Bile Duct Strictures 

Updated: Oct 16, 2019
Author: William R Brugge, MD; Chief Editor: Praveen K Roy, MD, AGAF 

Overview

Background

Bile duct stricture (also called biliary stricture) is an uncommon but challenging clinical condition that requires a coordinated multidisciplinary approach involving gastroenterologists, radiologists, and surgical specialists. Unfortunately, most benign bile duct strictures are iatrogenic, resulting from operative trauma[1] (see image below). Bile duct strictures may be asymptomatic but, if ignored, can cause life-threatening complications, such as ascending cholangitis,[2, 3] liver abscess, and secondary biliary cirrhosis.

Focal intrahepatic benign bile duct stricture afte Focal intrahepatic benign bile duct stricture after cholecystectomy.

However, not all bile duct strictures are benign. Pancreatic cancer and cholangiocarcinoma is the most common cause of malignant biliary strictures[4, 5, 6, 7] (see image below). Most of these patients die of complications of tumor invasion and metastasis rather than from the bile duct stricture per se. Nonetheless, both benign and malignant bile duct strictures can be associated with distressing symptoms and excessive morbidity.[8]

Endoscopic retrograde cholangiopancreatographic ch Endoscopic retrograde cholangiopancreatographic cholangiogram demonstrating an isolated mid-hepatic duct stricture as a result of pancreatic cancer.

For patient education resources, see Digestive Disorders Center and Infections Center, as well as Cirrhosis and Gallstones.

Pathophysiology

Strictures of the bile duct can be benign or malignant. Benign strictures develop when the bile ducts are injured in some way. The injury may be a single acute event, such as damage to the bile ducts during surgery or trauma to the abdomen; a recurring condition, such as pancreatitis or bile duct stones; or a chronic disease, such as primary sclerosing cholangitis (PSC). After the injury, an inflammatory response ensues, which is followed by collagen deposition, fibrosis, and narrowing of the bile duct lumen.

Periductal onion skin fibrosis seen in primary scl Periductal onion skin fibrosis seen in primary sclerosing cholangitis.
Periductal lymphocytic and plasma cell infiltrate Periductal lymphocytic and plasma cell infiltrate that is consistent with autoimmune cholangiopathy.

Depending on the nature of the insult, bile duct strictures can be single or multiple. Atrophy of the hepatic segment or lobe drained by the involved bile ducts, associated with hypertrophy of the unaffected segments, can occur, especially with chronic high-grade strictures. These changes can eventually progress to secondary biliary cirrhosis and the development of portal hypertension.

Malignant strictures are usually the result of either a primary bile duct cancer (ie, causing a narrowing of the bile duct lumen and obstructing the flow of bile) or extrinsic compression of the bile ducts by a neoplasm in an adjacent organ, such as the gallbladder, pancreas, or liver (see image below).

Endoscopic retrograde cholangiopancreatographic ch Endoscopic retrograde cholangiopancreatographic cholangiogram demonstrating a long bile duct stricture that represents external compression by gallbladder cancer.

Etiology

Bile duct strictures can be benign or malignant.

Benign biliary strictures

Benign bile duct strictures causes include the following:

  • Postoperative injury after cholecystectomy: Approximately 80% of benign strictures occur following injury during a cholecystectomy. Injury to bile ducts can occur during either laparoscopic or open cholecystectomy. Most strictures after a laparoscopic procedure are short and occur more commonly in the common hepatic duct (ie, distal to the confluence of the right and left hepatic ducts).

  • After open cholecystectomy, strictures are more common in the CBD. This phenomenon is likely due to the ease with which this area may be accessed by the laparoscope. Most iatrogenic injuries go unrecognized at the time of operation. Because of sepsis or peritonitis, the clinical status of the patient with an unrecognized biliary tract injury can deteriorate rapidly, thus early diagnosis is imperative.

  • The causes of benign bile duct strictures are usually surgical inexperience, failure to recognize abnormal biliary anatomy and congenital anomalies, acute inflammation, misplacement of clips, excessive use of cautery, and excessive dissection around the major bile ducts, resulting in ischemic injury. However, a significant proportion of strictures occur during operations described as simple and uneventful. Bile duct strictures can also occur as unexpected complications after other surgeries, such as gastrectomy, pancreatic surgery, or hepatic and portal vein surgery.

  • Pancreatitis: Jaundice due to an obstruction of the intrapancreatic segment of the CBD occurs in patients with chronic pancreatitis and accounts for approximately 10% of the benign strictures. Acute pancreatitis, pseudocyst, and pancreatic abscess are also uncommonly associated with the development of bile duct strictures.

  • Primary sclerosing cholangitis (PSC): PSC is a disease that causes strictures, beading, and irregularities of the intrahepatic and extrahepatic bile ducts. Approximately 70% of PSC cases are associated with inflammatory bowel disease. The extent and distribution of bile duct involvement is variable.

  • Human immunodeficiency virus (HIV) cholangiopathy: Patients with HIV cholangiopathy usually have advanced acquired immunodeficiency syndrome (AIDS) with CD4 lymphocyte counts less than 100/mm3 and poor long-term survival prognoses. Cryptosporidium and cytomegalovirus may be responsible for more than 90% of cases. Other causes of HIV cholangiopathy, occurring in fewer than 10% of patients, include microsporidia, Mycobacterium avium-intracellulare (MAI), Cyclospora, Isospora, and Cryptococcus. Most patients present with severe right upper quadrant pain, nausea, vomiting, and fever.

  • Orthotopic liver transplantation (OLT)[9, 10, 11, 12, 13] : Bile duct strictures usually occur 2-6 months after OLT. Anastomotic strictures are more common, with choledochocholedochostomy site strictures being more common than choledochojejunostomy site strictures. Hepatic artery ischemia after OLT also can present as an anastomotic stricture, a hilar stricture, or diffuse stricturing of the biliary tree. Other causes of strictures after OLT are ABO incompatibility, ischemia-reperfusion injury, and chronic allograft rejection.

  • A study by Sundaram et al investigated the relationship between biliary strictures and transplantation in the era of the Model for End-Stage Liver Disease (MELD).[14] The study concluded that even when using multivariate analysis to allow for other risk factors, transplantation in the post-MELD era is an independent predictor for stricture development. Further studies are needed to determine the etiology of this increase.

