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, including
gram-positive bacilli, in addition to growth in aerobic conditions infections associated with immunosuppression (case 2, lung
and positive staining with the modified Ziehl–Neelsen stain with transplantation; case 3, HSCT complicated by graft-versus-host
the absence of staining with the standard Ziehl–Neelsen stain. disease and concurrent opportunistic infections) and intravascular
Presumptive Nocardia isolates were then referred to the Microbio- devices (case 1, bioprosthetic mitral valve; case 4, Permacath for
logical Diagnostic Unit Public Health Laboratory for confirmation hemodialysis).
and species identification via 16S rRNA PCR and sequencing.
Susceptibility testing was performed using Etests (bioMérieux, Literature review
Lyon, France) on Mueller–Hinton agar incubated for 72 h.
Minimum inhibitory concentration interpretations were per- One hundred and ten publications were identified which
formed using Clinical and Laboratory Standards Institute (CLSI) described 277 cases of Nocardia bacteremia. Twenty-five of these
breakpoints (CLSI, 2011). publications involving 143 unique cases had insufficient individual
The medical records of all patients with positive blood cultures patient data available regarding host factors, microbiology, clinical
for Nocardia species during the study period were examined. disease, and outcomes so were excluded from detailed analysis.
Patient demographic characteristics, clinical features (particularly These publications are summarized in Table 2. Immunosuppres-
related to immunosuppression, disease presentation, treatment, sion status for those with Nocardia bacteremia was discernible in
and patient outcome), and microbiology results were collected and 14 of the 25 publications, with 71 of 79 patients (90%) found to be
summarized. immunosuppressed. Intravascular device status was available in
four of the 25 publications, with 21/38 (55%) patients having an
Literature review intravascular device in situ at the time of their Nocardia
bacteremia.
A systematic literature review using the Preferred Reporting Eighty publications described 134 cases that had sufficient
Items for Systematic Reviews and Meta-Analyses (PRISMA) of individual patient data available and were included in the analysis
individual participant data guidelines (Stewart et al., 2015) was (Figure 1). These publications are summarized in Table 3. Including
performed to identify cases of Nocardia bacteremia described in the four cases described at our institution, a total of 138 cases of
E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207 199
Table 1
Nocardia bacteremia cases: single-center retrospective review, 2010–2017.
Case Age Medical comorbidities Device Clinical Positive Nocardia Treatment/duration Outcome/ (years)/ disease microbiology/ species follow-up sex incubation
time
1 70/M T2DM, colorectal cancer, IHD, Bio- Endocarditis, 2/8 blood N. veterana Repeat MVR. TMP–SMX and meropenem/ Survived/
CKD stage 3, MVR prosthetic central cultures 12 days. Linezolid and ertapenem/23 days. 12 months
MVR nervous (BACTEC)/4 Clarithromycin and ertapenem/12 days.
system days Clarithromycin and TMP–SMX/10 months
Mitral valve
tissue/3 days
2 63/M Lung transplant 10 months Nil Pulmonary, 3/17 blood N. farcinica/ N. TMP–SMX and meropenem/28 days. TMP– Survived/
a
prior, osteoporosis, pleural cultures kroppenstedtii SMX/36 days 12 months gastroparesis (BACTEC)/3 days
Lung tissue
and BAL/3
days
3 63/F Multiple myeloma, allogeneic PICC line Pulmonary, 2/4 blood N. farcinica PICC line removal. Died day
HSCT 6 months prior, CMV pleural cultures/4 TMP–SMX and meropenem/38 days 38 VRE
colitis and pneumonitis, days (bacT/ bacteremia
gastrointestinal and ALERT)
cutaneous GVHD BAL/3 days
4 63/M ESKD due to membrano- Permacath Pulmonary 2/3 blood N. nova Permacath removal. TMP–SMX and Survived/
proliferative GN, cultures/3 imipenem/30 days. TMP–SMX/5 months 12 months
hemodialysis, IVDU, COPD, days (bacT/ HCV ALERT)
3/3 urine cultures/2
days
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, mitral valve replacement; PICC, peripherally inserted central catheter; T2DM, Type 2 diabetes mellitus; TMP–SMX, trimethoprim–sulfamethoxazole;
VRE, vancomycin-resistant Enterococcus.
a
16S rRNA sequencing failed to resolve identification between N. farcinica and N. kroppenstedtii.
