Three-day antibiotic treatment for acute cholangitis due to choledocholithiasis with successful biliary duct drainage: A single-center retrospective cohort study Masaaki Satake a, *, Yukihiro Yamaguchi b a Department of Gastroenterology, Kenwakai Otemachi Hospital, Kitakyusyu, Japan b Internal medicine, Kenwakai Otemachi Hospital, Kitakyusyu, Japan A R T I C L E I N F O Article history: Received 13 March 2020 Received in revised form 23 April 2020 Accepted 25 April 2020 Keywords: Acute cholangitis Choledocholithiasis Antibiotic treatment Endoscopic biliary drainage Mortality A B S T R A C T Objectives: Given that the optimal antibiotic treatment duration for acute cholangitis with successful biliary drainage remains unknown, this study aimed to validate whether antibiotic treatment duration could be reduced to 3 days among patients presenting the same. Methods: This retrospective study included patients who presented with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage through endoscopic retrograde cholangiopancreatography (ERCP). After that, 30-day mortality rates and 3- month recurrence rates following short-course antibiotic treatment (SCT, 3 days) and long-course antibiotic treatment (LCT, 4 days) were compared. Results: A total of 96 patients were analyzed, among whom 22 (22.9%) received SCT, and 74 (77.1%) received LCT. The SCT and LCT groups had a median antibiotic treatment duration of 1.5 (range 1–3) and seven (range 4–17) days, respectively. Moreover, the SCT and LCT groups exhibited no significant differences in cholangitis grades, 30-day mortality rates (0%, 0/22 and 2.7%, 2/74, respectively), 3-month recurrence rates, length of hospitalization, and acute bacteremic cholangitis rates. Conclusions: This study suggests that antibiotic treatment for 3 days may be adequate for patients with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage. © 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc- nd/4.0/). 1. Introduction Acute cholangitis is the acute inflammation of the bile ducts, for which a prominent increase in the number of bacteria within the bile duct and a rise in bile duct pressure are crucial (Kiriyama et al., 2018). Increased biliary pressure has been found to influence defensive mechanisms within the host, such as tight junctions, Kupffer cell function, bile flow, and IgA production, resulting in higher incidences of septicemia and endotoxemia among such patients (Sung et al., 1992). Acute cholangitis treatment mainly includes antibiotic therapy and biliary decompression according to disease severity, the absence of which leads to high mortality risk (Kiriyama et al., 2018; Lee et al., 2015; Mukai et al., 2018; Gomi et al., 2018). In patients with intra-abdominal infections, a larger RCT (the STOP-IT trial) demonstrated that a fixed 4-day course of antimicrobial therapy was as effective as a longer, symptom- based duration of treatment (average of 8-days of antimicrobial therapy) (Sawyer et al., 2015). Intra-abdominal infection guide- lines published by the Surgical Infection Society recommend limiting antibiotic treatment to four days in patients who have had adequate source control, evidence for which was graded as very high (grade 1-A) (Mazuski et al., 2017). On the other hand, the Tokyo Guidelines 2018 (TG18) recommend 4–7 days of antibiotic treatment for patients with acute cholangitis once the source of infection is controlled, but evidence for this was graded as low (level C) (Gomi et al., 2018). Most patients with acute cholangitis who had undergone successful biliary drainage exhibit improved clinical presentation (e.g., fever) within a few days after the procedure. Furthermore, prolonged antibiotic treatment could lead to the development and increase of antibiotic-resistant bacteria * Corresponding author. Department of Gastroenterology, Kenwakai Otemachi Hospital, Fukuoka, Japan; 15-1, Otemachi, Kokurakika-ku, Kitakyushu, Fukuoka, 803-8543, Japan. Tel.: +81-93-592-5511; fax: +81-93-592-5231. E-mail address: [email protected] (M. Satake). https://doi.org/10.1016/j.ijid.2020.04.074 1201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). International Journal of Infectious Diseases 96 (2020) 343–347 Contents lists available at ScienceDirect International Journal of Infectious Diseases journal home page: www.elsevier.com/locat e/ijid
Three-day antibiotic treatment for acute cholangitis due to choledocholithiasis with successful biliary duct drainage: A single-center retrospective cohort study
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Three-day antibiotic treatment for acute cholangitis due to choledocholithiasis with successful biliary duct drainage: A single-center retrospective cohort studyMasaaki Satakea,*, Yukihiro Yamaguchib
aDepartment of Gastroenterology, Kenwakai Otemachi Hospital, Kitakyusyu, Japan b Internal medicine, Kenwakai Otemachi Hospital, Kitakyusyu, Japan
A R T I C L E I N F O
Article history: Received 13 March 2020 Received in revised form 23 April 2020 Accepted 25 April 2020
Keywords: Acute cholangitis Choledocholithiasis Antibiotic treatment Endoscopic biliary drainage Mortality
A B S T R A C T
Objectives: Given that the optimal antibiotic treatment duration for acute cholangitis with successful biliary drainage remains unknown, this study aimed to validate whether antibiotic treatment duration could be reduced to 3 days among patients presenting the same. Methods: This retrospective study included patients who presented with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage through endoscopic retrograde cholangiopancreatography (ERCP). After that, 30-day mortality rates and 3- month recurrence rates following short-course antibiotic treatment (SCT, 3 days) and long-course antibiotic treatment (LCT, 4 days) were compared. Results: A total of 96 patients were analyzed, among whom 22 (22.9%) received SCT, and 74 (77.1%) received LCT. The SCT and LCT groups had a median antibiotic treatment duration of 1.5 (range 1–3) and seven (range 4–17) days, respectively. Moreover, the SCT and LCT groups exhibited no significant differences in cholangitis grades, 30-day mortality rates (0%, 0/22 and 2.7%, 2/74, respectively), 3-month recurrence rates, length of hospitalization, and acute bacteremic cholangitis rates. Conclusions: This study suggests that antibiotic treatment for 3 days may be adequate for patients with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage. © 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).
