# Impact of prior antibiotics on infected pancreatic necrosis microbiology in ICU patients: a retrospective cohort study

Charlotte Garret, Emmanuel Canet, Stéphane Corvec, David Boutoille, Matthieu Péron, Isabelle Archambeaud, Aurélie Le Thuaut, Jean-Baptiste Lascarrou, Frédéric Douane, Marc Lerhun, et al.

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Charlotte Garret, Emmanuel Canet, Stéphane Corvec, David Boutoille, Matthieu Péron, et al. Impact of prior antibiotics on infected pancreatic necrosis microbiology in ICU patients: a retrospective cohort study. Annals of Intensive Care, 2020, 10 (1), pp.82. 10.1186/s13613-020-00698-0. hal-05454264

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# Impact of prior antibiotics on infected pancreatic necrosis microbiology in ICU patients: a retrospective cohort study

Charlotte Garret<fnref n="1" />*, Emmanuel Canet<fnref n="1" />, Stéphane Corvec², David Boutoille³, Matthieu Péron⁴, Isabelle Archambeaud⁴, Aurélie Le Thuaut⁵, Jean-Baptiste Lascarrou<fnref n="1" />, Frédéric Douane⁶, Marc Lerhun⁴, Nicolas Regenet⁴, Emmanuel Coron⁴ and Jean Reignier<fnref n="1" />

**Abstract**

**Background:** Recent guidelines advise against prophylactic antibiotics in patients with necrotizing pancreatitis, advocating instead a step-up drainage and necrosectomy strategy with antibiotics as dictated by microbiological findings. However, prompt antibiotic therapy is recommended in patients with sepsis or septic shock, a possible presentation of infected pancreatic necrosis (IPN). Consequently, in many critically ill patients with IPN, pancreatic samples are collected only after broad-spectrum antibiotic therapy initiation. Whether this prior antibiotic exposure alters the microbiological findings is unknown. The main objective was to determine whether prior antibiotic expo- sure sterilized the samples collected during procedures for suspected IPN in patients admitted to the intensive care unit (ICU) for acute pancreatitis with suspected IPN. We retrospectively studied 56 consecutive ICU patients admitted with suspected IPN. We collected details on the microbiological samples and antimicrobials used. A definite diagnosis of IPN was given when bacteria were identified in pancreatic samples.

**Results:** In all, 137 pancreatic samples were collected, including 91 (66.4%) after antibiotic therapy initiation. IPN was confirmed in 48 (86%) patients. The proportion of positive samples was 74 (81.3%) in antibiotic-exposed patients and 32/46 (69.5%) in unexposed patients (p = 0.58). Of the 74 positive samples from exposed patients, 62 (84%) had organisms susceptible to the antibiotics used. One-third of samples contained more than one organism. Among patients with IPN, 37.5% had positive blood cultures. Multidrug- or extensively drug-resistant bacteria were identified at some point in half the patients. *Enterobacter cloacae* complex was more frequent in the exposed group (p = 0.02), as were Gram-negative anaerobic bacteria (p = 0.03).

**Conclusion:** Antibiotic exposure before sampling did not seem to affect culture positivity of pancreatic samples to confirm IPN, but may affect microbiological findings. Our results suggest that, in patients with sepsis and suspected IPN, antibiotics should be started immediately and pancreatic samples obtained as soon as possible thereafter. In other situations, antibiotics can be withheld until the microbiological results of pancreatic samples are available, to ensure accurate targeting of the spectrum to bacterial susceptibility patterns.

ClinicalTrials.gov number NCT03253861

**Keywords:** Acute pancreatitis, Infected pancreatic necrosis, Multidrug-resistant infection, Step-up approach

**Background**

Severe acute pancreatitis is a common reason for intensive care unit (ICU) admission and is associated with long hospital stays and high morbidity and mortality

<figure><img src="image_4.png" /></figure>

<footnote>*Correspondence: charlotte.garret@chu-nantes.fr</footnote>

<footnote n="1">¹ Service de Médecine Intensive et Réanimation, Centre Hospitalier Universitaire de Nantes, 1 Place Alexis Ricordeau, 44093 Nantes, France
Full list of author information is available at the end of the article</footnote>
rates [1, 2]. Infected pancreatic necrosis (IPN) develops in about one-third of patients, who are then at increased risk for death [3]. International guidelines about the management of IPN [4–8] recommend a step-up strategy, based on findings from randomized controlled trials [9, 10]. The first step is minimally invasive (percutaneous or endoscopic) drainage combined with broad-spectrum antibiotic therapy. When this fails, minimally invasive endoscopic or surgical necrosectomy is performed. Microbiological studies are performed on all drainage and necrosectomy samples.

Prophylactic antibiotic therapy was not helpful in preventing IPN in several randomized controlled trials, and is therefore not recommended [11–13]. However, most international guidelines [4, 5, 14, 15] fail to provide recommendations about using antibiotics in patients with IPN, perhaps due to the scarcity of relevant published data. Canadian guidelines [16] recommend reserving antibiotics for patients with confirmed IPN and tailoring the antibiotic regimen to the species and sensitivities of the bacteria recovered from necrotic tissue samples. However, these guidelines also suggest that empirical antibiotic therapy may be considered before the culture results are available.

For sepsis and septic shock, in contrast, there is a clear recommendation to start antibiotics as early as possible [17]. Because sepsis and septic shock are possible presentations of IPN, many patients with IPN therefore receive antibiotics before the diagnosis of IPN is made or before a pancreatic sample can be collected. Furthermore, patients with IPN may require immediate antibiotic therapy for a co-existing infection at another site. The penetration of antibiotics within foci of pancreatic necrosis has been poorly evaluated but may be limited [18–26]. Thus, whether antibiotic exposure before the collection of pancreatic samples sterilizes the microbiological findings is unclear. Importantly, studies have documented a rise in the proportion of patients with pancreatic samples positive for multidrug-resistant bacteria (MDRB) up to values of 52% [27] and 63% [28]. Limiting the development of bacterial resistance by restricting the use of antibiotics is clearly a major public health goal [29–31]. If antibiotic exposure before pancreatic sampling hinders the identification of causative organisms, then exposed patients might not only have poorer outcomes, but also require longer and/or broader antibiotic treatments at higher risk for selecting resistant strains, and negative samples may not be sufficient reason to stop the antibiotics.