Nocardia bacteremia were assessed. Clinical factors associated with Concurrent infection
Nocardia bacteremia are presented in Table 4.
Seventeen percent of patients had concurrent infections with
Age and sex other pathogens at the time of presentation with Nocardia
bacteremia; 11/23 patients had a bacterial infection (coagulase-
The median age was 58 years, with an interquartile range (IQR) negative Staphylococcus, Klebsiella pneumoniae, Escherichia coli,
of 44–69 years. Patients ranged in age from 3 weeks to 91 years. Pseudomonas aeruginosa, Mycobacterium tuberculosis, Acinetobacter
Seventy percent were male. baumannii, and Corynebacterium species), 9/23 patients had a viral
infection (cytomegalovirus and herpes simplex virus), and 6/23
Underlying conditions patients had a fungal infection (Aspergillus species, Pneumocystis
jirovecii, Zygomycetes, and Candida species).
Eighty-one percent of cases were immunocompromised. The
most common cause of immunosuppression was corticosteroid Microbiology
use (49%), followed by hematological malignancy (20%), SOT (20%),
SOM (19%), and HSCT (15%). Microbiological data are presented in Table 5. In cases where
Twenty-nine percent of patients with Nocardia bacteremia had the time to positivity was described (48/136), the median
endovascular devices. The most common devices were central incubation time to detection of Nocardia bacteremia was 4 days.
venous catheters (CVCs) (31/40). Only 12 out of the 138 cases (9%) BACTEC (Becton Dickinson, New Jersey, USA) was the most
either had no intravascular device or were not immunocompro- commonly described blood culture system used (27/39, 69%),
mised. Two of these patients were people who inject drugs (PWID). and 16S rRNA sequencing was the most common method of
identification of Nocardia species (57/91, 63%).
Clinical presentation In 38% of cases, the blood was the only site where Nocardia was
identified. The most common site of isolation of Nocardia in
Pulmonary infection was the most common concurrent site of addition to blood culture was from the respiratory tract (22%).
clinical disease, with 67% of patients affected. Extrapulmonary Significant taxonomic changes within the Nocardia genus have
disease was also common, with 28% of patients having evidence of occurred over the past 20 years, making species-level comparison
CNS disease,17% skin or soft tissue disease, and 15% pleural disease. over this time difficult. Despite this significant limitation, Nocardia
Eleven percent of patients had endocarditis and urinary tract farcinica made up over half of the of the 83 blood culture isolates
infection, respectively. In 14% of cases, no other site apart from identified to the species level (46/83, 55%). Antimicrobial
bloodstream infection was identified. Of note, 33% of those with susceptibility testing (AST) results were reported in 77/136 cases
intravascular devices had no other site of infection identified, (56%), with the AST method described in 56/136 cases (41%). The
compared to 7% patients without intravascular devices. isolates that caused Nocardia bacteremia in this review were
200 E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207
Table 2
Literature review of publications with cases of Nocardia bacteremia covering the years 1999–2018: studies excluded from further analysis due to insufficient individual patient
data.
