Antimicrobial therapy for acute cholangitis: Tokyo Guidelines

Antimicrobial agents should be administered to all patients with suspected acute cholangitis as a priority as soon as possible. Bile cultures should be performed at the earliest opportunity. The important factors which should be considered in selecting antimicrobial therapy include the agent's activity against potentially infecting bacteria, the severity of the cholangitis, the presence or absence of renal and hepatic diseases, the patient's recent history of antimicrobial therapy, and any recent culture results, if available. Biliary penetration of the microbial agents should also be considered in the selection of antimicrobials, but activity against the infecting isolates is of greatest importance. If the causative organisms are identifi ed, empirically chosen antimicrobial drugs should be replaced by narrower-spectrum antimicrobial agents, the most appropriate for the species and the site of the infection.

# Introduction
In the medical treatment, of acute cholangitis, antimicrobial agents should be chosen empirically and carefully. As soon as a diagnosis of acute cholangitis is considered, antimicrobial agents should be selected empirically, with careful consideration of several factors, including antimicrobial activity against the causative bacteria, the severity of the cholangitis, the presence/ absence of renal and hepatic disease, a recent (1-year) history of antimicrobial therapy, local susceptibility patterns (antibiogram), and (although controversies still exist) the biliary penetration of the antimicrobial agents. Whenever any presumptive or empirical antimicrobial agents are used, they should be switched for the best available narrower-spectrum agents to avoid superinfection or the emergence of antimicrobial resistance as a cause of treatment failure. Long-term administration without an acceptable rationale should be avoided. In this article, we review previous bacteriological studies and clinical trials. We also provide current recommendations for the antimicrobial agents to be used for acute cholangitis, in an evidence-and consensus-based manner, on the basis of discussions at the Tokyo International Consensus Meeting.

