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Review Article bersichtsarbeit

Viszeralmedizin 2014;30:297302 Published online: October 6, 2014


DOI: 10.1159/000368335

Calculated Antibiosis of Acute Cholangitis and


Cholecystitis
Till Bornscheuer Stefan Schmiedel

1. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Keywords Schlsselwrter
Biliary infection Acute cholangitis Gallenwegsinfektion Akute Cholangitis
Acute cholecystitis Antimicrobial therapy Akute Cholezystitis Antimikrobielle Therapie
Calculated antimicrobial therapy Kalkulierte antimikrobielle Therapie
Empirical therapy Presumptive therapy Empirische Therapie Kalkulierte antibiotische Therapie
Antibiotic therapy Antibiotische Therapie

Summary Zusammenfassung
Background: The aim of this article is to present the Hintergrund: In diesem Artikel sollen aktuelle Empfehlun-
most recent suggestions for the therapy of acute cholan- gen zur antimikrobiellen Therapie der akuten Cholangitis
gitis and cholecystitis based on a review of the current und Cholezystitis basierend auf einer Literaturrecherche
literature. Methods: We performed a systematic litera- prsentiert werden. Methoden: Es wurde eine systemati-
ture search in the Medline, PubMed, and Google Scholar sche Literaturrecherche der oben angegebenen Schls-
databases using the keywords mentioned above. This selwrter in den Datenbanken Medline, PubMed und
article is strongly influenced by the publication of the Google Scholar durchgefhrt. Der Artikel ist stark beein-
Tokyo Guidelines for the management of acute cholangi- flusst von den Verffentlichungen der Tokyo Guideli-
tis and cholecystitis (TG07, TG13) in 2007 and 2013. nes zur Behandlung der akuten Cholangitis und Chole-
These were the first practical guidelines targeting diag- zystitis. Hierbei handelte es sich um die ersten konkreten
nosis and treatment of acute cholangitis and cholecysti- Empfehlungen zur Diagnose und Behandlung der akuten
tis. These guidelines are based on the best published Cholangitis und Cholezystitis basierend auf den Verf-
evidence and a consensus conference of international fentlichungen zu diesem Thema sowie einer Konsensus-
experts in the field. Results and Conclusion: Acute chol- konferenz. Ergebnisse und Schlussfolgerung: Die akute
angitis and acute cholecystitis are common conditions Cholangitis und Cholezystitis sind hufige Erkrankungen,
that may result in progressively severe infection and die, wenn nicht adquat behandelt, zu fortschreitenden
death when not treated appropriately. Beside supportive schweren Infektionen und Tod fhren knnen. Neben
therapy and antiobstructive measures, therapy with anti- supportiver Therapie und antiobstruktiven Manahmen
microbial agents is an important component in the man- stellt eine antimikrobielle Therapie einen wichtigen Teil
agement of affected patients. Here, we discuss the use of der Behandlung bei betroffenen Patienten dar. Die zur in-
antimicrobial agents that are suitable for the first-line itialen Therapie dieser Erkrankungen geeigneten anti-
management of these infections. Empirical therapy de- mikrobiellen Substanzen sollen hier diskutiert werden.
pends upon the knowledge of local microbial epidemiol- Die empirische Therapie basiert dabei auf der Kenntnis
ogy and patient-specific factors affecting the selection of der lokalen mikrobiellen Epidemiologie und auf patien-
appropriate agents. tenspezifischen Faktoren, welche die Auswahl geeigne-
ter Substanzen beeinflussen.
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2014 S. Karger GmbH, Freiburg Dr. med. Stefan Schmiedel


1662-6664/14/0305-0297$39.50/0 1. Department of Medicine
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Fax +49 761 4 52 07 14 University Hospital Hamburg-Eppendorf