Our primary objective was to investigate whether the microbiology of pancreatic samples from critically ill patients with suspected IPN was sterilized according to whether antibiotics were started before or only after sample collection. The secondary objective was to describe

the bacterial species recovered and their resistance patterns in the groups previously exposed vs. unexposed to antibiotics.

## Methods

### Study design and setting

We performed a retrospective cohort study in consecutive patients admitted from 1 January 2012 to 2031 December 2015 to the ICU of the Hôtel-Dieu University Hospital, Nantes, France, for acute pancreatitis with suspected IPN. The study data were extracted from the electronic health records of each patient (Millennium database, Nantes, France).

The ethics committee of the French Intensive Care Society approved the study (#CE SRLF16-09). In accordance with French law on retrospective studies of anonymized data, informed consent was not required.

### Patient eligibility criteria and definitions

Critically ill adults (≥ 18 years) admitted to our ICU during the study period for acute pancreatitis (ICD-10 codes K85.0 to K85.9) were identified by searching the hospital electronic database. The electronic health records of all identified patients were reviewed by one of us (CG). According to the Atlanta classification [32], acute pancreatitis was classified as moderately severe in patients with transient organ failure resolving within 48 h and/or local or systemic complications without persistent organ failure and as severe in patients with organ failure persisting for more than 48 h. Organ failure was defined as a modified Marshall score (33) ≥ 2 for the renal, respiratory, and/or cardiovascular system (Additional file 1). Among patients with moderately severe or severe acute pancreatitis, those who had suspected IPN were identified. Suspected IPN was defined as computed tomography (CT) evidence of pancreatic or peripancreatic necrosis and performance of an invasive pancreatic procedure (percutaneous or endoscopic fluid drainage and/or endoscopic or surgical necrosectomy) [9, 10]. Patients with suspected IPN and available data on the microbiology of the pancreatic samples were included in the study.

Definite IPN was defined as either CT evidence of a collection containing extraluminal gas or a positive culture of pancreatic tissue obtained by drainage or necrosectomy [9]. Possible IPN was defined as pancreatic and/or peripancreatic necrosis requiring drainage/necrosectomy, persistent sepsis, and negative cultures of the pancreatic samples, in the absence of infection at another site [7].

### Data collection and outcomes

For each patient, we collected demographics, comorbidities, CT findings including the CT Severity Index (CTSI)
calculated by a radiologist, pancreatic procedures (percu-
taneous or endoscopic transluminal drainage and endo-
scopic or surgical necrosectomy), and the treatments
used in the ICU including antibiotics. At our institu-
tion, intensivists, gastroenterologists, and digestive sur-
geons are available 24 h a day, 7 days a week and work
together to manage patients with acute pancreatitis. For
patients with IPN, our local policy is to apply the step-up
approach described by van Santvoort et al. [9]. Selection
of the antibiotics and the duration of antibiotic ther-
apy are at the discretion of the attending physician. We
recorded the following complications: hollow organ per-
foration requiring a surgical, radiological, or endoscopic
procedure; bowel ischemia confirmed by CT, endoscopy,
or surgery; abdominal and/or gastrointestinal bleeding
requiring a surgical, radiological, or endoscopic proce-
dure, and gastrointestinal bleeding with loss of more than
500 mL of blood/24 h. We also collected ICU and hospi-
tal mortality. The microbiological data were recorded in
detail, with the number and nature of the samples, col-
lection method, culture results, and antimicrobial sus-
ceptibility test findings. Each sample indicates a separate
procedure. Bacteria were classified into four categories
according to their antibiotic susceptibility profile [33]:
bacteria without acquired antimicrobial resistance, mul-
tidrug-resistant bacteria (MDRB, defined as acquired
non-susceptibility to at least one agent in three or more
antimicrobial categories); extensively drug-resistant bac-
teria (XDRB, defined as non-susceptibility to at least one
agent in all but two or fewer antimicrobial categories);
and pandrug-resistant bacteria (defined as resistant to
all agents in all antimicrobial categories). We compared
patients who were started on antibiotics more than 24 h
before the first pancreatic sample was collected (exposed
group) to the other patients (unexposed group).

Statistical analysis

Quantitative variables were described as median and
interquartile range [IQR] and compared using the
Mann–Whitney tests, whereas qualitative variables were
described as number (%) and compared using Fisher’s
test. All tests were two-sided and *p* values lower than 5%
were considered to indicate significant associations. Sta-
tistical tests were conducted using the SAS 5.0.1 software
package (SAS Institute Inc., Cary, NC).

Results

Study population

Figure 1 is the patient flowchart. Of 148 patients admit-
ted for moderately severe or severe acute pancreatitis, 56
had suspected IPN and were included. Table 1 reports
their main characteristics. Of the 56 patients, 33 (59%)
were and 23 were not started on antibiotics more than

24 h before collection of the first pancreatic sample. No
significant differences in baseline features or outcomes
were found between the exposed and unexposed groups
(Table 1). CT showed gas bubbles within necrotic collec-
tions in 14 (25%) patients. The median number of pancre-
atic samples per patient was 2 [1–3] and the total number
of samples in the 56 patients was 137. The sample cul-
tures were positive in 48 (85.7%) patients, and 8 patients
(14.3%), IPN was considered as possible. Of these 48
patients with a definite diagnosis of IPN, 18 (37.5%) had
positive blood cultures, with the same bacterial species as
in the pancreatic samples.

Antimicrobial therapy and culture positivity in the exposed
and unexposed groups

In the 33 patients in the exposed group, the reasons for
previous antibiotic exposure were suspected IPN with-
out shock (n=10, 30%), suspected IPN with septic shock
(n=10, 30%), and extra-abdominal infection (n=13,
39%; 6 for pneumonia, 3 for catheter-related infection,
and 1 for urinary tract infection). The median time on
antibiotics before sampling was 7 [3–10] days. The antibi-
otics used before sampling were broad-spectrum penicil-
lins in half the patients (Table 2). The median duration of
overall antimicrobial therapy in the ICU was 47 [28–77]
days, and the number of antibiotics received overall in
the ICU was significantly higher in the exposed group
(5 [4–8] days versus 3 [2–5] days, p=0.002).Of the 137
samples, 91 (66.4%) were from exposed patients. Of the
91 samples from exposed patients, 74 (81.3%) were posi-
tive, and of the 41 samples from unexposed patients, 32
(78%) were positive. The proportion of positive cultures
was not significantly different between the exposed and
unexposed groups (Table 1).

