From contamination to infective endocarditis—a population-based retrospective study of Corynebacterium isolated from blood cultures
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Corynebacterium is a genus that can contaminate blood cultures and also cause severe infections like infective endocarditis (IE). Our purpose was to investigate microbiological and clinical features associated with contamination and true infection. A retrospective population-based study of Corynebacterium bacteremia 2012–2017 in southern Sweden was performed. Corynebacterium isolates were species determined using a matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Patient were, from the medical records, classified as having true infection or contamination caused by Corynebacterium through a scheme considering both bacteriological and clinical features and the groups were compared. Three hundred thirty-nine episodes of bacteremia with Corynebacterium were identified in 335 patients of which 30 (8.8%) episodes were classified as true infection. Thirteen patients with true bacteremia had only one positive blood culture. Infections were typically community acquired and affected mostly older males with comorbidities. The focus of infection was most often unknown, and in-hospital mortality was around 10% in both the groups with true infection and contamination. Corynebacterium jeikeium and Corynebacterium striatum were significantly overrepresented in the group with true infection, whereas Corynebacterium afermentans was significantly more common in the contamination group. Eight episodes of IE were identified, all of which in patients with heart valve prosthesis. Six of the IE cases affected the aortic valve and six of seven patients were male. The species of Corynebacterium in blood cultures can help to determine if a finding represent true infection or contamination. The finding of a single blood culture with Corynebacterium does not exclude true infection such as IE.
KeywordsCorynebacterium Bacteremia Infective endocarditis Contamination Blood culture
Corynebacterium is a genus of Gram-positive rods comprising more than 100 species of which a large proportion has been associated to human infections . Corynebacterium diphtheriae is the most well-known of these species, but over the last decades, more attention has been drawn to non-diphtheriae Corynebacterium species as human opportunistic pathogens .
When Corynebacterium is isolated from blood cultures, the finding is often dismissed as a contamination from normal skin flora rather than recognized as a pathogen causing true infection. Studies investigating different cohorts have indicated that between 44 and 71% of patients with Corynebacterium bacteremia have true infection [2, 3, 4]. Some studies have only used a bacteriological criterion (≥ 2 positive blood cultures) [2, 3] whereas other studies also considered clinical features and acknowledge that intravascular devices are risk factors for true Corynebacterium infection [4, 5, 6]. The lack of a uniform definition of contamination and infection hampers the possibility to draw conclusions about the incidence of true Corynebacterium infections. Moreover, available studies describe limited number of cases and have a retrospective design [2, 3, 4, 5, 7].
Corynebacterium can cause infective endocarditis (IE) and is a rare etiology of such infections . Knowledge on Corynebacterium IE comes mainly from case reports or systematic reviews of the literature. From a large systematic review it was concluded that Corynebacterium IE mainly affects the left side of the heart (95% of cases) and that men constituted 72% of described cases . In this case review, 19% of cases represented valve prosthesis IE and the mortality rate was high (40%) . Interestingly, a difference in clinical presentation between different species of corynebacterial was noted .
Species determination of corynebacteria has been challenging  but the introduction of matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) has provided a practical tool for this purpose [10, 11]. It has been shown that species determination of Corynebacterium can be performed with sufficient precision using improved databases and lower cutoff scores in the analysis of spectra . Several studies have investigated the features of infections with specific Corynebacterium species. Of non-diphtheriae corynebacteria, Corynebacterium striatum and Corynebacterium jeikeium have often been reported as pathogens [3, 5, 7, 9, 12]. However, at present, there is insufficient data on how species determination of corynebacteria can help to determine the risk for true infection or even IE in patients with Corynebacterium bacteremia.
The present study aims to determine risk factors for true Corynebacterium infection, including IE, in a large retrospective population-based cohort of patients with positive blood cultures.