## Q1. how to detect causative organisms of acute cholangitis?
Bile/blood culture should be performed at all available opportunities (recommendation B). [fig_ref] Table 1: Bacterial culture positive rates in bile [/fig_ref] lists the positive rates of bacterial cultures in bile in various biliary diseases. While bile is sterile in individuals without any biliary disease, a positive bile culture is common in various biliary diseases. In patients with acute cholangitis and choledocholithiasis, a positive bile culture is correlated with progression to severe cholangitis and a high mortality rate (level 2b-3b). [bib_ref] Consequences of preopera tive cholangitis and its treatment on the outcome of..., Pitt [/bib_ref] [bib_ref] Bacteriological study of choledochal bile in patients with common bile duct stones,..., Maluenda [/bib_ref] Also, care should be exercised regarding the postoperative occurrence of infective complications in patients with positive bile cultures (level 5). [bib_ref] Microfl ora of the biliary tree and liver -clinical correlates, Claesson [/bib_ref] These facts emphasize the importance of early antimicrobial therapy.
It was reported that microbial organisms contained in bile from various biliary diseases were of intestinal bacterial fl ora origin . Aerobic bacteria such as Escherichia coli, Klebsiella, Enterococcus, and Enterobacter are most frequently isolated, whereas Streptococcus spp., Pseudomonas, and Proteus are less frequently isolated (level 2b-3b). [bib_ref] Bacteriological study of choledochal bile in patients with common bile duct stones,..., Maluenda [/bib_ref] [bib_ref] Bacteriology and antimicrobial susceptibility in biliary tract disease: an audit of 10-year's..., Chang [/bib_ref] [bib_ref] Simultaneous bacteriologic assessment of bile from gallbladder and common bile duct in..., Csendes [/bib_ref] [bib_ref] Counts of bacteria and pyocites of choledochal bile in controls and in..., Csendes [/bib_ref] [bib_ref] The significance of bacteriological fi ndings at cholecystectomy, Brismar [/bib_ref] [bib_ref] Biliary bacteremia at various stages of acute cholecystitis, Jarvinen [/bib_ref] Although anaerobic bacteria such as Clostridium and Bacteroides are often isolated, most of these patients have polymicrobial infections with aerobic bacteria (level 5). [bib_ref] Acute (ascending) cholangitis, Hanau [/bib_ref] [bib_ref] Biliary tract infections: a guide to drug treatment, Westphal [/bib_ref] [bib_ref] Acute cholangitis, Sinanan [/bib_ref] There are reports that anaerobic bacteria are often detected patients with severe acute cholangitis (level 2b-3b). [bib_ref] Gangrenous cholecystitis and acute cholangitis associated with anaerobic bacteria in bile, Marne [/bib_ref] [bib_ref] Microfl ora of the gallbladder related to duration of acute cholecystitis, Claesson [/bib_ref] [bib_ref] Anaerobic and aerobic bacteriological studies in biliary tract disease, Nielsen [/bib_ref] Moreover, it should also be kept in mind for the estimation of causative bacteria in acute cholangitis, whether the infection is community-acquired or hospital-acquired. When it is community-acquired, intestinal microorganisms such as E. coli, Klebsiella, and Enterococcus are likely to be the causative bacteria. By contrast, we have to take into account that, in patients with hospital-acquired type infections, especially those in a postoperative state or those with indwelling stents and malignancies, more resistant organisms, i.e., methicillinresistant Staphylococcus aureus (MRSA), vancomycinresistant enterococcus (VRE), and Pseudomonas, are frequently detected as causative microorganisms.
Many patients with cholangitis with a microbialpositive blood culture have the same species of bacteria in blood as those isolated from bile cultures (level 3b), [bib_ref] Gangrenous cholecystitis and acute cholangitis associated with anaerobic bacteria in bile, Marne [/bib_ref] and the positive rate increases with the co-existence of acute cholangitis due to biliary obstruction (level 2b). [bib_ref] Consequences of preopera tive cholangitis and its treatment on the outcome of..., Pitt [/bib_ref] The blood culture-positive rates in acute cholangitis have been reported to vary from 21% to 71% (level 5). [bib_ref] Acute (ascending) cholangitis, Hanau [/bib_ref] [bib_ref] Biliary tract infections: a guide to drug treatment, Westphal [/bib_ref] [bib_ref] Acute cholangitis, Sinanan [/bib_ref] [bib_ref] Cholangitis: pathogenesis, diagnosis, and treatment, Hanau [/bib_ref] Patients with bacteremia are frequently resistant to treatment regimens (level 4), [bib_ref] An analysis of infectious failures in acute cholangitis, Thompson [/bib_ref] and bacteremia is correlated with the duration of hospitalization, the incidence of postoperative renal failure, and the mortality rate (level 2b). [bib_ref] Consequences of preopera tive cholangitis and its treatment on the outcome of..., Pitt [/bib_ref] These fi ndings underscore the importance of antisepsis therapy, as outlined in the Surviving Sepsis Campaign guidelines of the Society of Critical Care Medicine. [bib_ref] for the Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines..., Dellinger [/bib_ref] There has been no good-quality evidence to support the importance of blood and bile culture in patients with . By contrast, there was a signifi cant discrepancy between Japanese and overseas panelists in regard to the importance placed on blood culture for all patients; while more than half of the overseas panelists agreed on the necessity for blood culture, most of the Japanese panelists disagreed . Representative reasons for the disagreement were that, usually, blood cultures did not provide any information beyond that provided by bile cultures, and that postoperative acute cholangitis in patients with a choledocho-jejuno anastomosis did not need intensive bacteriological studies. It is, however, rational to rule out bacteremia, when possible, in patients with severe cholangitis, as this would affect the duration of antimicrobial therapy.

## Q2. how are antimicrobial agents used for patients with acute cholangitis?
- Antimicrobial agents should be administered to all patients diagnosed as having acute cholangitis (recommendation A); the Antimicrobial agents should be administered as soon as the diagnosis of acute cholangitis is suspected or established.
- For patients with moderate (grade II) or severe (grade III) acute cholangitis, antimicrobial agents should be administered for a minimum duration of 5-7 days. More prolonged therapy could be required, depending on the presence of bacteremia and the patient's clinical response, judged by fever, white blood cell count, and Creactive protein, when available (recommendation A). - For patients with mild (grade I) acute cholangitis, the duration of antimicrobial therapy could be shorter (2 or 3 days) (recommendation A).
An important and fruitful discussion was held regarding the duration of antimicrobial therapy for patients with acute cholangitis (see "Discussion"). In summary, patients with moderate (grade II) or severe (grade III) acute cholangitis should receive a minimum duration of therapy of 5-7 days, and then, based on the anatomy of the disease and the presence of bacteremia, and their clinical responses, patients may need more prolonged therapy. However, for the large group of patients with mild (grade I) cholangitis, 2 or 3 days of antimicrobial therapy is likely to be suffi cient. Needlessly prolonged antimicrobial therapy risks adverse reactions to the antimicrobials, and intensifi es pressure for the development and acquisition of resistant bacteria.