  • Mirizzi syndrome: This condition is observed in 1% of patients with cholecystectomies. Extrinsic compression of the common hepatic duct due to a gallstone impacted in the Hartmann pouch or cystic duct results in jaundice and cholangitis. Repeated episodes of inflammation can lead to formation of a stricture (type I) or pressure necrosis leading to the formation of a cholecystocholedochal fistula (type II).

  • Radiation[15, 16] : Bile duct strictures can occur as a late complication of radiation therapy to the upper abdomen for cancer or lymphoma, sometimes presenting many years after treatment.

  • Blunt abdominal trauma: This can lead to bile duct strictures, which usually have a delayed presentation.

  • Polyarteritis nodosa and systemic lupus erythematosus (SLE): These are autoimmune diseases involving small- to medium-sized arteries. They can present (rarely) as extrahepatic biliary obstruction secondary to biliary strictures.

  • Tuberculosis[17] and histoplasmosis: These conditions have rarely been reported to cause bile duct strictures in individuals who are immunocompetent.

  • Chemotherapeutic drugs: Hepatic artery infusion of 5-fluorodeoxyuridine (FdUrd, FUDR) or other chemotherapeutic drugs may cause bile duct strictures.

  • Sphincter of Oddi dysfunction or papillary stenosis: Patients usually present with biliary colic after cholecystectomy. The anomaly is in the smooth muscle surrounding the terminal portion of the CBD, with an abnormal basal sphincter pressure of greater than 40 mm Hg.

  • Choledochal cysts: Choledochal cysts are uncommon anomalies of the biliary system manifested by cystic dilatation of the extrahepatic biliary tree, intrahepatic biliary tree, or both. This condition is found most frequently in Asian persons and in females. Associated hepatobiliary complications include recurrent cholangitis, bile duct stricture, cholelithiasis, choledocholithiasis, and recurrent acute pancreatitis.

  • Recurrent pyogenic cholangitis: This condition (previously known as Oriental cholangiohepatitis) and hepatolithiasis are prevalent in Southeast Asia and present a difficult management problem. Recurrent pyogenic cholangitis is characterized by recurrent attacks of suppurative cholangitis with strictures and dilatation of bile ducts and numerous pigment stones in the intrahepatic and extrahepatic bile ducts. It is thought to be precipitated by an infestation of liver flukes and round worms. In the United States, this disease is observed mostly in Asian immigrants.

  • Inflammatory strictures: In addition to pancreatitis, choledocholithiasis can also cause chronic inflammation and fibrosis, leading to strictures of the CBD and sphincter of Oddi.

  • Endoscope-related strictures: Postendoscopic sphincterotomy stricture is possible.

  • Idiopathic: A few cases of idiopathic benign bile duct strictures have been reported.

  • Miscellaneous: Strictures have been described in association with duodenal diverticulum, Crohn disease, hepatic artery aneurysm, cystic fibrosis with liver involvement, eosinophilic cholecystitis, and cholangitis.

Malignant biliary strictures

Malignant causes of bile duct strictures include the following:

  • Pancreatic cancer: In the United States, adenocarcinoma of the pancreas is the most common cause of malignant biliary obstruction. Pancreatic cancer accounts for nearly 33,000 cases of cancer each year and has become the fifth leading cause of cancer mortality. Pancreatic cancer usually presents in the sixth and subsequent decades of life.

  • Mucinous cystadenocarcinoma: This pancreatic tumor may invade the bile duct and cause obstruction, which characteristically results in extrusion of mucin from the lumen.

  • Ampullary carcinoma: Adenocarcinoma of the ampulla of Vater usually arises from a benign adenoma. This condition is less common than pancreatic cancer, but symptoms of obstructive jaundice (80%) or pancreatitis are observed relatively early in its course. Both benign and malignant ampullary tumors can occur sporadically, or in the setting of genetic syndromes. The incidence of ampullary tumors is increased 200-300 fold in patients with hereditary polyposis syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC).

  • Gallbladder carcinoma: Extension of the cancer beyond the gallbladder can cause long bile duct strictures and obstruction, and it is a poor prognostic sign. In the United States, gallbladder cancer is the fifth most common gastrointestinal malignancy, with 6000 new cases each year. Gallbladder cancer occurs at a higher frequency in Native Americans and in people from Asia, Africa, and Latin America.

  • Cholangiocarcinoma: This cancer arises from the biliary epithelium and is usually seen in association with choledochal cysts, PSC, chronic ulcerative colitis, and infestation by liver flukes. Obstructive jaundice is the major clinical manifestation of cholangiocarcinoma. Cholangiocarcinoma is more common in the upper portions of the biliary tree (hilar or Klatskin tumor) than in the lower portions of the biliary tree (distal bile duct cancer), but it can also be diffuse in 10% of cases (see image below).

    Endoscopic retrograde cholangiopancreatographic im Endoscopic retrograde cholangiopancreatographic image of a cholangiocarcinoma at the bifurcation of the right and left hepatic ducts (Klatskin tumor).
  • For unclear reasons, the incidence of intrahepatic cholangiocarcinoma has been rising over the past 2 decades in Europe, North America, Asia, Japan, and Australia, whereas rates of extrahepatic cholangiocarcinoma are declining internationally.

  • Hepatocellular cancer: This is the most common primary liver malignancy. Hepatocellular cancer is the fourth leading cause of cancer-related death in the world and the third most common among men. Hepatocellular cancer is more common in the Far East than in the United States and is usually associated with cirrhosis resulting from hepatitis B or hepatitis C. The condition can present (rarely) with features of invasion of the extrahepatic biliary system as the predominant clinical manifestation.

  • Lymphoma and metastatic cancers to the liver and nodes in the porta hepatis: These cancers can sometimes be the cause of malignant bile duct strictures. Colorectal carcinoma, adenocarcinoma of the lung, pancreatic carcinoma, and renal cell carcinoma are the common tumors that metastasize to the liver. Metastatic porta lymphadenopathy may cause high-grade obstruction of the common hepatic duct.

Epidemiology

United States data

Although quite uncommon, the exact prevalence of bile duct strictures is unknown. One major category of bile duct strictures is postoperative bile duct stricture, which usually occurs as a result of a technical mishap during cholecystectomy, causing bile duct injury. Data from many large series of patients in the United States have revealed that the incidence rate of major bile duct injury is 0.2-0.3% after open cholecystectomy and 0.4-0.6% after a laparoscopic cholecystectomy.

