22 Infections in Biliary Surgery

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271

INTRODUCTION

Although infection is not often the primary cause of disease in the biliary

system, it is a common complication. Obstructing conditions such as gall-

stones, benign strictures, or endoluminal or extraluminal bile duct malig-

nancies lead susceptible patients to develop infectious complications,

which are caused by microorganisms. Gram-negative aerobic organisms

(Enterobacteriaceae species), anaerobes, fungi, or a combination colonize

the biliary system and in settings of obstruction can cause cholangitis.

Biliary infections, also called infectious cholangitides, can manifest acutely

or more indolently. Local infections can lead to cholangitis and subsequent

liver abscesses that may spread hematogenously to cause septicemia or sep-

tic shock, requiring immediate endoscopic or surgical intervention . Bacteria

predominantly cause infectious cholangitides in the Western society, while

in other parts of the world parasites play a larger role in the development of

biliary tract infections. In the last 30 years, immunocompromised patients

(e.g., patients with AIDS or posttransplant) with viral cholangitides repre-

sent a more dicult population to treat by clinicians and surgeons.

It is well recognized that patients undergoing hepato-pancreatico-

biliary surgery are at risk for infectious complications that are not limited

to skin or intra-abdominal locations, but also within the biliary system and

the liver parenchyma, potentially leading to the development of pyogenic

liver abscesses. A very ne balance exists between the host defense mecha-

nisms and infections of the biliary system when obstructing lesions of the

biliary tree are addressed by endoscopic, percutaneous, or surgical means.

BACKGROUND

e biliary system and the liver represent a unique environment to protect

the human body from hematogenous dissemination of toxins, microorgan-

isms, and enteric pathogens delivered by the gastrointestinal system to the

liver. e inferior and superior mesenteric venous systems drain into the

portal vein, ultimately reaching the hepatic sinusoids where the blood is

detoxied before reaching the suprahepatic veins. Typically, bile within the

gallbladder and the biliary system is sterile in the absence of gallstones,

obstruction, or communication with the gastrointestinal tract via either

disease-driven stula or endoscopic or surgical interventions. It is the

presence of infected bile, or bacteribilia—secondary to gallstones, benign

and malignant obstruction, diagnostic or therapeutic interventions—that

cause infections in the hepatobiliary system.

BACTERIOLOGY

In patients with symptomatic gallstones or acute or chronic cholecysti-

tis, the incidence of positive bile cultures ranges between 11% and 30%.

Infections in Biliary Surgery

Massimo Arcerito and Rebecca M. Minter

Section III / Biliary272

Acute cholecystitis, often characterized by fever and leukocytosis,

m o

nstrates a higher rate of positive bile cultures as compared with

chronic cholecystitis (46% vs. 22%). Cholangitis secondary to endobiliary

stents, stones, or tumor presents with a positive bile culture in 100% of cases.

e most common bacteria isolated are of gastrointestinal origin, speci-

cally Escherichia coli (25% to 50%) followed by Klebsiella (15% to 20%) and

Enterobacter species (5% to 10%) are the most common Gram-negative spe-

cies. Anaerobes such as Clostridium perfringens and Bacteroides can also be

present but are more commonly observed in the setting of recurrent chol-

angitis or following hepatobiliary surgical interventions. Candida species

have been more often identied in the bile of critically ill patients. Achieving

adequate drainage of the biliary tree by treating the underlying obstruction

is critical for successful treatment, typically in conjunction with broad-spec-

trum antibiotic therapy covering both aerobic and anaerobic pathogens.

HOST DEFENSE MECHANISM

Physical, chemical, and immunologic properties are required to protect the

liver from invasion by pathogens and toxins. Table 22.1 represents the fea-

tures of the hepatobiliary host defense mechanism that function in a coor-

dinated fashion to prevent invasion by microorganisms within the biliary

system.

