Infections of the Liver and Biliary System (, 75 Cholangitis, ) Costi D. Sifri and Lawrence C. Madoff

SHORT VIEW SUMMARY

Definition regions. They affect men about 10 times more } Amebic liver abscesses are caused by invasive } A is the end result of a frequently than women. strains of histolytica. Tens of millions in the United States have number of pathologic processes resulting in a } Diagnosis focal, purulent bacterial collection in the liver. ; 1% to 3% are complicated by } Symptoms are often nonspecific, and a high An amebic liver abscess is an invasive acute cholecystitis. } index of suspicion is required. complication of intestinal amebiasis resulting } Approximately 120,000 cholecystectomies } Diagnostic imaging, especially by in a focal collection of nonpurulent fluid in the occur each year in the United States. ultrasonography, radionuclide liver. } Between 2% and 15% of cases occur without cholescintigraphy, computed tomography, or Cholecystitis is inflammation/bacterial infection gallstones, known as “acalculous } magnetic resonance imaging, is essential. For of the gallbladder often resulting from cholecystitis.” pyogenic liver abscesses, it is often coupled obstructing gallstones. Acalculous cholecystitis } In endemic regions, parasites such as Ascaris with diagnostic/therapeutic aspiration. is a similar process in the absence of and Clonorchiss may cause biliary disease. Therapy gallstones. Microbiology } Cholangitis is inflammation/infection of the } Some pyogenic processes require prompt } Pyogenic liver abscesses may be bile ducts. recognition and urgent image-guided drainage monomicrobial, especially when caused by or definitive surgery. Epidemiology bacteremia, or polymicrobial, involving aerobic } Antibiotics directed at the suspected An estimated 1 to 4 cases of pyogenic liver gram-negative bacilli and anaerobes. } pathogens play an important role as adjuncts abscess occur per 100,000 persons each year. } Hypermucoviscous Klebsiella pneumoniae to surgery, or, in limited cases, they may be the Amebic liver abscesses are rare—about 1 case (typically K1 and K2 strains) are now an } sole form of therapy, (e.g., small pyogenic liver per million persons annually in the United important cause of pyogenic liver abscess, abscesses [see Tables 75.4 and 75.6], amebic States—but are more common in endemic particularly in parts of Asia but increasingly liver abscess). elsewhere.

LIVER ABSCESS exceed the rate of E. disparr colonization.4–11 In addition, other Entamoeba LiverLiver abscesses fall bbroadlyroad into two categories: amebic and pyogenic. species have been identified; these include Entamoeba moshkovskii, Amebic liver abscess represents a distinct clinical entity caused by invasive which causes noninvasive , and Entamoeba bangladeshi, which infection. It has a distinct pathogenesis that is is of unknown virulence. Because these species are indistinguishable characterized by the specific induction of hepatocyte apoptosis by the by light microscopy, the presence of Entamoeba in the stool is not organism. Further discussions of the epidemiology, genetics, and biology sufficient to establish the cause of a liver abscess. Men and women of E. histolytica and of intestinal amebiasis can be found elsewhere in experience equivalent rates of E. histolytica infection, but adult men this volume (see Chapters 98 and 272). Pyogenic liver abscess, by contrast, are at a 10-fold higher risk for invasive disease ( or extracolonic does not represent a specific but is the end result of a disease) than other populations.12 The reason for this disparity remains number of pathologic processes that cause a suppurative infection of uncertain, although gender differences in complement-mediated killing the liver parenchyma. of E. histolytica and cytokine responses to amebic liver infection have been proposed.13,14 In addition, testosterone has been shown to be a Epidemiology/Etiology risk factor for the development of amebic liver abscesses in experimental Amebic Liver Abscess animals.15,16 In the United States, amebic liver abscess has become a rare disease that is found almost exclusively in travelers and immigrants. In 1994, Pyogenic Liver Abscess the last year in which incidence data were collected, there were only The incidence of pyogenic liver abscess is about 1 to 4 cases per 100,000 2983 cases of amebiasis; the percentage of cases complicated by abscess individuals annually in the United States and Europe.17–20 This incidence is unknown, but it is probably well under 10%, roughly 1 case per has been relatively stable, with a slight increasing trend in more recent million persons per year.1 Worldwide, contamination of food and drinking case series that may reflect changes in the true incidence or improved water has maintained E. histolytica infection second only to malaria as detection.19 In Asia, the incidence of pyogenic liver abscess may be 5- to a cause of death from . The epidemiology of this disease 10-fold higher and is associated with the emergence of community- has been greatly informed by the appreciation that a closely related acquired Klebsiella pneumoniae infection.21,22 Pyogenic liver abscess is nonpathogenic species, Entamoeba dispar, colonizes between 5% and a disease of middle-aged persons, with a peak incidence in the fifth 25% of persons.2,3 E. disparr has no apparent propensity for invasive and sixth decades of life; this pattern mirrors the prevalence in the disease, even among patients with acquired immunodeficiency syndrome population of biliary disease, which is now the major cause of pyogenic (AIDS). In industrialized countries, most asymptomatic individuals liver abscess. No significant sex, ethnic, or geographic differences seem to with Entamoeba in their stool are colonized with E. dispar, whereas in exist in disease frequency, in contrast to the epidemiology of amebic liver highly endemic regions, asymptomatic infection with E. histolytica may abscess. About one-half of patients have a solitary abscess. Right-sided 1037 1038 abscesses are most common, followed by left-sided abscesses and then 1. Biliary tree. Cholangitis (discussed later) is now the major abscesses involving the caudate lobe. This distribution probably reflects identifiable cause of pyogenic liver abscess. In such cases, the relative mass of each lobe, although more complicated explanations, multiple abscesses are usually present and anaerobes are s such as patterns of hepatic blood flow, have been proposed. infrequent. The underlying biliary obstruction is usually a result of disease, but it can also be caused by an Pathogenesis and Pathophysiology obstructing tumor, an occluded stent, overwhelming ndrome y Amebic Liver Abscess cryptosporidiosis, or Ascaris lumbricoides migration into the Infection with E. histolytica results from ingestion of in fecally biliary tree. contaminated food or water. Excystation occurs in the intestinal lumen, 2. Hepatic artery. Any systemic bacteremia (e.g., endocarditis, and trophozoites migrate to the colon, where they adhere by means of line sepsis) can spread to the liver via this route. Patients who a lectin that specifically binds galactose N-acetyl-d-galactosamine (the die of overwhelming sepsis frequently have extensive or Clinical S j Gal/GalNAc lectin) on colonic epithelium and multiply by binary microabscess formation in their livers at autopsy, but fission.23,24 At high densities, trophozoite encystation is initiated, and macroscopic liver abscess formation in patients who recover Ma

