNA

ND

Died

ro

India

Single-center retrospective review

Wadhwa et al., 2017

No

No

16S rRNA

BMD

ND

2

Yes

No

16S rRNA

ND

Died

1

Yes

No

16S rRNA

ND

Survived

4

15

4/4

ND

ND

ND

3/4 Survived

Single-center retrospective review

1

19

Yes

ND

ND

ND

Died

USA

Multicenter retrospective review

7

23

5/7

4/7

16S rRNA

ND

2/7 Survived

2015

France

Case report

1

1

Yes

No

16S rRNA

BMD

Survived

Poisnel et al., 2015

2015

France

Case report

1

1

Yes

No

16S rRNA

BMD

Died

de Clerck et al., 2014

2013

Belgium

Case report

1

1

Yes

No

16S rRNA

ND

Died

Wang et al., 2014

20022012

USA

Single-center retrospective review

12

132

12/12

7/12

16S rRNA

BMD

7/12 Survived

Cattaneo et al., 2013

20022012

Italy

Multicenter retrospective review

3

10

3/3

ND

Phenotypic

ND

1/3 Survived

Jo

1

al P

ur n

USA

re

61

33

South Africa

Case report

1

1

Yes

Hopler et al., 2013

2013

Austria

Case report

1

1

Yes

Leli et al., 2013

2013

Italy

Case report

1

1

Patel et al., 2013

2013

India

Case report

1

1

of

2013

No

ND

ND

ND

No

MALDI-TOF MS

ND

Died

ro

Goussard et al., 2013

ND

MALDI-TOF MS

ND

Died

Yes

No

ND

ND

Survived

-p

Yes

2012

France

Case series

1

2

No

Yes

16S rRNA

DD

Died

Budzik et al., 2012

2012

USA

Case report

1

1

No

No

16S rRNA

ND

Died

2012

India

Case report

1

1

No

No

ND

ND

Died

Tanioka et al., 2012

2012

Japan

Case report

1

1

Yes

No

16S rRNA

ND

Survived

Castelli et al., 2011

2011

Brazil

Case report

1

1

Yes

No

ND

ND

Survived

Hu et al., 2011

2011

China

Case report

1

1

Yes

No

16S rRNA

ND

Died

Liu et al., 2011

2011

Taiwan

Case report

1

1

Yes

No

16S rRNA

BMD

Died

Namnyak et al., 2011

2011

ur n

Santos et al., 2011

al P

Patil et al., 2012

19802010

re

de Montmollin et al., 2012

UK

Case report

1

1

Yes

No

16S rRNA

DD

Died

Spain

Single-center retrospective review

2

19

Yes

ND

Phenotypic

DD/Etest

1/2 Survived

2011

Iran

Case series

1

5

Yes

Yes

16S rRNA

DD

Survived

Watson et al., 2011

2011

USA

Case report

1

1

Yes

Yes

16S rRNA

BMD

Survived

Yu et al., 2011

2011

China

Case report

1

1

Yes

No

ND

ND

Survived

Al-Tawfiq and AlKhatti, 2010

2010

Saudi Arabia

Case report

1

1

Yes

No

16S rRNA

ND

Died

Jo

Shojaei et al., 2011

34

South Korea

Case report

1

1

No

Kawakami et al., 2010

2010

Japan

Case report

1

1

Yes

Timoteo et al., 2010

2010

Portugal

Case report

1

1

Taiwan

Single-center retrospective review

3

113

South Korea

Case report

1

Taiwan

Multi-center retrospective review

The Netherlands

Case report

Tuo et al., 2008

20002004

Van Luin et al., 2008

2008

16S rRNA

ND

Survived

Yes

ND

ND

Survived

3/3

ND

16S rRNA

Agar dilution

1/3 Survived

1

Yes

No

16S rRNA

ND

Died

8

29

5/8

6/8

Phenotypic

ND

7/8 Survived

1

1

Yes

No

16S rRNA

ND

Survived

Multi-center retrospective review

1

22

No

Yes

Phenotypic

ND

Survived

Case report

1

1

No

No

Phenotypic

ND

Survived

Case report

1

1

Yes

No

ND

ND

Survived

USA

Single-center case control study

3

35

3/3

1/3

Phenotypic

BMD

3/3 Survived

No

-p

2008

Survived

re

Park et al., 2008

BMD

al P

Tan et al., 2010

19982008

Yes

16S rRNA

of

2010

No

ro

Heo et al., 2010

Brazil

Liff et al., 2007

2007

USA

Naik et al., 2007

2007

USA

Peleg et al., 2007