Division of the bile canaliculi from the bloodstream is required to

protect the biliary system from pathogen invasion by the vascular system,

and vice versa. is extraordinary property is provided by the hepatic tight

junctions. ese junctions are able to build a barrier between the biliary

channels and hepatic sinusoids. e liver is the core metabolic center in

humans and is responsible for fundamental physiologic functions includ-

ing fatty acid, amino acid, and carbohydrate metabolism; bile secretion;

and detoxication. Because of the highly vascularized nature of the liver

and its hepatocytes, a microvascular network is maintained in place by

the hepatic tight junctions. Deregulation of tight junction expression dis-

mantles the parenchymal network, causing liver disease and malignant

transformation. Hepatic tight junctions also represent a physical barrier

within the liver preventing ascending biliary infection. Any obstruction of

Defense Mechanisms

Physical Antegrade ow of bile into the duodenum

Sphincter of Oddi preventing reux of gastrointestinal

content into biliary system

Tight junctions between bile canaliculi and hepatic

sinusoids

Chemical Bile salts possess bacteriostatic and bacteriocidal

properties

Immunologic Kupffer cells phagocytose bacteria and bacterial

products and play a critical role in bilirubin

metabolism through phagocytosis of senescent

erythrocytes

IgA secreted by biliary epithelium

Fibronectin and complement (C3, C4, and Factor B)

play a critical role in opsonizing pathogens in liver

Hepatobiliary Host Defense Mechanisms

TABLE

22.1

Chapter 22 / Infections in Biliary Surgery 273

the portal vein, pre-, intra- or posthepatic, will cause portal hypertension

with the development of portosystemic shunts. ose shunts will bypass

the liver parenchyma and will allow the toxins and enteric pathogens to

reach the systemic circulation.

Additional physical features of the hepatobiliary system serve to pre-

vent ascending infection. Specically, the sphincter of Oddi that prevents

reux of enteric content into the biliary tree when bile ows antegrade into

the duodenum represents a dynamic physical barrier against ascending

biliary infection. After cholecystectomy, there may be a decreased force of

antegrade bile ow due to the loss of gallbladder contraction with retro-

grade reux of enteric contents leading to colonization of the biliary tree.

In addition, any surgical or endoscopic intervention on the biliopancreatic

sphincter (e.g., sphincterotomy, placement of endobiliary stent, or creation

of a biliary–enteric bypass) leads to loss of this physical barrier, permitting

direct reux of enteric content into the biliary tree. e mere presence of

bacteria in the bile does not always lead to infection; however, in the setting

of distal obstruction one must watch closely for signs and symptoms of an

ascending infection.

e second protective element in the host defense mechanisms is

the chemical component. Specically, the presence of bile salts in the bile

provides an excellent protection against enteric pathogens possessing both

bacteriostatic and bactericidal properties. Jaundice due to mechanical

obstruction of the bile duct leads to overgrowth of intestinal ora due to

the absence of bile and bile salts within the gastrointestinal tract, predis-

posing patients to develop cholangitis when the obstruction is treated with

endobiliary or surgical decompression. Fungal contamination of the bile is

commonly observed in patients with biliary obstruction. is fungal coloni-

zation is secondary to the absence of bile salts that also possess antifungal

properties, particularly against Candida albicans species.

e third protective element is the immunologic and humoral com-

ponent. e liver parenchyma contains several immunologic active cells

whose function is to alter and metabolize toxins coming from the gas-

trointestinal tract. Kuper cells represent the largest population of tis-

sue macrophages. Kuper cells possess Fc, C3, and scavenger receptors

that are known to phagocytize a wide variety of both opsonized and non-

opsonized materials including bacteria and bacterial products. In addi-

tion, Kuper cells play a dened role in bilirubin metabolism, controlling

infections in the biliary system. Approximately 75% of bilirubin is derived

from the breakdown of senescent erythrocytes by macrophages. Two iso-

enzymes HO-1 and HO-2 are involved in this process. HO-1, also known

as heat shock protein-32, is induced by stressors and is contained in the

endoplasmic reticulum and perinuclear envelope of Kuper cells in the

liver. Overall, Kuper cells are responsible for the removal of senescent

erythrocytes from the blood circulation by scavenger receptors. Depletion

of Kuper cells in the liver reduces HO-1 expression and bilirubin produc-

tion, predisposing to a variety of biliary infections. Liver resections also

reduce the presence of Kuper cells and therefore reduce their immuno-

logic eects in the liver initially following resection. Immunoglobulin A

(IgA), as part of the humoral component, is produced and secreted into

the hepatic system by the gallbladder and intra- and extrahepatic biliary

epithelium protecting against infectious pathogens. In addition, comple-

ment C3 and C4, factor B, and bronectin play a major role in opsonizing

pathogens and helping the biliary system to defend itself from the con-

tinuous exposure to pathogens. Any alteration of these defense mecha-

nisms predisposes to colonization and development of infection in the

hepatobiliary system (Table 22.1).