Of the 74 positive samples from exposed patients, 62
were positive for bacteria showing in vitro susceptibility
to the pre-sampling antibiotics. Of these 62 samples, 30
were collected after more than 24 h, but less than 7 days
on antibiotics and 32 after more than 7 days on antibiot-
ics (Table 3).

Bacteria recovered in pancreatic samples (Table 3)

Of the 107 positive samples, 36 (33.4%) contained more
than one bacterial species. In all, 162 different species
were identified. Aerobic bacteria accounted for 82% of
the species recovered, anaerobic bacteria for 14%, and
*Candida* for 4%. *Escherichia coli* was the most com-
mon microorganism recovered from pancreatic samples
(Table 3). The distribution of bacterial species was similar
in the exposed and unexposed groups, except for *Entero-
bacter cloacae* complex which was more frequent in the
exposed group (*p* = 0.02), as were Gram-negative anaero-
bic bacteria (*p* = 0.03). Of 18 patients with positive blood
<figure><img src="image_5.png" /></figure>

cultures, only 3 (16%) were polymicrobial, with the same bacterial species as in the pancreatic samples. Of the remaining 15 patients with monomicrobial blood culture, 10 had the same bacterial species as in the monomicrobial pancreatic samples and 5 had only one of the bacterial species recovered in the polymicrobial pancreatic samples. Of the 156 bacterial species recovered from the 106 positive samples, 34 (22%) were MDRB and 17 (11%) were XDRB, with no significant difference between the exposed and unexposed groups (Additional file 2). Of the 56 patients, 25 (45%) developed a drug-resistant pancreatic infection including 15 with an MDRB and 10 with an XDRB. The 10 patients with an XDRB infection had a mean of 4.6±2 pancreatic procedures and consistently required surgical necrosectomy. These 10 patients were all exposed to prolonged broad-spectrum antibiotic therapy before sampling. Among them, 5 kept the same bacterial species in serial samples, with the acquisition of resistances over time. Adjusting the antibiotic regimen to

the susceptibility test results failed to sterilize the pancreatic samples, even after several weeks (Additional file 3). Of the 56 patients, 4 (7%) had pancreatic cultures positive for *Candida* at some point, including one who also had a blood culture positive for *Candida*.

## Patient outcomes in the exposed and unexposed groups

No significant differences were demonstrated between the two groups for the main complications, ICU stay length, ICU mortality, or hospital mortality.

## Discussion

The main finding from this retrospective cohort study is that the microbiology of pancreatic samples from critically ill patients with suspected IPN was not sterilized in patients on antibiotics for more than 24 h at sample collection. Thus, no significant differences were found between the exposed and unexposed groups regarding the proportion of positive samples, or identification of
<table><caption>Table 1 Baseline features of the study patients overall and in the antibiotic-exposed and unexposed groupsª</caption><thead><tr><th></th><th>Suspected IPN, n = 56</th><th>Exposed, n = 33</th><th>Unexposed, n = 23</th><th>P value</th></tr></thead><tbody><tr><td>Age, y, median [IQR]</td><td>58 [45.5;67.5]</td><td>54.5 [45.5;64]</td><td>63 [45;68.5]</td><td>0.89</td></tr><tr><td>Males, n (%)</td><td>47 [84]</td><td>26 [78]</td><td>21 [91]</td><td>0.28</td></tr><tr><td>BMI, median [IQR]</td><td>26.3 [23.6;29.5]</td><td>25.7 [23, 29]</td><td>26.9 [24.9;33]</td><td>0.18</td></tr><tr><td>Origin of pancreatitis</td><td></td><td></td><td></td><td></td></tr><tr><td>Biliary</td><td>16 (29)</td><td>9 (27)</td><td>7 (30.5)</td><td>0.95</td></tr><tr><td>Alcohol abuse</td><td>23 (51)</td><td>14 (43)</td><td>9 (39)</td><td></td></tr><tr><td>Other<sup>b</sup></td><td>17 (30)</td><td>10 (30)</td><td>7 (30.5)</td><td></td></tr><tr><td>SAPS II<sup>c</sup>, median [IQR]</td><td>38 [28;52]</td><td>37 [24;52]</td><td>39 [31;52]</td><td>0.73</td></tr><tr><td>CTSI<sup>d</sup>, median [IQR]</td><td>6 [4, 9]</td><td>6 [4, 9]</td><td>6 [4, 9]</td><td>0.79</td></tr><tr><td>No organ failure<sup>e</sup>, n (%)</td><td>1 (2)</td><td>0</td><td>1 (5)</td><td>0.76</td></tr><tr><td>1 or 2 organ failures, n (%)</td><td>41 (73)</td><td>24 (73)</td><td>17 (74)</td><td></td></tr><tr><td>≥3 organ failures, n (%)</td><td>14 (25)</td><td>9 (27)</td><td>5 (21)</td><td></td></tr><tr><td>Type of organ failure, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Respiratory failure</td><td>52 (93)</td><td>31 (94)</td><td>21 (92)</td><td>0.99</td></tr><tr><td>Mechanical ventilation</td><td>43 (77)</td><td>24 (73)</td><td>19 (83)</td><td>0.52</td></tr><tr><td>Circulatory failure</td><td>34 (61)</td><td>20 (61)</td><td>14 (61)</td><td>0.99</td></tr><tr><td>Renal failure</td><td>33 (59)</td><td>18 (55)</td><td>15 (65)</td><td>0.58</td></tr><tr><td>Time from ICU admission to first procedure for IPN, days, median [IQR]</td><td>21 [12, 29]</td><td>25 [15, 36]</td><td>19 [10–25]</td><td>0.61</td></tr><tr><td>IPN outcomes</td><td></td><td></td><td></td><td></td></tr><tr><td>Total number of procedures for IPN, median [IQR]</td><td>2 [1–3]</td><td>2 [1.5–3]</td><td>2 [1–2.75]</td><td>0.99</td></tr><tr><td>Confirmed IPN (positive sample culture), n (%)</td><td>48 (85.7)</td><td>30 (90)</td><td>18 (78)</td><td>0.25</td></tr><tr><td>Number of positive samples/total number of samples (%)</td><td>106 (77)</td><td>74/91 (81)</td><td>32/46 (70)</td><td>0.58</td></tr><tr><td>Patients developing a multidrug-resistant infection<sup>f</sup>, n (%)</td><td>15 (27)</td><td>8 (24)</td><td>6 (26)</td><td>0.99</td></tr><tr><td>Patients developing an extensively drug resistant infection<sup>g</sup>, n (%)</td><td>10 (17.8)</td><td>6 (18)</td><td>4 (17)</td><td>0.99</td></tr><tr><td>Patients with concomitant positive blood culture, n (%)</td><td>18 (32)</td><td>8 (24)</td><td>10 (43)</td><td>0.15</td></tr><tr><td>Other outcomes</td><td></td><td></td><td></td><td></td></tr><tr><td>Perforation of hollow organ, n (%)</td><td>5 (9)</td><td>4 (12)</td><td>1 (4)</td><td>0.63</td></tr><tr><td>Bowel ischemia, n (%)</td><td>3 (5)</td><td>2 (6)</td><td>1 (4)</td><td>0.99</td></tr><tr><td>Intestinal bleeding, n (%)</td><td>11 (20)</td><td>5 (15)</td><td>6 (26)</td><td>0.33</td></tr><tr><td>ICU stay, days, median [IQR]</td><td>24.5 [7–47]</td><td>23 [8–48]</td><td>28 [6–44]</td><td>0.54</td></tr><tr><td>Hospital stay, days, median [IQR]</td><td>66.5 [42–96]</td><td>68 [46.5–96]</td><td>63 [42–101]</td><td>0.68</td></tr><tr><td>ICU mortality, n (%)</td><td>9 (16)</td><td>5 (15)</td><td>4 (17)</td><td>0.99</td></tr><tr><td>Hospital mortality, n (%)</td><td>9 (16)</td><td>5 (15)</td><td>4 (17)</td><td>0.99</td></tr></tbody></table>