19952005

Quinn et al., 2007

2007

UK

Case report

1

1

Yes

No

ND

ND

Survived

Sharma et al., 2007

2007

USA

Case report

1

1

Yes

Yes

ND

ND

Survived

Ansari et al., 2006

2006

USA

Case report

1

1

Yes

No

16S rRNA

ND

Survived

Daniel and Ravenel., 2007

2007

USA

Case report

1

1

Yes

No

ND

ND

Survived

Elsayed et al., 2006

2006

Canada

Case series

2

2

2/2

0/2

16S rRNA

BMD

1/2 Survived

Jo

Chedid et al., 2007

ur n

19771998

35

2005

USA

Case series

1

2

Yes

Lai et al., 2005

2005

Taiwan

Case report

1

1

Yes

Routh et al., 2005

2004

USA

Case report

1

1

Yes

Severo et al., 2005

2005

Brazil

Case report

1

1

Bozbeyoglu et al., 2004

2004

Turkey

Case report

1

1

Christidou et a. 2004

2004

Greece

Case report

1

Feng et al., 2004

2004

Taiwan

Case report

Lai et al., 2004

2004

Taiwan

Case report

Lederman and Crum, 2004

2004

USA

Moshfeghi et al., 2004

2004

USA

Queipo-Zaragoza et al., 2004

19802004

Spain

Boell et al., 2003

2003

USA

Daikos et al., 2003

2003

Figgis et al., 2003 Ramchandran et al., 2003

of

Hitti and Wolff, 2005

ND

BMD

Died

No

16S rRNA

BMD

Survived

No

ND

ND

Survived

Yes

No

16S rRNA

ND

Died

Yes

No

ND

ND

Survived

1

Yes

No

16S rRNA

Etest

Died

1

1

Yes

Yes

ND

ND

Died

1

1

Yes

Yes

ND

ND

Survived

Case series

1

5

Yes

Yes

ND

ND

Survived

Case report

1

1

Yes

No

ND

ND

Survived

Single-center retrospective review

1

5

Yes

ND

Phenotypic

Agar dilution

Survived

Case report

1

1

No

Yes

Phenotypic

DD

Survived

Greece

Case report

1

1

No

Yes

Phenotypic

BMD

Survived

2003

Australia

Case report

1

1

No

No

Phenotypic

ND

Survived

2003

India

Case report

1

1

Yes

No

Phenotypic

ND

Survived

-p

re

al P

ur n

Jo

ro

No

Singh et al., 2003

2003

India

Case report

1

1

No

No

Phenotypic

BMD

Survived

Qu et al., 2003

2003

USA

Case report

1

1

Yes

No

Phenotypic

ND

Survived

Canada

Single-center retrospective review

2

6

Yes

ND

Phenotypic

ND

0/2 Survived

Daly et al., 2003

19972000

36

Thailand

Case report

1

1

Yes

Fadilah et al., 2001

2001

Malaysia

Case report

1

1

Yes

Italy

Multi-center retrospective review

4

26

Farina et al., 2001

19931997

of

2002

Yes

ND

ND

Survived

Yes

ND

ND

Survived

ro

Vachvanichsanong et al., 2002

4/4

ND

Phenotypic

DD

3/4 Survived

No

Yes

ND

ND

Survived

2001

China

Case report

1

1

Watson et al., 2001

2001

Australia

Case report

1

1

No

No

ND

Etest

Survived

Kontoyiannis et al., 2000

2000

USA

Case series

2

2

2/2

2/2

ND

ND

2/2 Survived

Kouppari et al., 2000

2000

Greece

Case report

1

1

Yes

No

Phenotypic

DD

Died

Torres et al., 2000

2000

USA

Case report

1

1

Yes

No

Phenotypic

DD

Died

Tsushima et al., 2000

2000

Japan

Case report

1

1

No

No

ND

ND

Survived

Bhave et al., 1999

1999

Australia

Case report

1

1

Yes

No

Phenotypic

DD

Survived

Smilak et al., 1999

1999

USA

Case report

1

1

Yes

No

ND

ND

Survived

Urbaniak-Kujda et al., 1999

1999

1

1

Yes

No

ND

ND

Died

re

al P

ur n Poland

-p

Lui et al., 2001

Case report

Jo

16S rRNA: 16S ribosomal RNA sequencing. BMD: broth microdilution. DD: disc diffusion. MALDI-TOF MS: matrix-assisted laser desorption ionization time of flight mass spectrometry. ND: not described, UK: United Kingdom. USA: United States of America.