International data

Data from Europe have shown a similar rate as that in the United States of occurrence of postoperative bile duct strictures.

Sex-related demographics

Data on the overall sex ratio of bile duct strictures are lacking. Some conditions causing bile duct strictures, such as PSC and chronic pancreatitis, are more common in men. The incidence of postcholecystectomy strictures is comparable in men and women.

Prognosis

The prognosis of patients with benign bile duct strictures is good. Patients who develop symptoms of biliary obstruction do well after surgical or endoscopic therapy.

Conversely, patients with HIV cholangiopathy or malignant biliary obstruction usually present at a late stage with widespread disease, and they generally have a dismal prognosis.

Morbidity/mortality

Bile duct strictures, independent of etiology, can cause significant morbidity from recurrent obstructive jaundice, right upper quadrant abdominal pain, biliary stones, and recurrent episodes of ascending cholangitis (see image below).

Multiple small bile duct stones seen on magnetic r Multiple small bile duct stones seen on magnetic resonance cholangiopancreatography (MRCP).

The major determinant of mortality in patients with bile duct strictures is the underlying disease condition. Patients with biliary strictures due to operative injury, radiation, trauma, or chronic pancreatitis generally have a good prognosis. Conversely, patients with bile duct strictures due to PSC and malignancy have a less favorable outcome.

Complications

Complications of bile duct strictures include development of stones in the gallbladder and bile ducts proximal to the stricture, pyogenic liver abscess due to recurrent episodes of ascending cholangitis, secondary biliary cirrhosis, and weight loss and malnutrition from steatorrhea, with fat-soluble vitamin deficiency.

Patient Education

Patients with biliary stents should be educated regarding how to recognize the symptoms of biliary obstruction and cholangitis that indicate blocked stents. Those with external drains should be taught how to flush their catheters until the catheters are internalized.

Patients with alcoholic chronic pancreatitis may benefit from counseling and alcohol abuse rehabilitation.

 

Presentation

History

In the absence of symptoms of the primary disease, most patients with bile duct strictures remain asymptomatic until the lumen of the bile duct is sufficiently narrowed to cause resistance to the flow of bile. Occasionally, patients may have intermittent episodes of right upper quadrant pain (biliary colic), with or without laboratory features of biliary obstruction. Patients most often present with features of obstructive jaundice. On occasion, a patient may present dramatically with sepsis and hypotension due to ascending cholangitis.

The clinical manifestations of obstructive jaundice may develop rapidly or slowly depending on the underlying cause. Patients may report right upper abdominal discomfort, pruritus, yellow discoloration of skin, and steatorrhea. With chronic cholestasis, xanthomas appear around the eyes, chest, back, and on extensor surfaces. Weight loss and deficiency of calcium and fat-soluble vitamins can occur. Patients also may report anorexia, nausea, vomiting, and cachexia. Insidious weight loss may suggest malignant obstruction.

Cholangitis occurs in the presence of partial or complete obstruction of the common bile duct (CBD), with increased intraluminal pressures, bacterial infection of the bile with multiplication of the organisms within the duct, and seeding of the bloodstream with bacteria or endotoxin. Cholangitis can rapidly become a life-threatening condition. Clinical presentation varies, with the Charcot triad of fever and chills, jaundice, and right upper quadrant abdominal pain occurring in most patients. A smaller proportion of those with cholangitis may also have altered mental status and hypotension (ie, Reynold pentad). In the absence of previous instrumentation, cholangitis is uncommon with malignant strictures.

The etiology of bile duct strictures is sometimes obvious at the time of presentation. In unclear cases, clues from the patient's history may help in making an accurate diagnosis. Most of the benign biliary strictures following injury during cholecystectomy go unrecognized at the time of surgery (in as many as 75% of cases). Presentation after more than 5 years may occur in 30% of cases; therefore, a history of recent or past cholecystectomy should be sought in all cases. Information about the postoperative period, especially excessive drainage from surgical wounds and drains and episodes of fever, jaundice, and abdominal distention, are important in patients presenting shortly after surgery.

A detailed history with emphasis on symptoms suggestive of pancreatitis, recurrent episodes of cholangitis, cholestatic disorders (eg, primary sclerosing cholangitis), hepatobiliary surgery,[9, 10, 11, 18, 12] trauma or radiation to the upper abdomen,[15, 16] alcohol abuse, intravenous drug use, or human immunodeficiency virus (HIV) infection[19, 20] should be obtained. This history provides valuable clues regarding the underlying disease and may prove useful in guiding management of patients with bile duct strictures.

Physical Examination

Asymptomatic patients with bile duct strictures may have unremarkable physical examination findings. Most patients with tight strictures have clinically apparent jaundice. Excoriations of the skin may be seen in patients with pruritus.

Patients presenting with cholangitis may also have fever and right upper quadrant tenderness in addition to jaundice (ie, Charcot triad), hypotension, and altered mental status (ie, Reynold pentad).

The presence of palmar erythema, Dupuytren contracture, gynecomastia, spider angiomas, ascites, and splenomegaly may suggest underlying cirrhosis and portal hypertension. A palpable, nontender gallbladder and jaundice are usually observed in patients with malignant obstruction. The presence of these symptoms is called the Courvoisier sign. An enlarged nodular liver may indicate malignancy involving the liver or a large right upper quadrant mass may indicate a malignancy involving the gallbladder. The presence of a friction rub or bruit may also suggest malignancy.

Patients with a major surgical injury to the bile duct and those with recurrent strictures and interventions may have evidence of a bile leak in the form of a biliary fistula, biliary peritonitis, or a biloma. These complications usually become evident early in the postoperative period but sometimes appear weeks to months later.

Attention should be given to the nutritional status of the patient. Features of fat-soluble vitamin deficiency may be present and should be sought.

 

DDx

Diagnostic Considerations

Patients presenting with acute ascending cholangitis should undergo urgent biliary drainage when an appropriate response to antibiotic therapy is not achieved or when the initial presentation is severe.