journal home page: www.elsevier .com/ locat e/ i j id
1. Introduction
Acute cholangitis is the acute inflammation of the bile ducts, for which a prominent increase in the number of bacteria within the bile duct and a rise in bile duct pressure are crucial (Kiriyama et al., 2018). Increased biliary pressure has been found to influence defensive mechanisms within the host, such as tight junctions, Kupffer cell function, bile flow, and IgA production, resulting in higher incidences of septicemia and endotoxemia among such patients (Sung et al., 1992). Acute cholangitis treatment mainly includes antibiotic therapy and biliary decompression according to disease severity, the absence of which leads to high mortality risk
* Corresponding author. Department of Gastroenterology, Kenwakai Otemachi Hospital, Fukuoka, Japan; 15-1, Otemachi, Kokurakika-ku, Kitakyushu, Fukuoka, 803-8543, Japan. Tel.: +81-93-592-5511; fax: +81-93-592-5231.
E-mail address: [email protected] (M. Satake).
https://doi.org/10.1016/j.ijid.2020.04.074 1201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International So license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
(Kiriyama et al., 2018; Lee et al., 2015; Mukai et al., 2018; Gomi et al., 2018).
In patients with intra-abdominal infections, a larger RCT (the STOP-IT trial) demonstrated that a fixed 4-day course of antimicrobial therapy was as effective as a longer, symptom- based duration of treatment (average of 8-days of antimicrobial therapy) (Sawyer et al., 2015). Intra-abdominal infection guide- lines published by the Surgical Infection Society recommend limiting antibiotic treatment to four days in patients who have had adequate source control, evidence for which was graded as very high (grade 1-A) (Mazuski et al., 2017). On the other hand, the Tokyo Guidelines 2018 (TG18) recommend 4–7 days of antibiotic treatment for patients with acute cholangitis once the source of infection is controlled, but evidence for this was graded as low (level C) (Gomi et al., 2018). Most patients with acute cholangitis who had undergone successful biliary drainage exhibit improved clinical presentation (e.g., fever) within a few days after the procedure. Furthermore, prolonged antibiotic treatment could lead to the development and increase of antibiotic-resistant bacteria
ciety for Infectious Diseases. This is an open access article under the CC BY-NC-ND
and a higher risk for adverse reactions (e.g., pseudomembranous colitis).
Although recent studies have investigated the shortening of antibiotic treatment for acute cholangitis (Uno et al., 2016; Kogure et al., 2011; van Lent et al., 2002; Doi et al., 2018), the optimal duration of antibiotic treatment for acute cholangitis with successful biliary drainage has remained unknown. Thus, the present retrospective cohort study aimed to validate whether the antibiotic treatment duration for patients with acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage could be reduced to 3 days.
2. Methods
2.1. Study setting
This retrospective cohort study was conducted from April 2014 to March 2019 at Kenwakai Otemachi Hospital in Fukuoka, Japan, a tertiary-care hospital with 499 beds. Patients were screened by reviewing their electronic medical records. Those who had unavailable 30-day mortality and 3-month recurrence data were contacted by telephone to determine the same. Patients hospital- ized for acute cholangitis or those with hospital-acquired acute cholangitis who had undergone successful biliary drainage through ERCP were included. This study was conducted following the guidelines stated in the Declaration of Helsinki and was approved by the ethics committee of Otemachi Hospital (Number 19009).
2.2. Patients
Patients presenting with acute cholangitis due to choledocho- lithiasis diagnosed according to the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (Kiriyama et al., 2013, 2018) who had undergone ERCP were evaluated for study inclusion. The exclusion criteria were as follows:
[1] < 20 years of age, [2] history of antibiotic hypersensitivity, [3] severe acute cholangitis, [4] inadequate drainage due to remaining biliary strictures, [5] biliary stent occlusion,
Figure 1. Patient sele
[6] sclerosing cholangitis, [7] a previous choledochojejunostomy, [8] previous heart valve replacement, [9] severe cardiovascular disease,
[10] receiving maintenance hemodialysis, [11] receiving cancer chemotherapy, steroids, or immunosuppres-
sive agents, and [12] concomitant infections.
Outcomes of short-course antibiotic treatment (SCT) (i.e., antibiotic treatment for 3 days) and long-course antibiotic treatment (LCT) (i.e., antibiotic treatment for 4 days) were then compared. Clinical information, such as age, sex, whether the infection was community- or hospital-acquired, activities of daily living, medical co-morbidities, vital signs, laboratory data, pathogens detected in blood and bile cultures, and antibiotics administered, were obtained from the electronic medical records.
2.3. Antibiotic treatment
Antibiotics provided to patients with acute cholangitis were determined by our hospital antibiotic manual based on the Tokyo Guidelines for the management of acute cholangitis and cholecys- titis (Gomi et al., 2013, 2018) as well as based on local antibiograms and the recommendations of infectious disease specialists. This manual recommends the administration of cefmetazole, ampicil- lin/sulbactam, or flomoxef for patients with Grade I and II cholangitis and piperacillin/tazobactam or meropenem for those with grade III cholangitis. Following positive blood cultures, an infectious disease physician recommended continuing or changing the empirical antibiotic regimen according to susceptibility testing results.
2.4. Endoscopic biliary drainage
ERCP was performed by an experienced therapeutic endo- scopist under moderate sedation using hydrochloride pethidine and midazolam. Following successful bile duct cannulation, cholangiography was performed to confirm the presence of bile duct stones. Bile cultures were obtained at the discretion of the endoscopist. The choice between stent placement (i.e., insertion of a 7-Fr plastic stent) and stone extraction was left to the discretion
ction flowchart.