Section III / Biliary274

BILIARY OBSTRUCTION

e etiology of biliary obstruction can be secondary to intrinsic causes like

cholangiocarcinoma, choledocholithiasis, or ampullary stenosis, extrinsic

causes like periampullary or pancreatic neoplasia or pancreatitis involving

the distal portion of the bile duct, or functional causes such as sphincter

of Oddi dysfunction. e use of endobiliary stents can often resolve the

obstruction, but predisposes the patient to develop biliary infection due

to the communication this creates with the gastrointestinal tract. In the

presence of biliary obstruction, the lack of bile ow is considered to be

a primary cause of bacterial overgrowth in the biliary system. Likewise,

obstruction leads to biliary hypertension with subsequent breaking down

of the hepatocyte tight junction and development of cholangiovenous

reux. is phenomenon allows the gastrointestinal endotoxins to colo-

nize the biliary–portal system and can lead to the formation of pyogenic

liver abscesses or biliary sepsis. e absence of bile salts with their bacte-

riostatic and bacteriocidal properties, which occurs in the setting of biliary

obstruction, leads to an increase in the number of enteric pathogens in the

intestinal tract.

No one clearly delineated mechanism denes how biliary obstruction

specically predisposes one to infectious complications. One theory sug-

gests that Kuper cell metabolism is diminished in the presence of biliary

obstruction. is leads to bacterial overgrowth with inability of the exist-

ing Kuper cells to clear the bacteria and bacterial products adequately.

Bacteria can then translocate to the systemic circulation through the

hepatic–sinusoid tight junctions. In addition, IgA production is limited by

biliary obstruction. Clinically, the presence of bacteria in the biliary tree

does not translate into cholangitis, but the combination of biliary obstruc-

tion and increased pressure in the biliary system determines a cascade of

events that can often lead to acute cholangitis.

INFECTIONS IN BILIARY SURGERY

Human bile is typically sterile but may become infected in the presence of

gallbladder and common bile duct stones or intrinsic or extrinsic inam-

matory or neoplastic diseases leading to obstruction. e pathophysiology

of infection is due either to translocation of intestinal pathogens via the por-

tal system or more commonly due to biliary intervention with incomplete

drainage. Any invasive endoscopic, radiologic, or surgical procedure on the

hepatobiliary system interferes with the usual host defense mechanism,

and the introduction of an indwelling biliary stent through any means con-

stitutes a foreign body within the biliary system. Biliary–enteric anastomo-

sis, sphincterotomy and sphincteroplasty, disruption of blood supply either

locally to the liver and biliary tree or systemically (shock), blood transfu-

sions, and the immune status of the patient are all additional important

contributors to the development of an ascending biliary infection.

Hepatic resection can also predispose to the development of bili-

ary infections. It is mandatory to analyze the hepatic reserve in patients

undergoing resection of hepatic parenchyma, particularly in those who

will require a bilioenteric anastomosis such as in the setting of cholan-

giocarcinoma. e reticuloendothelial system immunologic function is

reduced after hepatic resection secondary to loss of functional liver mass.

Increasingly, preoperative portal vein embolization is being utilized in prep-

aration of planned extended hepatic resection to provide sucient post-

operative hepatic metabolic and host defense function by inducing growth

of the planned hepatic remnant. A recent Cochrane review of 521 patients

evaluating the use of perioperative antibiotics, duration of antibiotics, and

Chapter 22 / Infections in Biliary Surgery 275

use of probiotics did not identify any clear predictors of morbidity or mor-

tality related to postoperative infectious complications for these variables.