37

Table 4. Clinical characteristics of 136 cases of Nocardia bacteremia Clinical characteristics

n = 138

Age, median [IQR]

58 [44-69]

Male, n (%)

96 (70)

67 (49)

Haematological malignancy

28 (20)

SOT

28 (20)

Solid organ malignancy

26 (19)

HSCT

21 (15)

Biological agent use

5 (4)

HIV

4 (3)

Total immunosuppressed

112 (81)

Chronic lung disease

16 (12)

ESKD

12 (9)

IVDU

3 (2)

CVC

31 (22)

Prosthetic cardiac valve

6 (4)

Vascular graft

1 (1)

Total intravascular device

re

lP

Intracardiac device

-p

Corticosteroid use

ro of

Underlying condition, n (%)

1 (1)

40 (29)

Pulmonary

ur na

Likely site of clinical Nocardia infection, n (%)

92 (67)

Central nervous system

38 (28)

Cutaneous

23 (17)

Pleural

21 (15) 15 (11)

Urinary tract

15 (11)

Jo

Endocarditis

Intraabdominal

13 (9)

Bone/joint

7 (5)

Ocular

6 (4)

Nil other site (blood only)

20 (14)

Antibiotic duration (n =97), median [IQR]

75 [25-182]

Antibiotic therapy (n =137), n (%) No antibiotics

5 (4)

38

Single agent

33 (24)

2 concurrent agents

73 (53)

3 concurrent agents

24 (18)

Sulphonamide

105 (77)

Carbapenem

71 (52)

Aminoglycoside

33 (26)

Fluoroquinolone

16 (12)

Linezolid

10 (7)

30-day mortality (n = 127)

35 (28)

Relapse (n = 127)

7 (5)

Overall mortality (n = 132)

53 (40)

Duration follow-up (n = 98), median (IQR)

ro of

Outcome, n (%)

120 [30-180]

CVC: central venous catheter. ESKD: end-stage kidney disease. HIV: Human immunodeficiency virus. HSCT: hematopoietic stem cell transplant. IVDU: intravenous drug use IQR: interquartile range. SOT: solid organ transplant. TMP-SMX: trimethoprim-sulfamethoxazole.

ur na

lP

re

-p

*Intravascular device removal status documented in 20/34 cases.

Table 5. Microbiological factors of 136 cases of Nocardia bacteremia

Jo

Microbiological factors

Time to positive blood culture (n = 48), median [IQR]

n = 138

4 [3-6]

Blood culture system (n = 39), n (%) BACTEC

27 (69%)

BacT/ALERT

12 (31%)

Nocardia detected in other specimens Respiratory

30 (22)

39

Tissue

24 (17)

Fluid

20 (14)

Urine

6 (4)

CVC tip

4 (3)

Nocardia detected only in blood cultures

52 (38)

Microbial identification system (n = 91), n (%) 16S rRNA sequencing

57 (63)

Phenotypic identification

32 (35)

MALDI-TOF MS

2 (2)

46 (33)

Nocardia nova complex

14 (10)

Nocardia cyriacigeorgica

5 (4)

Nocardia veteran

4 (3)

Nocardia brasiliensis

3 (2)

Other*

11 (8)

Not identified to species level

55 (40)

-p

Nocardia farcinica

ro of

Nocardia species

AST performed

77 (56)

AST method described

56 (41)

AST method, (n = 56)

Broth microdilution Etest

24 (43)

lP

Disc diffusion

re

Antimicrobial susceptibility, n (%)

23 (41) 4 (7) 3 (5)

ur na

Agar dilution Nocardia species susceptible, n (%)

43 (98)

Amoxicillin-clavulanic acid (n = 29)

14 (48)

Ceftriaxone (n = 26)

15 (58)

Ciprofloxacin (n = 38)

18 (47)

Clarithromycin (n = 25)

14 (56)

Doxycycline (n = 16)

5 (31)

Imipenem (n = 40)

34 (85)

Linezolid (n =21)

21 (100)

Minocycline (n = 18)

7 (39)

TMP-SMX (n = 45)

40 (89)

Tobramycin (n = 20)

9 (41)

Jo

Amikacin (n = 44)

AST: antimicrobial susceptibility. MALDI-TOF MS: matrix-assisted laser desorption ionization time of flight mass spectrometry. TMP-SMX: trimethoprim-sulfamethoxazole. *Other Nocardia species: 1 case of each, including N. pseudobrasiliensis, N.

40

Jo

ur na

lP

re

-p

ro of

concava, N. kroppenstedtii, N. mikamii, N. kruczakiae, N. puris, N. higoensis, N. otitidiscavarium, N. harenae and N. cerradoensis

41