Publication Period Country Study type Number of Number of Immuno- Intravascular Identification AST Mortality
of patients with patients in suppression device method method
study bacteremia study
Hemmersbach- 1996– USA Single-center 12 51 12/12 ND 16S rRNA BMD ND
Miller et al., 2013 retrospective
2018 review
Majeed et al., 1997– USA Single-center 2 54 2/2 ND 16S rRNA BMD ND 2018 2016 retrospective
review
Mazzaferri 2011– Italy Single-center 1 14 ND ND 16S rRNA BMD Survived
et al., 2018 2015 retrospective
review
Steinbrink 1994– USA Single-center 10 112 7/10 3/10 MALDI-TOF ND 7/10
et al., 2018 2015 retrospective MS Survived
review
Yu et al., 2018 2010– China Single-center 4 32 4/4 ND 16S rRNA BMD 1/4 2016 retrospective Survived
review
Takiguchi et al., 1995– Japan Single-center 1 30 ND ND 16S rRNA BMD ND 2017 2015 retrospective
review
Coussement 2000– Europe (Belgium, France, Multi-center 9 117 9/9 ND 16S rRNA ND ND
et al., 2016 2014 Spain, Switzerland, case–control
Netherlands) study
Chen et al., 2009– China Single-center 3 17 ND ND Phenotypic ND ND 2014 2013 retrospective
review
Yang et al., 2000– China Single-center 5 40 3/5 ND Phenotypic ND ND 2014 2013 retrospective
review
Rosman et al., 1996– Israel Single-center 8 39 ND ND Phenotypic Etest ND 2013 2011 retrospective
review
Wang et al., 1988– Taiwan Single-center 1 81 ND ND Phenotypic DD ND 2015 2006 retrospective
review
Hardak et al., 1996– Israel Single-center 6 53 6/6 5/6 Phenotypic/ Etest 5/6
2012 2000 retrospective 16S rRNA Survived
review
Al Akhrass 1998– USA Single-center 17 17 17/17 10/17 Phenotypic/ BMD 13/17
et al., 2011 2010 retrospective 16S rRNA Survived
review
Bibi et al., 2011 1990– Pakistan Single-center 4 120 ND ND Phenotypic DD ND 2005 retrospective
review
Tremblay et al., 1998– Canada Multi-center 18 718 ND ND Phenotypic/ BMD ND
2011 2008 retrospective 16S rRNA
review
Ambrosioni 1989– Switzerland Single-center 1 28 Yes ND ND ND Died
et al., 2010 2009 retrospective
review
Minero et al., 1995– Spain Single-center 2 37 2/2 ND 16S rRNA BMD ND 2009 2006 retrospective
review
Castro and 1999– USA Single-center 1 25 Yes ND ND ND ND Espinoza, 2004 retrospective
2007 review
Martinez 1989– Spain Single-center 2 31 ND ND Phenotypic DD ND
Tomas et al., 2001 retrospective
2007 review
Mootsikapun 1996– Thailand Single-center 4 70 1/4 ND ND DD ND
et al., 2005 2001 retrospective
review
Matulionyte 1989– Switzerland Single-center 1 20 Yes ND Phenotypic/ Etest Survived
et al., 2004 2003 retrospective 16S rRNA
review
Hui et al., 2003 1995– Australia Single-center 1 35 ND ND 16S rRNA DD ND 2000 retrospective
review
Saubolle and 1998– USA Single-center 23 470 ND ND 16S rRNA BMD ND Sussland, 2002 retrospective
2003 review
Torres et al., 1998– USA Single-center 5 42 5/5 3/5 Phenotypic BMD ND 2002 2001 retrospective
review
USA 2 12 ND ND Phenotypic DD ND
E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207 201
Table 2 (Continued)
Publication Period Country Study type Number of Number of Immuno- Intravascular Identification AST Mortality
of patients with patients in suppression device method method study bacteremia study Dominguez 1994– Single-center
and Antony, 1997 retrospective
1999 review
16S rRNA, 16S ribosomal RNA sequencing; AST, antimicrobial susceptibility testing; 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.
resistant to amikacin in 2% (1/44), trimethoprim–sulfamethoxa- Sulfonamide-containing antibiotics were used in 74% of
zole (TMP–SMX) in 11% (5/45), and imipenem in 15% (6/40). No patients, mostly in the form of TMP–SMX. Amongst these patients,
linezolid resistance was described in the 21 cases for which it was 30-day all-cause mortality was 21%. Carbapenems were used in
reported. 49% of cases, in whom 30-day all-cause mortality was also 21%.
Where intravascular device management was described, 21/26
Treatment (81%) patients had the device removed as part of the management
of their Nocardia bacteremia; 30-day all-cause mortality in this
The duration of treatment was described in 97/136 patients. The group was 5%. Device management was not described for 14/40
median total duration of treatment was 75 days (IQR 25–182 days). patients (35%).
Five patients received no antibiotics (4%). Limited information was
available for these cases, as they were reported as part of Outcome
retrospective analyses, however Nocardia bacteremia was consid-
ered clinically significant in each of these cases (Garg et al., 2015; In the 127/138 patients for whom 30-day all-cause mortality
Tuo et al., 2008). Two of these patients died. Four had intravascular was described, 28% of patients died. When Nocardia bacteremia
devices, including the three patients who survived; device was associated with CNS or pulmonary disease, 30-day all-cause
management was not described. Thirty-three patients received mortality was 32% and 30%, respectively. When associated with
single-agent antibiotic therapy (24%); 30-day all-cause mortality in endocarditis or an intravascular device, 30-day all-cause mortality
these patients was 36%. The remaining 97 patients received two or was 13% and 8%, respectively. Treatment outcomes were described
more concurrent antimicrobial agents (71%); 30-day all-cause for 132/138 patients; however the follow up-period varied
mortality in these patients was 20%. between the cases. The follow-up period was described for 98/
Figure 1. Systematic literature review flowchart.