ACUTE ASCENDING CHOLANGITIS

Cholangitis is caused by an acute bacterial infection of the bile duct. In

1877, Charcot rst described the triad of fever, jaundice, and right upper

quadrant pain. When shock and altered mental status are included in the

classic clinical scenario, it is referred to as Reynolds pentad. e develop-

ment of cholangitis requires biliary bacterial contamination, stagnant bile,

and increased intrabiliary pressure (>20 cm H

O). Cholangitis is a serious

medical problem; mortality ranges between 3.5% and 65%. Interestingly, the

severity of acute cholangitis has been shown to correlate with intrabiliary

pressure. e most common cause of cholangitis is partial biliary obstruc-

tion. Complete obstruction is less likely to be associated with bacterobilia

and therefore is less likely to present as cholangitis. Elevated biliary pres-

sure increases biliary ductule permeability, allowing pathogens to enter the

bloodstream. Two decades ago, the most common cause of acute cholan-

gitis was choledocholithiasis. In more recent years, other causes of chol-

angitis have increased, including altered biliary anatomy due to surgical

intervention and instrumentation of the biliary tree. Malignancy accounts

for 10% to 30% of all cases of cholangitis. Bile cultures are polymicrobial in

30% to 80% of patients who have undergone placement of endobiliary stents

or biliary–enteric anastomosis; these patients often are colonized with anti-

biotic-resistant organisms. e most common aerobic isolated organisms

in culture from these patients are E. coli, Klebsiella, Enterococcus species;

Enterobacter, Pseudomonas, Serratia and Proteus species, and Bacteroides

fragilis are the most common anaerobic enteric pathogens. C. albicans is

the most common fungus in bile cultures in patients who have undergone

biliary manipulation.

e diagnosis of acute cholangitis is made based upon clinical pre-

sentation. All patients must be aggressively resuscitated and started on

broad-spectrum antibiotics immediately. Blood cultures are obtained at

presentation, and bile cultures are also obtained as soon as possible to

guide antibiotic therapy. Initial antibiotic coverage is broad and is tailored

to the severity of the clinical presentation, the patient’s history of prior anti-

biotic usage, hepatic and renal function, allergies, and any prior culture

data. Typically, community-acquired cholangitis is more commonly asso-

ciated with a single biliary organism (most commonly Klebsiella, E. coli, or

Enterococcus), and treatment with a short course (3 to 5 days) of a penicillin/

β-lactamase inhibitor combination (e.g., piperacillin/tazobactam or ampi-

cillin/sulbactam) is usually eective. Patients presenting with greater

clinical severity often have anaerobic bacteria contributing to the infection,

and patients in the hospital may have infection due to resistant and/or mul-

tiple organisms such as Pseudomonas, methicillin-resistant Staphylococcus

aureus, and vancomycin-resistant enterococci. Antibiotic choice must be

tailored to address these conditions. Patients presenting with moderate

or severe cholangitis should also be treated with intravenous penicillin/

β-lactamase inhibitors; however, if resistant organisms are suspected then

the addition of appropriate antibiotics for methicillin-resistant bacteria like

vancomycin or daptomycin for coverage of suspected vancomycin-resistant

Enterococcus should be added. Double coverage for Pseudomonas should

also be considered if the infection is occurring in a hospitalized patient

who is not responding to rst-line therapy. If the patient does not respond

to the initial antibiotic choice, then addition of uoroquinolones and car-

bapenems should be considered along with antifungal coverage. Antibiotics

Section III / Biliary276

should be continued a minimum of 7 days for moderate to severe cases of

cholangitis; however, the clinical context, culture data, and response of the

patient will ultimately dictate the choice and length of antibiotic course

required (Table 22.2).

Drainage of the biliary tree is a central tenet to the treatment of

ascending cholangitis, and must occur as soon as possible in a patient with

sepsis secondary to ascending cholangitis. us, following administration

of antibiotics and initiation of resuscitation and necessary supportive care,

either endoscopic retrograde cholangiopancreatography (ERCP) or percu-

taneous transhepatic cholangiography (PTC) is the next step in manage-

ment. If the patient presents with hemodynamic instability or respiratory

compromise, then appropriate supportive management must be initiated

prior to transporting the patient for a planned biliary drainage procedure.