M. Satake, Y. Yamaguchi / International Journal of Infectious Diseases 96 (2020) 343–347 345
of the endoscopist according to the patient's condition and bile characteristics. Stent placement or complete stone extraction was considered as a successful endoscopic biliary drainage.
2.5. Outcome
Primary outcomes included 30-day mortality rate and 3-month recurrence rate, defined as the recurrence of symptoms after complete cure of the disease within 3 months after the onset. Secondary outcomes included length of hospitalization and acute bacteremic cholangitis rates.
2.6. Statistical analysis
Continuous and categorical variables were compared using Student's t-test and Fisher's exact test, respectively. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (Kanda, 2013). More precisely, it is a modified version of R
Table 1 Clinical characteristics of the patients receiving short- and long-course antibiotics.
SCT(n = 2
age, mean SD 79.5 9.1 sex, male,n (%) 12 (54.5) community-acquired, n (%) 17 (77.3)
ADL, no-assistance, n (%) 16 (72.7) severity, n (%)
Grade I, n (%) 10 (45.5) Grade II, n (%) 12 (54.5)
Morbidity, n (%) 18 (81.8) Diabetes mellitus, n (%) 4 (18.2)
Heart disease, n (%) 6 (27.3)
Chronic kidney disease, n (%) 4 (18.2)
Cerebrovascular disease, n (%) 7 (31.8)
Solid organ malignancies, n (%) 3 (13.6)
Psychiatry, n (%) 9 (40.9)
Chronic liver disease 0
Chronic pulmonary disease 0
Cholelithiasis, n (%) 6 (27.3)
Antithrombotic Drugs user, n (%) 6 (27.3)
Body temperature at diagnosis, oC (mean) 37.6
WBC at diagnosis, /mm3 (mean) 10936
CRP at diagnosis, mg/dl (mean) 4.55
Total bilirubin at diagnosis, mg/dl (mean) 2.71
Albumin at diagnosis, g/dl (mean,) 3.42
Time of ERCP, min, mean SD 28.1 15 Time to drainage, day, mean SD 4.45 2.4 Therapy
Bile duct drainage, n (%) 2 (9.09)
Exclusion of stones, n (%) 20 (90.9) Duration of AMT after drainage, day (median) 1.5 (1–3) Duration of first AMT, day, mean SD 6.27 2.3 Duration of total AMT, day, mean SD 6.27 2.3 Antibiotics
CMZ, n (%) 12 (54.5) ABPC/SBT, n (%) 7 (31.8)
FMOX, n (%) 1 (4.5)
SBT/CPZ, n (%) 2 (9.0)
commander designed to add statistical functions frequently used in biostatistics. A p-value of <0.05 was considered to indicate statistical significance.
3. Results
During the study period,157 patients with acute cholangitis due to choledocholithiasis who had undergone ERCP were identified. After excluding 61 patients based on the exclusion criteria, 96 patients were ultimately analyzed (Figure 1). Among the analyzed patients, 22 (22.9%) received SCT, while 74 (77.1%) received LCT. Acute cholangitis was mild in 40 patients and moderate in 56 patients.
The characteristics of all patients included herein are summa- rized in Table 1. The SCT and LCT groups had a median antibiotic treatment duration of 1.5 (range 1–3) and seven (range 4–17) days, respectively. More patients in the SCT group had solid organ malignancies compared with those in the LCT group (13.6% vs.1.4%, respectively; p = 0.03). Community-acquired cholangitis tended to be higher in the SCT group than in the LCT group, although the
2) LCT(n = 74) P-value
41 (55.4) 0.08 41 (55.4) 0.21
0.81 30 (40.5) 44 (59.5)
49 (66.2) 0.2 10 (45.5) 0.73 14 (18.9) 0.39 8 (10.8) 0.46 23 (31.1) 1 1 (1.4) 0.03 20 (27.0) 0.29 0 NA 0 NA 35 (47.3) 0.14 17 (23.0) 0.78 15 (20.3) 0.56 37.9 0.38 11127 0.86 6.73 0.11 3.04 0.51 3.39 0.86
.5 28.1 19.8 0.99 2 3.15 2.27 0.02
0.35 14 (18.9)
60 (81.1) 7 (4–17) 7 8.93 4.40 0.008 7 11.1 3.84 < 0.001
45 (60.8) 13 (17.6) 10 (13.5) 0 3 (4.1) 1 (1.4) 1 (1.4) 1 (1.4) ADL, activities of daily living WBC, white blood cell CRP, C-reactive protein AMT, antimicrobial treatment FMOX, Flomoxef CTRX, Ceftriaxone ABPC, Ampicillin CPFX, Ciproflixacin
Table 4 Primary and secondary outcomes of patients receiving short- and long-course antibiotics.
SCT LCT P-value
30-days mortality, n (%) 0 2 (2.7) 1 Recurrence cholangitis within 3 months, n (%)
2 (9.1) 1 (1.6) 0.13
Bacteremia, n (%) 9 (40.9) 47 (63.5) 0.08 Hospitalization, day, mean SD 19.5 21.6 21.3 21.1 0.73
SCT, short-course antibiotic treatment. LCT, long-course antibiotic treatment. SD, standard deviation.
Table 2 Blood and bile culture results.
SCT LCT P-value
Blood culture performed (%) 20 (90.9) 68 (91.9) 1 Positive blood cultures (%) 9/20 (45.0) 47/68 (69.1) 0.07 Bile duct culture performed (%) 7 (31.8) 25 (33.8) 1 Positive bile duct cultures (%) 5/7 (71.4) 21/25 (84.0) 0.59
SCT, short-course antibiotic treatment. LCT, long-course antibiotic treatment.
346 M. Satake, Y. Yamaguchi / International Journal of Infectious Diseases 96 (2020) 343–347
difference was not significant (p = 0.08). No significant difference in cholangitis grades was observed between the two groups. The duration from acute cholangitis diagnosis to endoscopic biliary drainage was longer in the SCT group than in the LCT group (p = 0.02). Cefmetazole sodium was the most frequently used antibiotic in both groups.