Other conditions to consider in patients with suspected bile duct strictures include the following:

  • Autoimmune cholangiopathy

  • Cholestasis associated with parenteral nutrition

  • Cholestasis associated with sepsis

  • Drug-induced cholestasis

  • Postoperative jaundice

  • Primary sclerosing cholangitis

  • Primary biliary cirrhosis

Differential Diagnoses

 

Workup

Laboratory Studies

Patients with partial bile duct obstruction have elevated serum alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (GGT, GGTP). The serum of patients with clinically apparent jaundice shows increases in total and conjugated bilirubin. Alkaline phosphatase levels are increased to more than 3 times normal. Elevated alkaline phosphatase levels are accompanied by increases in gamma-glutamyl transpeptidase and 5' nucleotidase, usually disproportionate to serum transaminase levels. Serum aminotransferase levels are usually less than 300 IU/mL.

The prothrombin time (PT) and international normalized ratio (INR) may be prolonged and can usually be normalized with parenteral administration of vitamin K. Total cholesterol and lipoprotein levels may be elevated in patients with chronic cholestatic disorders.

In malignant bile duct strictures with complete obstruction, the level of total serum bilirubin is generally much higher than that observed in benign strictures, and a bilirubin level of greater than 20 mg/dL is highly suggestive of malignant obstruction. Again, in malignant strictures causing only partial obstruction (eg, Klatskin tumor), a rise in the alkaline phosphatase level may not be accompanied by a rise in the bilirubin level.

Other laboratory abnormalities sometimes observed are anemia, elevated amylase and lipase levels, and an elevated erythrocyte sedimentation rate (ESR) and lactic dehydrogenase (LDH) level.

Several tumor markers may be helpful in the diagnosis of malignant bile duct strictures. A serum carbohydrate antigen 19-9 (CA19-9) value of greater than 100 U/mL is 55-65% sensitive for cholangiocarcinoma and gallbladder cancer.[21]

One study found that serum trypsinogen-2 is a useful marker for diagnosing patients with cholangiocarcinoma.[22] It is unclear whether trypsinogen-2 could be a new method to screen PSC or whether tumor marker combinations would be more useful. Elevated carcinoembryonic antigen levels may be present in 50-70% of cases of pancreatic cancer, and alpha-fetoprotein (AFP) levels are elevated in as many as 60% cases of hepatocellular carcinoma.

Imaging Studies

In patients presenting acutely with features of cholangitis, the initial radiologic study should be an urgent right upper quadrant ultrasonogram. If the ultrasonographic (US) examination findings show dilated bile ducts but do not provide clues to the site or cause of the obstruction, magnetic resonance cholangiopancreatography (MRCP) or abdominal computed tomography (CT) scanning should be performed next. In some patients, endoscopic retrograde cholangiopancreatography (ERCP) may be needed for definitive diagnosis and has the advantage of providing a therapeutic option as well (see images below).

Endoscopic retrograde cholangiopancreatographic im Endoscopic retrograde cholangiopancreatographic image of a cholangiocarcinoma at the bifurcation of the right and left hepatic ducts (Klatskin tumor).
Endoscopic retrograde cholangiopancreatographic ch Endoscopic retrograde cholangiopancreatographic cholangiogram demonstrating a long bile duct stricture that represents external compression by gallbladder cancer.
Endoscopic retrograde cholangiopancreatographic im Endoscopic retrograde cholangiopancreatographic image of a cholangiogram in a patient with cholangiocarcinoma whose condition has been treated with a metal stent.
Endoscopic retrograde cholangiopancreatographic ch Endoscopic retrograde cholangiopancreatographic cholangiogram of a solitary benign stricture of the distal bile duct. Resection demonstrated sclerosing cholangitis.
Endoscopic retrograde cholangiopancreatographic ch Endoscopic retrograde cholangiopancreatographic cholangiogram demonstrating an isolated mid-hepatic duct stricture as a result of pancreatic cancer.
Endoscopic retrograde cholangiopancreatographic ch Endoscopic retrograde cholangiopancreatographic cholangiogram demonstrating diffuse stricturing of the intrahepatic ducts that is consistent with primary sclerosing cholangitis.

Ultrasonography

Ultrasonography (US) is generally considered the imaging modality of choice for the initial screening of biliary disorders.[23] US does not use ionizing radiation to create the image, and it is the least invasive radiologic technique for imaging the biliary tract. The technique is portable, quick, and is the technique of choice in pregnant women and in patients with contrast allergies. US can help differentiate between intrinsic liver diseases and extrahepatic obstruction. Furthermore, US is more sensitive for detecting stones in the gallbladder.

US can accurately detect dilatation of intrahepatic and extrahepatic bile ducts, thus providing indirect evidence for the presence of bile duct strictures. However, US is less accurate for determining the etiology and level of obstruction.

Cholangiocarcinoma and PSC may cause biliary obstruction without ductal dilatation, and some benign strictures with partial obstruction may not be associated with biliary dilatation.

The sensitivity of US also depends on the degree of obstruction; it has been found to be 94% with a serum bilirubin level of greater than 10 mg/dL but only 47% with bilirubin levels of less than 10 mg/dL. The sensitivity increases with the serum bilirubin concentration and the duration of jaundice.

Computed Tomography Scanning

Spiral computed tomography (SCT) and multidetector CT (MDCT) scanning are highly sensitive for the diagnosis of biliary obstruction, particularly when these modalities are performed with oral and intravenous contrast agents.

Similar to US, CT scanning also helps detect intrahepatic and extrahepatic bile duct dilatation; however, the main value of CT scanning is its ability to detect the site of obstruction with greater accuracy than US and to help predict the cause of obstruction, especially malignant obstruction. CT scanning is rather insensitive for detecting stones in the common bile duct (CBD).

CT cholangiography scanning is another technique that rivals endoscopic retrograde cholangiopancreatography (ERCP) in delineating biliary tract abnormalities but has not achieved widespread use because of some adverse reactions to the contrast material.

CT scanning is superior to US in visualizing the distal CBD area, because gas artifacts may obscure this region when examined by US.

Other important areas that can be seen better on CT scans are the porta hepatis, pancreas, and liver parenchyma.

Magnetic Resonance Cholangiopancreatography

Since its introduction, magnetic resonance cholangiopancreatography (MRCP) has rapidly become an important tool for visualizing the biliary system.

MRCP takes advantage of the fact that bile has a high signal intensity on T2-weighted images, whereas the surrounding structures do not enhance and can be suppressed during image analysis.[24]

MRCP is as sensitive as ultrasonography (US) for helping detect cholelithiasis and is superior to US for helping diagnose common bile duct (CBD) stones, malignant biliary obstruction, and benign pancreatic disease (see image below).