Information@Karger.com Accessible online at: Martinistrae 52, 20246 Hamburg, Germany
www.karger.com www.karger.com/vim sschmiedel@bni-hamburg.de
Introduction Table 1. Etiology of
Cholelithiasis
acute cholangitis
(modified according Benign biliary stricture
Patients exhibiting one of the local signs of inflammation, After surgical, endoscopic, or other invasive
to [8])
such as Murphys sign, a mass, pain, jaundice, or tenderness in procedures, ERCP complications
the right upper quadrant, and systemic inflammation are diag- Inflammatory factors (oriental cholangitis etc.)
nosed as having acute cholangitis or cholecystitis. Patients Sclerosing cholangitis
with clinical findings that are confirmed by diagnostic imaging Malignancies
Bile duct tumor
are also diagnosed with acute cholangitis or cholecystitis. In
Gallbladder tumor
these patients, a therapy with appropriate antimicrobial
Pancreatic tumor
agents is an important component of the management. The Duodenal tumor or diverticulum
goal of antimicrobial therapy in acute cholangitis and chole- Pancreatitis
cystitis is to limit the systemic septic response and local in- Parasites in bile ducts
flammation [1]. External compression or adhesion
Acute cholangitis and cholecystitis are common conditions Fibrotic papilla
that may result in progressively severe infection, particularly Obstruction by blood clot

in debilitated hosts. An appropriate treatment is required in


the acute phase. Severe acute cholangitis or cholecystitis may
result in early death if appropriate medical care is not pro- Table 2. Microor-
Organisms Proportion, %
vided [26]. An attempt to develop a clinical guidance was ganisms isolated from
provided by the Tokyo Guidelines (TG) 2007 in which inter- bile cultures among Gram-negative organisms
national standards for diagnostics and severity assessment cri- patients with acute Escherichia coli 3144
biliary infections Klebsiella spp. 920
teria for acute cholecystitis and cholangitis were defined for
(modified according Pseudomonas spp. 0.519
the first time [2]. to [10, 11])
Enterobacter spp. 59
Here, we discuss antimicrobial agents that are suitable for
Acinetobacter spp.
the first-line management of these infections. We focus pri- Citrobacter spp.
marily on empirical therapy (presumptive therapy), which is Gram-positive organisms
provided before the infecting isolates are identified. Such Enterococcus spp. 334
therapy depends upon the knowledge of local microbial epi- Streptococcus spp. 210
demiology and patient-specific factors affecting the selection Staphylococcus spp.
of appropriate agents [3]. Anaerobes 420

Etiology and Pathogenesis


Table 3. Common
Proportion, %
isolates from patients
Acute biliary infections are systemic infectious diseases with bacteremic Community-acquired
requiring prompt treatment. Acute cholangitis and cholecys- biliary tract infections Escherichia coli 3562
titis are conditions with acute inflammation and infection of (modified according Klebsiella spp. 1228
the biliary system, which are often accompanied by chills, to [10, 11]) Pseudomonas spp. 414
right upper quadrant pain, and jaundice (Charcot trias); Enterobacter spp. 27
sometimes, lethargy, confusion, and shock are additionally Acinetobacter spp. 3
Citrobacter spp. 26
present. In many cases, biliary obstruction plays a leading
Healthcare-associated
role in the pathogenesis and is sometimes complicated by ab-
Enterococcus spp. 1023
scess formation [7]. Frequent causes of biliary obstruction Streptococcus spp. 69
are choledocholithiasis, benign biliary stenosis, strictures Staphylococcus spp. 2
after biliary interventions as well as after ischemic (SSC) or Anaerobes 1
sterile inflammation (PSC), and stenosis caused by malig- Others 17
nant tumors. An overview of common underlying causes for
biliary obstruction and inflammation is given in table 1 [8].
Quite often, acute cholangitis and cholecystitis are due to cuses on the majority of cases, which are due to bacterial
biliary obstruction and ascending infection of the bile. In the infections.
vast majority of cases, bacteria are the causative infective or- The bacteria commonly found in biliary tract infections are
ganisms for acute biliary infections. In some populations, im- well known. Most of these bacteria originate from the upper
munosuppressed viral (cytomegalovirus) or parasitic agents and lower intestine (table 2, 3) [10, 11]. The bile of healthy
(cryptosporidia, isospora) [9] may be found. This article fo- subjects is generally aseptic. However, bile cultures are posi-
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tive for microorganisms in 16% of the patients, in 72% of Management
those with acute cholangitis, in 44% in chronic cholangitis pa-
tients, and in 50% of those with biliary obstruction [1012]. Patients suspected of having acute cholangitis or cholecys-
titis should be admitted to a hospital for further evaluation.
An early assessment of disease severity is essential for all of
Table 4.Diagnostic criteria for acute cholangitis (TG13) (modified these patients (table 4, 5) [1].
according to [12])a