202 E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207
Table 3
Literature review of publications with cases of Nocardia bacteremia covering the years 1999–2018: studies with sufficient individual patient data to be included in the
summary of the literature.
Publication Period Country Study type Number of Number of Immuno- Intravascular Identification AST Mortality
of patients with patients in suppression device method method
study bacteremia study
Okimoto et al., 2019 Japan Case report 1 1 Yes No ND ND Died
2019
Hazim and 2018 USA Case report 1 1 Yes No ND ND Survived
Mansoor, 2018
Hemar et al., 2018 1998– France Single-center 1 9 Yes ND 16S rRNA Etest Died 2017 retrospective
review
Jackson and 2018 USA Case report 1 1 No No ND ND Survived
Shorman, 2018
Garner et al., 2017 2017 USA Case report 1 1 Yes No ND ND Survived
Haussaire et al., 2004– France Multi-center 9 41 9/9 ND 16S rRNA DD 5/9 2017 2014 retrospective Survived
review
Jackson et al., 2017 2017 USA Case report 1 1 No No ND ND Survived
Majeed et al., 2017 2017 USA Case report 1 1 Yes No 16S rRNA ND Died
Wadhwa et al., 2010– India Single-center 2 12 1/2 1/2 Phenotypic ND 1/2 2017 2015 retrospective Survived
review
Kuretski et al., 2016 2016 USA Case report 1 1 No No ND ND Survived
Lim et al., 2016 2016 USA Case report 1 1 Yes Yes 16S rRNA ND Died
McGuinness et al., 1997– Australia Single-center 1 61 No No 16S rRNA BMD ND 2016 2014 retrospective
review
Piukovics et al., 2016 Hungary Case series 1 2 Yes No 16S rRNA ND Died
2016
Scorey and Daniel, 2016 Australia Case report 1 1 Yes No 16S rRNA ND Survived
2016
Shannon et al., 2003– USA Single-center 4 15 4/4 ND ND ND 3/4 2016 2013 retrospective Survived
review
De la Cruz et al., 2006– USA Single-center 1 19 Yes ND ND ND Died 2015 2012 retrospective
review
Garg et al., 2015 11-year USA Multi-center 7 23 5/7 4/7 16S rRNA ND 2/7 period retrospective Survived
review
Piau et al., 2015 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., 2013 Belgium Case report 1 1 Yes No 16S rRNA ND Died
2014
Wang et al., 2014 2002– USA Single-center 12 132 12/12 7/12 16S rRNA BMD 7/12 2012 retrospective Survived
review
Cattaneo et al., 2002– Italy Multi-center 3 10 3/3 ND Phenotypic ND 1/3 2013 2012 retrospective Survived
review
Goussard et al., 2013 South Africa Case report 1 1 Yes No ND ND ND
2013
Hopler et al., 2013 2013 Austria Case report 1 1 Yes No MALDI-TOF ND Died
MS
Leli et al., 2013 2013 Italy Case report 1 1 Yes ND MALDI-TOF ND Died
MS
Patel et al., 2013 2013 India Case report 1 1 Yes No ND ND Survived
de Montmollin 2012 France Case series 1 2 No Yes 16S rRNA DD Died
et al., 2012
Budzik et al., 2012 2012 USA Case report 1 1 No No 16S rRNA ND Died
Patil et al., 2012 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 UK Case report 1 1 Yes No 16S rRNA DD Died
2011
Santos et al., 2011 1980– Spain Single-center 2 19 Yes ND Phenotypic DD/ 1/2 2010 retrospective Etest Survived
review
Shojaei et al., 2011 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 Al- 2010 Saudi Case report 1 1 Yes No 16S rRNA ND Died
Khatti, 2010 Arabia
E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207 203
Table 3 (Continued)
Publication Period Country Study type Number of Number of Immuno- Intravascular Identification AST Mortality
of patients with patients in suppression device method method
study bacteremia study
Heo et al., 2010 2010 South Korea Case report 1 1 No Yes 16S rRNA BMD Survived
Kawakami et al., 2010 Japan Case report 1 1 Yes No 16S rRNA ND Survived
2010
Timoteo et al., 2010 2010 Portugal Case report 1 1 No Yes ND ND Survived