## Q3. what are the most important factors for consideration in antimicrobial drug selection? (1) antimicrobial activity against causative bacteria (2) severity of cholangitis (3) presence/absence of renal and hepatic disease (4) past history of antimicrobial administration to the patient (5) local susceptibility patterns (antibiogram) of the suspected causative organisms (6) biliary penetration of the antimicrobial agents.
The dose of the antimicrobial agent should be reduced for patients with reduced renal function. Because most cephalosporin, penicillin, aminoglycoside, and carbapenem antimicrobial drugs are excreted by the kidneys, the dose is reduced for patients with nephropathy and decreased renal function. The Sanford guide to antimicrobial therapy, 2003 [bib_ref] The Sanford guide to antimicrobial therapy, Gilbert [/bib_ref] and Goodman and Gilman's the pharmacological basis of therapeuticsrecommend that renal function be estimated by the following formula:
Creatinine clearance predicted from serum creatinine (0.85 for females) = (140  age)(optimum body weight (kg)) / (72  serum creatinine mg/dl) where male optimum body weight is 50.0 kg + 0.91 kg/ cm (150 cm and taller) and female optimum body weight is 45.5 kg + 0.91 kg/cm (150 cm and taller).

## Drug dosage adjustment should be done in patients with decreased renal function. the sanford guide to antimicrobial therapy and goodman and gilman's the pharmacological basis of therapeutics should be consulted (recommendation a).
Drug dosage adjustment for ceftriaxone is not necessary in patients with renal failure. But dose adjustment of ceftriaxone is indicated for patients with severe hepatic impairment. [bib_ref] The Sanford guide to antimicrobial therapy, Gilbert [/bib_ref] In addition, when biliary obstruction that blocks the enterohepatic circulation of bile is present, the administration of third-and fourth-generation cephalosporins may replace the intestinal fl ora and disturb vitamin K absorption, in turn risking coagulopathic hemorrhage. This phenomenon, leading to bleeding tendency, can be enhanced in patients with comorbid liver diseases or liver failure due to severe acute cholangitis. Intravenous administration of vitamin K may be indicated in these situations.

## Q4. should biliary penetration be considered important in the selection of therapeutic antimicrobials in acute cholangitis?

## Biliary penetration should be considered in the selection of antimicrobial agents in acute cholangitis (recommendation a).
It has been debated whether antimicrobials with good biliary penetration should be recommended for acute cholangitis. Indeed, there was a common belief, particularly in Japan, that antimicrobial agents with excellent biliary penetration are more effective for the treatment of acute cholangitis. However, there are no clinical or experimental data to strongly support the recommendation of antimicrobials with excellent biliary penetration for these patients. In fact, in most patients with acute cholangitis, biliary obstruction is usually present, and antimicrobial drugs may not be detected in bile even if they demonstrate excellent biliary excretion in normal conditions (level 3b-4). [bib_ref] Antibiotics, biliary sepsis, and bile duct stones, Leung [/bib_ref] [bib_ref] Biliary excretion of aztreonam in patients with biliary tract disease, Martinez [/bib_ref] [bib_ref] Effect of biliary obstruction on the hepatic excretion of imipenem-cilastatin, Leung [/bib_ref] [bib_ref] The effect of obstruction on the biliary excretion of cefoperazone and ceftazidime, Leung [/bib_ref] [bib_ref] Decreased biliary excretion of piperacillin after percutaneous relief of extrahepatic obstructive jaundice, Blenkharn [/bib_ref] [bib_ref] Biliary excretion of ciprofl oxacin and piperacillin in the obstructed biliary tract, Van Den Hazel [/bib_ref] [bib_ref] Excretion of antibiotics into human bile juice in patients with obstructive jaundice..., Takada [/bib_ref] [bib_ref] Decreased biliary excretion of cefamandole after percutaneous biliary decompression in patients with..., Levi [/bib_ref] Nevertheless, at the Consensus Meeting, we reached a consensus that the importance of biliary penetration should be emphasized for the empirical selection of antimicrobial agents . For details, see "Discussion at the Tokyo International Consensus Meeting." In [fig_ref] Table 3: Intravenous antimicrobial drugs with good biliary penetration [/fig_ref] , we list antimicrobial agents with good biliary penetration.