Endoscopic decompression is preferred; however, PTC drainage may be

necessary if endoscopic decompression of the biliary tree is not possible. If

a patient presents with a clinical picture of ascending cholangitis and has

an indwelling biliary stent, then this stent and the biliary tree should be

interrogated to ensure that there is complete drainage of the biliary system

and that the stent is functioning and is not occluded. Plastic indwelling bili-

ary stents require replacement approximately every 8 to 12 weeks (depend-

ing on stent diameter and number of stents) to prevent occlusion. Metal

biliary stents (typically only placed in patients with biliary obstruction sec-

ondary to advanced malignancy) are larger in diameter and have a lower

incidence of occlusion; however, sludge and stones can develop within and

above these stents leading to the development of cholangitis. Endoscopic

and percutaneous intervention is then required to achieve drainage of the

biliary system. If the underlying cause of the cholangitis is choledocholi-

thiasis, then clearance of the biliary system can also typically be accom-

plished with either endoscopic or percutaneous interventions to clear the

Clinical Severity Antibiotic Selection

Duration of

Treatment

Mild (Community

Acquired)

Pipericillin/tazobactam or ampicillin/

sulbactam

3–5 d

Moderate/Severe

Pipericillin/tazobactam and

metronidazole (rst-line)

Addition of carbapenems or

uoroquinolones, and Fluconazole

if fail to respond clinically

Minimum 7 d

Hospital Acquired/

Resistant

Organisms

Anticipated

Pipericillin/tazobactam and

metronidazole (rst-line)

Addition of carbapenems or

uoroquinolones, and Fluconazole

if fail to respond clinically

Addition of Vancomycin for methicillin-

resistant S. aureus, daptomycin for

vancomycin-resistant Enterococcus,

or additional anti-Pseudomonas

coverage should also be considered

Minimum 7 d

Antibiotic regimen should be narrowed once culture data are available.

Course will be determined based upon clinical context and response to therapy.

Antibiotic Choice for Treatment of Acute Cholangitis

TABLE

22.2

Chapter 22 / Infections in Biliary Surgery 277

common bile duct, or if a stone is impacted to drain the biliary tree either

internally or externally with a biliary stent. Operative intervention is rarely

the rst-line therapy for biliary drainage as endoscopic and percutaneous

drainage have lower morbidity and mortality and can usually be achieved

in a timely manner. If, however, these modalities of biliary drainage are not

available for a decompensating patient with severe ascending cholangitis,

then operative decompression of the biliary tree should be pursued.

ACUTE CHOLECYSTITIS

Acute cholecystitis represents sudden inammation of the gallbladder, and

is typically associated with severe right upper quadrant pain, fever, and leu-

kocytosis. Usually, this disease is secondary to cholelithiasis with the acute

development of an impacted stone at Hartmann’s pouch or the cystic duct

in the majority of patients (90% to 95%). Acalculous cholecystitis presents

in a similar manner to acute cholecystitis without gallstone involvement

and usually occurs in critically ill patients representing approximately 10%

of acute cholecystitis cases. Infected bile might play a role in the develop-

ment of acute cholecystitis; however, many patients with acute cholecysti-

tis do not have infected bile. Csendes et al. analyzed 467 patients with bile

samples obtained for aerobic and anaerobic culture from healthy control

patients and patients with various biliary diseases including acute chole-

cystitis, cholelithiasis, and gallbladder hydrops. Only 22% to 46% of patients

with the included biliary diseases had a bile culture that was positive for

aerobic or anaeroboic organisms. Healthy control patients had sterile bile

as would be expected.  e most common isolated organisms in the bile were

E. coli, Enterococcus species, Klebsiella, and Enterobacter. Complications of

acute cholecystitis include gallbladder empyema, perforation, and emphy-

sematous cholecystitis. Clinically, any prolonged right upper quadrant pain

associated with leukocytosis with or without fever should trigger an evalu-

ation for cholecystitis. Abdominal ultrasound and radionuclide scintigra-

phy represent the two primary diagnostic tests to conrm the diagnosis.

Ultrasound will show the presence of gallbladder wall thickening usually

in the presence of gallstones with pericholecystic uid, while radionuclide

study will demonstrate uptake of the radiotracer by the liver with excretion

into the common bile duct and duodenum within 1 to 2 hours without lling

or visualization of the gallbladder. Failure to visualize the gallbladder with

radionuclide tracer simply conrms obstruction of the cystic duct but does

not conrm a diagnosis of acute cholecystitis. However, it can be useful for

dierentiating symptomatic cholelithiasis from cholecystitis in the setting

of operative decision making.