Multiple small bile duct stones seen on magnetic r Multiple small bile duct stones seen on magnetic resonance cholangiopancreatography (MRCP).

The presence of biliary dilatation can be accurately detected by MRCP in 97-100% of patients. The level of obstruction is correct in almost 87% cases.

In one study, sensitivity for the detection of any abnormality was 89% and the specificity was 92%; for the detection of malignancy, sensitivity was 81% and specificity was 100%. These results were equivalent to the figures for ERCP (91% sensitivity and 92% specificity for any abnormality; 93% sensitivity and 94% specificity for malignant diseases). High-quality MRCP examinations require a high level of patient cooperation.

Bile duct calculi also appear as low signal intensity. CBD strictures and stones can be differentiated as a cause of obstruction in most cases.

MRCP is also very useful in helping identify cholangiocarcinoma, which characteristically appears as enhancement in delayed images. More importantly, MRCP provides valuable staging information because of its ability to help visualize the hepatic parenchyma and surrounding vascular structures in the same examination.

Benign strictures due to sclerosing cholangitis are multifocal and alternate with slight dilatation or normal-caliber bile ducts, producing a beaded appearance.

Dilatation of both the pancreatic and bile ducts using MRCP is highly suggestive of a pancreatic head malignancy. Side-branch ectasia is the most prominent and specific feature of chronic pancreatitis. Thus, MRCP provides a viable alternative to ERCP and allows imaging of the biliary tree when ERCP is unsuccessful; however, MRCP does not currently allow any intervention to be performed, such as stone extraction, stent insertion, or biopsy.

Hepatic Iminodiacetic Acid Scanning

A hepatic iminodiacetic acid (HIDA) scan is a radionuclide scanning technique commonly used for the diagnosis of acute cholecystitis and biliary leaks. HIDA scanning can help determine the clearance of bile across strictures and surgical anastomosis, thus providing a functional assessment of incomplete strictures and surgical anastomosis.

HIDA scanning is also useful for distinguishing cholangitis from cholecystitis. HIDA scan findings suggest complete biliary obstruction if the small intestine is not visualized in 60 minutes.

However, HIDA scans are insensitive for helping detect biliary dilatation or the site and cause of bile duct obstruction.

Other Tests

Cytology[25, 26]

Cytologic sampling is best performed by brushing the bile duct stricture during ERCP or percutaneous transhepatic cholangiography (PTC). Under optimal conditions and using a variety of techniques, cytology sampling can provide a cytologic diagnosis in 75% of cholangiocarcinomas and 50% of pancreatic carcinomas. The results in practice are more disappointing.

Routine cytology and histology yield a high specificity but low sensitivity for determining the etiology of bile duct strictures. Advanced cytologic techniques such as digital image analysis (DIA) and fluorescence in situ hybridization (FISH) identify chromosomal abnormalities and improve sensitivity while maintaining high specificity.

DIA and FISH enhance the accuracy of standard techniques in the evaluation of indeterminate bile duct strictures, allowing the diagnosis of malignancy in a substantial number of patients with false-negative cytology and histology. The sensitivity of FISH could improve the clinical management of patients being evaluated for malignant bile duct strictures by enabling a definitive diagnosis at earlier stages in the clinical evaluation.

Cytologic brushing of bile duct strictures is usually performed with wire guidance across the stricture. A plastic brush collects the cytologic specimen from the lining of the bile duct during an ERCP. There is little morbidity associated with brushing of the bile duct.

Histologic sampling of a bile duct stricture is performed with an unguided biopsy forceps. This technique is particularly effective for exophytic lesions.

Procedures

Endoscopic retrograde cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) has been used for the examination of the pancreaticobiliary region for more than 30 years and remains the criterion standard.

The endoscope used for ERCP is a side-viewing duodenoscope that has the capacity to control the direction of catheters as they exit the instrument channel of the scope. The endoscopist localizes the ampulla of Vater, which is on the medial wall of the second portion of duodenum; and the entrance to the bile and pancreatic ducts contained within the ampulla of Vater is then cannulated with specialized catheters. This is followed by injection of contrast media into the bile and pancreatic ducts under continuous fluoroscopic monitoring, with visualization of the anatomy of the intrahepatic and extrahepatic bile ducts and the pancreatic duct.

ERCP is a valuable technique in biliary disease because other diagnostic maneuvers (eg, sphincter of Oddi manometry) and therapeutic interventions (eg, stone extraction, biliary drainage, stent placement) can be carried out at the same time as the primary diagnosis. The success rate of ERCP is often 90-95%, with a complication rate of approximately 3-5%. The success rate of ERCP is decreased in the presence of a Billroth II, Whipple, or Roux-en-Y anatomy.

ERCP can help detect intrahepatic and extrahepatic biliary dilatation, stones, and the site of bile duct stricture with the highest sensitivity and specificity (both approximately 90-100%). ERCP findings are also valuable for helping differentiate malignant from benign biliary obstruction. Infectious causes of biliary obstruction can be diagnosed using collected bile samples or brushings.

Usually, ERCP is highly diagnostic for primary sclerosing cholangitis (PSC). ERCP findings show areas of irregular stricturing and dilatation (ie, beading) of the intrahepatic and extrahepatic biliary tree. However, the risk of cholangitis is greater in patients with PSC. Care should be taken to avoid poor biliary drainage after ERCP in patients with PSC.

ERCP is also the criterion standard for the diagnosis of AIDS-related cholangitis and is essential for differentiating PSC from AIDS-related cholangitis.

Nevertheless, ERCP is associated with significant complications, including pancreatitis, bleeding, perforation, infection, and cardiopulmonary depression from conscious sedation.

Endoscopic ultrasonography

Endoscopic ultrasonography (EUS) involves the use of echoendoscopes, which have an US transducer mounted at the end of a side-viewing or oblique-viewing endoscope.

The linear-array EUS system also has color Doppler capability, enabling the endosonographer to be able to differentiate between vascular and fluid-filled structures. The extrahepatic bile duct is readily imaged from the duodenum.

The instrument also has a small biopsy channel for fine-needle aspiration (FNA) and fine-needle injection.

The pancreas, common bile duct (CBD), and the gallbladder are in close proximity to the distal stomach and the duodenum and can be viewed. EUS can help detect choledocholithiasis, especially small stones, with a sensitivity of more than 95%.

