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Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species
Pancreatology xxx (2018) 1e5
Contents lists available at ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species Sebastian Rasch*, Ulrich Mayr, Veit Phillip, Roland M. Schmid, Wolfgang Huber, Hana Algül, Tobias Lahmer €t München, Ismaninger Straße 22, 81675, München, Germany Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universita
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 March 2018 Received in revised form 9 July 2018 Accepted 11 July 2018 Available online xxx
Background and objectives: Candida infections are frequent in necrotising pancreatitis. Candidemia is associated with very high mortality and its risk due to infected pancreatic necrosis is unknown. So we aimed to assess potential risk factors and the risk of candidemia in necrotising pancreatitis. Methods: We retrospectively searched our clinical database for the diagnosis necrotising pancreatitis from 2007 till March 2017 and entered relevant information in a database for statistical analysis. Results: in total, 136 patients met the inclusion criteria. Candida infected pancreatic necrosis were found in 54 patients and 7 patients developed candidemia. Patients with Candida infected necrosis had a significantly higher in hospital mortality (35.2% versus 13.4%, p ¼ 0.003). The highest mortality was observed in patients with candidemia (57.1% versus 20.2%, p ¼ 0.042). Male gender (OR 0.32, CI 0.13 e0.78, p ¼ 0.013) and post-ERCP pancreatitis (OR 4.32, CI 1.01e18.36, p ¼ 0.048) had a significant impact on the risk of Candida infections of pancreatic necrosis. Candidemia was significantly more frequent in patients with Candida infected necrosis (11.1% versus 1.2%, p ¼ 0.016). Candida albicans was the most common species followed by Candida glabrata. Conclusion: Candidemia is a relevant complication of necrotising pancreatitis and associated with high mortality. If patients do not respond to antibiotic therapy empiric antifungal therapy should be discussed. © 2018 Published by Elsevier B.V. on behalf of IAP and EPC.
Keywords: Pancreatitis Necrosis Candida Candidemia Risk factor
1. Introduction With an incidence of 30e45/100.000 person years acute pancreatitis is a frequent disease [1e3]. The overall mortality is about 5% but strongly depends on the severity of the disease [4,5]. According to the revised Atlanta classification of 2011, acute pancreatitis can be classified as mild, moderately severe or severe. Moderately severe and severe pancreatitis is characterized by local and systemic complications. Typical local complications include acute necrotic collections in the early phase and walled-off necrosis in the late phase of the disease [6]. This so called necrotising pancreatitis evolves in about 4e47% of the patients with acute pancreatitis and, particularly in case of infected necrosis, it is associated with high morbidity and mortality rates [4,7,8]. Fungal infections of necrosis in acute pancreatitis are very common and especially Candida albicans is one of the most frequently cultured
* Corresponding author. E-mail address: [email protected] (S. Rasch).
pathogens [7]. In the available data of fungal pancreatic infections, pancreatic pseudocysts are usually not distinguished from walledoff necrosis. But pseudocysts and walled-off necrosis are characterised by a divergent course of the disease and distinct complications [9e11]. While fungal colonisation, e.g. of the respiratory tract, is mainly considered as risk factor for fungal infections and is a common finding in severely ill patients, invasive mycosis itself has a substantial mortality. In particular, candidemia has a mortality rate of over 60% and, similar to other pathogens, source control within 24 h and early effective antifungal therapy can significantly reduce mortality in candidemia [12]. Accordingly, treatment of fungal infections of pancreatic necrosis is recommended by current guidelines [13]. However, treatment is often delayed by the insensitivity and time needed to yield growth in cultured necrotic specimen [13,14]. Furthermore, neither the actual risk nor the role of markers like 1,3 Beta - d - Glucan or risk scores of candidemia have been evaluated in necrotising pancreatitis [13]. Considering the high prevalence of candida infections in pancreatic necrosis, we aim to assess the prevalence and potential
https://doi.org/10.1016/j.pan.2018.07.005 1424-3903/© 2018 Published by Elsevier B.V. on behalf of IAP and EPC.