If a diagnosis of acute cholecystitis is suspected, the role of antibiotic

therapy is debated. Antibiotic therapy is not recommended beyond rou-

tine perioperative antibiotics for uncomplicated acute cholecystitis. e

Infectious Disease Society of America currently recommends that antibiot-

ics should be administered for acute cholecystitis in the setting of a leuko-

cytosis exceeding 12,500 WBC/mm

, fever greater than 38.5 C, suggestion

of emphysematous cholecystitis manifest as evidence of air in the wall of

the gallbladder, and in elderly, diabetic, or immunocompromised patients.

ese patients should receive intravenous antibiotics with piperacillin/

tazobactam or a second- or third-generation cephalosporin with duration

tailored to clinical improvement.

Laparoscopic cholecystectomy is typically performed as deni-

tive management of acute cholecystitis unless the patient is felt to have

prohibitive operative risk. In these high-risk patients, percutaneous cho-

lecystostomy can be performed in radiology under ultrasound guidance

Section III / Biliary278

and local anesthesia for management of their cholecystitis. Patients with

uncomplicated acute cholecystitis who do not undergo denitive opera-

tive management will usually see resolution of their symptoms 5 to 7 days

after presentation. Cholecystectomy is typically delayed in these settings

to 6 weeks or greater following their initial presentation; however, this

delay in intervention is associated with an increased conversion rate to

an open procedure of approximately 15% to 20% in most recent series.

Acute cholecystitis can present with severe complications including

gallbladder empyema, emphysematous cholecystitis, and perforation of the

gallbladder. Gallbladder perforation is a rare occurrence (5%) in the set-

ting of acute cholecystitis and can occur within a few days or few weeks

of a patient’s presentation with acute cholecystitis. Presenting symptoms of

these serious complications are more severe than the usual presentation of

acute cholecystitis, and prompt surgical intervention is mandatory to pre-

vent signicant morbidity or mortality.

CONCLUSIONS

Physical, chemical, and immunologic properties of the liver and biliary

system characterize the host defense mechanisms protecting the hepa-

tobiliary system from infectious organisms. Although infection is not

often the primary cause of biliary tract disease, it is a common complica-

tion. Many patients with gallstones obstructing the biliary tree develop

infectious complications caused by normal gastrointestinal ora such as

Enterobacteriaceae, Klebsiella, E. coli, and B. fragilis. Local infection can

result in cholangitis and pyogenic liver abscesses or invade the bloodstream

causing bacteremia, septicemia or septic shock. Removing the underlying

obstruction in the biliary tree is a prerequisite to successful therapy. Broad-

spectrum antibiotics, covering both aerobes and anaerobes, are almost

universally utilized. Acute cholecystitis and acute cholangitis can be a pri-

mary infection due to gallstones or could be a secondar y event due to endo-

scopic, radiologic, or surgical instrumentation to the biliary tree. Treatment

of systemic infection, resuscitation, and treatment of the underlying source

of infection with either cholecystectomy or gallbladder drainage in the set-

ting of acute cholecystitis or relief of biliary obstruction in the setting of

acute cholangitis are critical to the successful treatment of patients pre-

senting with these conditions.

Gallbladder Disease

Henry A. Pitt

Section III / Biliary280

aggregate to form large multilamellar liquid vesicles that then precipitate

cholesterol monohydrate crystals. Several pronucleating factors includ-

ing mucin glycoproteins, immunoglobulins, and transferrin accelerate the

precipitation of cholesterol in bile.

For gallstones to cause clinical symptoms, they must obtain a size suf-

cient to produce a mechanical injury to the gallbladder or obstruction of

the biliary tree. Growth of stones may occur in two ways: (a) progressive

enlargement of individual crystals or stones or (b) fusion of individual crys-

tals or stones to form a larger conglomerate (Fig. 23.1A). In addition, defects

FIGURE 23.1 A. Pure cholesterol gallstones. B. Cholesterol gallstones

with calcium.

(Continued)

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