Microbiology and species determination
Data on patients with blood cultures positive for Corynebacterium were collected from the registry of the Laboratory for Clinical Microbiology in the county of Skåne, Sweden, for the years 2012 to 2017. A blood culture was regarded to be positive irrespective of if one or two bottles yielded growth. The laboratory is the only one in Skåne, a province with a population of 1,329,000 inhabitants (January 1, 2017, data from Statistics Sweden (available at https://www.scb.se), and all cultures from this province (including nine hospitals and all primary care facilities) are handled by our laboratory. From 2012 through late 2014, the BacT/Alert blood culture system (bioMérieux, Marcy l’Etoile, France) was used and was replaced by the BACTEC FX blood culture system (Becton Dickinson, Franklin Lakes, USA) in December 2014. The laboratory receives approximately 75,000 blood culture bottles/year of which roughly 12% grow bacteria. The isolates had been identified by MALDI-TOF MS and the majority of them were identified at genus level only. For the study, stored isolates were re-cultured on blood agar plates under aerobic conditions, and when sufficient growth was observed (at between 24 and 120 h), samples were analyzed by the direct colony method using MALDI-TOF MS (version Microflex MALDI-TOF MS, software FlexControl 3.4 and MALDI Biotyper (MBT) Compass 4.1, with MBT Compass Library, DB-7854 MSP (Bruker, Bremen, Germany). In cases where a low score was achieved, we also used a standard ethanol-formic acid extraction method described by the instrument manufacturer. The cutoff of 1.7 for species determination as suggested by Alatoom et al.  and also others  was employed. Resistance was determined according to EUCAST protocols, and breakpoints were defined according to EUCAST guidelines (available at EUCAST.org).
Patients and definitions
Medical records were studied retrospectively. Records inaccessible and patients under the age of 18 were excluded from further analysis. The regional ethics committee of Lund University approved of the study (2017/1002). An episode was defined as a clinical situation where Corynebacterium was isolated from blood and the episode was concluded after 2 weeks of effective antibiotic treatment. Thus, if Corynebacterium was isolated from the same patient within 14 days, this was regarded as persistent bacteremia whereas a positive culture after 14 days was regarded as a new episode. Data collected included age, gender, the use of immunosuppressive treatment, underlying medical conditions according to Charlson , and criteria for IE according to Duke . Nosocomial infections were defined as an infection evident at 48 h or more past hospital admission. Focus of infection was defined by fulfillment of the following three criteria (i) the isolation of the relevant bacterium from the site of infection, (ii) signs and symptoms of focal infection, and iii) radiological signs of focal infection . In-hospital mortality was recorded.
Definitions of true infection depending on the number of positive cultures
Two or more positive blood cultures
Infection confirmed by temperature > = 38 OR hypotension (systolic blood pressure < 100 mmHg) OR chills OR leukocytosis (> 12 × 109/L)
No other more likely pathogen in blood culture explains confirmed infection
No other focal infection where other bacteria are more likely explains symptoms of patient, where focal infection is defined by two of the following (a–c):
a. Isolation of pathogens other than Corynebacterium at site of infection
b. Typical signs or symptoms of focal infection
c. Imaging results compatible with focal infection
Additional criteria in cases with one positive blood culture
Foreign intravascular devicea present > 48 h prior to blood sample OR Corynebacterium isolated at site of infection
For categorial data, statistical analysis was performed using two-sided χ2 test (Pearson) for multiple comparisons or Fischer’s exact test for pairwise comparisons. Continuous variables were investigated for difference using Mann-Whitney U test. A p value of < 0.05 was regarded as statistically significant.
Description of the cohort
Characteristics of patients with true infection and contamination
True infection (n = 30)
Contamination (n = 309)
p value for difference
Age years (IQR1)
Female gender, n (%)
Community site of acquisition
Focus of infection
Bone and joints
Identification and characterization of isolates
Microbiology of true infections and contamination
True infection (n = 30)
Contamination (n = 309)
p for difference
Two or more positive blood cultures
Species of Corynebacterium, n (%)
Not determined to species
Of isolates from true infections, the majority were resistant to penicillin and clindamycin (25 and 24 of 30 tested isolates, respectively), whereas a majority of isolates were sensitive to fluoroquinolones and rifampicin (13 of 24 and 18 of 21 isolates, respectively). All isolates tested were sensitive to vancomycin (n = 30, median MIC 0.5) and linezolid (n = 22).