Please cite this article in press as: Rasch S, et al., Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species, Pancreatology (2018), https://doi.org/10.1016/j.pan.2018.07.005
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S. Rasch et al. / Pancreatology xxx (2018) 1e5
risk factors of invasive candidiasis and candidemia in necrotising pancreatitis by this retrospective analysis. 2. Materials and methods We performed a unicenter retrospective analysis of patients with necrotising pancreatitis between 2007 and March 2017 at the tertiary referral center Klinikum rechts der Isar der Technischen €t München. We screened our administrative diagnosis Universita database for patients with pancreatitis (International Classification of Diseases (ICD)-10 code K85 and K86). Candida infection of pancreatic necrosis requires confirmation by microbiology. So only patients with necrotising pancreatitis requiring invasive treatment (percutaneous and/or transgastric/transduodenal drainage, surgical/percutaneous and/or endoscopic necrosectomy) in the late phase of pancreatitis (>10 d after onset of symptoms) were included in the study. Necrotising pancreatitis was classified according to the revised Atlanta classification [6]. We identified 136 patients that met the inclusion criteria. Patients with microbiological evidence of Candida species in blood samples or in pancreatic walled-off necrosis formed the study group, those without were assigned to the control group. Only microbiology specimen obtained at first intervention of the walled-off necrosis were included to distinguish infection from colonisation. For Candida resistance profiles EUCAST breakpoints were used. Patients with suspected or proven invasive Candidiasis were initially treated with an Echinocandin until susceptibility testing was available. The study was approved by the local ethics committee €t für Medizin der Technischen Uni(Ethikkommission der Fakulta €t München, project number 5726/13). Written consent was versita specifically waived by the approving institutional review board. Statistical analysis was performed using IBM SPSS Statistics 22 (SPSS Inc, Chicago, Illinois, USA). Samples were checked for normal distribution using the Shapiro-Wilk test. Variables were not normally distributed. Accordingly, descriptive data are presented as median, range and interquartile range (IQR). Risk ratios are displayed as odds ratio (OR) with 95% confidence interval (CI). To compare qualitative parameters, chi-square test was used and in small samples (expected frequency of test variable less than 5) Fisher's exact test was used. For the analysis of quantitative parameters, Mann-Whitney-U test was employed. All statistical tests were two-sided with a level of significance (p-value) of 5%. A multivariate logistic regression model was used to identify risk factors for Candida infection of pancreatic necrosis. Factors with a p-value below 0.1 in univariate analysis or a high probability according to our data or the literature were included in multivariate regression analysis. 3. Results In total, 136 patients with necrotising pancreatitis requiring intervention were treated at our institution, 54 had proven Candida infected necrosis and 7 developed candidemia (Fig. 1 and Table 1). No patient was under immunosuppressive therapy. Most patients (84.6% - 115/136) were treated with at least two different interventions (percutaneous, endoscopic and/or surgical). In 18.5% (10/54) Candida species were cultured in specimen obtained by two different treatment modalities. In both, necrotic specimen and blood cultures, Candida albicans was the most frequently isolated Candida species (Table 2). In general, Candida albicans was also the most frequently isolated pathogen in pancreatic necrosis after Enterococcus faecium. In all patients (7/7) who developed candidemia there was evidence of Candida infection or colonisation of different organ systems. In 66.7% (4/6) the same Candida species was identified in the
Fig. 1. Flow chart of patient selection.
necrosis and in the blood culture. More than 1 Candida species in pancreatic necrosis was cultured in 18.5% (10/54) of the patients. Patients with Candida infected pancreatic necrosis had a significantly higher in hospital mortality comparing to patients without Candida infection (Table 1). Patients with candidemia had the highest in hospital mortality (57.1% (4/7) versus 20.2% (26/129), p ¼ 0.042). In multivariate logistic regression analysis genesis, gender, alcohol and nicotine abuse were analysed for their impact on Candida infections of pancreatic necrosis (Table 3). Fungal infection of pancreatic necrosis was found more often in patients with a post-ERCP pancreatitis (OR 4.32, CI 1.01e18.36, p ¼ 0.048) and less frequent in men (OR 0.32, CI 0.13e0.78, p ¼ 0.013).
4. Discussion Contrary to intra-abdominal infections in general, fungal infections of pancreatic necrosis are very common [14]. In older studies the rate of primary infection of pancreatic necrosis with Candida species ranges from 0-40% [15e18]. However, in these older studies surgical necrosectomy was the standard treatment. More conservative and less invasive treatment of necrotising pancreatitis resulted in a decrease in overall mortality from almost 40%e11% [7,16]. As hospitalisation is a risk factor for candidiasis, this more conservative management with preferably late interventions might explain the high rate of primary candidiasis of pancreatic necrosis in our study population [13]. And as it is associated with an excess of morbidity and mortality, Candida infection of pancreatic necrosis is a relevant problem. These patients not only required more interventions and a longer treatment in hospital but also had a significantly increased mortality [14]. Whether colonisation with Candida species is of pathologic relevance or a concomitant feature in critically ill patients is an
Please cite this article in press as: Rasch S, et al., Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species, Pancreatology (2018), https://doi.org/10.1016/j.pan.2018.07.005
S. Rasch et al. / Pancreatology xxx (2018) 1e5
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Table 1 Patient characteristics (*p 0.05).