A. Systemic inflammation
Fever and/or chills Patient Assessment
Laboratory evidence of inflammation
All patients with suspected or proven cholangitis or chole-
B. Cholestasis
Jaundice
cystitis (table 6) should be evaluated and grouped according
Abnormal liver function tests to the TG13 severity assessment criteria (table 7) [1, 2].
Early diagnosis, early biliary drainage or treatment for eti-
C. Imaging
ology, and antimicrobial administration are fundamental for
Biliary dilatation
Evidence of the etiology on imaging (obstruction, stricture, stone,
the treatment for acute cholangitis/cholecystitis not only in
stent, empyema etc.) severe and moderate but also in mild disease.
a
Therefore, it is recommended that patients with acute chol-
Suspected diagnosis: One item in A and one item in either B or C.
angitis/cholecystitis who do not respond to the initial medical
treatment (general supportive care and antimicrobial therapy)
undergo early biliary drainage or treatment for etiology, and,
Table 5.Severity assessment criteria for acute cholangitis/cholecystitis in the case of cholecystitis, surgical therapy.
(TG13) (modified according to [12])

Grade I
Grade I (mild) acute cholangitis/cholecystitis does not meet the criteria Diagnostic Procedures
of Grade III (severe) or Grade II (moderate) acute cholangitis

Grade II Identifying the causative organism is an essential step in


Grade II (moderate) acute cholangitis/cholecystitis at initial diagnosis is the management of acute biliary infections.
associated with any two of the following conditions: Blood cultures are not routinely recommended for non-severe
Abnormal WBC count (>12,000/mm3, <4,000/mm3) acute cholecystitis. The Surgical Infection Society and the Infec-
High fever (>39.0 C)
tious Diseases Society of America (SIS-NA/IDSA) guidelines
Age (>75 years)
Hyperbilirubinemia (total bilirubin >5 mg/dl) from 2010 advise against routine blood cultures for community-
acquired intra-abdominal infections, since the results do not
Grade III change the management and outcomes [13, 14]. Positive rates of
Grade III (severe) acute cholangitis/cholecystitis is associated with blood cultures among patients with acute cholangitis ranged from
cardiac, renal, neurological, respiratory, hepatic, and hematological
21 to 71% [15]. However, we would recommend taking cultures as
dysfunction
it is simple, easy to take, and might mandate changes in therapy.

Table 6.Antimicrobial recommendations for acute biliary infections (TG13) (modified according to [1])

Cholangitis and cholecystitis, severity

grade I grade I grade III healthcare-associated

Anti-microbial ampicillin/sulbactam is not piperacillin/tacobactam; piperacillin/tacobactam piperacillin/tacobactam


agent recommended without ceftriaxone, cefotaxim, vancomycin, linezolid, vancomycin, linezolid,
an aminoglycoside; cefepim, ceftacidim; daptomycin; ceftriaxone, daptomycin; cefepim,
cefazolin, cefotiam, ciprofloxacin, levofloxacin cefotaxim, cefepim, ceftaci- ceftacidim metronidazole
cefuroxime, ceftriaxone, metronidazole, moxifloxacin dim, metronidazole vanco- vancomycin, linezolid,
cefotaxim metronidazole metronidazole; impinem/ mycin, linezolid, daptomy- daptomycin; imipenem/
celastin, meropenem vanco- cin; impinem/celastin, cilastin, meropenem
mycin, linezolid, daptomycin meropenem vancomycin, vancomycin, linezolid,
linezolid, daptomycin; daptomycin
impinem/celastin,
meropenem vancomycin,
linezolid, daptomycin
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and Cholecystitis
Table 7. Agents and regimens that may be
Infection Regimen
used for the initial empiric treatment of biliary
infection in adults (SIS/IDSA 2010) (modified Community-acquired acute cholecystitis of cefazolin, cefuroxime, or ceftriaxone
according to [14]) mild-to-moderate severity
Community-acquired acute cholecystitis imipenem-cilastatin, meropenem, doripenem,
of severe physiologic disturbance, piperacillin-tazobactam, ciprofloxacin,
advanced age, or immunocompromised levofloxacin, or cefepime, each in combination
state with metronidazole
Acute cholangitis following bilio-enteric imipenem-cilastatin, meropenem, doripenem,
anastamosis of any severity piperacillin-tazobactam, ciprofloxacin,
evofloxacin, or cefepime, each in combination
with metronidazole
Health care-associated biliary infection imipenem-cilastatin, meropenem, doripenem,
of any severity piperacillin-tazobactam, ciprofloxacin,
levofloxacin, or cefepime, each in combination
with metronidazole, vancomycin added to each
regimen