## Q5. what are the results of clinical trials regarding antimicrobial therapy in acute cholangitis?
The combination of ampicillin and an aminoglycoside was regarded as a standard regimen for cholangitis in the 1980s (level 4-5), [bib_ref] Acute cholangitis, Boey [/bib_ref] [bib_ref] Factors in management of acute cholangitis, Thompson [/bib_ref] and most randomized controlled trials (RCTs) have concluded that recently developed antimicrobial drugs had effectiveness and usefulness equivalent to that of ampicillin and aminoglycosides ( to the clinical trials available so far, piperacillin, ampicillin and an aminoglycoside, and several cephalosporins, are recommended for the treatment of acute cholangitis. However, at present antimicrobial agents widely used for acute cholangitis, including penicillin/-lactamase inhibitors, carbapenems, and the third-and fourthgeneration cephalosporins, have not been tested in these RCTs. In this regard, we recommend the alternative regimens for antimicrobial agents stated in the Tokyo Guidelines. The recommendations were reached in a consensus-based manner, as follows.

## Q6. what are the current recommendations for antimicrobial therapy in acute cholangitis? - antimicrobial drugs should be selected according to the severity assessment (recommendation a). - empirically administered antimicrobial agents should be changed for more appropriate agents according to the identifi ed causative microorganisms and their sensitivity to antimicrobials (recommendation a).
In the Infectious Diseases Society of America (IDSA) guidelines for intraabdominal infections, the selection of antimicrobial agents is based on the severity of the infection. In the Tokyo Guidelines, the selection of antimicrobial agents is based on the severity of acute cholangitis. However, it should be emphasized that there is little high-level evidence that supports this notion. It was widely accepted at the Consensus Meeting that empirically administered antimicrobial agents should be changed for more appropriate agents according to the identifi ed causative microorganisms and their sensitivity to antimicrobials .
In any guidelines, recommended doses of antimicrobials, ideally based on body weight, should also be provided. However, the dose administered can vary in each country, depending on medical practices and legal regulations. For instance, it was known and discussed at the Consensus Meeting that the legally approved doses of antimicrobials in Japan are different from those used in the United States and Europe. Therefore, recommended doses of antimicrobial agents are not provided in the Tokyo Guidelines, and doses should be determined according to local rules and regulations. Similarly, the cost of the agents, which should also be discussed, varies in [bib_ref] Prospective randomized comparison of mezlocillin therapy alone with combined ampicillin and gentamicin..., Gerecht [/bib_ref] Cholangitis Mezocillin 83% (20/24) P < 0.01 Ampicillin + gentamicin 41% (9/22) [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] [bib_ref] Broad spectrum penicillin as an adequate therapy for acute cholangitis, Thompson [/bib_ref] Cholangitis Piperacillin 70% NS Ampicillin + tobramycin 69% [bib_ref] Prospective randomized comparison of pefl oxacin and ampicillin plus gentamicin in the..., Chacon [/bib_ref] [bib_ref] Prospective randomized comparison of pefl oxacin and ampicillin plus gentamicin in the..., Chacon [/bib_ref] Cholangitis + cholecystitis Pefl oxacin 98% (49/50) NS Ampicillin + gentamicin 95.7% (45/47) organisms. Of note, the ratio of penicillin to tazobactam is different in Japan (4 : 1) from that in the United States (8 : 1).

## Q7. is there any difference between japan and the united states in the use of antimicrobial agents for acute cholangitis?
On the basis of pharmacokinetics and pharmacodynamics, there is a signifi cant difference between the United States and Japan in antimicrobial dosing regimens. For details, see "Discussion", for discussions held at the Tokyo International Consensus Meeting. As a consequences of the inappropriate dosing regimens in Japan, inadequate clinical responses may be seen in Japanese patients. Moreover, the overuse of broad spectrum agents such as carbapenems has been another problem in Japan. Unpublished data from a major global pharmaceutical company indicate that Japan consumes half of the carbapenems produced worldwide. This could be evidence of the overuse of carbapenems in Japan.