Tan et al., 2010 1998– Taiwan Single-center 3 113 3/3 ND 16S rRNA Agar 1/3 2008 retrospective dilution Survived
review
Park et al., 2008 2008 South Korea Case report 1 1 Yes No 16S rRNA ND Died
Tuo et al., 2008 2000– Taiwan Multi-center 8 29 5/8 6/8 Phenotypic ND 7/8 2004 retrospective Survived
review
Van Luin et al., 2008 Netherlands Case report 1 1 Yes No 16S rRNA ND Survived
2008
Chedid et al., 2007 1977– Brazil Multi-center 1 22 No Yes Phenotypic ND Survived 1998 retrospective
review
Liff et al., 2007 2007 USA Case report 1 1 No No Phenotypic ND Survived
Naik et al., 2007 2007 USA Case report 1 1 Yes No ND ND Survived
Peleg et al., 2007 1995– USA Single-center 3 35 3/3 1/3 Phenotypic BMD 3/3
2005 case control Survived
study
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 USA Case report 1 1 Yes No ND ND Survived
2007
Elsayed et al., 2006 2006 Canada Case series 2 2 2/2 0/2 16S rRNA BMD 1/2
Survived
Hitti and Wolff, 2005 USA Case series 1 2 Yes No ND BMD Died
2005
Lai et al., 2005 2005 Taiwan Case report 1 1 Yes No 16S rRNA BMD Survived
Routh et al., 2005 2004 USA Case report 1 1 Yes No ND ND Survived
Severo et al., 2005 2005 Brazil Case report 1 1 Yes No 16S rRNA ND Died
Bozbeyoglu et al., 2004 Turkey Case report 1 1 Yes No ND ND Survived
2004
Christidou et al., 2004 Greece Case report 1 1 Yes No 16S rRNA Etest Died
2004
Feng et al., 2004 2004 Taiwan Case report 1 1 Yes Yes ND ND Died
Lai et al., 2004 2004 Taiwan Case report 1 1 Yes Yes ND ND Survived
Lederman and 2004 USA Case series 1 5 Yes Yes ND ND Survived
Crum, 2004
Moshfeghi et al., 2004 USA Case report 1 1 Yes No ND ND Survived
2004
Queipo-Zaragoza 1980– Spain Single-center 1 5 Yes ND Phenotypic Agar Survived
et al., 2004 2004 retrospective dilution
review
Boell et al., 2003 2003 USA Case report 1 1 No Yes Phenotypic DD Survived
Daikos et al., 2003 2003 Greece Case report 1 1 No Yes Phenotypic BMD Survived
Figgis et al., 2003 2003 Australia Case report 1 1 No No Phenotypic ND Survived
Ramchandran 2003 India Case report 1 1 Yes No Phenotypic ND Survived
et al., 2003
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
Daly et al., 2003 1997– Canada Single-center 2 6 Yes ND Phenotypic ND 0/2 2000 retrospective Survived
review
Vachvanichsanong 2002 Thailand Case report 1 1 Yes Yes ND ND Survived
et al., 2002
Fadilah et al., 2001 2001 Malaysia Case report 1 1 Yes Yes ND ND Survived
Farina et al., 2001 1993– Italy Multi-center 4 26 4/4 ND Phenotypic DD 3/4 1997 retrospective Survived
review
Lui et al., 2001 2001 China Case report 1 1 No Yes ND ND Survived
Watson et al., 2001 2001 Australia Case report 1 1 No No ND Etest Survived
Kontoyiannis et al., 2000 USA Case series 2 2 2/2 2/2 ND ND 2/2
2000 Survived
Kouppari et al., 2000 Greece Case report 1 1 Yes No Phenotypic DD Died
2000
Torres et al., 2000 2000 USA Case report 1 1 Yes No Phenotypic DD Died
Tsushima et al., 2000 Japan Case report 1 1 No No ND ND Survived
2000
Bhave et al., 1999 1999 Australia Case report 1 1 Yes No Phenotypic DD Survived
Smilack, 1999 1999 USA Case report 1 1 Yes No ND ND Survived
204 E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207
Table 3 (Continued)
Publication Period Country Study type Number of Number of Immuno- Intravascular Identification AST Mortality
of patients with patients in suppression device method method
study bacteremia study
Urbaniak-Kujda 1999 Poland Case report 1 1 Yes No ND ND Died
et al., 1999
16S rRNA, 16S ribosomal RNA sequencing; AST, antimicrobial susceptibility testing; 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.