n gender m/f median age nicotine abuse alcohol abuse hospitalisation in days genesis alcoholic biliary iatrogen/post-ERCP toxic/drug induced unknown patients with percutaneous drainage/necrosectomy transmural endoscopic drainage/ necrosectomy surgery median number of interventions candidemia in hospital mortality
in total
no evidence of Candida spec. In necrosis positive cultures for Candida spec. in necrosis p
136 1.9:1 (89/47) 58 (IQR 46e70; range 18e89) 45.0% (49/109) 55.6% (65/117) 47 (IQR 28e84; range 1e368)
82 (60.3%) 2.5:1 (59/23) 57.5 (IQR 46e70; range 18e85) 50.8% (31/61) 65.7% (44/67) 42 (IQR 26.75e65; range 1e277)
54 (39.7%) 1.25:1 (30/24) 59 (IQR 47e69; range 24e89) 37.5% (18/48) 42.0% (21/50) 70 (IQR 35.25e115.25; range 12e368)
31.6% (43/136) 29.4% (40/136) 14.0% (19/136) 4.4% (6/136) 20.6% (28/136)
35.4% (29/82) 25.6% (21/82) 11.0% (9/82) 4.9% (4/82) 23.2% (19/82)
25.9% (14/54) 35.2% (19/54) 18.5% (10/54) 3.7% (2/54) 16.7% (9/54)
0.247 0.230 0.214 1.0 0.359
69.7% (95/136) 63.2% (86/136)
64.6% (53/82) 43.9% (36/82)
77.8% (42/54) 74.1% (50/54)
0.102 0.001*
20.6% (28/136) 3 (IQR 2e7; range 1e78) 5.1% (7/136) 22.1% (30/136)
23.2% (19/82) 3 (IQR 2e6; range 1e78) 1.2% (1/82) 13.4% (11/82)
16.7% (9/54) 4 (IQR 1e8.25; range 1e17) 11.1% (6/54) 35.2% (19/54)
0.359 0.194
0.049* 0.558 0.165 0.011* 0.004*
0.016* 0.003*
Table 2 Candida species identified in pancreatic necrosis and blood cultures with susceptibility to antimycotic drugs. Candida species
blood culture
pancreatic necrosis
Resistance to Amphotericin
Fluconazole
Voriconazole
Echinocandins: Caspofungin
Micafungin 0% (0/14) 0% (0/9) 50% (1/2) 0% (0/1) 0% (0/1)
C.albicans C.glabrata C.krusei C.tropicalis C.parapsylosis C.dubilensis C. lusitaniae
3 1 1 1 1
38 18 4 2 0 1 1
0% (0/41) 0% (0/19) 20% (1/5) 0% (0/3) 0% (0/1) 0% (0/1) 0% (0/1)
4.9% (2/41) 100% (18/19) 100% (5/5) 0% (0/3) 0% (0/1) 0% (0/1)
2.4% (1/41) 44% (8/18) 20% (1/5) 0% (0/3) 0% (0/1) 0% (0/1)
0% 0% 0% 0% 0% 0%
(0/34) (0/14) (0/0) (0/2) (0/1) (0/1)
Total
7
64
1.4% (1/71)
35.7% (25/70)
14.7% (10/68)
0% (0/52)
3.7% (1/27)
(As the standard in susceptibility testing of Candida has changed during the study period, the number of tested specimen for each drug varies.).