Bile cultures should be obtained at the beginning of any The antimicrobial therapy should be initiated as soon as
surgical or endoscopic procedure. Cultures of bile and tissue the diagnosis of cholangitis or cholecystitis is suspected. While
should be performed when perforation, emphysematous antibiotics should be administered immediately for patients
changes, or necrosis of gallbladder are noted during cholecys- with suspected septic shock, up to 4 h could be spent for ob-
tectomy. Positive rates of bile cultures range from 59 to 93% taining definitive diagnosis in other patients. In all patients,
for acute cholangitis and from 29 to 67% for acute cholecysti- antimicrobial therapy should be started before any invasive
tis. Table 2 shows common microbial isolates from bile cul- procedure [1, 2, 10, 17, 19, 20].
tures among patients with acute biliary infections [1115]. To this day, only few randomized controlled trials have
In patients with confirmed cholangitis or cholecystitis, man- evaluated the effect of antimicrobial therapy on acute cholan-
agement consists of three cornerstones: i) supportive care, ii) gitis and/or cholecystitis [1]. All these studies, except one
empiric antibiotic coverage, and iii) biliary drainage in acute from 2012, are outdated and were conducted in part with anti-
cholangitis and final surgical treatment for acute cholecystitis. biotics no longer used in clinical practice. Comparisons of
Supportive care consists of fluid reconstitution, pain man- these trials are quite complex as they differ in tested antibiot-
agement, and management of complications [1, 14, 16]. For ics, study design, and tested population. However, all of them
biliary drainage in acute cholangitis, endoscopic retrograde demonstrated that the chosen antibiotics had a comparable
cholangiopancreatography (ERCP) is the treatment of choice. effectiveness and usefulness with ampicillin and an aminogly-
The optimal point of time depends on the severity of illness coside, which was considered to be the standard regime for
[17]. Early laparoscopic cholecystectomy is the standard de- acute cholecystitis in the 1980s [21]. The nowadays widely
finitive management for acute calculous cholecystitis [18]. used penicillin and -lactamase inhibitors, the carbapenems,
and the third- and fourth-generation cephalosporins were
mainly not tested in these randomized controlled trials. In
Antimicrobial Therapy for Cholangitis and spite of this, the TG for antimicrobial therapy for acute chol-
Cholecystitis angitis and cholecystitis (TG13) updated in 2013 and the SIS/
IDSA 2010 define recommendations for antimicrobial treat-
The rationale for antimicrobial therapy is to prevent both a ment depending on severity of illness and the community-ac-
systemic septic response and a local inflammation. Further- quired and healthcare-associated nature of biliary infections
more, it should prevent infections after surgical procedures as [1, 14]. Tables 6 and 7 summarize antimicrobial recommenda-
well as intrahepatic abscess formation. The selection of antibi- tions of TG13 and SIS/IDSA for acute community-acquired
otics is essential since inadequate initial antibiotic therapy is cholangitis.
an independent predictor of mortality [19]. Several antibiotic regimes based on different antimicrobial
Before choosing an antimicrobial therapy several points classes seem to be reasonable. For cholecystitis and cholangi-
should be considered: suspected pathogens, local epidemiol- tis with mild-to-moderate severity, the TG13 guidelines in-
ogy and resistance patterns, pharmacodynamics and pharma- clude penicillin-, cephalosporin-, carbapenem-, monobactam-,
cokinetics, the history of antimicrobial usage, severity of ill- and, with limitations, fluorchinolone-based therapy regimes.
ness, nosocomial or community-acquired nature of infection, In contrast, the SIS/IDSA guidelines for mild-to-moderate
and allergies or adverse reactions [1]. cholangitis/cholecystitis recommend only cephalosporin-
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based regimes. The use of ampicillin/sulbactam as a mono- than antimicrobial treatment for up to 4 days [25]. In patients
therapy is no longer recommended because of high rates of with mild cholecystitis, the TG13 recommend to stop antimi-
resistance to this agent among community-acquired Escheri- crobial therapy within 24 h after cholecystectomy is per-
chia coli [14]. In face of the increasing number of multidrug- formed. In grade IIII cholangitis as well as in cholecystitis
resistant Gram-negative bacteria (MDRGN bacteria) and before definitive surgical therapy, the antimicrobial therapy