Table 2 details the blood and bile culture results. More than 90% of the patients in both groups underwent blood cultures. No significant difference in the proportion of positive blood cultures was observed between the SCT and LCT groups (45.0% and 69.1%, respectively). Less than 40% of patients in both groups underwent bile duct culture, among which more than 70% had positive results. More positive bile duct cultures were observed than positive blood cultures. Table 3 summarizes the pathogens detected during blood and bile duct cultures. Escherichia coli was the most frequently identified pathogen in blood and bile duct cultures from both groups.
The primary and secondary outcomes are presented in Table 4. Accordingly, no significant differences in 30-day mortality rates (0%, 0/22 and 2.7%, 2/74 for the SCT and LCT group, respectively) and 3-month recurrence rates were observed between both
Table 3 Pathogens detected in blood and bile duct cultures.
Blood culture SCT LCT
Escherichia coli 7 28 Klebsiella pneumoniae 1 11 Klebsiella oxytoca 0 4 Enterobacter spp. 0 3 Aeromonas hydrophila 0 3 Morganella morganii 0 1 Enterococcus species 2 3 Staphylococcus species 1 2 Corynebacterium striatum 0 1 Actinomyces spp. 0 1 Bacteroides spp. 1 1 Clostridium spp. 0 1 Total 12 58
Bile duct culture SCT LCT
Escherichia coli 2 10 Klebsiella pneumoniae 1 1 Klebsiella oxytoca 1 0 Enterobacter spp. 1 3 Pseudomonas aeruginosa 0 1 Citrobacter spp. 0 2 Aeromonas caviae 0 1 Stenotrophomonas maltophilia 0 1 Fusobacterium varium 0 1 Enterococcus spp. 2 9 Streptococcus spp. 1 2 Corynebacterium striatum 0 1 Bacteroides spp. 1 2 Clostridium spp. 0 2 Candida albicans 0 1 Total 9 37
SCT, short-course antibiotic treatment. LCT, long-course antibiotic treatment. spp, species.
groups. Although the LCT group were hospitalized longer than the SCT group, no significant difference was found (p = 0.73). Moreover, the LCT group had a higher acute bacteremic cholangitis rate than the SCT group, albeit not significantly (p = 0.08).
4. Discussion
Although the TG18 recommend 4–7 days of antibiotic therapy for patients with acute cholangitis after controlling the source of infection (Gomi et al., 2018), the findings presented here suggest that SCT (3 days) was not inferior to LCT (4 days) among patients with mild to moderate acute cholangitis due to choledocholithiasis, who had undergone successful biliary duct drainage.
Several previous studies have investigated shorter treatment durations for acute cholangitis. After investigating antibiotic treatment duration for acute cholangitis with Gram-negative bacteremia, Uno et al. (2016) concluded that a treatment duration of < 2 weeks may be adequate. However, the study mentioned above compared two different periods and had an inherent selection bias. Kogure et al. (2011) conducted a prospective study on fever-based antibiotic therapy for acute cholangitis wherein antibiotics were administered for 3 days after successful endo- scopic biliary drainage. This study, however, did not establish a control group for comparison. Van Lent et al. (2002) concluded that short-duration (3 days) antibiotic treatment for acute cholangitis following adequate biliary duct drainage and fever abatement, appeared to be sufficient.
Nonetheless, their mortality (11%) and recurrence (24%) rates were higher than those of the present study. Doi et al. (2018) showed that shortened (six days) antibiotic treatment duration for acute bacteremic cholangitis with successful biliary drainage may be a reasonable option, though antibiotic treatment duration was determined as the “total” duration and not that after successful biliary drainage. By examining the outcomes of antibiotic treatment duration after successful biliary drainage, the present study allowed for a better comparison for the 30-day mortality rate and the 3-month recurrence rate. As such, we believe that the current study has been first to report that SCT (3 days) was not inferior to LCT (4 days) among patients with mild to moderate acute cholangitis due to choledocholithiasis.
According to the TG18, bacteremia with Gram-positive bacteria, such as Enterococcus ssp. and Streptococcus ssp., can be better treated with two weeks of antibiotic therapy (Gomi et al., 2018). Infectious disease specialists generally tend to recommend long antibiotic treatment durations for bacteremic cholangitis. A recent multicenter study on 6433 patients with acute cholangitis showed that among 3170 who underwent blood cultures, 40.1% showed positive results (Gomi et al., 2017). In the present study, 45.0% and 69.1% of the patients in the SCT and LCT groups, respectively had bacteremic cholangitis, which were higher than those presented in previous studies. However, no significant difference in the 30-day mortality rate and 3-month recurrence rate was observed between
M. Satake, Y. Yamaguchi / International Journal of Infectious Diseases 96 (2020) 343–347 347
both groups. Prolonged antibiotic treatment can lead to the development and/or increase of antibiotic-resistant bacteria. Louis Rice, among others, concluded that reducing the length of antibiotic courses may be effective in reducing antibiotic resis- tance (Rice, 2008; Hayashi and Paterson, 2011). Also, Rice proposed a mechanism whereby shorter antibiotic courses reduced selective pressure on bacterial flora, thereby preventing resistance (Rice, 2008; Hayashi and Paterson, 2011). However, shortening the duration of antibiotic treatment would only be desirable on the condition that it was effective and safe. Thus, treatment duration of 3 days may be ideal for patients with acute cholangitis who had undergone successful biliary drainage.