Table 3 Variables of multivariate regression model (Dependent variable: candida infection of pancreatic necrosis). Independent variables
rationale for inclusion of the variable in the regression model
p
OR
95% Confidence interval
Gender Smoking status Alcohol abuse Genesis
p ¼ 0.049 in univariate analysis p ¼ 0.011 in univariate analysis
0,013 0,551 0,062 0,191 0,118 0,048
0,32 1,36 0,36 2,38 2,55 4,32
0,13 0,50 0,13 0,65 0,79 1,01
alcoholic biliary iatrogen/post-ERCP
distribution of genesis of necrotising pancreatitis differs significantly between patients with Candida infected necrosis and those without (p ¼ 0.007)
ongoing debate. Similar to colonisation, Candida infections in necrotising pancreatitis might also just be a concomitant incident and the high morbidity and mortality might also just reflect the severity of the disease in these patients. According to our data, Candidemia is significantly more frequent in patients with Candida infected necrosis. Consequently, treatment of confirmed fungal infections of pancreatic necrosis is indicated, which is in coherence with current guidelines and previous reports [13,18,19]. The distribution of Candida species in candidemia on our cohort was similar to other reports in the literature [20]. There was a relevant number of infections by Candida glabrata and krusei, and these species can be resistant to fluconazol. As the distribution of Candida species might vary between different hospitals, the choice of antifungal treatment should be adapted to the local Candida prevalence. In our institution, we prefer echinocandins as initial
0,78 3,71 1,05 8,73 7,93 18,36
treatment until the species is identified in cultures [21]. This approach is in line with recent recommendations and guidelines [13,19]. But cultures have a low sensitivity in detecting candidiasis [22]. Delayed treatment until blood cultures become positive is associated with increased mortality, and blood cultures are only positive in about one third of the patients with invasive candidiasis and candidemia [12,23e25]. Only 1,3 Beta -d- Glucan has proven some ability to early identify intra-abdominal invasive candidiasis. But as only 4% of all intra-abdominal infections are fungal infections, compared to almost 40% in patients with necrotising pancreatitis, the significance of 1,3 Beta -d- Glucan testing in necrotising pancreatitis is limited [14,26]. This demonstrates the need for prospective validation of risk scores or diagnostic screening tools. For risk stratification we tried to identify factors predisposing for Candida superinfections. Established risk factors of
Please cite this article in press as: Rasch S, et al., Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species, Pancreatology (2018), https://doi.org/10.1016/j.pan.2018.07.005
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Table 4 Established risk factors of invasive candidiasis [27].
[3] High APACHE II score/Admission to ICU Mechanical ventilation Neutropenia and immunosuppressive therapy Presence of central venous catheters Use of broad-spectrum antibiotics Parenteral nutrition Renal insufficiency and haemodialysis (Abdominal) Surgery Pancreatitis Diabetes mellitus
invasive candidiasis are summarized in Table 4 [27]. As suspected infection was the most frequent indication for intervention, all patients were on broad spectrum antibiotic treatment. Unfortunately many of these risk factors often cannot be avoided due to the severity of the disease. So most patients were also exposed to other established risk factors like admission to intensive care unit (76.5% 104/136), central venous catheters (79.4% - 108/136) or parenteral nutrition. Consequently we focused on identifying additional hazards. While Pappas et al. demonstrated that male sex is a risk factor for mortality in candidemia. [28], in our cohort female patients female gender was associated with more Candida superinfections. The same accounts for post-ERCP pancreatitis. With a high prevalence of intra-abdominal candidiasis after gastrointestinal perforation and in particular after gastroduodenal perforation, this finding is not surprising as a dislocation of Candida species by accidental cannulation of the pancreatic duct while ERCP is possible [29,30]. As colonisation in critically ill patients is a frequent finding and candidemia is the most frequent hospital acquired bloodstream infection, there is some data supporting a prophylactic antifungal treatment [13,31]. However, the role of an empiric antifungal treatment in necrotising pancreatitis remains unclear. Considering the high mortality of candidemia empiric treatment should be discussed in patients that do not respond to initial antibiotic therapy, especially in patients with post-ERCP pancreatitis. The results of this study are limited by the retrospective, moncenter study design. Prospective trials to identify further biomarkers or risk factors of candidiasis and evaluate the role of an empiric antifungal treatment in necrotising pancreatitis are needed.
[4]
[5] [6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
5. Conclusion Candidemia is a relevant complication of necrotising pancreatitis and associated with high morbidity and mortality. As Candidemia occurs significantly more often in patients with Candida infected pancreatic necrosis, obtaining cultures from pancreatic necrosis and several blood cultures is of importance. Particularly in patients with post-ERCP pancreatitis empiric antifungal therapy should be discussed if they do not respond to antibiotic therapy.