## Q8. how should antimicrobial drugs be administered for acute cholangitis associated with biliary obstruction?
The presence of biliary obstruction may significantly infl uence the biliary penetration of the antimicrobial, as well as acting as a persistent source of infection. Therefore, patients with acute cholangitis, especially those with severe (grade III) disease, should have immediate biliary drainage along with appropriate antimicrobial therapy (recommendation A).
When biliary obstruction is present, even an antimicrobial drug with excellent biliary excretion may not enter the bile tract (level 3b-4). [bib_ref] Antibiotics, biliary sepsis, and bile duct stones, Leung [/bib_ref] [bib_ref] Biliary excretion of aztreonam in patients with biliary tract disease, Martinez [/bib_ref] [bib_ref] Effect of biliary obstruction on the hepatic excretion of imipenem-cilastatin, Leung [/bib_ref] [bib_ref] The effect of obstruction on the biliary excretion of cefoperazone and ceftazidime, Leung [/bib_ref] [bib_ref] Decreased biliary excretion of piperacillin after percutaneous relief of extrahepatic obstructive jaundice, Blenkharn [/bib_ref] [bib_ref] Biliary excretion of ciprofl oxacin and piperacillin in the obstructed biliary tract, Van Den Hazel [/bib_ref] [bib_ref] Excretion of antibiotics into human bile juice in patients with obstructive jaundice..., Takada [/bib_ref] [bib_ref] Decreased biliary excretion of cefamandole after percutaneous biliary decompression in patients with..., Levi [/bib_ref] The active transfer of antimicrobial drugs into bile is not restored early after the biliary obstruction has been relieved (level 4). [bib_ref] Biliary excretion of ciprofl oxacin and piperacillin in the obstructed biliary tract, Van Den Hazel [/bib_ref] Therefore, immediate biliary drainage, as well as the admin- Ciprofl oxacin, levofl oxacin, pazufl oxacin One of above + metronidazole (to cover anaerobes) Carbapenems
Meropenem, imipenem/cilastatin, doripenem different countries and was not addressed in the Tokyo Guidelines.

## Antibacterials selected for the three grades of acute cholangitis
Mild (grade I) acute cholangitis Mild (grade I) cases of the disease are often caused by a single intestinal organism, such as E. coli, and therefore monotherapy with one of the following antimicrobial drugs should be chosen. Because intestinal organisms producing -lactamase, which are resistant to penicillins and cefazoline, are likely to be detected, the use of a penicillin/-lactamase inhibitor, such as piperacillin/ tazobactam, 37 or ampicillin/sulbactam is recommended (see [fig_ref] Table 5: Antibacterials for grade I acute cholangitis [/fig_ref].
Moderate (grade II) and severe (grade III) acute cholangitis ( How long should antimicrobial agents be given for patients with acute cholangitis?
Joseph S. Solomkin (USA): The other point I will make, just to relay our experience in North America, is that there is increasing emphasis on shortened duration of therapy, and typically now the standard recommendation for treatment would be approximately 7-10 days until the patient is afebrile, has resolved their infection clinically, and is taking oral intake. There are a lot of people who think that that is too long; that in fact 5 days may be the optimal therapy, so I think that is another very important area to look at, because certainly the longer patients are on these very broadspectrum agents, the greater the potential harm in terms of superinfection and toxicity. Henry A. Pitt (USA): That was my point as well. I give a short course if there is no bacteremia, and then try to stop quickly, but I give a real course of 7-10 days if there is bacteremia.
Joseph Solomkin: Has anybody . . . I would just like to ask one question since I think you people have more experience than I do with this; if a patient has an episode of cholangitis, is short-course treatment -say 5 days -is there a risk they will develop liver abscesses? So when we are talking about the duration of therapy, should that be a factor in it? Henry Pitt: I think it depends a lot on the exact clinical situation. I mean, we see cholangitis most often now in patients who have indwelling stents, who come in and they get their stent changed, and then the bile is fl owing again and the cholangitis goes away quickly, and they either have had a liver abscess or not when they come in, and you fi gure that out, if they do not respond to the usual therapy and/or they have blood cultures.
Serafi n C. Hilvano (Philippines): I would also agree that we set a minimum number of days for the therapy.
Thomas R. Gadacz (USA): There are a lot of specifi cs that have been brought up, such as liver abscess, you would treat a patient for a long period of time. Patients where the acute cholangitis may be simply be due to a plugged-up stent which gets changed very quickly, in which case short-term therapy would be probably very appropriate. So I think that the absolute determination here is not one that that is trying to be a solution, but really a guideline and that is stated in the question, "should be." The specifi c situation then could be altered depending upon what the exact condition is.
[table] Table 1: Bacterial culture positive rates in bile (%) in various biliary diseases [/table]
[table] Table 4: (level 2b).[30][31][32][33][34][35] Therefore, according [/table]
[table] Table 3: Intravenous antimicrobial drugs with good biliary penetration (level 4)18 [/table]
[table] Table 5: Antibacterials for grade I acute cholangitis [/table]