EUS and EUS-guided FNA is a sensitive technique for the diagnosis and staging of cholangiocarcinoma and gallbladder, ampullary, and pancreatic cancer because it can also help detect the involvement of regional lymph nodes and vascular invasion by the tumor (an advantage over ERCP in this regard).

EUS is also superior to computed tomography (CT) scanning for tumor, node, and metastases (TNM) staging of luminal and pancreaticobiliary malignancies. Porta hepatis lymph nodes are particularly well seen with EUS, in contrast to the relative inability of CT scanning to evaluate the porta region.

In more recent years, EUS-guided biliary stenting has become possible with the availability of EUS-guided stents. EUS stenting is performed through the duodenal wall and into the bile duct. In Europe, a dumbbell metal stent is available.

Percutaneous transhepatic cholangiography

Since the 1960s, percutaneous transhepatic cholangiography (PTC) has been used for the diagnosis and treatment of biliary tract disorders.

The technique consists of introducing a 22- or 23-gauge needle through the skin in the right ninth or tenth intercostal space in the midaxillary line and advancing into the liver parenchyma under fluoroscopic guidance. Contrast material is injected while the needle is slowly withdrawn, until the bile ducts are opacified.

Indications for PTC in bile duct strictures are the presence of biliary-enteric anastomosis (eg, Roux-en-Y anastomosis with hepaticojejunostomy, choledochojejunostomy, Billroth II gastrectomy), the presence of complex hilar strictures, or when ERCP is unsuccessful. Both the right and left ductal systems can be accessed using this technique.

The success rate of PTC approaches 100% when ducts are dilated. This technique is used for complex intrahepatic strictures or when ERCP is not possible.

Therapeutic intervention, including biliary drainage, dilation of benign bile duct strictures, extraction of biliary tract stones, or placement of a stent across a malignant stricture also can be performed at the same time (see images below).

This image is an example of an intraoperative chol This image is an example of an intraoperative cholangiogram performed during a laparoscopic cholecystectomy.
Percutaneous transhepatic cholangiogram with ballo Percutaneous transhepatic cholangiogram with balloon dilation of a postoperative bile duct stricture.

Complications, including sepsis, bile leak, intraperitoneal hemorrhage, hemobilia, hepatic and perihepatic abscess, pneumothorax, and skin infection and granuloma at the catheter entry site, can occur in as many as 10% of cases.

PTC is contraindicated in patients with bleeding diatheses and significant ascites. Patients should be warned before the procedure about the possibility of external drainage.

Fistulography

In postsurgery patients with an external biliary fistula or T tube, contrast medium can be injected into the biliary system through the tube or the fistula. This outlines the intrahepatic and extrahepatic bile ducts and delineates the site of stricture and the anatomy of the fistula.

This study can precipitate cholangitis; therefore, patients should receive antibiotic prophylaxis.

Histologic Findings

Surgically resected segments of the biliary tree will show the etiology of the bile duct stricture. In benign lesions the involved segment of the bile duct is surrounded by a collar of fibrosis causing a narrowing of the lumen (see image below). This is accompanied by a variable amount of inflammatory cellular infiltrate comprising a mixture of neutrophils, lymphocytes, plasma cells, and eosinophils. The mucosa of the strictured segment usually is atrophic, with areas of squamous metaplasia.

Periductal onion skin fibrosis seen in primary scl Periductal onion skin fibrosis seen in primary sclerosing cholangitis.

In cholangiocarcinoma, there will be evidence of adenocarcinoma in the cross-sectional histology of the bile duct. In contrast, in autoimmune disease, the hallmark finding is dense lymphocytic and plasma cell infiltration (see image below).

Periductal lymphocytic and plasma cell infiltrate Periductal lymphocytic and plasma cell infiltrate that is consistent with autoimmune cholangiopathy.

Staging

Staging systems have been developed for bile duct strictures due to operative trauma, cholangiocarcinoma, and HIV disease. The choice of operative repair of a bile duct stricture depends on the location of the stricture. Strictures involving the common bile duct (CBD) and low common hepatic duct are easier to repair compared with strictures that are more proximal.

In 1982, Bismuth proposed an anatomic classification of bile duct strictures, based on the location, into the following 5 types:

  • Type 1: This is a low common hepatic duct stricture. At least 2 cm of the hepatic duct is intact.

  • Type 2: This is a mid common hepatic duct stricture. The hepatic duct stump is smaller than 2 cm.

  • Type 3: This is a hilar stricture. The common hepatic duct is not involved, but the confluence of right and left hepatic ducts is intact.

  • Type 4: In this type of bile duct stricture, the hilar confluence is destroyed. The right and left hepatic ducts are separated.

  • Type 5: The aberrant right sectorial duct is involved, alone or with the CBD.

The modified Bismuth and Corlette classification of hilar cholangiocarcinoma is the most widely adopted anatomic classification of this tumor. The following 4 types are recognized:

  • Type 1: The confluence of the hepatic ducts is not involved, but the tumor is generally within 2 cm of the hilum.

  • Type 2: The obstruction is limited to the confluence of the right and left hepatic ducts.

  • Type 3a: The confluence is involved, with extension of the tumor into the right hepatic duct.

  • Type 3b: The confluence is involved, with extension of the tumor into the left hepatic duct.

  • Type 4: The tumor is multicentric or extends into the right and left hepatic ducts.

Using endoscopic retrograde cholangiopancreatography (ERCP), four distinct patterns of human immunodeficiency virus (HIV) cholangiopathy have been described, as follows:

  • Papillary stenosis: This occurs in approximately 15-25% of patients. A smooth distal tapering of the CBD associated with proximal dilatation greater than 8 mm is present. Contrast is retained beyond 30 minutes.

  • Sclerosing cholangitis: This pattern is observed in 20% of patients and is characterized by focal strictures and dilatations involving intrahepatic and extrahepatic bile ducts. The caliber of the extrahepatic ducts is normal.

  • Combined papillary stenosis and sclerosing cholangitis: This is the most common pattern of HIV cholangiopathy and is observed in more than 50% of cases.

  • Long strictures of extrahepatic bile ducts: This pattern is observed in approximately 15% of patients. The strictures are 1-2 cm long and do not have features suggesting another cause, such as previous biliary surgery or pancreatitis.

 

Treatment

Approach Considerations

Patients with bile duct strictures who develop obstructive jaundice complicated by fever, infection, or duodenal obstruction are often admitted for urgent inpatient treatment of obstruction and/or infection.