136 patients, with a median of 120 days (IQR 30–180 days). Overall treatment and high overall all-cause mortality. In this review,
all-cause mortality of Nocardia bacteremia was 40%, with blood cultures were the only positive microbiological specimen in
microbiological relapse in 5%. 38% of cases, thus serving as an important non-invasive diagnostic
test for nocardiosis. Immunosuppression and intravascular devices
Discussion were most commonly associated with Nocardia bacteremia in this
review, with 91% of cases having one of these factors present.
This systematic review represents the largest and most Compared to the previous review of the literature incorporating
extensive review of Nocardia bacteremia to date. Although rare, Nocardia bacteremia cases published between 1966 and 1997
Nocardia bacteremia is an important diagnosis due to the specific (Kontoyiannis et al., 1998), the more recent cases had an older
antimicrobial and supportive management strategies required for median age (57 vs 47 years), were more likely to have an
Table 4 Table 5
Clinical characteristics of 138 cases of Nocardia bacteremia. Microbiological factors of 138 cases of Nocardia bacteremia.
Clinical characteristics N = 138 Microbiological factors N = 138
–
Age, years, median (IQR) 58 (44 69) Time to positive blood culture (days) (n = 48), median (IQR) 4 (3–6)
Male, n (%) 96 (70) Blood culture system (n = 39), n (%)
Underlying condition, n (%) BACTEC 27 (69)
Corticosteroid use 67 (49) BacT/ALERT 12 (31)
Hematological malignancy 28 (20) Nocardia detected in other specimens, n (%)
SOT 28 (20) Respiratory 30 (22)
Solid organ malignancy 26 (19) Tissue 24 (17)
HSCT 21 (15) Fluid 20 (14)
Biological agent use 5 (4) Urine 6 (4)
HIV 4 (3) CVC tip 4 (3)
Total immunosuppressed 112 (81) Nocardia detected only in blood cultures, n (%) 52 (38)
Chronic lung disease 16 (12) Microbial identification system (n = 91), n (%)
ESKD 12 (9) 16S rRNA sequencing 57 (63)
IVDU 3 (2) Phenotypic identification 32 (35)
CVC 31 (22) MALDI-TOF MS 2 (2)
Prosthetic cardiac valve 6 (4) Nocardia species, n (%)
Vascular graft 1 (1) Nocardia farcinica 46 (33)
Intracardiac device 1 (1) Nocardia nova complex 14 (10)
Total intravascular device 40 (29) Nocardia cyriacigeorgica 5 (4)
Likely site of clinical Nocardia infection, n (%) Nocardia veteran 4 (3)
Pulmonary 92 (67) Nocardia brasiliensis 3 (2)
a
Central nervous system 38 (28) Other 11 (8)
Cutaneous 23 (17) Not identified to species level 55 (40)
Pleural 21 (15) Antimicrobial susceptibility, n (%)
Endocarditis 15 (11) AST performed 77 (56)
Urinary tract 15 (11) AST method described 56 (41)
Intra-abdominal 13 (9) AST method (n = 56), n (%)
Bone/joint 7 (5) Disc diffusion 24 (43)
Ocular 6 (4) Broth microdilution 23 (41)
Nil other site (blood only) 20 (14) Etest 4 (7)
–
Antibiotic duration (days) (n = 97), median (IQR) 75 (25 182) Agar dilution 3 (5)
Antibiotic therapy (n = 137), n (%) Nocardia species susceptible, n (%)
No antibiotics 5 (4) Amikacin (n = 44) 43 (98)
Single agent 33 (24) Amoxicillin–clavulanic acid (n = 29) 14 (48)
2 concurrent agents 73 (53) Ceftriaxone (n = 26) 15 (58)
3 concurrent agents 24 (18) Ciprofloxacin (n = 38) 18 (47)
Sulfonamide 105 (77) Clarithromycin (n = 25) 14 (56)
Carbapenem 71 (52) Doxycycline (n = 16) 5 (31)
Aminoglycoside 33 (26) Imipenem (n = 40) 34 (85)
Fluoroquinolone 16 (12) Linezolid (n = 21) 21 (100)
Linezolid 10 (7) Minocycline (n = 18) 7 (39)
Outcome, n (%) TMP–SMX (n = 45) 40 (89)
30-day mortality (n = 127) 35 (28) Tobramycin (n = 20) 9 (41)
Relapse (n = 127) 7 (5)
AST, antimicrobial susceptibility testing; CVC, central venous catheter; IQR,
Overall mortality (n = 132) 53 (40)
interquartile range; MALDI-TOF MS, matrix-assisted laser desorption ionization
Duration of follow-up (days) (n = 98), median (IQR) 120 (30–180)
time-of-flight mass spectrometry; TMP–SMX, trimethoprim–sulfamethoxazole.