Klebsiella in the community, it should be noted that these or- should be continued for 47 days. If bacteremia with Gram-
ganisms are not sufficiently covered by cephalosporins, peni- positive cocci such as Enterococcus sp. or Streptococcus spp. is
cillin derivatives, or fluorchinolones [21, 22]. If more than 10 present, a minimum duration of 2 weeks is recommended in
20% of isolates in the community are resistant, empiric ther- some publications and guidelines, though the rationale re-
apy should cover these resistant organisms until susceptibility mains unclear [1, 10, 25]. We believe that a shorter course of
data are available [14]. treatment is feasible when sufficient antibiotic bioavailability
One randomized prospective trial from 2012 evaluated the is granted and when the antibiotic is tailored according to
effect of preoperative antibiotic treatment in 84 patients who pathogen susceptibility.
underwent delayed cholecystectomy. In this study, there were Patients who tolerate oral food intake may be treated with
no statistically significant differences regarding duration of oral antimicrobial therapy [26]. The selection of oral antimi-
hospitalization and rate of readmission between patients who crobial agents should be guided by susceptibility patterns of
received antibiotic treatment with amoxicillin/clavulanic acid the organisms identified [1, 7].
until discharge and those who received no antibiotic treat-
ment [23]. However, it should be noted that the chosen antibi-
otics are no longer recommended as monotherapy, and both Summary and Recommendations
the TG from 2013 and the guidelines by the SIS/IDSA still
recommend the initiation of antimicrobial therapy when in- Current guidelines for the management of acute cholangi-
fection is suspected. The data of one recently published paper tis and cholecystitis recommend the following procedures.
justify the use of broad-spectrum antimicrobial regimens for Due to a lack of evidence from well-designed studies all cur-
the empirical treatment of acute cholangitis in patients under- rent recommendations dealing with antimicrobial therapy are
going stent therapy to minimize the risk of a therapy failure mainly based on expert opinion.
before antimicrobial susceptibility testing is available [24]. Patients suspected of having acute cholangitis or cholecys-
For grade III cholangitis and cholecystitis, both guidelines titis should be admitted to a hospital. A clinical assessment
recommend antimicrobial regimes with antipseudomonal ac- should be performed for severity grading.
tivity for initial therapy as Pseudomonas aeruginosa could be Blood culture should be taken before initiating empiric an-
detected in approximately 20% of the patients in recent stud- tibiotic therapy and, whenever feasible, bile cultures should
ies [15, 22]. Additionally, Enterococcus sp. is an important be taken.
pathogen in patients with grade III community-acquired chol- Empiric, antibiotic therapy tailored according to clinical
angitis or cholecystitis. Therefore, vancomycin should be and epidemiological findings must get initiated early (<4
added in all cases of severe acute cholangitis or cholecystitis h).
to cover Enterococcus sp. [13, 14]. Adjunctive therapy (fluid management, pain management,
For all patients with a biliary-enteric anastomosis, coverage antipyretics) should be administered.
of anaerobic pathogens is recommended irrespective of the Drainage therapy must get offered early in the course of
severity of illness [1, 14]. illness, preferably by means of ERCP. For cholecystitis, de-
Treatment of healthcare-associated biliary infection should finitive surgical therapy must be evaluated from the
be based on an empirical antimicrobial treatment that in- beginning.
cludes agents with antipseudomonal activity. The TG13 ex- In mild cholecystitis, antibiotic therapy may be stopped
pand this recommendation to include empirical coverage 24 h after surgery.
against multidrug-resistant bacteria [1]. Empirical antibiotics should be tailored after the results of
Once results of susceptibility testing become available, susceptibility testing become available.
treatment should be narrowed. Antimicrobial therapy should be given for 47 days.
So far, no well-designed and randomized controlled trials
have evaluated the optimal treatment duration for commu-
nity-acquired and healthcare-associated cholangitis or chole- Disclosure Statement
cystitis. One observational study from 2013 showed that anti-
No financial disclosures or conflicts of interest.
microbial therapy for more than 4 days after urgent cholecys-
tectomy was not associated with fewer surgical site infections
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