Patients presenting with ascending cholangitis may need to be admitted to the intensive care unit, especially if they have altered mental status and hypotension. These patients should be started on broad-spectrum antibiotics with good gram-negative and anaerobic coverage.

In addition, urgent drainage and decompression of the biliary tree may be required when an appropriate response to antibiotic therapy is not achieved.

Patients with bile duct strictures amenable to endoscopic therapy can be treated in an inpatient or outpatient setting. Those requiring surgery generally have a longer hospital stay, especially in the postoperative period.

Medical Care

Medical treatment consists of managing complications of bile duct strictures until definitive therapy can be instituted. Most patients who present with cholangitis have a response to antibiotics and supportive management. Patients who are elderly and frail and those presenting with hypotension or altered mental status are best treated in an intensive care unit.

The common organisms that cause cholangitis are Escherichia coli and Klebsiella, Enterococcus, Proteus, Bacteroides, and Clostridium species. Empiric antibiotic therapy should be effective against these organisms.

Traditionally, a combination of a penicillin, aminoglycoside (gentamicin), and metronidazole has been the preferred regimen. Newer penicillins, such as piperacillin/tazobactam or imipenem/cilastatin, also have excellent activity against anaerobes, enterococci, and gram-negative cocci.

Approximately 70-80% of patients respond to medical therapy and do not need urgent intervention. Patients not having a response to empiric antibiotic therapy within 24 hours or those with hypotension requiring vasopressors, disseminated intravascular coagulation, or multiorgan failure should be considered for immediate biliary decompression, which can be performed surgically, percutaneously, or endoscopically. Endoscopic or percutaneous decompression is often associated with lower morbidity and should be considered first.

There is no special diet and no restriction on physical activity is required for patients with bile duct strictures.

Consultations

Obtain consultations with the following specialists:

  • Gastroenterologist

  • Surgeon

  • Infectious disease specialist

  • Interventional radiologist

  • Oncologist

Transfer

As noted above, management of bile duct strictures is a complex problem requiring a multidisciplinary approach. The patient should be in a specialized center where expertise in diagnostic and therapeutic ERCP and biliary interventional radiology is available. Surgical therapy should also be performed in centers with staff experienced in performing hepatobiliary and pancreatic surgery.

Surgical Care

Patients with cholangitis whose condition fail to improve with conservative treatment usually require urgent decompression of the obstructed biliary system. Treatment options for bile duct strictures include (1) endoscopic or percutaneous balloon dilatation and insertion of an endoprosthesis or (2) surgery.

Decompression of the biliary system

Decompression is usually performed endoscopically, with placement of a nasobiliary tube or stent after sphincterotomy.

Alternatives to endoscopic retrograde cholangiopancreatography (ERCP) are percutaneous transhepatic biliary drainage and surgical decompression. However, operative biliary decompression is associated with much higher morbidity and mortality compared with endoscopic therapy.

Endoscopic management

Benign biliary strictures (eg, postcholecystectomy, after liver transplantation) can be treated effectively with endoscopic therapy, which achieves a symptomatic and biochemical response in most cases.

Studies have shown that the long-term success rate of endoscopic stenting is comparable to that of surgery, with similar recurrence rates. Therefore, surgery should probably be reserved for those patients with complete ductal obstruction and for those in whom endoscopic therapy has failed.

Endoscopic therapy generally involves a sphincterotomy, which is performed at the first endoscopic session simultaneously with the placement of one or two 10F-12F stents across the area of obstruction. Dilatation of the stricture may be necessary if the stricture is too tight.

The insertion of a second stent may be possible only during a second endoscopy session. Thereafter, elective replacement of the stents seems desirable to prevent cholangitis secondary to stent occlusion because polyethylene stents generally clog in 3-4 months.

Sphincterotomy and endoscopic balloon dilatation

The combination of sphincterotomy and endoscopic balloon dilatation alone is not a reliable method of treating benign strictures.

Percutaneous treatment by balloon dilatation followed by short- to intermediate-term stent placement appears to provide a more durable result.

Endoscopic biliary stenting

This procedure is an alternative to surgery for the initial treatment of jaundice and cholangitis in patients with bile duct strictures due to chronic pancreatitis.

The morbidity and mortality rates associated with biliary stent insertion are low. Endoscopic therapy appears to be effective in this situation; however, the efficacy of this treatment in the long-term management of bile duct strictures from pancreatitis is limited by frequent stent blockages and migration and should be considered an alternative to surgery only in high-risk surgical candidates.

The role of metallic stents in this situation needs further evaluation. Opinions vary considerably regarding the clinical significance of bile duct strictures secondary to pancreatitis in asymptomatic patients and the appropriate treatment of these lesions. The low incidence of cholangitis and secondary biliary cirrhosis in association with asymptomatic bile duct strictures may justify a less aggressive approach.

In a multicenter, open-label, parallel, randomized clinical trial involving patients with treatment-naive, benign biliary strictures (N=112), investigators found evidence that fully covered, self-expandable metallic stents (cSEMS) are not inferior to multiple plastic stents in achieving biliary stricture resolution after 12 months. The cSEMS stricture resolution rate after no more than 12 months of endoscopic therapy was 50 of 54 patients (92.6%), compared with 41 of 48 patients (85.4%) for plastic stents. Furthermore, the mean number of endoscopic retrograde cholangiopancreatography procedures (ERCPs) to achieve stricture resolution was lower for cSEMS than for plastic stents.[27]

In an open-label, multicenter, randomized trial involving patients with confirmed anastomotic biliary strictures (ABSs), Tal et al found that patients who were treated with covered self-expandable metallic stents (cSEMS) required fewer endoscopic interventions for achieving similar efficacy as patients who were treated with multiple plastic stents (MPS). The initial treatment success rate was 95.8% (23/24) in the MPS group and 100% (24/24) in the cSEMSs group.[28]

Endoscopic therapy for PSC

Endoscopic therapy of primary sclerosing cholangitis (PSC) is palliative. The main goal is to improve pruritus and relieve jaundice before transplantation.

The treatment involves balloon dilatation of strictures, stone removal, and placement of plastic stents.

Endoscopic stent therapy is a safe and effective treatment modality for an acute exacerbation of disease caused by dominant extrahepatic bile duct strictures in patients with PSC. Stent therapy is generally not effective for multiple intrahepatic ductal strictures.