[21]
[22]
[23]
Acknowledgements [24]
The authors do not have any conflicts of interest or competing financial interests to disclose. [25]
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Contents lists available at ScienceDirect
Pancreatology journal homepage: www.elsevier.com/locate/pan
Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species Sebastian Rasch*, Ulrich Mayr, Veit Phillip, Roland M. Schmid, Wolfgang Huber, Hana Algül, Tobias Lahmer €t München, Ismaninger Straße 22, 81675, München, Germany Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technische Universita
a r t i c l e i n f o
a b s t r a c t
Article history: Received 16 March 2018 Received in revised form 9 July 2018 Accepted 11 July 2018 Available online xxx
Background and objectives: Candida infections are frequent in necrotising pancreatitis. Candidemia is associated with very high mortality and its risk due to infected pancreatic necrosis is unknown. So we aimed to assess potential risk factors and the risk of candidemia in necrotising pancreatitis. Methods: We retrospectively searched our clinical database for the diagnosis necrotising pancreatitis from 2007 till March 2017 and entered relevant information in a database for statistical analysis. Results: in total, 136 patients met the inclusion criteria. Candida infected pancreatic necrosis were found in 54 patients and 7 patients developed candidemia. Patients with Candida infected necrosis had a significantly higher in hospital mortality (35.2% versus 13.4%, p ¼ 0.003). The highest mortality was observed in patients with candidemia (57.1% versus 20.2%, p ¼ 0.042). Male gender (OR 0.32, CI 0.13 e0.78, p ¼ 0.013) and post-ERCP pancreatitis (OR 4.32, CI 1.01e18.36, p ¼ 0.048) had a significant impact on the risk of Candida infections of pancreatic necrosis. Candidemia was significantly more frequent in patients with Candida infected necrosis (11.1% versus 1.2%, p ¼ 0.016). Candida albicans was the most common species followed by Candida glabrata. Conclusion: Candidemia is a relevant complication of necrotising pancreatitis and associated with high mortality. If patients do not respond to antibiotic therapy empiric antifungal therapy should be discussed. © 2018 Published by Elsevier B.V. on behalf of IAP and EPC.
Keywords: Pancreatitis Necrosis Candida Candidemia Risk factor
1. Introduction With an incidence of 30e45/100.000 person years acute pancreatitis is a frequent disease [1e3]. The overall mortality is about 5% but strongly depends on the severity of the disease [4,5]. According to the revised Atlanta classification of 2011, acute pancreatitis can be classified as mild, moderately severe or severe. Moderately severe and severe pancreatitis is characterized by local and systemic complications. Typical local complications include acute necrotic collections in the early phase and walled-off necrosis in the late phase of the disease [6]. This so called necrotising pancreatitis evolves in about 4e47% of the patients with acute pancreatitis and, particularly in case of infected necrosis, it is associated with high morbidity and mortality rates [4,7,8]. Fungal infections of necrosis in acute pancreatitis are very common and especially Candida albicans is one of the most frequently cultured
* Corresponding author. E-mail address: [email protected] (S. Rasch).
pathogens [7]. In the available data of fungal pancreatic infections, pancreatic pseudocysts are usually not distinguished from walledoff necrosis. But pseudocysts and walled-off necrosis are characterised by a divergent course of the disease and distinct complications [9e11]. While fungal colonisation, e.g. of the respiratory tract, is mainly considered as risk factor for fungal infections and is a common finding in severely ill patients, invasive mycosis itself has a substantial mortality. In particular, candidemia has a mortality rate of over 60% and, similar to other pathogens, source control within 24 h and early effective antifungal therapy can significantly reduce mortality in candidemia [12]. Accordingly, treatment of fungal infections of pancreatic necrosis is recommended by current guidelines [13]. However, treatment is often delayed by the insensitivity and time needed to yield growth in cultured necrotic specimen [13,14]. Furthermore, neither the actual risk nor the role of markers like 1,3 Beta - d - Glucan or risk scores of candidemia have been evaluated in necrotising pancreatitis [13]. Considering the high prevalence of candida infections in pancreatic necrosis, we aim to assess the prevalence and potential
https://doi.org/10.1016/j.pan.2018.07.005 1424-3903/© 2018 Published by Elsevier B.V. on behalf of IAP and EPC.