a
CVC, central venous catheter; ESKD, end-stage kidney disease; HIV, Human Other Nocardia species: 1 case of each, including N. pseudobrasiliensis, N.
fi
immunode ciency virus; HSCT, hematopoietic stem cell transplant; IVDU, concava, N. kroppenstedtii, N. mikamii, N. kruczakiae, N. puris, N. higoensis, N.
intravenous drug use; IQR, interquartile range; SOT, solid organ transplant. otitidiscaviarum, N. harenae, and N. cerradoensis.
E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207 205
intravascular device (29% vs 14%), and were somewhat more likely activity, concomitant bacteremia with less fastidious organisms,
to be immunosuppressed (81% vs 70%). HSCT (15% vs 3%) and SOM insufficient blood culture sampling in immunocompromised
(19% vs 3%) were more commonly seen; however people living patients presenting with pulmonary infection, or inadequate
with HIV (3% vs 14%) were less prevalent in the present study duration of incubation, with up 14 days required to identify visible
compared with the earlier review. Potential risk factors found to be colonies of Nocardia on solid media. Importantly, there may also be
similar in both reviews included male predominance (70% vs 72%), an underrepresentation of Nocardia bacteremia in this analysis,
corticosteroid use (49% vs 44%), hematological malignancy (20% vs with ascertainment bias due to blood cultures being more
19%), SOT (20% vs 22%), and PWID (2% vs 8%). frequently performed in patients with severe illness or high
Clinical presentation was similar between the Nocardia bacter- temperature. Strategies to optimize the isolation of Nocardia from
emia reviews, with pulmonary involvement the most common blood cultures include prolonged blood culture incubation up to 21
concomitant site of Nocardia infection (67% vs 64%); CNS days in duration and blood culture collection in patients with
involvement (28% vs 19%) and endocarditis were seen in similar clinical features suggestive of nocardiosis prior to empiric
proportions (11%, respectively). Concurrent infections were also antimicrobial therapy, particularly those who present with a
common, affecting 17% of the more recent cases and 29% of cases in pulmonary or CNS focus in the context of immunosuppression or
the earlier review. Despite significant advancements in medical fever with an intravascular device in situ.
care over the past 20 years, overall mortality was also similar in the Due to variable host factors, clinical syndromes, antimicrobial
two reviews (40% vs 50%). This likely reflects the significant agents, duration of antimicrobials, and intravascular device
immunosuppression and comorbid status of the population management strategies used, conclusions regarding treatment
affected by Nocardia bacteremia. regimens are limited. However, it is clear that combination
The proportion of immunosuppressed patients with nocardio- sulfonamide-based antimicrobial therapy remains the cornerstone
sis reported in the literature ranges between 61% and 78% (Beaman of treatment. Intravascular device removal is also commonly
and Beaman, 1994; Beaman et al., 1976; Curry, 1980), somewhat employed. These treatment principles are supported by the results
lower than in the bacteremic group analyzed in this review. demonstrated in this review, with improved 30-day mortality in
However, it remains difficult to explain overall low rates of those treated with TMP–SMX and when two or more antimicrobial
Nocardia bacteremia described in patients with nocardiosis, agents were used.