Several limitations of the present study are worth considering. First, this was a retrospective single-center study with a potential selection bias. However, we included consecutive patients who presented with acute cholangitis due to choledocholithiasis and received antibiotic treatment after successful endoscopic biliary drainage. Second, we excluded patients with severe cholangitis, given that this group all received LCT. Prospective studies, including those with severe cholangitis, would nonetheless be needed to confirm our findings, although ensuring the safety of patients with severe cholangitis would be difficult. Third, given that choledocholithiasis was the cause of biliary obstruction in both groups, our findings on acute cholangitis due to malignant and benign biliary obstruction remain unclear. Furthermore, considering that patients with acute cholangitis due to biliary stent occlusion were excluded from this study, further studies that include such patients would be needed to confirm whether our findings apply to such a group.
In conclusion, the present study suggests that a treatment duration of 3 days may be adequate for patients with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage. Nevertheless, future prospective multicenter trials would be needed to sufficiently confirm our results regarding the optimal treatment duration for acute cholangitis with successful biliary drainage.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of interest
This study design was approved by an ethics review board.
Acknowledgments
We thank Dr. Daisuke Kawamura, Gastroenterology at Kenwa- kai Otemachi Hospital and Dr. Yuushi Hisada, Gastroenterology at
Tobata Kenwa Hospital, providing clinical data on gastroentero- logical procedures. We would like to thank Enago (www.enago.jp) for the English language review.
References
Doi A, Morimoto T, Iwata K. Shorter duration of antibiotic treatment for acute bacteraemic cholangitis with successful biliary drainage: a retrospective cohort study. Clin Microbiol Infect. 2018;24:1184–9 https://doi.org/10.1016/j. cmi.2018.01.021..
Gomi H, Takada T, Hwang TL, Akazawa K, Mori R, Endo I, et al. Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis. J Hepatobiliary Pancreat Sci. 2017;24:310–8 https://doi. org/10.1002/jhbp.452..
Gomi H, Solomkin JS, Schlossberg D, Okamoto K, Takada T, Strasberg SM, et al. TG18 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepato-biliary Pancreat Sci 2018;25:3–16 https://doi.org/10.1002/jhbp.518..
Gomi H, Solomkin JS, Takada T, Strasberg SM, Pitt HA, Yoshida M, et al. TG13 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20:60e70 https://doi.org/10.1007/s00534-012-0572-0..
Hayashi Y, Paterson DL. Strategies for reduction…
aDepartment of Gastroenterology, Kenwakai Otemachi Hospital, Kitakyusyu, Japan b Internal medicine, Kenwakai Otemachi Hospital, Kitakyusyu, Japan
A R T I C L E I N F O
Article history: Received 13 March 2020 Received in revised form 23 April 2020 Accepted 25 April 2020
Keywords: Acute cholangitis Choledocholithiasis Antibiotic treatment Endoscopic biliary drainage Mortality
A B S T R A C T
Objectives: Given that the optimal antibiotic treatment duration for acute cholangitis with successful biliary drainage remains unknown, this study aimed to validate whether antibiotic treatment duration could be reduced to 3 days among patients presenting the same. Methods: This retrospective study included patients who presented with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage through endoscopic retrograde cholangiopancreatography (ERCP). After that, 30-day mortality rates and 3- month recurrence rates following short-course antibiotic treatment (SCT, 3 days) and long-course antibiotic treatment (LCT, 4 days) were compared. Results: A total of 96 patients were analyzed, among whom 22 (22.9%) received SCT, and 74 (77.1%) received LCT. The SCT and LCT groups had a median antibiotic treatment duration of 1.5 (range 1–3) and seven (range 4–17) days, respectively. Moreover, the SCT and LCT groups exhibited no significant differences in cholangitis grades, 30-day mortality rates (0%, 0/22 and 2.7%, 2/74, respectively), 3-month recurrence rates, length of hospitalization, and acute bacteremic cholangitis rates. Conclusions: This study suggests that antibiotic treatment for 3 days may be adequate for patients with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage. © 2020 The Authors. Published by Elsevier Ltd on behalf of International Society for Infectious Diseases. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-
nd/4.0/).
journal home page: www.elsevier .com/ locat e/ i j id
1. Introduction
Acute cholangitis is the acute inflammation of the bile ducts, for which a prominent increase in the number of bacteria within the bile duct and a rise in bile duct pressure are crucial (Kiriyama et al., 2018). Increased biliary pressure has been found to influence defensive mechanisms within the host, such as tight junctions, Kupffer cell function, bile flow, and IgA production, resulting in higher incidences of septicemia and endotoxemia among such patients (Sung et al., 1992). Acute cholangitis treatment mainly includes antibiotic therapy and biliary decompression according to disease severity, the absence of which leads to high mortality risk
* Corresponding author. Department of Gastroenterology, Kenwakai Otemachi Hospital, Fukuoka, Japan; 15-1, Otemachi, Kokurakika-ku, Kitakyushu, Fukuoka, 803-8543, Japan. Tel.: +81-93-592-5511; fax: +81-93-592-5231.
E-mail address: [email protected] (M. Satake).
https://doi.org/10.1016/j.ijid.2020.04.074 1201-9712/© 2020 The Authors. Published by Elsevier Ltd on behalf of International So license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
(Kiriyama et al., 2018; Lee et al., 2015; Mukai et al., 2018; Gomi et al., 2018).
In patients with intra-abdominal infections, a larger RCT (the STOP-IT trial) demonstrated that a fixed 4-day course of antimicrobial therapy was as effective as a longer, symptom- based duration of treatment (average of 8-days of antimicrobial therapy) (Sawyer et al., 2015). Intra-abdominal infection guide- lines published by the Surgical Infection Society recommend limiting antibiotic treatment to four days in patients who have had adequate source control, evidence for which was graded as very high (grade 1-A) (Mazuski et al., 2017). On the other hand, the Tokyo Guidelines 2018 (TG18) recommend 4–7 days of antibiotic treatment for patients with acute cholangitis once the source of infection is controlled, but evidence for this was graded as low (level C) (Gomi et al., 2018). Most patients with acute cholangitis who had undergone successful biliary drainage exhibit improved clinical presentation (e.g., fever) within a few days after the procedure. Furthermore, prolonged antibiotic treatment could lead to the development and increase of antibiotic-resistant bacteria
ciety for Infectious Diseases. This is an open access article under the CC BY-NC-ND
and a higher risk for adverse reactions (e.g., pseudomembranous colitis).