Please cite this article in press as: Rasch S, et al., Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species, Pancreatology (2018), https://doi.org/10.1016/j.pan.2018.07.005
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risk factors of invasive candidiasis and candidemia in necrotising pancreatitis by this retrospective analysis. 2. Materials and methods We performed a unicenter retrospective analysis of patients with necrotising pancreatitis between 2007 and March 2017 at the tertiary referral center Klinikum rechts der Isar der Technischen €t München. We screened our administrative diagnosis Universita database for patients with pancreatitis (International Classification of Diseases (ICD)-10 code K85 and K86). Candida infection of pancreatic necrosis requires confirmation by microbiology. So only patients with necrotising pancreatitis requiring invasive treatment (percutaneous and/or transgastric/transduodenal drainage, surgical/percutaneous and/or endoscopic necrosectomy) in the late phase of pancreatitis (>10 d after onset of symptoms) were included in the study. Necrotising pancreatitis was classified according to the revised Atlanta classification [6]. We identified 136 patients that met the inclusion criteria. Patients with microbiological evidence of Candida species in blood samples or in pancreatic walled-off necrosis formed the study group, those without were assigned to the control group. Only microbiology specimen obtained at first intervention of the walled-off necrosis were included to distinguish infection from colonisation. For Candida resistance profiles EUCAST breakpoints were used. Patients with suspected or proven invasive Candidiasis were initially treated with an Echinocandin until susceptibility testing was available. The study was approved by the local ethics committee €t für Medizin der Technischen Uni(Ethikkommission der Fakulta €t München, project number 5726/13). Written consent was versita specifically waived by the approving institutional review board. Statistical analysis was performed using IBM SPSS Statistics 22 (SPSS Inc, Chicago, Illinois, USA). Samples were checked for normal distribution using the Shapiro-Wilk test. Variables were not normally distributed. Accordingly, descriptive data are presented as median, range and interquartile range (IQR). Risk ratios are displayed as odds ratio (OR) with 95% confidence interval (CI). To compare qualitative parameters, chi-square test was used and in small samples (expected frequency of test variable less than 5) Fisher's exact test was used. For the analysis of quantitative parameters, Mann-Whitney-U test was employed. All statistical tests were two-sided with a level of significance (p-value) of 5%. A multivariate logistic regression model was used to identify risk factors for Candida infection of pancreatic necrosis. Factors with a p-value below 0.1 in univariate analysis or a high probability according to our data or the literature were included in multivariate regression analysis. 3. Results In total, 136 patients with necrotising pancreatitis requiring intervention were treated at our institution, 54 had proven Candida infected necrosis and 7 developed candidemia (Fig. 1 and Table 1). No patient was under immunosuppressive therapy. Most patients (84.6% - 115/136) were treated with at least two different interventions (percutaneous, endoscopic and/or surgical). In 18.5% (10/54) Candida species were cultured in specimen obtained by two different treatment modalities. In both, necrotic specimen and blood cultures, Candida albicans was the most frequently isolated Candida species (Table 2). In general, Candida albicans was also the most frequently isolated pathogen in pancreatic necrosis after Enterococcus faecium. In all patients (7/7) who developed candidemia there was evidence of Candida infection or colonisation of different organ systems. In 66.7% (4/6) the same Candida species was identified in the
Fig. 1. Flow chart of patient selection.
necrosis and in the blood culture. More than 1 Candida species in pancreatic necrosis was cultured in 18.5% (10/54) of the patients. Patients with Candida infected pancreatic necrosis had a significantly higher in hospital mortality comparing to patients without Candida infection (Table 1). Patients with candidemia had the highest in hospital mortality (57.1% (4/7) versus 20.2% (26/129), p ¼ 0.042). In multivariate logistic regression analysis genesis, gender, alcohol and nicotine abuse were analysed for their impact on Candida infections of pancreatic necrosis (Table 3). Fungal infection of pancreatic necrosis was found more often in patients with a post-ERCP pancreatitis (OR 4.32, CI 1.01e18.36, p ¼ 0.048) and less frequent in men (OR 0.32, CI 0.13e0.78, p ¼ 0.013).
4. Discussion Contrary to intra-abdominal infections in general, fungal infections of pancreatic necrosis are very common [14]. In older studies the rate of primary infection of pancreatic necrosis with Candida species ranges from 0-40% [15e18]. However, in these older studies surgical necrosectomy was the standard treatment. More conservative and less invasive treatment of necrotising pancreatitis resulted in a decrease in overall mortality from almost 40%e11% [7,16]. As hospitalisation is a risk factor for candidiasis, this more conservative management with preferably late interventions might explain the high rate of primary candidiasis of pancreatic necrosis in our study population [13]. And as it is associated with an excess of morbidity and mortality, Candida infection of pancreatic necrosis is a relevant problem. These patients not only required more interventions and a longer treatment in hospital but also had a significantly increased mortality [14]. Whether colonisation with Candida species is of pathologic relevance or a concomitant feature in critically ill patients is an
Please cite this article in press as: Rasch S, et al., Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species, Pancreatology (2018), https://doi.org/10.1016/j.pan.2018.07.005
S. Rasch et al. / Pancreatology xxx (2018) 1e5
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Table 1 Patient characteristics (*p 0.05).
n gender m/f median age nicotine abuse alcohol abuse hospitalisation in days genesis alcoholic biliary iatrogen/post-ERCP toxic/drug induced unknown patients with percutaneous drainage/necrosectomy transmural endoscopic drainage/ necrosectomy surgery median number of interventions candidemia in hospital mortality
in total
no evidence of Candida spec. In necrosis positive cultures for Candida spec. in necrosis p
136 1.9:1 (89/47) 58 (IQR 46e70; range 18e89) 45.0% (49/109) 55.6% (65/117) 47 (IQR 28e84; range 1e368)
82 (60.3%) 2.5:1 (59/23) 57.5 (IQR 46e70; range 18e85) 50.8% (31/61) 65.7% (44/67) 42 (IQR 26.75e65; range 1e277)
54 (39.7%) 1.25:1 (30/24) 59 (IQR 47e69; range 24e89) 37.5% (18/48) 42.0% (21/50) 70 (IQR 35.25e115.25; range 12e368)
31.6% (43/136) 29.4% (40/136) 14.0% (19/136) 4.4% (6/136) 20.6% (28/136)
35.4% (29/82) 25.6% (21/82) 11.0% (9/82) 4.9% (4/82) 23.2% (19/82)
25.9% (14/54) 35.2% (19/54) 18.5% (10/54) 3.7% (2/54) 16.7% (9/54)
0.247 0.230 0.214 1.0 0.359
69.7% (95/136) 63.2% (86/136)
64.6% (53/82) 43.9% (36/82)
77.8% (42/54) 74.1% (50/54)
0.102 0.001*
20.6% (28/136) 3 (IQR 2e7; range 1e78) 5.1% (7/136) 22.1% (30/136)
23.2% (19/82) 3 (IQR 2e6; range 1e78) 1.2% (1/82) 13.4% (11/82)
16.7% (9/54) 4 (IQR 1e8.25; range 1e17) 11.1% (6/54) 35.2% (19/54)
0.359 0.194
0.049* 0.558 0.165 0.011* 0.004*
0.016* 0.003*
Table 2 Candida species identified in pancreatic necrosis and blood cultures with susceptibility to antimycotic drugs. Candida species
blood culture
pancreatic necrosis
Resistance to Amphotericin
Fluconazole
Voriconazole
Echinocandins: Caspofungin
Micafungin 0% (0/14) 0% (0/9) 50% (1/2) 0% (0/1) 0% (0/1)
C.albicans C.glabrata C.krusei C.tropicalis C.parapsylosis C.dubilensis C. lusitaniae
3 1 1 1 1
38 18 4 2 0 1 1
0% (0/41) 0% (0/19) 20% (1/5) 0% (0/3) 0% (0/1) 0% (0/1) 0% (0/1)
4.9% (2/41) 100% (18/19) 100% (5/5) 0% (0/3) 0% (0/1) 0% (0/1)
2.4% (1/41) 44% (8/18) 20% (1/5) 0% (0/3) 0% (0/1) 0% (0/1)
0% 0% 0% 0% 0% 0%
(0/34) (0/14) (0/0) (0/2) (0/1) (0/1)
Total
7
64
1.4% (1/71)
35.7% (25/70)
14.7% (10/68)
0% (0/52)
3.7% (1/27)
(As the standard in susceptibility testing of Candida has changed during the study period, the number of tested specimen for each drug varies.).
Table 3 Variables of multivariate regression model (Dependent variable: candida infection of pancreatic necrosis). Independent variables
rationale for inclusion of the variable in the regression model
p
OR
95% Confidence interval
Gender Smoking status Alcohol abuse Genesis
p ¼ 0.049 in univariate analysis p ¼ 0.011 in univariate analysis
0,013 0,551 0,062 0,191 0,118 0,048
0,32 1,36 0,36 2,38 2,55 4,32
0,13 0,50 0,13 0,65 0,79 1,01
alcoholic biliary iatrogen/post-ERCP
distribution of genesis of necrotising pancreatitis differs significantly between patients with Candida infected necrosis and those without (p ¼ 0.007)
ongoing debate. Similar to colonisation, Candida infections in necrotising pancreatitis might also just be a concomitant incident and the high morbidity and mortality might also just reflect the severity of the disease in these patients. According to our data, Candidemia is significantly more frequent in patients with Candida infected necrosis. Consequently, treatment of confirmed fungal infections of pancreatic necrosis is indicated, which is in coherence with current guidelines and previous reports [13,18,19]. The distribution of Candida species in candidemia on our cohort was similar to other reports in the literature [20]. There was a relevant number of infections by Candida glabrata and krusei, and these species can be resistant to fluconazol. As the distribution of Candida species might vary between different hospitals, the choice of antifungal treatment should be adapted to the local Candida prevalence. In our institution, we prefer echinocandins as initial
0,78 3,71 1,05 8,73 7,93 18,36
treatment until the species is identified in cultures [21]. This approach is in line with recent recommendations and guidelines [13,19]. But cultures have a low sensitivity in detecting candidiasis [22]. Delayed treatment until blood cultures become positive is associated with increased mortality, and blood cultures are only positive in about one third of the patients with invasive candidiasis and candidemia [12,23e25]. Only 1,3 Beta -d- Glucan has proven some ability to early identify intra-abdominal invasive candidiasis. But as only 4% of all intra-abdominal infections are fungal infections, compared to almost 40% in patients with necrotising pancreatitis, the significance of 1,3 Beta -d- Glucan testing in necrotising pancreatitis is limited [14,26]. This demonstrates the need for prospective validation of risk scores or diagnostic screening tools. For risk stratification we tried to identify factors predisposing for Candida superinfections. Established risk factors of
Please cite this article in press as: Rasch S, et al., Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species, Pancreatology (2018), https://doi.org/10.1016/j.pan.2018.07.005
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S. Rasch et al. / Pancreatology xxx (2018) 1e5
Table 4 Established risk factors of invasive candidiasis [27].
[3] High APACHE II score/Admission to ICU Mechanical ventilation Neutropenia and immunosuppressive therapy Presence of central venous catheters Use of broad-spectrum antibiotics Parenteral nutrition Renal insufficiency and haemodialysis (Abdominal) Surgery Pancreatitis Diabetes mellitus
invasive candidiasis are summarized in Table 4 [27]. As suspected infection was the most frequent indication for intervention, all patients were on broad spectrum antibiotic treatment. Unfortunately many of these risk factors often cannot be avoided due to the severity of the disease. So most patients were also exposed to other established risk factors like admission to intensive care unit (76.5% 104/136), central venous catheters (79.4% - 108/136) or parenteral nutrition. Consequently we focused on identifying additional hazards. While Pappas et al. demonstrated that male sex is a risk factor for mortality in candidemia. [28], in our cohort female patients female gender was associated with more Candida superinfections. The same accounts for post-ERCP pancreatitis. With a high prevalence of intra-abdominal candidiasis after gastrointestinal perforation and in particular after gastroduodenal perforation, this finding is not surprising as a dislocation of Candida species by accidental cannulation of the pancreatic duct while ERCP is possible [29,30]. As colonisation in critically ill patients is a frequent finding and candidemia is the most frequent hospital acquired bloodstream infection, there is some data supporting a prophylactic antifungal treatment [13,31]. However, the role of an empiric antifungal treatment in necrotising pancreatitis remains unclear. Considering the high mortality of candidemia empiric treatment should be discussed in patients that do not respond to initial antibiotic therapy, especially in patients with post-ERCP pancreatitis. The results of this study are limited by the retrospective, moncenter study design. Prospective trials to identify further biomarkers or risk factors of candidiasis and evaluate the role of an empiric antifungal treatment in necrotising pancreatitis are needed.
[4]
[5] [6]
[7]
[8]
[9] [10]
[11]
[12]
[13]
[14]
[15]
[16]
[17]
[18]
[19]
[20]
5. Conclusion Candidemia is a relevant complication of necrotising pancreatitis and associated with high morbidity and mortality. As Candidemia occurs significantly more often in patients with Candida infected pancreatic necrosis, obtaining cultures from pancreatic necrosis and several blood cultures is of importance. Particularly in patients with post-ERCP pancreatitis empiric antifungal therapy should be discussed if they do not respond to antibiotic therapy.
[21]
[22]
[23]
Acknowledgements [24]
The authors do not have any conflicts of interest or competing financial interests to disclose. [25]
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Please cite this article in press as: Rasch S, et al., Increased risk of candidemia in patients with necrotising pancreatitis infected with candida species, Pancreatology (2018), https://doi.org/10.1016/j.pan.2018.07.005