IPN infected pancreatic necrosis, IQR interquartile range, BMI body mass index, SAPS II Simplified Acute Physiology Score version II, CTSI Computed Tomography Severity Index, ICU intensive care unit

MDRB or XDRB, whereas *Enterobacter cloacae* complex and Gram-negative anaerobic bacteria were more frequent in the exposed group. Also, complications and mortality were similar in the two groups. Finally, the patient characteristics before the first sample collection

were not significantly different between the exposed and unexposed groups.

Organ failure is common in patients with IPN [34]. The recommendation when following the step-up strategy is to wait at least 4 weeks if possible before performing a

<footnote>ª Exposure was defined as patients who were started on antibiotics more than 24 h before the first pancreatic sample was collected</footnote>

<footnote>ᵇ Other causes of pancreatitis: hypertriglyceridemia, drugs, endoscopic retrograde cholangiopancreatography, and unknown</footnote>

<footnote>ᶜ The SAPS II can range from 0 (least severe) to 163 (most severe, with a 100% predicted risk of death); patients with a score of 50 have a 46.1% predicted risk of death</footnote>

<footnote>ᵈ The CTSI can range from 0 to 10; the predicted risk of death is 6% for values in the 4–6 range and 17% for values in the 7–10 range</footnote>

<footnote>ᵉ Organ failure was defined as a modified Marshall score (Supplemental Digital Content 1) ≥ 2 for the renal, respiratory, or cardiovascular system</footnote>

<footnote>f Multidrug-resistant bacteria were defined as bacteria with acquired non-susceptibility to at least one agent in three or more antimicrobial categories</footnote>

<footnote>g Extensively drug-resistant bacteria were defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories</footnote>
<table><caption>**Table 2** Characteristics of antimicrobial therapy: main molecule used and duration</caption><thead><tr><th></th><th>Total patients n = 56</th><th>Exposed group<sup>a</sup> n = 33</th><th>Unexposed group n = 23</th><th>P value</th></tr></thead><tbody><tr><td>First line antimicrobial therapy, n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Penicillin (amoxicillin and Peni M)</td><td>6 (11)</td><td>2 (6)</td><td>4 (17)</td><td>0.4</td></tr><tr><td>Amoxicillin-clavulanic acid</td><td>10 (18)</td><td>4 (12)</td><td>6 (26)</td><td>0.3</td></tr><tr><td>Piperacillin-tazobactam</td><td>16 (29)</td><td>9 (27)</td><td>7 (30)</td><td>1</td></tr><tr><td>Carbapenem</td><td>11 (19)</td><td>10 (30)</td><td>1 (4)</td><td>0.08</td></tr><tr><td>Cephalosporin</td><td>11 (19)</td><td>7 (21)</td><td>4 (17)</td><td>1</td></tr><tr><td>Fluoroquinolone</td><td>1 (2)</td><td>1 (3)</td><td>0</td><td>1</td></tr><tr><td>Cotrimoxazole</td><td>1 (2)</td><td>0</td><td>1 (4)</td><td>0.42</td></tr><tr><td>Metronidazole</td><td>33 (59)</td><td>17 (52)</td><td>16 (70)</td><td>0.51</td></tr><tr><td>Aminoglycoside</td><td>11 (19)</td><td>7 (21)</td><td>4 (17)</td><td>1</td></tr><tr><td>Anti-fungal</td><td>6 (11)</td><td>4 (12)</td><td>2 (9)</td><td>1</td></tr><tr><td>Time of overall antimicrobial therapy in ICU (median in days [IQR])</td><td>47 [28–77]</td><td>50 [28–88]</td><td>38.5 [26–61]</td><td>0.18</td></tr><tr><td>Number of overall different antimicrobial agents in ICU (median [IQR])</td><td>4 [2–6]</td><td>5 [4–8]</td><td>3 [2–5]</td><td>0.002</td></tr></tbody></table>

Italic value indicates significance of P value (P < 0.05)

pancreatic procedure. During this period, antibiotics are often given due to sepsis or septic shock or to a documented infection outside the pancreas (e.g., nosocomial pneumonia, catheter-related infection, or bacteraemia). Negative samples collected while the patient was receiving antibiotics may indicate absence of an infection, presence of an infection that is responding to antibiotics, or a false-negative result. In our study, most of the patients with suspected IPN had positive cultures, with no difference between the exposed and unexposed groups. Thus, pancreatic sample cultures seem to preserve their diagnostic value even in patients on antibiotics and, in addition, provide valuable antimicrobial susceptibility information. If the cultures are negative, the diagnosis of IPN should be reappraised. Moreover, as in previous studies [9, 10], our results showed a high proportion of patients (86%) with a confirmed IPN by positive sample culture collected during drainage procedure or necrectomy. These findings are consistent with international recommendations [4, 7, 8, 15, 16] advocating against the routine use of fine needle aspiration to confirm IPN.