In carefully selected patients with PSC who do not have cirrhosis, resection and long-term stenting remain good options. Patients with cirrhosis should undergo liver transplantation.

The role of endoscopy in the treatment of secondary biliary stricture associated with conditions such as HIV infection remains undefined. These patients have advanced acquired immunodeficiency syndrome (AIDS); however, AIDS-related cholangitis per se rarely causes death. ERCP and sphincterotomy may help to relieve an individual patient's pain and improve the quality of life.

Endoscopic therapy for malignant strictures

The treatment of malignant bile duct strictures requires consideration of a number of factors, the most important being the extremely low survival and cure rates associated with the disease. Most patients die from malignant bile duct strictures within 6-12 months.

The primary objective in unresectable disease is to provide palliation of the jaundice. Given the morbidity and mortality associated with an operative procedure, nonoperative techniques of palliation are preferred.

Self-expanding metal stents provide effective palliation of malignant biliary strictures and should be considered as an alternative to open surgery.

Metallic stents, although more expensive and not removable once placed, remain patent longer than polyethylene stents; usually a single session of metal stenting can palliate biliary obstruction and, therefore, may be a better choice for the treatment of malignant strictures.

With tumors affecting the bifurcation of the hepatic ducts (Klatskin tumor, shown below), stents can be placed into both the right and left intrahepatic ducts to provide decompression. However, stent placement is technically more difficult in patients with proximal tumors.

Endoscopic retrograde cholangiopancreatographic im Endoscopic retrograde cholangiopancreatographic image of a cholangiocarcinoma at the bifurcation of the right and left hepatic ducts (Klatskin tumor).

Metal stents may become occluded as a result of tumor ingrowth through the open mesh design. A covered, self-expanding metal has been introduced in an effort to reduce the frequency of tumor ingrowth.

More recently, radiofrequency ablation of bile duct strictures has become possible with the introduction of a commercial radiofrequency ablation biliary probe. Ablation therapy may provide prolonged patency of strictures or stents.

Percutaneous transhepatic cholangioplasty and biliary stenting

Similar to endoscopy, the percutaneous balloon dilatation of benign (especially after orthotopic liver transplantation [OLT]) and malignant bile duct strictures and the insertion of plastic or metallic stents are also well tolerated by patients. The stents provide good drainage.

This procedure is executed in a few stages as the tract through the liver is dilated gradually to pass the optimal-size stent. The stent may be completely internalized, with one lumen in the duodenum and the other proximal to the stricture, or it may be an internal-external stent, with one lumen outside and one distal to the stricture.

Percutaneous therapy is associated with a 5-10% rate of major complications.

Operative treatment

Surgical management of benign bile duct strictures is necessary for patients with a low surgical risk in whom endoscopic therapy has failed. Surgical management consists of restoration of biliary enteric continuity, which usually is achieved with a defunctionalized Roux-en-Y jejunal loop by means of hepaticojejunostomy, choledochojejunostomy, or intrahepatic cholangiojejunostomy.

Biliary-enteric anastomosis is a safe, effective, and lasting therapy for biliary strictures. However, before definitive operative therapy for bile duct strictures is performed, patients must be stabilized and, if possible, biliary drainage should be achieved either endoscopically or percutaneously.

Patients with long-standing bile duct strictures due to pancreatitis may require pancreaticoduodenectomy. However, surgical drainage has been associated with considerable morbidity and mortality.

In patients with PSC without cirrhosis, resection of the extrahepatic bile ducts and long-term transhepatic stenting are alternatives to nonoperative dilation with or without stenting and may be associated with a better outcome.

Surgical therapy of malignant bile duct strictures consists of either attempting a curative resection of the tumor or performing a palliative operation. Unfortunately, the surgical cure rate of pancreatic, bile duct, and gallbladder carcinoma causing malignant strictures is dismal. Careful staging of the tumor should be performed in order to select patients who are likely to have surgically resectable disease.

Surgical intervention is recommended for patients who are otherwise healthy, whose disease appears to be localized, or in those with duodenal or gastric outlet obstruction.

Palliative surgery is directed toward relieving jaundice by creating a biliary-enteric anastomosis, and if a gastric or duodenal outlet obstruction is present or is a likely possibility, a gastrojejunostomy should be created at the same time. Although palliative surgery is effective in achieving its goal of circumventing the obstruction, no survival advantage has been described when compared with nonoperative techniques. Thus, for most patients, palliative surgery is not necessary.

Outpatient Care

Patients with bile duct strictures with percutaneous drains should have their catheters flushed with 5-10 mL of saline once or twice every day to prevent catheter blockage.

Patients should be monitored closely for recurrence of cholangitis and obstructive jaundice, which can occur if the biliary drainage catheters or stents are occluded or if they migrate.

Those treated with biliary stenting with plastic stents or balloon dilatation of bile duct strictures need periodic follow-up with a gastroenterologist or interventional radiologist for stent changes and periodic stricture dilatation.

Patients with external biliary drains should also seek follow-up with an interventional radiologist for catheter exchanges every 2-3 months for internalization of drains.

Those with a malignant obstruction treated with metallic endoprosthesis should be monitored with periodic liver function testing. Progressively abnormal liver function tests suggest stent dysfunction.

 

Medication

Medication Summary

The goals of pharmacotherapy in those with bile duct strictures are to eradicate the infection, prevent complications, and reduce morbidity.

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of this clinical setting.

Piperacillin and tazobactam sodium (Zosyn)

Antipseudomonal penicillin plus beta-lactamase inhibitor. Inhibits biosynthesis of cell wall mucopeptide and is effective during the stage of active multiplication.

Imipenem and cilastatin (Primaxin)

For the treatment of multiple-organism infections in which other agents do not have broad-spectrum coverage or are contraindicated due to potential toxicity.

Metronidazole (Flagyl, Protostat)

Imidazole ring-based antibiotic active against various anaerobic bacteria and protozoa. Used in combination with other antimicrobial agents (except for Clostridium difficile enterocolitis).

Gentamicin (Garamycin, Gentacidin)

Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.

Not the DOC. Consider if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms.

Dosing regimens are numerous; adjust the dose based on CrCl and changes in volume of distribution. May be given IV/IM.

Penicillin G (Pfizerpen)

Interferes with the synthesis of cell wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms.