J Gastroenterol DOI 10.1007/s00535-014-0960-0
ORIGINAL ARTICLE—LIVER, PANCREAS, AND BILIARY TRACT
Clinical efficacy of intravenous doripenem in patients with acute biliary tract infection: a multicenter, randomized, controlled trial with imipenem/cilastatin as comparator Susumu Tazuma • Yoshinori Igarashi • Kazuo Inui • Hirotaka Ohara • Toshio Tsuyuguchi • Shomei Ryozawa • The BTI Therapy Research Group
Received: 11 March 2014 / Accepted: 1 April 2014 Ó Springer Japan 2014
Abstract Background We conducted a randomized controlled trial to evaluate the clinical efficacy and safety of intravenous doripenem (DRPM) in patients with biliary tract infection requiring biliary drainage in comparison with imipenem/ cilastatin (IPM/CS). Methods After the initial collection of bile, patients were randomly assigned by the registration system of the Clinical Research Organization to receive intravenous drip infusion of DRPM 0.5 g or IPM/CS 0.5 g three times daily in a randomized, open-label manner. Results A total of 127 patients were enrolled in the trial (DRPM 62, IPM/CS 65). The characteristics of the 122 patients evaluated for efficacy were well balanced, except for the percentage of patients previously receiving antimicrobials, which was higher in the DRPM group than in
Members of the BTI Therapy Research Group (see the list of collaborators) are given in the Appendix.
the IPM/CS group. The clinical response rate was not significantly different between the DRPM group (93.1 %, 54/58 patients) and the IPM/CS group (93.8 %, 60/64). Non-inferiority assessment using confidence intervals demonstrated the non-inferiority of DRPM–IPM/CS. The incidence of adverse events, for which a causal relationship with either treatment was not ruled out, was 3.3 % (2/60) in the DRPM group and 3.1 % (2/65) in the IPM/CS group, and none was serious. Conclusions The clinical efficacy of DRPM in treating moderate or severe biliary tract infection requiring drainage was comparable to that of IPM/CS. DRPM was associated with no serious adverse events and a low incidence of adverse events. The results of this trial demonstrate that DRPM is a useful therapeutic option for moderate or severe biliary tract infection. Keywords Biliary tract infection Doripenem Imipenem/cilastatin Randomized controlled trial (RCT)
Electronic supplementary material The online version of this article (doi:10.1007/s00535-014-0960-0) contains supplementary material, which is available to authorized users. S. Tazuma (&) Department of General Internal Medicine, Hiroshima University Graduate School of Medical Science, Programs of Applied Medicine, Clinical Pharmacotherapy, Hiroshima, Japan e-mail:
[email protected] Y. Igarashi Division of Gastroenterology and Hepatology, Toho University Omori Medical Center, Tokyo, Japan K. Inui Department of Internal Medicine, Banbuntane Houtokukai Hospital, Fujita Health University School of Medicine, Nagoya, Japan
H. Ohara Department of Community-based Medical Education, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan T. Tsuyuguchi Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan S. Ryozawa Saitama Medical University International Medical Center, Saitama, Japan
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Introduction Acute biliary tract infection is prevalent to frequently progress to sepsis. Accordingly, quick and accurate diagnosis and unerring judgment to perform surgical drainage and initiate antimicrobial chemotherapy with appropriate antimicrobials in its early stage are important in management. However, only few randomized controlled trials (RCTs) of antimicrobials for acute biliary infection have been performed, and therefore, no guidelines existed for the treatment of biliary tract infection in Western countries or Japan before 2005. Thereafter, in Japan, the Guidelines for the Management of Acute Cholangitis and Cholecystitis (first edition) [1] were developed in 2005, followed by the Tokyo Guidelines, which were presented to the international community in 2007 [2]. Unfortunately, evidence remains insufficient to establish criteria for antimicrobial selection. In this regard, third and fourth generation cephems and carbapenems are widely used in empirical antimicrobial therapy of biliary tract infection [3]; then, the increased emergence of extended spectrum b-lactamase (ESBL)producing Gram-negative bacilli resistant to cephems and of multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) was recently reported [4]. Our biliary tract infection study group has conducted and reported on three clinical trials [5–7]. Few studies have investigated the efficacy of antimicrobials in relation to disease severity. In 2005, doripenem (DRPM), a new carbapenem for i.v. infusion with strong antimicrobial activity against P. aeruginosa and few effects on the central nervous system (and low risk of convulsions), was launched in Japan. This drug is highly effective against not only aerobic Gram-negative and Gram-positive bacteria, but also anaerobic bacteria [8]. In addition, it suppressed the growth of antimicrobial-resistant P. aeruginosa [9, 10]. However, the usefulness of DRPM against biliary tract infection has not been studied well. Since mild cases improve without antimicrobial treatment, we conducted a multicenter, randomized, open-label clinical trial to evaluate the efficacy and safety of DRPM in comparison with imipenem/cilastatin (IPM/CS) for moderate or severe biliary traction infection.
Methods Subjects This trial included patients, aged 20 years or older, with moderate or severe acute cholangitis or cholecystitis who were hospitalized at medical institutions participating in this trial (see Appendix) between 1 July 2010 and 30 June 2013. Patients meeting any of the following criteria were excluded from the trial: those with serious underlying/
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concomitant diseases who were ineligible for assessment of therapeutic effects; those with a history of drug-induced allergy or serious adverse events, for which a causal relationship with b-lactams (carbapenems, cephems, and penicillin) was not ruled out (adverse drug reactions [ADRs]); those with convulsive disorders, such as epilepsy, or a history of such diseases, or with central nervous system diseases accompanied by convulsions at baseline; women who were pregnant or possibly pregnant, or were lactating; those suspected of having infections, such as methicillin-resistant Staphylococcus aureus (MRSA), resistant to the test drug; those with obvious postoperative failure of sutures; and those who had not responded to other carbapenems. Also excluded were patients previously enrolled in this trial, those requiring treatment with drugs not approved for concomitant use in the protocol, and those assessed as ineligible for participation in the trial by the investigator. Further, patients with severe cardiac dysfunction or renal impairment (requiring hemodialysis) were not allowed to participate in the trial. This trial was registered with the University Hospital Medical Information Network (UMIN) (registration No. UMIN000003852). Informed consent This trial was conducted based on ethical principles that have their origin in the Declaration of Helsinki. Written informed consent was obtained from all patients who had the target disease, met all of the inclusion criteria, and none of the exclusion criteria. Patients (or legally authorized representatives) provided informed consent after full explanation of the objectives and content of this clinical trial using written information for patients and an informed consent form according to the ‘‘Human Rights of Patients: Explanation and Consent.’’ Severity assessment and randomization Prior to drainage, the severity of cholecystitis or cholangitis was classified as moderate or severe for each patient, according to the Guidelines for the Management of Acute Cholangitis and Cholecystitis (first edition). Based on this rating, patients were randomly assigned to the DRPM group or the IPM/CS group by the registration system of the Clinical Research Organization (CRO) using diagnosis and severity as allocation factors. Test drug and method of administration The DRPM group was administered DRPM (FINIBAXÒ 0.5 g for intravenous drip infusion) 0.5 g three times daily by i.v. drip infusion over 30 or 60 min. The IPM/CS group
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was administered IPM/CS (TIENAMÒ 0.5 g for intravenous drip infusion) 0.5 mg three times daily over 30 or 60 min. For patients with decreased renal function, the doses of DRPM and IPM/CS were appropriately reduced as necessary according to the package inserts. Concomitant drugs Concomitant use of sodium valproate formulations (Depakene and Selenica) was prohibited. Switching to or adding other antimicrobials, antifungal agents, or i.v. immunoglobulin formulations was prohibited for 3 days after the start of treatment.
was assessed according to the following criteria: (1) definitely related, (2) probably related, (3) possibly related, or (4) not related. An ADR was defined as an event classified into (1), (2), or (3). The severity of each event was assessed using the following 3-point scale: (1) not serious, (2) slightly serious, or (3) serious. The assessments were made based on clinical symptoms, laboratory data, and diagnostic imaging data by the authors themselves and investigators at trial sites (see Appendix).
Assessment Items and schedule of observation Patient characteristics Patient’s sex, age, height, weight, use of surgical interventions such as drainage, and their details, underlying disease, complications, prior antimicrobial use, concomitant use of antimicrobials and their details, as well as the history of hospitalization within 1 year, admission to a nursing home, use of hemodialysis, the presence of malignant tumor, and the status of immune function assessed as ‘‘Depressed’’ by administration of immunosuppressants, antitumor agents, and steroids, were noted. Observation of clinical symptoms Temperature, heart rate, and respiratory rate were measured prior to, during, and after treatment. Clinical laboratory tests Hematology (white blood cell, platelet, and red blood cell counts) and blood biochemistry (TP, Alb, amylase, AST, ALT, LDH, ALP, GGT, T-Bil, BUN, Cre, Na, K, Cl, FBS, T-cho, and CRP) were performed. Bacteriological examination For bacteriological examination, bile was collected at the baseline and end of treatment, and stored in Kenki-Porter II containers (for transportation and storage of specimens; Terumo Clinical Supply Co., Ltd). After isolation and identification of bacteria, the sensitivity to antimicrobials was determined. Adverse events For each accompanying sign or clinically significant abnormal change, a causal relationship with the test drug
Severity at the start of the trial The severity of cholecystitis or cholangitis was classified as moderate or severe for each patient according to the Guidelines for the Management of Acute Cholangitis and Cholecystitis (first edition) [1] (S1, S2). Clinical efficacy Based on clinical symptoms and signs, and laboratory test findings (S1, S2), a clinical response to the test drug was assessed for each patient according to the following criteria: (1) good (clinical findings attributable to infection improved within 7 days after the start of treatment); (2) fair (clinical findings attributable to infection tended to improve by 7 days after the start of treatment and improved after the end of treatment); or (3) poor (clinical findings attributable to infection did not improve [unchanged or worsened] within 7 days after the start of treatment or did not tend to improve and the test drug was switched to other drugs, including other antimicrobials). Bacteriological efficacy The bacteriological response to the test drug was assessed according to the following criteria at the end of treatment or the study based on the eradication status of the presumed causative bacteria: (1) eradication (the causative bacteria [including presumed causative bacteria] were clearly eradicated from properly sampled and cultured specimens after treatment or signs and symptoms markedly improved, and sampling was not possible at the end of the trial),; (2) decrease or partial eradication (the causative bacteria [including presumed causative bacteria] were clearly reduced quantitatively on quantitative culture, or some of the multiple causative bacteria were eradicated); (3) replacement (the original causative bacteria were eradicated by treatment, but different strains were
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detected at the same site after the start of treatment accompanied by clear signs and symptoms of infection); (4) persistence (the original causative bacteria [including presumed causative bacteria] were detected at the infection site after the end of treatment irrespective of the presence or absence of inflammation); and (5) unknown (the causative bacteria were unknown or changes in the number of the causative bacteria were unclear). The test drug was rated as bacteriologically effective when the rating was (1)–(3). Statistical analysis Assuming that the response rate in the DRPM group was 95 % based on the results of the previous clinical trial, when the data were analyzed with a non-inferiority margin of 10 % and a power of 0.8, and the response rate in the IPM/CS group was B 92 %, 57 patients were needed for each group to claim non-inferiority of DRPM–IPM/CS. Accordingly, 120 patients (DRPM, 60; IPM/CS, 60) were planned to be included in this trial. Non-inferiority assessment based on the clinical response rate was made using confidence intervals with a non-inferiority margin of 10 % at a significance level of one-sided 0.025. The significance of differences in the other parameters was tested at a significance level of two-sided 0.05 by Fisher’s exact probability test or Student’s t test, depending on the test parameter and the nature of the measurement.
Results
Fig. 1 Distribution of patients
Table 1 Assignment of infection type and severity DRPM group
IPM group
P value*
Cholangitis
33 (53.2 %)
38 (58.5 %)
0.595
Cholecystitis
23 (37.1 %)
22 (33.8 %)
0.715
Mixed
6 (9.7 %)
5 (7.7 %)
0.760
62
65
47 (75.8 %) 15 (24.2 %)
53 (81.5 %) 12 (18.5 %)
62
65
Infection
Severity Moderate Severe
0.517 0.430
* Fisher’s exact test
Registered patients
Patient assignment
A total of 127 patients were enrolled in the trial (DRPM 62, IPM/CS 65). Two patients in the DRPM group died the day after the start of the trial while they were in shock. They were defined as inclusion/exclusion violation (enrollment of patients ineligible for efficacy assessment) and excluded from the trial. The remaining 125 patients were included in safety analysis (DRPM 60, IPM/CS 65). Also excluded were three patients (DRPM 2, IPM/CS 1) whose response could not be assessed because they dropped out of the trial due to the following reasons: one cutaneous reaction requiring discontinuation of administration, one complication of pneumonia leading to difficulty of the assessment of drug efficacy, and one lacking essential data, for whom it was also considered difficult to evaluate the efficacy of antibiotics. A total of 122 patients (DRPM 58, IPM/CS 64) were included in the analysis of patient characteristics, clinical efficacy, and bacteriological efficacy (Fig. 1).
The distribution of moderate and severe patients was compared between the DRPM and IPM/CS groups for each disease (Table 1). Patients with acute cholangitis accounted for the majority, followed by those with acute cholecystitis and those with both acute cholangitis and cholecystitis, in this order. Most cases were moderate in severity. Comparison of the percentage of severe patients between the two groups revealed a trend of more patients with acute cholangitis assigned to the DRPM group and more patients with acute cholecystitis assigned to the IPM/CS group.
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Patient characteristics The characteristics of patients evaluated for efficacy (DRPM 58, IPM/CS 64) are presented in Table 2. Most patients, except for two in the DRPM group and three in the IPM/CS group, underwent drainage such as endoscopic nasobiliary drainage (ENBD) or percutaneous transhepatic
J Gastroenterol Table 2 Patient characteristics Item
DRPM group
IPM/CS group
Gender
58
64
Male
42 (72.4 %)
38 (59.4 %)
Female
16 (27.6 %)
26 (40.6 %)
Age (mean ± SD)
74 ± 11.5
73 ± 12.8
C 80 years
19 (32.8 %)
21 (33.3 %)
\ 80 years
39 (67.2 %)
42 (66.7 %)
160.4 ± 8.3 (56) 57.0 ± 11.4 (57)
157.6 ± 11.4 (57) 55.2 ± 11.4 (58)
6.8 ± 2.9 (58)
6.7 ± 2.5 (64)
2
3
Height (mean ± SD) Weight (mean ± SD) Dosing periods (mean ± SD)
P value*
0.181
1.000
Drainage No Yes
56
61
ENBD
7
7
PTGBD Others
16 33
19 35
1.000 0.964
Prior administration of antimicrobials
Clinical efficacy
Yes
40 (69.0 %)
31 (48.4 %)
No
18 (31.0 %)
33 (51.6 %)
0.028
History of hospitalization within 1 year Yes
22 (37.9 %)
17 (27.0 %)
No
36 (62.1 %)
46 (73.0 %)
Yes
4 (6.9 %)
4 (6.6 %)
No
54 (93.1 %)
57 (93.4 %)
Yes
1 (1.7 %)
0 (0.0 %)
No
57 (98.3 %)
63 (100.0 %)
0.244
Nursing home resident 1.000
Use of hemodialysis 0.479
Malignant diseases (other than biliary tract system) Yes No
10 (17.2 %) 48 (82.8 %)
underwent surgery for gastric cancer were included in the DRPM group, and two of them received drainage; one PTBD and one EBS, whereas the other was not drained. In the IPM/CS group, one case underwent surgery for esophageal cancer, and received PTGBD. There was no statistically significant between-group difference in the distribution of a history of hospitalization within 1 year, admission to a nursing home, use of hemodialysis, the presence of malignant tumor, and the status of immune function. In addition, comorbidities included diabetes mellitus (DM), hypertension, dyslipidemias, chronic viral hepatitis, and the rate was 11/58 for the DRPM group, and 11/64 for IPM/CS (P value 0.818) (data not shown). However, the percentage of patients previously receiving antimicrobials was significantly higher in the DRPM group than in the IPM/CS group (P = 0.028) (Table 2). The most common prior antimicrobial was sulbactam/cefoperazone (SBT/CPZ) for both groups (S3). The mean and median durations of treatment with the test drug were approximately 7 days for both groups (Fig. 2).
9 (14.3 %) 54 (85.7 %)
0.803
0.719
Malignant diseases (biliary tract system) Yes
3 (5.2 %)
5 (7.9 %)
No
55 (94.8 %)
58 (92.1 %)
Status of immune function Depressed
7 (12.1 %)
2 (3.2 %)
Competent
51 (87.9 %)
61 (96.8 %)
0.086
* Fisher’s exact test ENBD endoscopic nasobiliary drainage, PTGBD percutaneous transhepatic gallbladder drainage
gallbladder drainage (PTGBD), or others, including percutaneous transhepatic gallbladder aspiration (PTGBA), percutaneous transhepatic biliary drainage (PTBD), endoscopic biliary stent (EBS), endoscopic sphincterotomy (EST), or endoscopic papillary balloon dilation (EPBD) (Table 2). There was no case with serious complication through the procedure of drainage. Three cases that
Table 3 shows the clinical efficacy by type of infection. The overall response rate (all patients with cholangitis and/ or cholecystitis) was 93.1 % in the DRPM group and 93.8 % in the IPM/CS group. There was no significant between-group difference (P = 1.000) (Fig. 3). Non-inferiority assessment using confidence intervals with a noninferiority margin of 10 % at a significance level of onesided 0.025 demonstrated the non-inferiority of DRPM– IPM/CS with a difference of -0.65 % (95 % confident interval [-9.46, 8.17]) in the clinical response rate between the two groups (DRPM and IPM/CS). The response rates in the DRPM and IPM/CS groups were, respectively, 100.0 and 94.6 % for patients with cholangitis, 90.9 and 90.9 % for those with cholecystitis, and 66.7 and 100.0 % for those with both cholangitis and cholecystitis. For any of the diseases, the between-group difference was not significant (P = 0.498, 1.000, and 0.455, respectively). Changes in body temperature, C-reactive protein (CRP), and white blood cell (WBC) count were investigated based on the data from patients evaluated for efficacy at baseline, Day 3, and the end of treatment. The body temperature at baseline was significantly higher in the DRPM group than in the IPM/CS group (P = 0.035). No difference was seen in the CRP and white blood cell count at baseline between the two groups. The changes from baseline in each of the parameters at Day 3 and the end of treatment were compared between the two groups. The change in body temperature was significantly higher in the DRPM group than in the IPM/CS group. The between-group differences in the other parameters were not significant (Fig. 4).
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Fig. 2 Duration of administration
Table 3 Clinical efficacy by the type of infection Infection
DRPM group n
Cholangitis
30
% Cholecystitis
22
% Cholangitis ? cholecystitis
6
% Total %
58
Good
IPM/CS group Fair
P value*
Poor
n
Good
Fair
Poor
37
35
2
0
94.6
5.4
0
20
0
2
90.9
0
9.1
5
5
0
0
100.0
0
0
64
60 93.8
2 3.1
2 3.1
30
0
0
100.0
0
0
20
2
0
90.9
9.1
0
22
4
1
1
66.7
16.7
16.7
54 93.1
3 5.2
1 16.7
0.498 1.000 0.455 1.000
* Fisher’s exact test
baseline was 87.2 % (41/47 patients) in the DRPM group and 94.8 % (47/50 patients) in the IPM/CS group. It was high in both groups, and was not significantly different between the groups (P = 0.308). Seventy-three and 76 strains were isolated from bile in the DRPM and IPM/CS groups, respectively (S4). The most prevalent strains were Enterococcus spp., Escherichia coli, and Klebsiella spp. in both groups. The bacteriological response rate was 69.0 % (29/42 patients) in the DRPM group and 78.3 % (36/46 patients) in the IPM/CS group. The between-group difference was not significant (P = 0.344) (S5). Safety
Fig. 3 Clinical response rate
Bacteriological efficacy The bacterial prevalence in patients evaluated for efficacy in whom bacteria were isolated from a bile sample at
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Of 60 patients in the DRPM group and 65 patients in the IPM/CS group who were evaluated for safety, two patients each in the two groups (3.3 and 3.1 %, respectively) presented with ADRs, including one patient with watery diarrhea and one patient with drug eruption in the DRPM group, and one patient with vomiting and one patient with pseudomembranous colitis in the IPM/CS group. All of the events improved after treatment discontinuation or other
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Fig. 4 Changes in body temperature (a), CRP (b) and WBC (c)
appropriate intervention and subsequently recovered. Neither unknown nor serious adverse events, other than these known events, occurred in this trial (S6).
Discussion Biliary tract infection (acute cholangitis and cholecystitis) is relatively common and often progresses to sepsis accompanied by systemic signs and symptoms. Concomitant shock and multiple organ dysfunction syndrome (MODS) are not uncommon and increase the severity of the pathological condition. For the treatment of biliary tract infection, therefore, reliable diagnosis, surgical drainage, and early chemotherapy with appropriate antimicrobials are important. For these purposes, it is essential to select effective antimicrobials against causative bacteria of biliary tract infection [11]. While b-lactams, such as third and fourth generation cephems and carbapenems, are widely used in empirical antimicrobial therapy of biliary tract infection in Japan, a recent increase in the emergence of ESBL producing Gram-negative bacilli resistant to third and fourth generation cephems and of multidrug-resistant P. aeruginosa is becoming a serious problem [12, 13]. DRPM is the newest carbapenem antimicrobial for i.v. infusion, and was launched in Japan in 2005, and subsequently in the USA in 2007 and Europe in 2008. DRPM has a broad antimicrobial spectrum and excellent antimicrobial activity. In particular, its antimicrobial activity against P. aeruginosa is the most potent among the carbapenem antimicrobials [6]. In a previous multicenter clinical trial, we confirmed the good efficacy and safety profile of DRPM in the treatment of acute biliary tract infection [7]. This multicenter, randomized, open-label trial was
conducted to evaluate the efficacy and safety of DRPM in comparison with IPM/CS for the purpose of further evaluating the efficacy of DRPM. In this trial, the efficacy of DRPM in biliary tract infection was investigated by disease and severity, and compared with IPM/CS based on the bacteriological response, as determined from the observed values in body temperature, white blood cells, and CRP before and after treatment and % changes from baseline, as well as the eradication status of causative bacteria. The percentage of patients previously receiving antimicrobials was significantly higher in the DRPM group than in the IPM/CS group. For the following reasons, however, prior antimicrobial use appears not to have substantially affected the efficacy evaluation of the test drug; most patients received antimicrobials only for a short period of time (1–2 days) prior to the start of treatment; the eradication rate of bacteria in the bile at baseline in the subgroup of prior antimicrobial use was not significant between the DRPM and IPM/CS groups, being 9.7 % (3/31 patients) and 9.1 % (2/22 patients), respectively (data not shown); the response rate in the subgroup previously receiving SBT/CPZ, which was the most commonly used prior antimicrobial, was 92.3 % (24/26 patients) in the DRPM group and 95 % (19/20 patients) in the IPM/CS group (data not shown), not substantially different from the overall response rate. There was no between-group difference in the distribution of patients with a history of hospitalization within 1 year or those admitted to a nursing home, which are associated with a high risk of the emergence of drugresistant causative bacteria [14]. The between-group differences in the distribution of old age, hemodialysis, tumor, and decreased immune function, which are known risk factors in the treatment of biliary tract infection [15], were not significant.
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The clinical response rate was 93.1 % in the DRPM group and 93.8 % in the IPM/CS group. There was no significant between-group difference. Non-inferiority assessment using confidence intervals demonstrated the non-inferiority of DRPM–IPM/CS with a difference of -0.65 % (95 % confident interval [-9.46, 8.17]) in the clinical response rate between the two groups (DRPM and IPM/CS). These high response rates were highly consistent with the results of our previous clinical trial (IPM/CS, 94.4 % [6]; DRPM, 92.4 % [7]). The % changes from baseline in the three parameters that are generally used as indexes of inflammatory response in the surgical field, including body temperature, CRP, and WBC [16], at Day 3 and the end of treatment were compared between DRPM and IPM/CS. All of the parameters followed a similar recovery pattern with both drugs. However, the baseline body temperature and the % changes from baseline were different between the two drugs, which can be explained by the fact that the body temperature at baseline was significantly high in the DRPM group and subsequent body temperature levels were not different between the drug groups, resulting in a significant difference in each % change. This may suggest the superiority of DRPM–IPM/CS in terms of its antipyretic effect. The main cause of biliary tract infection is cholestasis and bacterial infection. For the treatment of biliary tract infection, biliary drainage and appropriate antimicrobial therapy are essential. Various routes have been suggested for bacterial infection, including hematogenous routes via the portal vein from the intestinal tract or the opening of the duodenum [17]. The percentage of bacteria isolated from the bile was 87.2 % (41/47 patients) in the DRPM group and 94.0 % (47/50 patients) in the IPM/CS group. It was not significantly different between the groups. The most prevalent strain was Escherichia coli, followed by Enterococcus spp. and Klebsiella spp., in this order. The results tended to be similar for both drugs and were consistent with the results of the previous clinical research [1, 18, 19]. Overall, comprehensive assessment based on the clinical response, improvement of clinical symptoms (% change), and the bacteriological response demonstrated that DRPM and IPM/CS had high and comparable efficacy. Recently, the 2007 Tokyo Guidelines were revised based on the review results of the guidelines and ‘‘TG13: Updated Tokyo Guidelines for acute cholangitis and acute cholecystitis’’ [20] was newly developed. The updated guidelines recommend full-dose antimicrobial therapy for the empiric treatment of acute cholangitis and acute cholecystitis. For DRPM, a high daily dose of 3 g (1 g per dose) was approved for the treatment of severe refractory infection in Japan in 2011 and in Europe in 2013. There are also high hopes for high-dose DRPM for the treatment of
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severe biliary tract infection in terms of saving lives and the shorter duration of treatment. To achieve these, the therapeutic effect and safety of high-dose DRPM need to be clarified in the near future by strictly classifying the disease severity of patients according to the 2013 Tokyo Guidelines [20]. Acknowledgments We express our deepest appreciation to the members of the Biliary Tract Infection (BTI) Therapy Research Group and to their institutions. For full details, please see the Appendix. Conflict of interest This clinical trial was conducted after approval was obtained from the clinical research ethics committee at each trial site. In the implementation of the trial, no conflict of interest (COI) occurred.
Appendix The BTI Therapy Research Group consists of the following physicians and their institutions: Susumu Tazuma, Department of General Internal Medicine, Hiroshima University Graduate School of Medical Science, Programs of Applied Medicine, Clinical Pharmacotherapy; Toshihide Ohya, Department of Gastroenterology, Chugoku Rosai General Hospital; Yoshihiro Hattori and Koichiro Nakashima, Department of Internal Medicine, Syoubara Red Cross Hospital; Yoshinari Furukawa, Department of Gastroenterology, Hiroshima Red Cross Hospital and Atomicbomb Survivors Hospital; Hironori Tokumo, Yasumasa Asamoto and Takashi Nakahara, Department of Gastroenterology and Hepatology, Hiroshima General Hospital; Shigeyuki Kushihata, Department of Internal Medicine, Medical Corporation Koujinkai Kajikawa Hospital; Kazushi Teramen, Department of Internal Medicine, Mitsubishi Mihara Hospital; Atsushi Yamaguchi, Department of Gastroenterology, National Hospital Organization, Kure Medical Center; Tetsuya Watanabe, Department of Internal Medicine, Otagawa Hospital; Masaki Inoue and Daisuke Komichi, Department of Gastroenterology, Akitsu Prefectural Hospital; Yoshinori Igarashi, Naoki Okano, Ken Ito and Takahiko Mimura, Division of Gastroenterology and Hepatology, Toho University Omori Medical Center; Kazuo Inui, Yuuta Nakamura, Kunihito Shiota and Nobuyuki Hattori, Department of Internal Medicine, Second Teaching Hospital, Fujita Health University School of Medicine; Hirotaka Ohara, Department of Communitybased Medicine Education, Nagoya City University Graduate School of Medical Sciences; Takahiro Nakazawa, Tomoaki Andoh, Kagetsu Hayashi, Itaru Naitoh, Fumihiro Okumura and Takashi Joh, Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences; Hajime Tanaka and Haruki Nakao, Department of Gastroenterology, Aichi Medical
J Gastroenterol
University School of Medicine; Toshio Tsuyuguchi, Hiroyuki Ishibashi, Kouichiro Okitsu, Daisuke Maruoka, Takao Nishikawa, Rei Tamura, Takayuki Kondo, Seiko Togo, Arata Oyamada, Syouko Minemura, Sadahiro Itoh, Hidehiro Kamezaki and Kazuhiko Ohnishi, Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University; Shomei Ryozawa, Hirotoshi Iwano, Noriko Ishigaki and Kumiko Taba, Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine; Miyuki Kaino, Fumie Kurokawa, Takeshi Iida, Noriyoshi Kusano and Yumiko Harima, Department of Gastroenterology, Yamaguchi Rosai Hospital.
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