IE caused by Corynebacterium
Characteristics of IE caused by Corynebacterium
No. of blood cultures
PCR on valve pos
PCR on valve pos
PCR on valve pos
PCR on valve pos
This work demonstrates that Corynebacterium is a rare cause of severe infections and that bacteremia often represent contamination. Since our cohort is population-based, we conclude that the incidence of Corynebacterium IE is around one in a million per year, whereas true bacteremia occurs in around four cases per million inhabitants per year. On several occasions, very significant infections such as culture-proven Corynebacterium-caused IE or spondylodiscitis were diagnosed in patients with only one positive blood culture. This indicates that the definitions used for differentiating between true infection and contamination should take into account both bacteriological and clinical factors. Simple definitions such as one blood culture equals contamination will miss true infections. Our definition included a demand on clinical symptoms of infection, lack of other more likely causes of infection, and either two positive blood cultures or one positive blood culture in conjunction with an intravascular device or isolation of Corynebacterium at the site of a focal infection. This was adapted from previous works on coagulase-negative staphylococci  which, similar to Corynebacterium, often contaminate blood cultures and on rare occasions cause severe infections. Our definition is more sensitive than simple microbiological definitions based only on the number of positive cultures but there is also a risk for introducing false positives. Some of the episodes where Corynebacterium was isolated from two blood cultures and no focus was identified could certainly also represent contamination, whereas some likely represent missed cases of IE. We believe, however, that a more inclusive definition of true infection is important in order not to miss severe infections caused by Corynebacterium.
From our results, we conclude that the species of Corynebacterium is an important factor in determining if a finding is likely to represent true infection or contamination. Thus, the finding of C. jeikeium in blood is a strong suggestion of an underlying true infection whereas the isolation of C. afermentans strongly indicates contamination. We therefore suggest that clinical laboratories should determine the species of all corynebacterial isolated from blood so that clinicians can use this information to determine if a given isolate is a contaminant or relevant pathogen.
Corynebacterium IE has been described in numerous case reports but large case series or cohort-based studies are lacking. Our description of eight episodes of Corynebacterium-caused IE is relevant as it represents a population-based account of this type of infection. Interestingly, all cases were related to valve prosthesis and this is clearly more than reported in a large review of published cases (19%) . The cases occurred both early after valve insertion and as late as 3 years after surgery suggesting that both intraoperative and hematogenous spread of bacteria occur. Our findings also demonstrate that the isolation of a Corynebacterium from blood in a patient with a heart valve prosthesis should evoke a strong suspicion of IE. Despite the potential severity of prosthesis-IE, the mortality was lower in our cohort (one of seven patients) than that reported from systematic reviews of case reports (40%) . This might be explained by a tendency of clinicians to mainly report dramatic presentations of IE. As in previous reviews on the topic, we observed a male dominance in Corynebacterium IE. Despite that our cohort is comparatively large, it is still too small to draw definite conclusions about the role of different Corynebacterium species in IE. It can be noted, however, that C. amycolatum, C. striatum, and C. jeikeium constitute a majority of cases and these species have been described previously to be common in Corynebacterium IE.
C. striatum has recently been shown to possess virulence factors, especially in terms of biofilm production, which implies that favorable conditions for the bacteria such as venous catheters constitute a risk environment for the growth of this particular bacterial species . Indeed, spread and adaption of certain C. striatum clones in hospital settings has been demonstrated recently . C. striatum is also known as a causative agent of a wide range of infections and for displaying or easily develop resistance to many antimicrobials [19, 20, 21, 22]. Apart from IE and sepsis, C. striatum–related infections can arise from the respiratory tract, urinary tract, or wounds . This is consistent with the findings in this study, where C. striatum was related to different types of infections.
The main strength of this study is that it is population-based and large. This allows for conclusions about incidences. Another strength is the combination of microbiological analyses and a careful analysis of clinical data which allow us to draw conclusions about the likelihood of different species to cause infection and contamination. The main limitation is that not all isolates were available for species determination and that there was a bias in which isolates had been saved. Isolates that the laboratory staff believed represented contaminations were less likely to be preserved, and this might have skewed the results from the species determination. The study was of course also limited by the retrospective design where only information recorded in the medical records were available for analysis. Despite that the study is population-based, of course, caution must be taken with extrapolation of the results to other geographical locations.
In conclusion, we demonstrate that Corynebacterium can cause severe infections and that species determination is an important tool to help clinicians in determining if a given patient has true infection caused by Corynebacterium. Therefore, we propose that microbiology laboratories should report the species of corynebacteria isolated from blood cultures.
We acknowledge the invaluable support by Mrs. Lena Hyllebusk at the Department of Clinical Microbiology. This work was supported by the Swedish Government Fund for Clinical Research (ALF), the foundations of Österlund and Skåne University Hospital, and the Royal Physiographic Society in Lund. Part of this work was presented as an abstract at the Swedish infectious diseases meeting in Jönköping May 2019.
Open access funding provided by Lund University.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflicts of interest.
All procedures performed were in accordance with the Swedish law on the ethics trial of research made on human subjects (SFS 2003:460) and were approved by the regional research ethics committee (ethics committee of Lund University, 2017/1002).
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