Although recent studies have investigated the shortening of antibiotic treatment for acute cholangitis (Uno et al., 2016; Kogure et al., 2011; van Lent et al., 2002; Doi et al., 2018), the optimal duration of antibiotic treatment for acute cholangitis with successful biliary drainage has remained unknown. Thus, the present retrospective cohort study aimed to validate whether the antibiotic treatment duration for patients with acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage could be reduced to 3 days.
2. Methods
2.1. Study setting
This retrospective cohort study was conducted from April 2014 to March 2019 at Kenwakai Otemachi Hospital in Fukuoka, Japan, a tertiary-care hospital with 499 beds. Patients were screened by reviewing their electronic medical records. Those who had unavailable 30-day mortality and 3-month recurrence data were contacted by telephone to determine the same. Patients hospital- ized for acute cholangitis or those with hospital-acquired acute cholangitis who had undergone successful biliary drainage through ERCP were included. This study was conducted following the guidelines stated in the Declaration of Helsinki and was approved by the ethics committee of Otemachi Hospital (Number 19009).
2.2. Patients
Patients presenting with acute cholangitis due to choledocho- lithiasis diagnosed according to the Tokyo Guidelines for the management of acute cholangitis and cholecystitis (Kiriyama et al., 2013, 2018) who had undergone ERCP were evaluated for study inclusion. The exclusion criteria were as follows:
[1] < 20 years of age, [2] history of antibiotic hypersensitivity, [3] severe acute cholangitis, [4] inadequate drainage due to remaining biliary strictures, [5] biliary stent occlusion,
Figure 1. Patient sele
[6] sclerosing cholangitis, [7] a previous choledochojejunostomy, [8] previous heart valve replacement, [9] severe cardiovascular disease,
[10] receiving maintenance hemodialysis, [11] receiving cancer chemotherapy, steroids, or immunosuppres-
sive agents, and [12] concomitant infections.
Outcomes of short-course antibiotic treatment (SCT) (i.e., antibiotic treatment for 3 days) and long-course antibiotic treatment (LCT) (i.e., antibiotic treatment for 4 days) were then compared. Clinical information, such as age, sex, whether the infection was community- or hospital-acquired, activities of daily living, medical co-morbidities, vital signs, laboratory data, pathogens detected in blood and bile cultures, and antibiotics administered, were obtained from the electronic medical records.
2.3. Antibiotic treatment
Antibiotics provided to patients with acute cholangitis were determined by our hospital antibiotic manual based on the Tokyo Guidelines for the management of acute cholangitis and cholecys- titis (Gomi et al., 2013, 2018) as well as based on local antibiograms and the recommendations of infectious disease specialists. This manual recommends the administration of cefmetazole, ampicil- lin/sulbactam, or flomoxef for patients with Grade I and II cholangitis and piperacillin/tazobactam or meropenem for those with grade III cholangitis. Following positive blood cultures, an infectious disease physician recommended continuing or changing the empirical antibiotic regimen according to susceptibility testing results.
2.4. Endoscopic biliary drainage
ERCP was performed by an experienced therapeutic endo- scopist under moderate sedation using hydrochloride pethidine and midazolam. Following successful bile duct cannulation, cholangiography was performed to confirm the presence of bile duct stones. Bile cultures were obtained at the discretion of the endoscopist. The choice between stent placement (i.e., insertion of a 7-Fr plastic stent) and stone extraction was left to the discretion
ction flowchart.
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of the endoscopist according to the patient's condition and bile characteristics. Stent placement or complete stone extraction was considered as a successful endoscopic biliary drainage.
2.5. Outcome
Primary outcomes included 30-day mortality rate and 3-month recurrence rate, defined as the recurrence of symptoms after complete cure of the disease within 3 months after the onset. Secondary outcomes included length of hospitalization and acute bacteremic cholangitis rates.
2.6. Statistical analysis
Continuous and categorical variables were compared using Student's t-test and Fisher's exact test, respectively. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria) (Kanda, 2013). More precisely, it is a modified version of R
Table 1 Clinical characteristics of the patients receiving short- and long-course antibiotics.
SCT(n = 2
age, mean SD 79.5 9.1 sex, male,n (%) 12 (54.5) community-acquired, n (%) 17 (77.3)
ADL, no-assistance, n (%) 16 (72.7) severity, n (%)
Grade I, n (%) 10 (45.5) Grade II, n (%) 12 (54.5)
Morbidity, n (%) 18 (81.8) Diabetes mellitus, n (%) 4 (18.2)
Heart disease, n (%) 6 (27.3)
Chronic kidney disease, n (%) 4 (18.2)
Cerebrovascular disease, n (%) 7 (31.8)
Solid organ malignancies, n (%) 3 (13.6)
Psychiatry, n (%) 9 (40.9)
Chronic liver disease 0
Chronic pulmonary disease 0
Cholelithiasis, n (%) 6 (27.3)
Antithrombotic Drugs user, n (%) 6 (27.3)
Body temperature at diagnosis, oC (mean) 37.6
WBC at diagnosis, /mm3 (mean) 10936
CRP at diagnosis, mg/dl (mean) 4.55
Total bilirubin at diagnosis, mg/dl (mean) 2.71
Albumin at diagnosis, g/dl (mean,) 3.42
Time of ERCP, min, mean SD 28.1 15 Time to drainage, day, mean SD 4.45 2.4 Therapy
Bile duct drainage, n (%) 2 (9.09)
Exclusion of stones, n (%) 20 (90.9) Duration of AMT after drainage, day (median) 1.5 (1–3) Duration of first AMT, day, mean SD 6.27 2.3 Duration of total AMT, day, mean SD 6.27 2.3 Antibiotics
CMZ, n (%) 12 (54.5) ABPC/SBT, n (%) 7 (31.8)
FMOX, n (%) 1 (4.5)
SBT/CPZ, n (%) 2 (9.0)
commander designed to add statistical functions frequently used in biostatistics. A p-value of <0.05 was considered to indicate statistical significance.
3. Results
During the study period,157 patients with acute cholangitis due to choledocholithiasis who had undergone ERCP were identified. After excluding 61 patients based on the exclusion criteria, 96 patients were ultimately analyzed (Figure 1). Among the analyzed patients, 22 (22.9%) received SCT, while 74 (77.1%) received LCT. Acute cholangitis was mild in 40 patients and moderate in 56 patients.
The characteristics of all patients included herein are summa- rized in Table 1. The SCT and LCT groups had a median antibiotic treatment duration of 1.5 (range 1–3) and seven (range 4–17) days, respectively. More patients in the SCT group had solid organ malignancies compared with those in the LCT group (13.6% vs.1.4%, respectively; p = 0.03). Community-acquired cholangitis tended to be higher in the SCT group than in the LCT group, although the
2) LCT(n = 74) P-value
41 (55.4) 0.08 41 (55.4) 0.21
0.81 30 (40.5) 44 (59.5)
49 (66.2) 0.2 10 (45.5) 0.73 14 (18.9) 0.39 8 (10.8) 0.46 23 (31.1) 1 1 (1.4) 0.03 20 (27.0) 0.29 0 NA 0 NA 35 (47.3) 0.14 17 (23.0) 0.78 15 (20.3) 0.56 37.9 0.38 11127 0.86 6.73 0.11 3.04 0.51 3.39 0.86
.5 28.1 19.8 0.99 2 3.15 2.27 0.02
0.35 14 (18.9)
60 (81.1) 7 (4–17) 7 8.93 4.40 0.008 7 11.1 3.84 < 0.001
45 (60.8) 13 (17.6) 10 (13.5) 0 3 (4.1) 1 (1.4) 1 (1.4) 1 (1.4) ADL, activities of daily living WBC, white blood cell CRP, C-reactive protein AMT, antimicrobial treatment FMOX, Flomoxef CTRX, Ceftriaxone ABPC, Ampicillin CPFX, Ciproflixacin
Table 4 Primary and secondary outcomes of patients receiving short- and long-course antibiotics.
SCT LCT P-value
30-days mortality, n (%) 0 2 (2.7) 1 Recurrence cholangitis within 3 months, n (%)
2 (9.1) 1 (1.6) 0.13
Bacteremia, n (%) 9 (40.9) 47 (63.5) 0.08 Hospitalization, day, mean SD 19.5 21.6 21.3 21.1 0.73
SCT, short-course antibiotic treatment. LCT, long-course antibiotic treatment. SD, standard deviation.
Table 2 Blood and bile culture results.
SCT LCT P-value
Blood culture performed (%) 20 (90.9) 68 (91.9) 1 Positive blood cultures (%) 9/20 (45.0) 47/68 (69.1) 0.07 Bile duct culture performed (%) 7 (31.8) 25 (33.8) 1 Positive bile duct cultures (%) 5/7 (71.4) 21/25 (84.0) 0.59
SCT, short-course antibiotic treatment. LCT, long-course antibiotic treatment.
346 M. Satake, Y. Yamaguchi / International Journal of Infectious Diseases 96 (2020) 343–347
difference was not significant (p = 0.08). No significant difference in cholangitis grades was observed between the two groups. The duration from acute cholangitis diagnosis to endoscopic biliary drainage was longer in the SCT group than in the LCT group (p = 0.02). Cefmetazole sodium was the most frequently used antibiotic in both groups.
Table 2 details the blood and bile culture results. More than 90% of the patients in both groups underwent blood cultures. No significant difference in the proportion of positive blood cultures was observed between the SCT and LCT groups (45.0% and 69.1%, respectively). Less than 40% of patients in both groups underwent bile duct culture, among which more than 70% had positive results. More positive bile duct cultures were observed than positive blood cultures. Table 3 summarizes the pathogens detected during blood and bile duct cultures. Escherichia coli was the most frequently identified pathogen in blood and bile duct cultures from both groups.
The primary and secondary outcomes are presented in Table 4. Accordingly, no significant differences in 30-day mortality rates (0%, 0/22 and 2.7%, 2/74 for the SCT and LCT group, respectively) and 3-month recurrence rates were observed between both
Table 3 Pathogens detected in blood and bile duct cultures.
Blood culture SCT LCT
Escherichia coli 7 28 Klebsiella pneumoniae 1 11 Klebsiella oxytoca 0 4 Enterobacter spp. 0 3 Aeromonas hydrophila 0 3 Morganella morganii 0 1 Enterococcus species 2 3 Staphylococcus species 1 2 Corynebacterium striatum 0 1 Actinomyces spp. 0 1 Bacteroides spp. 1 1 Clostridium spp. 0 1 Total 12 58
Bile duct culture SCT LCT
Escherichia coli 2 10 Klebsiella pneumoniae 1 1 Klebsiella oxytoca 1 0 Enterobacter spp. 1 3 Pseudomonas aeruginosa 0 1 Citrobacter spp. 0 2 Aeromonas caviae 0 1 Stenotrophomonas maltophilia 0 1 Fusobacterium varium 0 1 Enterococcus spp. 2 9 Streptococcus spp. 1 2 Corynebacterium striatum 0 1 Bacteroides spp. 1 2 Clostridium spp. 0 2 Candida albicans 0 1 Total 9 37
SCT, short-course antibiotic treatment. LCT, long-course antibiotic treatment. spp, species.
groups. Although the LCT group were hospitalized longer than the SCT group, no significant difference was found (p = 0.73). Moreover, the LCT group had a higher acute bacteremic cholangitis rate than the SCT group, albeit not significantly (p = 0.08).
4. Discussion
Although the TG18 recommend 4–7 days of antibiotic therapy for patients with acute cholangitis after controlling the source of infection (Gomi et al., 2018), the findings presented here suggest that SCT (3 days) was not inferior to LCT (4 days) among patients with mild to moderate acute cholangitis due to choledocholithiasis, who had undergone successful biliary duct drainage.
Several previous studies have investigated shorter treatment durations for acute cholangitis. After investigating antibiotic treatment duration for acute cholangitis with Gram-negative bacteremia, Uno et al. (2016) concluded that a treatment duration of < 2 weeks may be adequate. However, the study mentioned above compared two different periods and had an inherent selection bias. Kogure et al. (2011) conducted a prospective study on fever-based antibiotic therapy for acute cholangitis wherein antibiotics were administered for 3 days after successful endo- scopic biliary drainage. This study, however, did not establish a control group for comparison. Van Lent et al. (2002) concluded that short-duration (3 days) antibiotic treatment for acute cholangitis following adequate biliary duct drainage and fever abatement, appeared to be sufficient.
Nonetheless, their mortality (11%) and recurrence (24%) rates were higher than those of the present study. Doi et al. (2018) showed that shortened (six days) antibiotic treatment duration for acute bacteremic cholangitis with successful biliary drainage may be a reasonable option, though antibiotic treatment duration was determined as the “total” duration and not that after successful biliary drainage. By examining the outcomes of antibiotic treatment duration after successful biliary drainage, the present study allowed for a better comparison for the 30-day mortality rate and the 3-month recurrence rate. As such, we believe that the current study has been first to report that SCT (3 days) was not inferior to LCT (4 days) among patients with mild to moderate acute cholangitis due to choledocholithiasis.
According to the TG18, bacteremia with Gram-positive bacteria, such as Enterococcus ssp. and Streptococcus ssp., can be better treated with two weeks of antibiotic therapy (Gomi et al., 2018). Infectious disease specialists generally tend to recommend long antibiotic treatment durations for bacteremic cholangitis. A recent multicenter study on 6433 patients with acute cholangitis showed that among 3170 who underwent blood cultures, 40.1% showed positive results (Gomi et al., 2017). In the present study, 45.0% and 69.1% of the patients in the SCT and LCT groups, respectively had bacteremic cholangitis, which were higher than those presented in previous studies. However, no significant difference in the 30-day mortality rate and 3-month recurrence rate was observed between
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both groups. Prolonged antibiotic treatment can lead to the development and/or increase of antibiotic-resistant bacteria. Louis Rice, among others, concluded that reducing the length of antibiotic courses may be effective in reducing antibiotic resis- tance (Rice, 2008; Hayashi and Paterson, 2011). Also, Rice proposed a mechanism whereby shorter antibiotic courses reduced selective pressure on bacterial flora, thereby preventing resistance (Rice, 2008; Hayashi and Paterson, 2011). However, shortening the duration of antibiotic treatment would only be desirable on the condition that it was effective and safe. Thus, treatment duration of 3 days may be ideal for patients with acute cholangitis who had undergone successful biliary drainage.
Several limitations of the present study are worth considering. First, this was a retrospective single-center study with a potential selection bias. However, we included consecutive patients who presented with acute cholangitis due to choledocholithiasis and received antibiotic treatment after successful endoscopic biliary drainage. Second, we excluded patients with severe cholangitis, given that this group all received LCT. Prospective studies, including those with severe cholangitis, would nonetheless be needed to confirm our findings, although ensuring the safety of patients with severe cholangitis would be difficult. Third, given that choledocholithiasis was the cause of biliary obstruction in both groups, our findings on acute cholangitis due to malignant and benign biliary obstruction remain unclear. Furthermore, considering that patients with acute cholangitis due to biliary stent occlusion were excluded from this study, further studies that include such patients would be needed to confirm whether our findings apply to such a group.
In conclusion, the present study suggests that a treatment duration of 3 days may be adequate for patients with mild to moderate acute cholangitis due to choledocholithiasis who had undergone successful biliary drainage. Nevertheless, future prospective multicenter trials would be needed to sufficiently confirm our results regarding the optimal treatment duration for acute cholangitis with successful biliary drainage.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of interest
This study design was approved by an ethics review board.
Acknowledgments
We thank Dr. Daisuke Kawamura, Gastroenterology at Kenwa- kai Otemachi Hospital and Dr. Yuushi Hisada, Gastroenterology at
Tobata Kenwa Hospital, providing clinical data on gastroentero- logical procedures. We would like to thank Enago (www.enago.jp) for the English language review.
References
Doi A, Morimoto T, Iwata K. Shorter duration of antibiotic treatment for acute bacteraemic cholangitis with successful biliary drainage: a retrospective cohort study. Clin Microbiol Infect. 2018;24:1184–9 https://doi.org/10.1016/j. cmi.2018.01.021..
Gomi H, Takada T, Hwang TL, Akazawa K, Mori R, Endo I, et al. Updated comprehensive epidemiology, microbiology, and outcomes among patients with acute cholangitis. J Hepatobiliary Pancreat Sci. 2017;24:310–8 https://doi. org/10.1002/jhbp.452..
Gomi H, Solomkin JS, Schlossberg D, Okamoto K, Takada T, Strasberg SM, et al. TG18 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepato-biliary Pancreat Sci 2018;25:3–16 https://doi.org/10.1002/jhbp.518..
Gomi H, Solomkin JS, Takada T, Strasberg SM, Pitt HA, Yoshida M, et al. TG13 antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20:60e70 https://doi.org/10.1007/s00534-012-0572-0..
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