In a study from England and Wales, antibiotics were given before the first pancreatic sample was collected in 439/712 (62%) patients [35], compared to 59% in our study. However, the inclusion criterion was acute pancreatitis, as opposed to suspected IPN in our study, and the patients were not all critically ill, with only 60/439 having sepsis. Furthermore, IPN was the reason for the first, second, and third courses of antibiotics in only 8, 0, and 1 patients, respectively, whereas in our study, a third of the patients had septic shock. Piperacillin/

tazobactam was the most common antimicrobial used (34%), similar to our cohort (30%). In a retrospective study of a prospective database in the US of 182 consecutive symptomatic patients who had undergone pancreatic procedures for walled-off necrosis, 41% had culture-proven IPN [36]. Of these patients with positive cultures, 70% received antibiotics within 14 days before sample collection; and of the patients exposed to antibiotics before first sample collection, 70% had proven IPN. These results are consistent with ours, as are reports that about a third of samples contain more than one identified organism and that Gram-negative bacteria predominate [27, 37–39].

About a third of our patients had MDRB or XDRB identified in their pancreatic samples. Highly resistant strains of several bacterial species are becoming increasingly common in ICU patients [31]. In addition, among patients with acute pancreatitis, 50% to 85% have been found to have highly resistant bacteria [27, 28, 39]. Infections due to MDRB and XDRB are associated with considerably higher morbidity, mortality, and healthcare costs compared to those due to less resistant bacteria [39]. Acute pancreatitis with IPN runs a prolonged course that is often punctuated by a series of complications. Thus, many patients have long ICU and hospital stays associated with a high risk of cross-transmission [29], receive multiple courses of antibiotics, and require more than one pancreatic procedure. After a drainage procedure, more than half the patients require necrectomy [9, 10]. The median number of procedures per patient in our study was 2. This

<footnote><sup>a</sup> Exposure was defined as patients who were started on antibiotics more than 24 h before the first pancreatic sample was collected</footnote>
<table><caption>**Table 3** Distribution of microorganisms recovered at the time of the first sampling in 107 positive samples in the groups exposed and unexposed to antibiotics</caption><thead><tr><th></th><th>Total patients with confirmed IPN<br>n=48 Species n=162 (100%)</th><th>Exposed group n=30<br>species n=97 (60%)</th><th>Unexposed group<br>n=18 species n=65<br>(40%)</th><th>P value</th></tr></thead><tbody><tr><td><strong>Bacteria</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Gram-negative enterobacteriaceae</td><td>82 (50.6)</td><td>49 (50.5)</td><td>33 (50.5)</td><td>1</td></tr><tr><td>Escherichia coli</td><td>36 (22.2)</td><td>16</td><td>20</td><td></td></tr><tr><td>Klebsiella pneumoniae</td><td>11 (6.8)</td><td>4</td><td>7</td><td></td></tr><tr><td>Klebsiella oxytoca</td><td>10 (6.2)</td><td>9</td><td>1</td><td></td></tr><tr><td>Enterobacter cloacae complex</td><td>14 (8.6)</td><td>13</td><td>1</td><td></td></tr><tr><td>Citrobacter freundii</td><td>2 (1.3)</td><td>0</td><td>2</td><td></td></tr><tr><td>Morganella morganii</td><td>3 (1.8)</td><td>3</td><td>0</td><td></td></tr><tr><td>Proteus mirabilis</td><td>3 (1.8)</td><td>2</td><td>1</td><td></td></tr><tr><td>Enterobacter aerogenes</td><td>2 (1.3)</td><td>1</td><td>1</td><td></td></tr><tr><td>Hafnia alvei</td><td>1 (0.6)</td><td>1</td><td>0</td><td></td></tr><tr><td>Gram-negative aerobic and anaerobic bacteria</td><td>13 (8.1)</td><td>11 (11)</td><td>2 (0.3)</td><td>0.13</td></tr><tr><td>Pseudomonas aeruginosa</td><td>10 (6.2)</td><td>9</td><td>1</td><td></td></tr><tr><td>Acinetobacter baumannii</td><td>1 (0.6)</td><td>1</td><td></td><td></td></tr><tr><td>Stenotrophomonas maltophilia</td><td>2 (1.3)</td><td>1</td><td>1</td><td></td></tr><tr><td>Gram-negative anaerobic bacteria</td><td>23 (14.2)</td><td>8 (8)</td><td>15 (23)</td><td>0.03</td></tr><tr><td>Bacteroides fragilis</td><td>10 (6.2)</td><td>2</td><td>8</td><td></td></tr><tr><td>Prevotella spp.</td><td>10 (6.2)</td><td>5</td><td>5</td><td></td></tr><tr><td>Other anaerobes</td><td>3 (1.8)</td><td>1</td><td>2</td><td></td></tr><tr><td>Gram-positive bacteria</td><td>38 (23.4)</td><td>22 (23)</td><td>14 (21)</td><td>0.85</td></tr><tr><td>Enterococcus faecalis</td><td>18 (11.1)</td><td>9</td><td>7</td><td></td></tr><tr><td>Enterococcus faecium</td><td>4 (2.4)</td><td>3</td><td>1</td><td></td></tr><tr><td>Streptococcus</td><td>6 (3.7)</td><td>4</td><td>2</td><td></td></tr><tr><td>Staphylococcus aureus</td><td>7 (4.4)</td><td>5</td><td>2</td><td></td></tr><tr><td>Staphylococcus epidermidis</td><td>3 (1.8)</td><td>1</td><td>2</td><td></td></tr><tr><td><strong>Fungi</strong></td><td></td><td></td><td></td><td></td></tr><tr><td>Candida</td><td>6 (3.7)</td><td>5 (0.5)</td><td>1 (0.2)</td><td>0.4</td></tr><tr><td>C. albicans</td><td>4 (2.4)</td><td>3</td><td>1</td><td></td></tr><tr><td>C. glabrata</td><td>2 (1.3)</td><td>2</td><td>0</td><td></td></tr></tbody></table>

Italic values indicate significance of P value (P < 0.05)

complicated course may increase the opportunities for developing highly resistant bacteria.

Candida was identified in only 7% of our patients. In previous studies, this proportion varied widely, from 5% to 68.5%, perhaps in part due to differences in patient selection criteria. Prophylactic antibiotic therapy increases the risk of fungal infections which are associated with increased morbidity and mortality rates [40–42] and is not recommended in international guidelines. The absence of prophylactic antibiotic therapy in our patients may explain the low frequency of fungal infections.

In our study, antibiotic therapy given before sample collection failed to sterilize the pancreatic samples, even when broad-spectrum agents were given for prolonged periods. One possible explanation is poor penetration

of the antibiotics into the fluid collections and necrotic foci. Very few data are available on this point. In two studies, after a single intravenous dose of ertapenem or imipenem, concentrations in pancreatic tissue and juice, respectively, were low but above the minimum inhibitory concentrations for the main pathogens responsible for intra-abdominal infections [22, 43, 44]. Several studies of animal models of acute pancreatitis [24–26] showed penetration within necrotic tissue to levels above the minimal inhibitory concentrations of common pathogens, and a single study [23] demonstrated good cefepime concentrations in pancreatic pseudocyst fluid or pancreatic resection specimens for cancer. However, pancreatic necrotic tissue during acute pancreatitis was not studied. If penetration is poor in necrotic tissue, then the sharp rise in highly resistant bacteria among patients with
acute pancreatitis supports the use of antibiotic-sparing strategies in patients with IPN [37]. Antibiotic de-escalation based on antimicrobial susceptibility test results is needed to reduce the development of resistance [29, 30]. The cornerstone of IPN management is the removal of infected fluids and necrotic tissues according to the step-up strategy. Systemic antibiotics alone are not recommended for IPN [4, 5, 15, 16].

Blood cultures were positive in about a third of our patients, in keeping with earlier findings [9]. Antibiotic therapy before blood sample collection from patients with severe sepsis has been reported to markedly decrease the likelihood of positive blood cultures, even when time from antibiotic initiation to sampling was short [45]. Thus, obtaining pancreatic samples is crucial in patients with suspected IPN. For patients in septic shock (about one-third in our study), antibiotics must be started immediately. For the other patients, the question is whether to withhold antibiotics until the causative agent is identified or to start antibiotics then discontinue them promptly if the microbiological tests are negative.

Moreover, the low frequency of fungal infections in our study suggests that antifungal agents may be appropriate only in patients with a documented fungal infection, and in those with septic shock provided the treatment is stopped if the samples are negative for fungi.

Regarding the recovered microorganisms, the exposed group had more *Enterobacter cloacae* complex and non-fermenting Gram-negative bacteria and the unexposed group more Gram-negative anaerobic bacteria. *Candida* also seemed more frequent in the exposed group ($n=5$ versus $n=1$) but the difference was not significant, probably due to the small sample size. These disparities in microbial findings can be explained by exposure to antibiotics, which had a median duration of 7 days before bacteriological sampling in the exposed group. Other patient outcomes in our study were comparable in the exposed and unexposed groups, except for a higher overall number of antibiotics in the exposed group. Similarly, in a 2019 retrospective cohort study of ICU patients with acute pancreatitis, mortality was not different between the groups with vs. without antibiotic therapy at ICU admission [46].

The main limitation of our study is the retrospective single center design, with no standardization of the antibiotic treatment strategy. No prophylactic antibiotics were used in any patients. However, we did not have information on antibiotic exposure before ICU admission, on the reason for the timing of interventions, or on the reasons for discontinuing antibiotic therapy. Few guidelines exist about when to start and stop antibiotics or which antibiotics to use. Empirical therapy with antibiotics active on gastrointestinal organisms followed by adjustments based

on antimicrobial susceptibility tests has been suggested [1, 7, 16]. We also had no information on nosocomial infections at extra-abdominal sites. In patients with multiple pancreatic fluid collections and/or necrotic foci, samples were not routinely obtained from all foci. This fact may have resulted in false-negative culture findings. Furthermore, patients categorized in the unexposed group may have received previous antimicrobial therapy for more than 24 h that may have affected the microbiological findings. However, given that cultures were positive in 86% of both patients exposed and unexposed to antibiotics within 24 h before sampling, in keeping with earlier data [9, 10], we are confident that previous antimicrobial therapy exposure is unlikely to have sterilized the samples. No information was available on intestinal carriage or known colonization of these patients, or on the mechanisms of acquired antibiotic resistance in the patients with highly resistant strains. Data on inflammatory status including body temperature, leukocytosis, and procalcitonin levels were also lacking, as they were not reliably recorded in the medical files. However, these data are of limited relevance in critically ill patients. Despite these limitations, our study provides the first evidence on the impact of prior antibiotics on pancreatic sample microbiology in patients managed with the currently recommended step-up strategy for suspected IPN and no prophylactic antibiotics. We collected a vast amount of information on the types and timing of antibiotic treatments, culture results, and antimicrobial susceptibilities.

## Conclusion

In patients admitted to the ICU with suspected IPN, starting antibiotic therapy more than 24 h before collection of the first pancreatic sample did not seem to sterilize microbiological cultures and had a limited impact on microbiological findings. The cultures were positive in most patients. It therefore seems appropriate to start empirical antibiotics immediately in patients with sepsis, septic shock, or a new organ failure. A pancreatic sample should then be obtained as soon as possible to identify the organism and assess the susceptibility profile. Given the high prevalence of bacteria exhibiting resistance to many agents, in other situations, antibiotic therapy may be best reserved for those patients with positive pancreatic samples may be appropriate, in order to limit the unnecessary use of antibiotics.

## Supplementary information

**Supplementary information** accompanies this paper at https://doi.org/10.1186/s13613-020-00698-0.
**Additional file 1: Table S1.** Modified Marshall scoring system for organ dysfunction.

**Additional file 2: Table S2.** Microbiological culture results in 23 patients with infected pancreatic necrosis and multidrug-resistant (MDR) or extensively drug-resistant (XDR) bacteria in pancreatic samples.

**Additional file 3: Table S3.** Details of antibiotic therapy and microbiological results of pancreatic samples in 10 patients with extensively drug-resistant bacteria during their hospital stays for infected pancreatic necrosis.

## Abbreviations

ICU: Intensive care unit; IPN: Infected pancreatic necrosis; MDRB: Multidrug-resistant bacteria; XDRB: Extensively drug-resistant bacteria.

## Acknowledgements

We are indebted to A. Wolfe, MD, for assistance in preparing and reviewing the manuscript.

## Authors' contributions

CG: initiation and contribution to the conception and design of the study, acquisition of data, interpretation of data, and drafting the manuscript. ECA: contribution to interpreting the data and major contribution to drafting the manuscript. SC analyzed and interpreted the microbiological data and contributed to draft the manuscript. DB interpreted the microbiological data and contributed to draft the manuscript. MP contributed to acquisition of data. IA contributed to acquisition and interpretation of data. ALT contributed to data analysis and interpretation, performed the statistical analysis. JBL contributed to draft the manuscript. FD contributed to acquisition of data, interpreted the CT findings. ML critically revised the manuscript for important intellectual content. N contributed to acquisition and interpretation of data. ECo critically revised the manuscript for important intellectual content. JR contributed to conceive and design the study and to draft the manuscript; critically revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

## Funding

This research received no specific funding from any funding agency in the public, commercial, or not-for-profit sectors.

## Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

## Ethics approval and consent to participate

The ethics committee of the French Intensive Care Society approved the study (#CE SRLF16-09). In accordance with French law on retrospective studies of anonymized data, informed consent was not required.

## Consent for publication

Not applicable to this retrospective study of anonymized data.

## Competing interests

The authors declare that they have no competing interests.

## Author details

¹ Service de Médecine Intensive et Réanimation, Centre Hospitalier Universitaire de Nantes, 1 Place Alexis Ricordeau, 44093 Nantes, France. ² Service de Bactériologie-Hygiène Hospitalière, CHU de Nantes, 1 Place Alexis Ricordeau, 44093 Nantes, France. ³ CRCINA, INSERM U1232, Université de Nantes, Nantes, France. ⁴ Service de Maladies Infectieuses et Tropicales, CHU de Nantes, 1 Place Alexis Ricordeau, 44093 Nantes, France. ⁵ Institut des Maladies de l'appareil Digestif, CHU de Nantes, 1 Place Alexis Ricordeau, 44093 Nantes, France.

⁶ Département de Biostatistiques, CHU de Nantes, 1 Place Alexis Ricordeau, 44093 Nantes, France.

Received: 29 January 2020 Accepted: 5 June 2020

Published online: 15 June 2020

## References

1. Forsmark CE, SwaroopVege S, Wilcox CM. Acute pancreatitis. N Engl J Med. 2016;375(20):1972-81.

2. Zerem E. Treatment of severe acute pancreatitis and its complications. World J Gastroenterol. 2014;20(38):13879-92.

3. Garret C, Péron M, Reignier J, Le Thuaut A, Lascarrou J-B, Douane F, et al. Risk factors and outcomes of infected pancreatic necrosis: retrospective cohort of 148 patients admitted to the ICU for acute pancreatitis. United Eur Gastroenterol J. 2018;6(6):910-8.

4. Pezzilli R, Zerbi A, Campra D, Capurso G, Golfieri R, Arcidiacono PG, et al. Consensus guidelines on severe acute pancreatitis. Dig Liver Dis. 2015;47(7):532-43.

5. Working Group IAP/APA Acute Pancreatitis Guidelines. IAP/APA evidence-based guidelines for the management of acute pancreatitis. Pancreatol Off J Int Assoc Pancreatol IAP Al. août 2013;13(4 Suppl 2):e1-15.

6. Sekimoto M, Takada T, Kawarada Y, Hirata K, Mayumi T, Yoshida M, et al. JPN Guidelines for the management of acute pancreatitis: epidemiology, etiology, natural history, and outcome predictors in acute pancreatitis. J Hepatobiliary Pancreat Surg. 2006;13(1):10-24.

7. Arvanitakis M, Dumonceau J-M, Albert J, Badaoui A, Bali MA, Barthet M, et al. Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) evidence-based multidisciplinary guidelines. Endoscopy. 2018;50(5):524-46.

8. Leppäniemi A, Tolonen M, Tarasconi A, Segovia-Lohse H, Gamberini E, Kirkpatrick AW, et al. 2019 WSES guidelines for the management of severe acute pancreatitis. World J Emerg Surg. 2019;19:14-27.

9. van Santvoort HC, Besselink MG, Bakker OJ, Hofker HS, Boermeester MA, Dejong CH, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010;362(16):1491-502.

10. van Brunschot S, van Grinsven J, van Santvoort HC, Bakker OJ, Besselink MG, Boermeester MA, et al. Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial. Lancet. 2017;391(10115):51-8.

11. Lim CLL, Lee W, Liew YX, Tang SSL, Chlebicki MP, Kwa ALH. Role of antibiotic prophylaxis in necrotizing pancreatitis: a meta-analysis. J Gastrointest Surg. 2015;19(3):480-91.

12. Isenmann R, Rünzi M, Kron M, Kahl S, Kraus D, Jung N, et al. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology. 2004;126(4):997-1004.

13. Villatoro E, Mulla M, Larvin M. Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis. Cochrane Database Syst Rev. 2010. https://doi.org/10.1002/14651858.CD002941.pub3.

14. Isayama H, Nakai Y, Rerknimitr R, Khor C, Lau J, Wang H-P, et al. Asian consensus statements on endoscopic management of walled-off necrosis. Part 2: Endoscopic management: Asian consensus on endoscopic management of WON. J Gastroenterol Hepatol. 2016;31(9):1555-65.

15. Yokoe M, Takada T, Mayumi T, Yoshida M, Isaji S, Wada K, et al. Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015. J Hepato-Biliary-Pancreat Sci. 2015;22(6):405-32.

16. Greenberg JA, Hsu J, Bawazeer M, Marshall J, Friedrich JO, Nathens A, et al. Clinical practice guideline: management of acute pancreatitis. Can J Surg. 2016;59(2):128-40.

17. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77.

18. Schubert S, Dalhoff A. Activity of Moxifloxacin, Imipenem, and Ertapenem against *Escherichia coli*, *Enterobacter cloacae*, *Enterococcus faecalis*, and *Bacteroides fragilis* in monocultures and mixed cultures in an in vitro pharmacokinetic/pharmacodynamic model simulating concentrations in the human pancreas. Antimicrob Agents Chemother. 2012;56(12):6434-6.

19. Wacke R, Forster S, Adam U, Mundkowski RG, Klar E, Hopt UT, et al. Penetration of moxifloxacin into the human pancreas following a single intravenous or oral dose. J Antimicrob Chemother. 2006;58(5):994-9.

20. GonzálezLópez J, MacíasGarcía F, LariñoNoia J, DomínguezMuñoz JE. Theoretical approach to local infusion of antibiotics for infected pancreatic necrosis. Pancreatology. 2016;16(5):719-25.

21. Bassi C, Pederzoli P, Vesentini S, Falconi M, Bonora A, Abbas H, et al. Behavior of antibiotics during human necrotizing pancreatitis. Antimicrob Agents Chemother. 1994;38(4):830-6.
22. Ikawa K, Kondo N, Nakashima A, Yoshizawa K, Morikawa N, Ikeda K, et al. Penetration of meropenem into human pancreatic juice. Scand J Infect Dis. 2013;45(5):404–6.

23. Delcenserie R, Dellion-Lozinguez MP, Yzet T, Lepointe B, Hary L, Badoui R, et al. Pancreatic concentrations of cefepime. J Antimicrob Chemother. 2001;47(5):711–3.

24. Papagoras D, Giamarellos-Bourboulis EJ, Kanara M, Douridas G, Paraskevopoulos I, Antzaklis G, et al. Pancreatic concentrations of cefepime in experimental necrotizing pancreatitis. J Chemother. 2003;15(1):43–6.

25. Sağlamkaya U, Mas MR, Yaşar M, Simşek I, Mas NN, Kocabalkan F. Penetration of meropenem and cefepim into pancreatic tissue during the course of experimental acute pancreatitis. Pancreas. 2002;24(3):264–8.

26. Gloor B, Worni M, Strobel O, Uhl W, Tcholakov O, Müller CA, et al. Cefepime tissue penetration in experimental acute pancreatitis. Pancreas. 2003;26(2):117–21.

27. De Waele JJ, Vogelaers D, Hoste E, Blot S, Colardyn F. Emergence of antibiotic resistance in infected pancreatic necrosis. Arch Surg. 2004;139(12):1371–5.

28. Lee H-S, Lee SK, Park DH, Lee SS, Seo DW, Kim MH, et al. Emergence of multidrug resistant infection in patients with severe acute pancreatitis. Pancreatol Off J Int Assoc Pancreatol. 2014;14(6):450–3.

29. Timsit J-F, Harbarth S, Carlet J. De-escalation as a potential way of reducing antibiotic use and antimicrobial resistance in ICU. Intensive Care Med. 2014;40(10):1580–2.

30. Bassetti M, De Waele JJ, Eggmann P, Garnacho-Montero J, Kahlmeister G, Menichetti F, et al. Preventive and therapeutic strategies in critically ill patients with highly resistant bacteria. Intensive Care Med. 2015;41(5):776–95.

31. Brusselaers N, Vogelaers D, Blot S. The rising problem of antimicrobial resistance in the intensive care unit. Ann Intensive Care. 2011;1:47.

32. Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG, et al. Classification of acute pancreatitis–2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013;62(1):102–11.

33. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2012;18(3):268–81.

34. Garret C, Péron M, Reignier J, Coron E. Risk factors and outcomes of infected pancreatic necrosis: retrospective cohort of 148 patients admitted to the ICU for acute pancreatitis. UEG J. 2018;6(6):910–8.

35. Barrie J, Jamdar S, Smith N, McPherson SJ, Siriwardena AK, O'Reilly DA. Mis-use of antibiotics in acute pancreatitis: insights from the United Kingdom's National Confidential Enquiry into patient outcome and death (NCEPOD) survey of acute pancreatitis. Pancreatol Off J Int Assoc Pancreatal. 2018;18(7):721–6.

36. Sahar N, Kozarek RA, Kanji ZS, Chihara S, Gan SI, Irani S, et al. The microbiology of infected pancreatic necrosis in the era of minimally invasive therapy. Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol. 2018;37(7):1353–9.

37. De Waele JJ, Rello J, Anzueto A, Moreno R, Lipman J, Sakr Y, et al. Infections and use of antibiotics in patients admitted for severe acute pancreatitis: data from the EPIC II study. Surg Infect. 2014;15(4):394–8.

38. Maraví-Poma E, Gener J, Alvarez-Lerna F, Olaechea P, Blanco A, Domínguez-Muñoz JE, et al. Early antibiotic treatment (prophylaxis) of septic complications in severe acute necrotizing pancreatitis: a prospective, randomized, multicenter study comparing two regimens with imipenem-cilastatin. Intensive Care Med. 2003;29(11):1974–80.

39. Moka P, Goswami P, Kapil A, Xess I, Sreenivas V, Saraya A. Impact of Antibiotic-Resistant Bacterial and Fungal Infections in Outcome of Acute Pancreatitis. Pancreas. 2018;47(4):489–94.

40. Kochhar R, Ahammed SKM, Chakrabarti A, Ray P, Sinha SK, Dutta U, et al. Prevalence and outcome of fungal infection in patients with severe acute pancreatitis. J Gastroenterol Hepatol. 2009;24(5):743–7.

41. Schwender BJ, Kolwijck E. Risk factors for the development of intra-abdominal fungal infections in acute pancreatitis. Pancreas. 2015;44(5):805–7.

42. Grewe M, Tsiotos GG, De-Leon EL, Sarr MG. Fungal infection in acute necrotizing pancreatitis. J Am College Surg. 1999;188(4):408–14.

43. Wittau M. Intraabdominal tissue concentration of ertapenem. J Antimicrob Chemother. 2006;57(2):312–6.

44. Brattström C, Malmborg AS, Tydén G. Penetration of imipenem into human pancreatic juice following single intravenous dose administration. Chemotherapy. 1989;35(2):83–7.

45. Cheng MP, Stenstrom R, Paquette K, Stabler SN, Akhter M, Davidson AC, et al. Blood culture results before and after antimicrobial administration in patients with severe manifestations of sepsis: a diagnostic study. Ann Intern Med. 2019;171(8):547–54.

46. Montravers P, Kantor E, Constantin J-M, Lefrant J-Y, Lescot T, Nesseler N, et al. Epidemiology and prognosis of anti-infective therapy in the ICU setting during acute pancreatitis: a cohort study. Crit Care. 2019;23(1):393.

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