despite up to one third having clinically disseminated disease In conclusion, both immunosuppression and intravascular
(Beaman and Beaman, 1994). Even in single-center studies of devices are associated with Nocardia bacteremia. The rarity of
patients with nocardiosis in the context of malignancy or SOT, Nocardia bacteremia, despite nocardiosis frequently presenting as
reported rates of Nocardia bacteremia are just 9–12% (Peleg et al., clinically disseminated disease, is not well explained. However,
2007; Torres et al., 2002; Wang et al., 2014). Single-center studies blood cultures remain an important diagnostic test in those at risk
of nocardiosis in HSCT recipients have demonstrated higher for nocardiosis, with modern automated blood culture systems
proportions of patients with Nocardia bacteremia (27–33%); efficiently supporting the isolation of Nocardia in these cases.
however this is still significantly less than the 47–83% reported Adequate blood culture sampling prior to empiric antimicrobials
to have clinically disseminated disease (Daly et al., 2003; Shannon and prolonged incubation may improve the yield of blood cultures
et al., 2016). in the setting of disseminated nocardiosis. Despite advances in
The association between intravascular devices and Nocardia medical therapy, Nocardia bacteremia still portends a poor overall
bacteremia has been described in single-center studies, with Al prognosis. We recommend an extended course of combination
Ahkrass et al. reporting 17 cases of Nocardia bacteremia in patients sulfonamide-based antimicrobial therapy, intravascular device
with cancer between 1998 and 2010 who had CVCs at the time of removal, and meticulous supportive care including reduction of
bacteremia (Al Akhrass et al., 2011). Ten (59%) of these had definite immunosuppression, as well as vigilance for co-infection with
or probable central line-associated bloodstream infections (CLAB- opportunistic pathogens in affected patients.
SIs) according to the US Centers for Disease Control and Prevention
guidelines (CDC, Atlanta, USA) (Centers for Disease Control and Funding
Prevention, 2019) and the remaining seven had disseminated
nocardiosis with pulmonary disease. Those with CLABSIs had This research did not receive any specific grant from funding
shorter hospital stays (median 5 vs 24 days) and improved 90-day agencies in the public, commercial, or not-for-profit sectors.
mortality rates (10% vs 43%) compared to those with disseminated
bacteremia (Al Akhrass et al., 2011). Our review also describes Ethical approval
improved outcomes in patients with Nocardia bacteremia associ-
ated with intravascular devices, with a low 30-day mortality The authors have read and complied with the journal’s ethical
observed in this patient group (8%). It was not possible to assess consent policy. No specific ethical approval was required for this
most cases included in this review against CLABSI criteria due to study.
the insufficient clinical and microbiological data provided.
However, 33% of those with intravascular devices had no other Conflict of interest
site of infection described, compared to only 7% in those without
intravascular devices. This suggests that intravascular devices may There are no conflicts of interest to declare.
play an important role in inoculation and early Nocardia infection
in these patients. Acknowledgements
Despite relatively low rates of Nocardia bacteremia even in
disseminated nocardiosis and immunosuppressed patients, blood The authors thank the Microbiology Unit, Alfred Health for
cultures were an important diagnostic method in this review, with culture and presumptive identification of Nocardia species, the
blood cultures representing the only positive microbiological Medical Diagnostics Unit Public Health Laboratory for 16S rRNA
specimen in 38% of cases. The BACTEC and BacT/ALERT automated PCR and sequencing, and the Infectious Diseases Unit, Alfred
blood culture systems appear efficient at recovering Nocardia Health for their clinical management of the patients described. The
species. In some cases, negative blood cultures may be due to authors also thank Anton Peleg, Sarah McGuinness, and Xiang Y.
empiric treatment of patients with antimicrobials with Nocardia Han for generously providing the authors with further information
206 E. Williams et al. / International Journal of Infectious Diseases 92 (2020) 197–207
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Minerva Access is the Institutional Repository of The University of Melbourne
Author/s: Williams, E; Jenney, AW; Spelman, DW
Title: Nocardia bacteremia: A single-center retrospective review and a systematic review of the literature
Date: 2020-03-01
Citation: Williams, E., Jenney, A. W. & Spelman, D. W. (2020). Nocardia bacteremia: A single-center retrospective review and a systematic review of the literature. INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES, 92, pp.197-207. https://doi.org/10.1016/j.ijid.2020.01.011.
Persistent Link: http://hdl.handle.net/11343/252320
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