I newly formed cysts are released into the stool to complete the life cycle. from septic shock is uncommon, underscoring the capacity of Most individuals experience asymptomatic infection, but approximately the liver to clear even large insults. art I 10% develop symptomatic colitis when invasion of the colonic mucosa 3. Portal vein. The portal venous system drains almost all of the P occurs. Spread to the liver via the portal system occurs in less than 1% abdominal viscera. Pylephlebitis from , of cases.2 A number of virulence factors have been implicated in the , omphalitis, inflammatory bowel disease, or development of amebic liver abscess, including small proteins (amoe- postoperative infection can result in pyogenic liver abscess. bapores) that punch holes in lipid bilayers of target cells, cysteine Untreated was historically a major cause in this proteases, and the Gal/GalNAc lectin.25–31 E. histolytica induces apoptosis category but was greatly diminished in importance with the in hepatocytes and , forming large, nonpurulent, “anchovy introduction of antibiotics. paste” abscesses that grow inexorably without treatment.32,33 The 4. Direct extension from a contiguous focus of infection. This may mechanism by which E. histolytica induces apoptosis is unknown, but occur with cholecystitis or subphrenic, perinephric, or other its importance is underscored by the resistance of caspase-3–deficient intraabdominal abscesses. mice to amebic liver abscess formation.34,35 Recently, an E. histolytica 5. Trauma. Any penetrating trauma to the liver, even as subtle surface protein that participates in apoptotic corpse phagocytosis, the as ingestion of a toothpick, can result in abscess formation. phagosome-associated transmembrane kinase (PATMK), was shown Blunt trauma can also predispose to pyogenic liver abscess to be required for intestinal amebiasis in a murine infection model; formation, presumably because of hepatic hematoma however, PATMK was found to not contribute to the development of formation and subsequent increased risk of seeding by experimental amebic liver abscess.36 By contrast, amoebapore expression bacteria. Similarly, hepatic destruction from sickle cell disease, was found to be required for the formation of liver abscesses but not tumor necrosis (either spontaneous or following iatrogenic amebic colitis.29 These findings suggest that the contribution of particular embolization), or can predispose to abscess amebic virulence factors to pathogenesis may be tissue specific, and formation. many of these factors have been recently reviewed.37 Host factors that predispose to abscess formation from “routine” Predisposition to liver disease is influenced by host genetics. In hepatic bacterial insults may be present in many cryptogenic abscesses. studies of Mexican mestizo children and adults, individuals with the Systemic illness such as diabetes mellitus, cardiopulmonary disease, major histocompatibility complex haplotype HLA-DR3 have an increased malignancy, and cirrhosis are common in patients with liver abscesses frequency of amebic liver abscess compared with healthy populations and may be predisposing factors. Diabetes was shown in one retrospective of the same socioeconomic background.38,39 Host factors thought to be study to impart a greater than threefold risk of development of pyogenic critical in the containment and clearance of invasive amebae include liver abscess.77 Conditions of dysfunction are associated with complement, neutrophils, interferon-γ, nitric oxide, and adaptive immune a marked predisposition for abscesses of the liver and elsewhere. For responses (see Chapter 272).13,14,40–44 example, one-third of patients with chronic granulomatous disease followed at the National Institutes of Health Clinical Center over four Pyogenic Liver Abscess decades developed pyogenic liver abscesses; 47% had recurrent abscesses.78 Pyogenic liver abscess does not represent a distinct pathophysiologic Finally, hemochromatosis conveys a particular susceptibility to abscesses process but occurs whenever the initial inflammatory response fails to caused by Yersinia enterocolitica.79 clear an infectious insult to the liver. Pyogenic liver abscesses are usually classified yb presumed route of hepatic invasion: (1) biliary tree, (2) Microbiology portal vein, (3) hepatic artery, (4) direct extension from contiguous Amebic Liver Abscess focus of infection, and (5) penetrating trauma. Ideally, this approach Although E. histolytica is the only species of Entamoeba known to cause defines the microbiology of the abscess and therefore guides empirical invasive infections, certain strains may be more proficient at causing antibiotic choice, but it is limited by the high frequency of cryptogenic liver disease than others. In surveys of clinical E. histolytica isolates, abscesses. The frequencies of the presumed routes of hepatic invasion genetically distinct strains recovered from amebic liver abscesses were are presented in Table 75.1.18,45–76 infrequently found to cause asymptomatic intestinal colonization or intestinal disease.80,81 More recently, Ali and colleagues82 analyzed paired isolates from patients with concurrent amebic liver abscesses and TABLE 75.1 Frequency of Route of Infection in intestinal infection. In all cases, the liver and intestinal amebae had Hepatic Abscess discordant genotypes, suggesting either that amebae undergo genetic reorganization during invasion or that only a subset of strains is capable ROUTE OF INFECTION FREQUENCY (%) of metastasizing to the liver. Biliary tree 40–50 Hepatic artery 5–10 Pyogenic Liver Abscess In light of the diverse pathologic processes that have been discussed, it Portal vein 5–15 is understandable that sweeping generalizations about the microbiology Direct extension 5–10 of pyogenic liver abscess are difficult.Th e picture is further complicated Trauma 0–5 because abscess material is rarely obtained before the administration of antibiotics. Even in the preantibiotic era, a high rate of sterile cultures Cryptogenic 20–40 was seen, probably reflecting inadequate culture techniques. Despite Modified from references 177, 18, 42–455, and 46–71. these difficulties, abscess cultures arep ositive in 80% to 90% of cases. 1039

TABLE 75.2 Microbiology of Liver Abscess TABLE 75.3 Signs and Symptoms of Liver Abscess TYPE OF UNCOMMON AMEBIC LIVER PYOGENIC LIVER ORGANISM COMMON (>10%) (1%–10%) FEATURE ABSCESS16,46–75,117 ABSCESS17,72,106–115 Cha p

Gram-negative Escherichia coli Pseudomonas Epidemiology ter 75 Klebsiella spp. Proteus Male-to-female ratio 5–18 1–2.4 Enterobacter

Citrobacter Age (yr) 30–40 50–60 Abscess, Cholangitis, Cholecystitis Infections of the Liver and Biliary System (Liver Serratia Duration (d) <14 (≈75% of cases) 5–26 Gram-positive Streptococcus (anginosus group) Staphylococcus aureus Mortality (%) 10–25 0–5 Enterococcus spp. β-Hemolytic streptococci Other viridans-group streptococci Symptoms and Signs (Approximate % of Cases) Anaerobic Bacteroides spp. Fusobacterium 80 80 Anaerobic streptococci Weight loss 40 30 Clostridium spp. Lactobacilli Abdominal pain 80 55 Diarrhea 15–35 10–20 The demonstration of anaerobic organisms in 45% of pyogenic liver Cough 10 5–10 83 abscesses by Sabbaj and colleagues in 1972 led to an increased aware- Jaundice 10–15 10–25 ness of fastidious pathogens, and in recent case series, anaerobes were a Right upper quadrant 75 25–55 recovered 15% to 30% of the time. Some of this decrease in the isolation tenderness of anaerobic organisms is probably attributable to the emergence of disease as the major underlying cause of pyogenic liver Laboratory Tests (Approximate % of Cases) abscess, but because of the difficulty in obtaining adequate culture data, Leukocytosis 80 75 these should be viewed as minimum estimates. There has also been an Elevated alkaline 80 65 increased appreciation that many liver abscesses are polymicrobial, with phosphatase estimates ranging from 20% to 50%, depending on the case series. If the source of the abscess is considered, abscesses with a biliary source Solitary lesion 70 70 are most likely to be polymicrobial, and cryptogenic abscesses are most frequently monomicrobial.61 Some observers have noted that solitary infections such as meningitis and endophthalmitis occur in 10% to 16% abscesses are more likely to be polymicrobial than are multiple ones.54,55 of all cases.98–100 Not surprisingly, K. pneumoniae has also become a Although this has not been universally observed61 and the small size frequent cause of pylephlebitis in this region.101 of these studies prevents conclusive statements, it does suggest two Infections are primarily caused by hypermucoviscous strains of K. alternative mechanisms for abscess formation. In the first, a synergistic pneumoniae of the capsular K1 (or occasionally K2) serotype.98,99 Chuang ) combination of organisms converges by chance to form a single abscess, and colleagues102 have identified a 25-kb chromosomal element containing and in the second, a highly pathogenic organism forms abscesses wherever 20 open reading frames that directs K1 capsular polysaccharide synthesis it was seeded. (CPS). Mutagenesis of one cps gene, magA (for mucoviscosity-associated In terms of specific pathogens (Table 75.2), Escherichia coli and K. gene A), abolishes hypermucoviscosity, increases sensitivity to phago- pneumoniae are by far the most common isolates. The latter has been cytosis and serum-mediated lysis, and reduces virulence in mice.103 increasingly recognized as a cause of community-acquired monomicrobial magA can also be used as a genetic marker for invasive serotype K1 K. liver abscesses (discussed later). Enterococci and viridans-group pneumoniae strains. Epidemic hypermucoviscous strains of K. pneumoniae streptococci are also common, primarily in polymicrobial abscesses. often produce other virulence determinants, including the regulator of Staphylococcus aureus, by contrast, is more commonly associated with mucoid phenotype protein RmpA and the iron-acquisition system monomicrobial abscesses. Although pyogenic liver abscesses due to aerobactin, encoded on a 170- to 180-kb large virulence plasmid (pLVPK) fungi, particularly Candida species, have been reported, they are not typically found in other K. pneumoniae strains.104 Isolates are comparatively rare and are excluded from most case series. characteristically highly drug sensitive, but recent outbreaks of often 16S ribosomal RNA sequencing may be a useful technique to identify fatal ventilator-associated pneumonia in China due to carbapenemase- the etiologic agent in instances in which cultures are negative. In a cohort producing hypermucoviscous K. pneumoniae raise the specter of life- of 20 Korean patients, only 45% of abscess fluid bacterial cultures were threatening, highly drug-resistant K. pneumoniae infections not only positive, compared with 90% of samples tested using 16S ribosomal RNA in hospitals, but potentially in the community.105 sequencing. Of interest, all samples were found to contain sequences of unknown bacteria.84 Whether these unknown organisms play a role in Clinical Manifestations the pathogenesis of pyogenic liver abscess remains to be determined. Amebic Liver Abscess Patients with amebic liver abscess typically present with fever and a Epidemic Klebsiella pneumoniae Pyogenic dull, aching pain localizing to the right upper quadrant, but jaundice Liver Abscess is rare. Only 15% to 35% of patients present with concurrent gastroin- In the mid-1980s, investigators in Taiwan first noted a distinctive testinal symptoms, including , vomiting, abdominal cramping, syndrome of monomicrobial K. pneumoniae pyogenic liver abscess in and diarrhea (Table 75.3).18,46–75,106–113 Symptoms are acute (<2 weeks’ individuals who were often diabetic but had no biliary tract disorders.85–87 duration) in about two-thirds of cases but can develop months to years Subsequently, community-acquired K. pneumoniae liver abscess has after travel to an endemic area.2,3 The presentation is indistinguishable become a major health problem in parts of Asia, accounting for 80% from pyogenic liver abscess on clinical grounds, and a careful search of all cases of pyogenic liver abscess in Taiwan and South Korea,88–90 for epidemiologic risk factors is of paramount importance. Corticosteroid and has been reported sporadically elsewhere in Asia, North America, use and male sex are well-established risk factors for invasive amebic Europe, Africa, and Australia, initially in persons of Asian ethnicity disease.12,106 (raising the possibility of genetic predisposition), but more recently also in individuals of non-Asian descent.90–97 Although mortality rates Pyogenic Liver Abscess for epidemic K. pneumoniae liver abscess are generally low, metastatic Only 1 patient in 10 presents with the classic triad of fever, jaundice, and right upper quadrant tenderness. Fever is common, often without aReferences 18, 52–54, 57, 65, 69, 70, 72, and 76. localizing signs but only with a general failure to thrive, including malaise, 1040 fatigue, anorexia, or weight loss (see Table 75.3). When present, localizing Patients with amebic liver abscess classically present with a single symptoms such as vomiting or abdominal pain are not specific. The large abscess in the right lobe of the liver, but the abscess can be anywhere duration of symptoms before presentation varied widely in most case and multiple lesions are not infrequent. Moreover, there is near-complete s series, and there was seldom agreement on an average duration. Butler overlap in the symptomatology of the two diseases (see Table 75.3). A and McCarthyy48 attempted to address this issue by stratifying according Spanish study found that age 45 or younger, presence of diarrhea, and to acute and chronic presentations. They found the former to be typically a solitary right lobar abscess favored amebic etiology.117 Distinguishing ndrome y associated with acute, identifiable abdominal pathology such as chol- amebic from pyogenic liver abscess is not possible with the use of clinical angitis or appendicitis, whereas abscesses that presented chronically criteria alone; however, a presumptive diagnosis of amebic liver abscess were often cryptogenic. Other series support an association between can be made in a patient with positive and a space-occupying etiology and chronicity. For example, Seeto and Rockey61 found that liver lesion on CT or ultrasonography. Serum amebic serology by enzyme hematogenous liver abscesses presented most acutely (3 days), and those immunoassay has a sensitivity of about 95% and is highly specific for or Clinical S j secondary to pylephlebitis had the longest duration of symptoms E. histolytica infection, especially in persons from nonendemic areas. (42 days). While E. histolytica serology can be negative in a minority of acute Ma

I presentations (symptom duration <2 weeks), a repeat serology determina- Diagnosis tion is usually positive.118–121 It should be remembered that a positive art I The diagnosis of liver abscess should be suspected in all patients with serology result only confirms present or prior E. histolytica infection P fever, leukocytosis, and a space-occupying liver lesion. Because of the and cannot distinguish colitis from extraintestinal disease. Antigen nonspecific symptoms on presentation, the initial clinical impression detection represents a complementary diagnostic method. A commercially is frequently wrong and may include cholangitis, pneumonia, hepatic available enzyme-linked immunosorbent assay (ELISA) that detects malignancy, intraabdominal catastrophe, or pneumonia.50 Before the the Gal/GalNAc lectin has been shown to be positive in more than 95% widespread use of noninvasive imaging, liver abscess was among the of serum samples and about 40% of stool or abscess specimens in patients most frequently identifiable causes of fever of unknown origin. Leuko- with amebic liver abscess.122,123 Several other US Food and Drug cytosis is present in most patients; recent studies69,70,73–75,77,114,115 report Administration (FDA)–approved ELISA antigen detection assays are leukocytosis in 68% to 88% of all patients, with mean white blood cell also available, but some may cross-react with E. dispar.124,125 Microscopic counts of 15,000 to 17,000/mm.3 An elevated alkaline phosphatase examination of the stool for cysts is of little value because E. histolytica concentration is the most frequently abnormal liver function test, cannot be distinguished from E. dispar. Examination of aspirated liver occurring in about two-thirds of patients with liver abscess, but a normal abscess pus is also not recommended, given that trophozoites are value does not exclude the diagnosis. Abnormalities of alanine amino- identified in only 11% to 25% of cases.122,126 transferase, aspartate aminotransferase, and bilirubin are generally small, There is growing interest in new diagnostic technologies for amebic although they may be more pronounced in some patients with biliary liver abscesses.127,128 While nucleic acid amplification of fecal specimens disease. Albumin concentration and prothrombin time tend to be normal (in the form of FDA-approved molecular multiplex panels for enteric or nearly so. Procalcitonin levels are typically elevated. Chest radiographs pathogens) is a highly sensitive method for the diagnosis of amebic are abnormal about half of the time but are of no real value in making colitis,129 patients with amebic liver abscesses generally do not have the diagnosis. Therefore, although laboratory studies may suggest liver concurrent intestinal E. histolytica infection.130 Polymerase chain reaction abnormalities, they are of no use in making the diagnosis of pyogenic has been shown to be a potential diagnostic tool for aspirated pus or liver abscess, and a high index of suspicion is required if the diagnosis other body fluids from patients with amebic liver abscess, but its use is is to be made in a timely fashion. Laboratory abnormalities may be of currently limited to research laboratories.125,128,130–133 Some investigators prognostic significance, most likely as markers of comorbidities. A have argued that in areas of low endemicity, suspected amebic liver multivariate analysis of risk factors found that a hemoglobin concentration abscess should be aspirated to exclude pyogenic liver abscess. Certainly, of less than 10 g/dL and a blood urea nitrogen concentration greater if there is no response to initial therapy, the abscess should be aspirated than 28 mg/dL were independent predictors of mortality in patients to confirm the diagnosis and to exclude pyogenic liver abscess. Bacterial found to have pyogenic liver abscess (odds ratios of 13 and 14, superinfection of amebic liver abscess has been described in about 1% respectively).65 to 5% of cases, frequently as a complication of drainage procedures.134 Once the diagnosis is suspected, radiographic imaging studies are Echinococcal cysts of the liver, which typically do not cause fever essential to diagnose pyogenic liver abscess.66 Ultrasonography and or tenderness, are distinguishable from amebic and pyogenic abscesses computed tomography (CT) scanning have proved particularly useful by CT but require separate consideration for aspiration (see Chapter for demonstration and drainage of abscesses. Ultrasonography is the 289). study of choice in patients with suspected biliary disease and in those who must avoid intravenous contrast or radiation exposure; it has a Therapy sensitivity of 70% to 90%. Contrast-enhanced CT scanning has improved Amebic Liver Abscess sensitivity (≈95%) and is superior for guiding complex drainage pro- Amebic liver abscess can almost always be treated with medical therapy cedures. Intravenous contrast is required for optimal imaging in two- alone. (750 mg three times daily) is typically given for thirds of patients.116 Magnetic resonance imaging (MRI) studies are 7 to 10 days.2,3 An alternative, (2 g daily for 3 days), has been seldom required, but they may be better at distinguishing abscesses used extensively in Europe and the developing world and has been from noninfectious liver lesions such as neoplasia. Fine-needle aspiration approved for use in the United States for the treatment of amebiasis.135 is the definitive diagnostic procedure, and MRI is a cumbersome tool Other with extended half-lives that are efficacious include for guiding drainage procedures. secnidazole and ornidazole; neither drug is approved in the United In patients with pyogenic liver abscess, blood cultures are positive States for treatment of amebic liver abscess, although secnidazole recently about half of the time. It is imperative that multiple sets of anaerobic received FDA approval for the treatment of bacterial vaginosis in adult and aerobic cultures be obtained because these are frequently the only women. Decreased fever and abdominal pain are usually observed within cultures obtained before antibiotic administration, and in about 7% of 3 to 5 days after initiation of therapy. Patients frequently remain colonized cases they are the only positive culture data obtained.54,61,73 The diagnosis with E. histolytica despite treatment and should be treated ultimately rests on obtaining purulent material from an aspiration of with , a nonabsorbable aminoglycoside with E. histolytica the abscess cavity, usually under radiographic guidance. Failure to obtain activity, to eliminate this condition.136,137 It is generally accepted that the expected pus should prompt a reevaluation of the differential uncomplicated amebic liver abscess does not require drainage. Percutane- diagnosis, considering liver , malignancy, and amebic liver abscess. ous image-guided aspiration has replaced surgical drainage and should Purulent material should always be sent for Gram stain, which may be employed if there is no response to appropriate therapy or the diagnosis provide the only clue to a mixed infection in patients heavily treated is uncertain, to exclude pyogenic liver abscess and bacterial superinfec- with antibiotics. The importance of prompt delivery of anaerobic tion. Drainage should also be considered for large lesions at risk for specimens under proper conditions cannot be stressed enough. rupture, particularly left-sided abscesses that can rupture into the 1041 pericardium.127 Percutaneous drainage has not been demonstrated to is successful in 69% to 90% of cases; the procedure is generally well shorten hospital stay or to hasten clinical improvement, with the exception tolerated and usually can be performed at the time of radiographic of one randomized controlled trial that found a salutary effect in patients diagnosis.60–62,64,147 Aspirated material should be sent for Gram stain Cha with large abscesses (>300 mL).107,138–143 and cultured for aerobic and anaerobic bacteria. Meticulous handling

of the specimen and rapid transportation to a qualified laboratory are p Pyogenic Liver Abscess essential for efficient recovery of anaerobes. Histopathologic biopsy ter 75 Unlike amebic liver abscess, pyogenic liver abscesses usually require specimens should also be obtained if possible. Depending on host and

drainage in addition to antibiotic therapy. Surgical drainage was tradition- epidemiologic factors, microbiologic evaluation for fungi, mycobacteria, Abscess, Cholangitis, Cholecystitis Infections of the Liver and Biliary System (Liver ally the treatment of choice and, in the preantibiotic era, the only hope and E. histolytica should be considered. The catheter is usually left in for cure. As early as 1953, McFadzean and associates144 reported the place until drainage becomes minimal, typically 5 to 14 days. Recent use of percutaneous drainage with antibiotic therapy to treat 14 patients studies suggest that the success rate for percutaneous drainage with with liver abscess. After ultrasonography and CT became widely available, antibiotic treatment is approximately 80% to 95%, even for large (>10 cm) multiple studies confirmed this approach and made image-guided pyogenic liver abscesses.148–150 drainage procedures the preferred primary therapy, although some still Percutaneous aspiration without catheter placement has received advocate surgical drainage (Fig. 75.1). Surgical intervention should be recent attention, with several studies reporting success rates between considered if percutaneous drainage fails or management of concurrent 58% and 88% for solitary abscesses 5 cm or smaller in diameter, similar intraabdominal disease is required, and also for some patients with to those observed with catheter placement.61,62,64,151–153 Success rates of multiple large or loculated abscesses.145,146 Percutaneous catheter drainage 94% to 98% were reported in two studies in which percutaneous aspira- tion without catheter placement was followed by close clinical monitoring and serial ultrasound studies as indicated. Both investigations found that reaspiration was required in about 50% of cases, and a minority of patients required three or more aspiration procedures.154,155 Therefore catheter placement may not be required in some patients, but prospective, randomized control trials are necessary to clarify the role of aspiration alone versus catheter placement in the management of hepatic abscess. Attempts to treat pyogenic liver abscess with antibiotics but no drainage have met with some success. Two early studies with a combined total of 25 patients found cure rates of 87% to 90%.156,157 These studies have been criticized because 68% of the patients underwent diagnostic aspiration and therefore had at least partial drainage. Moreover, this success rate was substantially higher than the conventional experience at the time, when undrained abscesses carried a mortality rate of 60% to 100%. The results may be subject to selection bias. Most patients did not have drainage because they were deemed poor surgical candidates. Even severely debilitated patients can tolerate percutaneous drainage, ) but the procedure may not always be required for cure: success rates A of 44% and 100% with medical therapy alone have been reported in small case series.61,149,153,158 Recent studies have also shown that chronic granulomatous disease–associated pyogenic liver abscesses may respond to conservative management with antibiotics and high-dose cortico- steroids, delaying and perhaps reducing the future need of percutaneous or open surgical drainage.159,160 However, until criteria for patient selection are better defined, medical management of pyogenic liver abscess should generally be reserved for patients with small abscesses not amenable to drainage and those patients in whom the risk of drainage is unac- ceptably high. Treatment with empirical antibiotics should begin as soon as the diagnosis of pyogenic liver abscess is suspected. Multiple blood cultures should be sent before antibiotic initiation, but delaying antibiotic therapy until abscess material is obtained is not necessary and is potentially dangerous. Antibiotic choice should be guided by the suspected source of the abscess (Table 75.4). Abscesses arising from a biliary source frequently involve enterococci and enteric gram-negative bacilli, whereas abscesses from a colonic or pelvic source are more commonly caused by enteric gram-negative bacilli and anaerobes. Metronidazole at B appropriately high doses should be included if amebic liver abscess is FIG. 75.1 Drainage of liver abscesses by percutaneous aspiration a consideration. Fluoroquinolones may be substituted for gentamicin, guided by computed tomography (CT). A 67-year-old man with a history but this may not be advisable in cases complicated by enterococcal of diabetes mellitus and rheumatoid arthritis and a distant history of a bacteremia. If a hematogenous (hepatic artery) source is suspected, Billroth II gastric resection, recently diagnosed with adenocarcinoma of the coverage should include an antibiotic with activity against S. aureus. stomach, presented with fever. A blood culture grew Escherichia coli. Pyogenic liver abscesses are usually treated parenterally for 2 to 3 The liver was imaged by CT (A), revealing multiple hypodense lesions in weeks, and a 4- to 6-week total course is completed with oral agents. the right hepatic lobe. The lesion was aspirated under radiologic guidance, Some have reported successful treatment with less than 2 weeks of and more than 500 mL of frank pus were drained. Cultures produced E. antibiotic therapy. The patient’s clinical response and follow-up imaging coli and several anaerobic bacterial species. Cytologic findings were consistent should be monitored to judge response to therapy for considerations with metastatic adenocarcinoma. A radiodense percutaneous drainage catheter was left in place (B), and the patient was treated with intravenous of antibiotic duration and the need for further aspiration. One-third antibiotics and continued drainage. Note the position of the catheter and of patients are readmitted or have emergency room visits following the decrease in size of the abscess. (Courtesy Lindsey Baden, MD, Brigham discharge from the hospital, which suggests that these individuals may and Women’s Hospital, Boston. From Johannsen EC, Sifri CD, Madoff LC. benefit from close outpatient follow-up and a multidisciplinary approach Pyogenic liver abscesses. Infect Dis Clin North Am. 2000;14:547–563, vii.) to care.161 Abscess cavities usually resolve completely after therapy, but 1042

TABLE 75.4 Antibiotic Therapy for Pyogenic Gallbladder distention Hepatic Abscess Edematous gallbladder wall s TYPE OF THERAPY AGENTS Cystic Monotherapy duct

ndrome β-Lactam–β-lactamase inhibitor Piperacillin-tazobactam y combinationa

a IIncnnccrrereasededd Carbapenem Imipenem-cilastin, meropenem, ertapenem, inintralallumumimiinanalalal doripenem ppreprreessusuuree Combination Therapy Gallstone impacted

or Clinical S in Hartmann's pouch j Cephalosporin-based Third- or fourth-generation cephalosporin

Ma (cefotaxime, ceftriaxone, ceftizoxime, Gallbladder

I Fluid secretion ceftazidime, cefepime) plus metronidazole distention Fluoroquinolone-based Fluoroquinolone (ciprofloxacin, levofloxacin, art I moxifloxacin) plus metronidazole Prostaglandin I2 P and E2 secretion aMetronidazole or tinidazole should be included for presumptive therapy of amebic abscess if suspected. FIG. 75.2 Pathogenesis of acute cholecystitis. Impaction of a gallstone leads to obstruction of the cystic duct and increased intraluminal pressure. An acute inflammatory response is in part mediated by prostaglandins. occasionally they persist despite prolonged courses of antibiotics. In Infection may then result from biliary stasis. (Modified from Indar AA, such cases, patients should be observed closely. Recurrent symptoms Beckingham IJ. Acute cholecystitis. BMJ. 2002;325:639–643.) such as fever or abdominal pain should prompt repeat imaging and possible reaspiration. include critical illnesses such as trauma, burns, and sepsis, as well as INFECTION OF THE human immunodeficiency virus (HIV) infection, immunosuppression, BILIARY SYSTEM diabetes, nonbiliary surgery, and childbirth.166 Some of these conditions InfectionsInfections of the biliarybiliary tract,tr including the common and predispose to ischemia in the gallbladder wall or stasis of bile, or both, gallbladder, are most often associated with obstruction to the flow of resulting in concentration of bile salts and leading to and bile. In the United States and many developed countries, gallstones are necrosis of the gallbladder wall. common and most often asymptomatic. In the United States, for example, it is estimated that 20 to 25 million adults have gallstones.162 In a small Cholangitis percentage of cases, gallstones may obstruct the cystic or common bile Cholangitis refers to inflammation or infection of the common bile ducts, resulting in inflammation. Approximately 120,000 cholecystec- duct. The normally sterile bile may become infected because of the loss tomies are performed every year in the United States for acute chole- of protective factors, including the flow of bile. Obstruction of the cystitis, most commonly secondary to impacted gallstones.163 Other leads to stasis, which favors the growth of bacteria; causes of biliary obstruction include tumors of the biliary tree or adjacent increased pressure predisposes to bacteremia. Other factors may involve structures, strictures secondary to surgery or other injury (including the loss of antibacterial activity of bile on the proximal , prior infection), and, in many geographic areas, infection by parasites allowing for greater growth of bacteria. Bacteria may then ascend to including Ascaris and Clonorchis. Stasis of bile, inflammation, and loss the biliary tract (hence the terms ascendingg and suppurative cholangitis). of mechanical barriers can lead to bacterial infection of the bile, which Other routes of infection have been proposed, including via the portal can result in severe morbidity and death. system or the lymphatics. Anastomosis of the bile duct to the small intestine, such as in a Whipple procedure, can lead to cholangitis. Primary Pathogenesis sclerosing cholangitis is a disease of immunologic origin and is not Cholecystitis covered here.167 AIDS cholangiopathy, which has many features of acute Only about 20% of patients with gallstones experience , cholangitis, is discussed later in this chapter. typified yb right upper quadrant pain after a fatty meal when the contract- ing gallbladder is prevented from emptying by an obstructing stone.163 Clinical Manifestations Biliary colic must be distinguished from the far more serious acute Patients with biliary tract disease most often present with pain in the cholecystitis, which occurs in 1% to 3% of persons with symptomatic right upper quadrant of the abdomen, although occasionally localizing gallstones. In this disease, biliary obstruction is accompanied by an findings are absent. The pain may radiate to the infrascapular region. intense inflammatory reaction. Obstruction is thought to lead to increased Cholecystitis and cholangitis are distinguished from simple biliary colic intraluminal pressure; may lead to compromised blood supply and by the continuous nature of the pain. The finding of tenderness in the lymphatic drainage; and, in the setting of supersaturated bile, leads to right upper quadrant on physical examination and the presence of acute inflammation. This process is mediated, at least in part,y b the Murphy sign (inhibition of inspiration by pain when the area of 164 prostaglandins, particularly prostaglandins I2 and E2 (Fig. 75.2). the gallbladder fossa is palpated), with or without a mass, are highly Infection is not thought to precipitate acute cholecystitis, but it may suggestive of biliary tract disease. Fever and tachycardia are frequent complicate 20% to 50% of cases. In a microbiologic study of biliary findings. Complications of acute cholecystitis, which occur in 10% to tract processes, 46% of patients presenting with acute cholecystitis had 15% of cases, include hepatic or intraabdominal abscess, necrosis or positive bile cultures, compared to 22% of patients with symptomatic gangrene of the gallbladder, and perforation, which in turn lead to gallstones but no evidence of acute cholecystitis and no positive cultures sepsis and . Emphysematous cholecystitis, usually diagnosed in normal controls.165 Untreated cholecystitis may resolve spontaneously, radiologically, occurs when the wall of the gallbladder is infected with but serious complications also occur at a high rate. Once infection is gas-forming organisms, including Clostridia, as well as aerobic and established, complications include gangrenous cholecystitis, emphyse- facultative gram-negative and gram-positive bacteria. It often occurs matous cholecystitis, gallbladder empyema, pyogenic liver abscess in diabetics, and it may suggest a more ominous prognosis.168,169 (discussed earlier), and bacteremia. Acalculous cholecystitis, particularly in a critically ill patient who is unresponsive, may produce subtle findings, such as unexplained fever Acalculous Cholecystitis or vague abdominal pain.170 A high index of suspicion is required because In 2% to 15% of cases, cholecystitis occurs in the absence of gallstones, serious complications such as gangrenous gallbladder and perforation although usually in the presence of other predisposing conditions. These frequently occur. 1043 Acute or is suggested by the Charcot triad (right upper quadrant or epigastric abdominal pain; fever or chills, or both; and jaundice), reported in 50% to 70% of patients.171 The additional, Cha less frequent signs of hypotension and altered mental status, in combina- tion with the Charcot triad, constitute the Reynolds pentad, which is p reportedly seen in less than 14% of patients with ascending cholangitis.172 ter 75 Symptoms and signs of an inflammatory response are usually present

and are reflected in the presence of fever, leukocytosis, and other markers. Abscess, Cholangitis, Cholecystitis Infections of the Liver and Biliary System (Liver Diagnosis Leukocytosis with a left shift is the most frequent laboratory abnormality in acute cholecystitis. Alkaline phosphatase and bilirubin are not usually elevated unless the common bile duct is involved. However, in one study of 217 patients with acute cholecystitis, 25% of patients without obstruction of the common bile duct had elevated bilirubin.173 Several also had elevations in amylase. The mechanism underlying these abnormalities is unclear but may be the passage of small stones or sludge through the common bile duct. The role of bile and blood cultures in the diagnosis of acute cholecystitis is not well established. International consensus practice guidelines (the “Tokyo Guidelines”) recommend obtaining bile and, when available, tissue cultures from patients with cholangitis or moderate-to-severe acute cholecystitis.174 The utility of routine blood cultures in cases of mild cholecystitis is less clear and are not routinely recommended.174 Similarly, guidelines of the Surgical Infection Society and the Infectious Diseases Society of America recom- FIG. 75.3 Pathogenesis of acalculous cholecystitis. Ultrasonographic mend against routinely collecting blood cultures from patients with visualization of the gallbladder (sagittal view) in a case of acalculous community-acquired intraabdominal infections, unless the patient is cholecystitis, demonstrating mural thickening and hypoechoic regions within 175 the gallbladder wall. (From Gore RM, Yaghmai V, Newmark GM, et al. immunocompromised or systemically toxic. Imaging benign and malignant disease of the gallbladder. Radiol Clin North Acute cholangitis results in presentation with the clinical findings Am. 2002;40:1307–1323, vi.) mentioned earlier. Abnormalities suggestive of sepsis syndrome, including leukocytosis, are frequently observed. Additional laboratory abnormalities include cholestatic with elevations in alkaline TABLE 75.5 Microbiology of Acute Cholecystitis phosphatase and bilirubin, particularly conjugated bilirubin. Elevations and Cholangitis in γ-glutamyl transpeptidase are often seen as well. Abnormal amylase may suggest an associated pancreatitis, and elevations in transaminases BACTERIA FREQUENCY (%) ) may indicate associated inflammation or infection of the liver paren- Gram-negative organisms chyma, or both. The Tokyo guidelines recommend obtaining aerobic Escherichia coli 31–44 and anaerobic cultures of bile aspirates and blood in cases of acute Klebsiella spp. 9–20 174 cholangitis. Bile cultures are positive in 59% to 93% of patients, and Pseudomonas aeruginosa 0.5–19 174,176 blood cultures are positive in 30% to 40%. Enterobacterr spp. 5–9 Gram-positive organisms Imaging Studies Enterococcus spp. 3–34 Ultrasonography can frequently establish the diagnosis of cholecystitis Streptococcus spp. 2–10 175 and is usually the first study obtained. A sonographic Murphy sign Staphylococcus aureus 0–4 (i.e., pain when the ultrasound transducer probes the gallbladder) is a useful diagnostic clue. In addition, the testing may be done at the bedside Anaerobes 4–20 of critically ill patients, is relatively inexpensive, and can directly visualize Modified from Gomi H, Solomkin JS, Schlossberg D, et al. Tokyo Guidelines 2018: stones, particularly in the gallbladder. Abnormalities such as gallbladder antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2018;25:3–16. wall thickening of greater than 4 mm, pericholecystic fluid, and intra- mural gas or ductal dilation are suggestive of cholecystitis (Fig. 75.3).163 The combination of stones and either wall thickening or a sonographic and mural thickening; and enhancement of the liver adjacent to the Murphy sign in the appropriate clinical picture were shown to have gallbladder, which is the CT equivalent of the scintigraphic “rim sign.” positive and negative predictive values exceeding 90%.177 Magnetic resonance (MR) cholangiography is a noninvasive technique Radionuclide cholescintigraphy (hepatobiliary iminodiacetic acid that has been used to visualize the bile ducts. In one study of 35 patients [HIDA] scanning) may be used if ultrasound fails to ascertain a diagnosis. comparing ultrasonography with MR cholangiography, the latter modality A technetium 99m (99mmTc)–labeled derivative of acetanilide iminodiacetic showed 100% sensitivity for the presence of stones but was less sensitive acid is injected intravenously and is secreted into the bile. It is taken than ultrasound in the detection of gallbladder wall thickening (69% up by the gallbladder, which can then be visualized. Failure of the vs. 96%).181 In a meta-analysis of 67 studies of MR cholangiography, gallbladder to accumulate the marker is highly suggestive of acute the technique was highly sensitive (99%) for the detection of biliary cholecystitis due to obstruction of the cystic duct. Normally, visualization obstruction and 92% sensitive for the detection of stones.182 A more of the common bile duct and small bowel occurs within 30 to 60 minutes; recent meta-analysis of 57 studies found the highest sensitivity (96%) failure to visualize these structures indicates obstruction within the with radionuclide cholescintigraphy, while ultrasonography had a common bile duct or at the ampulla. In one study of cholescintigraphy sensitivity of 81%, and MRI had a sensitivity of 85%.183 The study showed in the diagnosis of acalculous cholecystitis in 62 critically ill patients, no important differences in specificity among the techniques. ultrasonography had a sensitivity of only 30%, whereas HIDA scanning had a sensitivity of 100% and a specificity of 88%.178 Microbiology CT is not commonly used for the initial evaluation of cholecystitis, Bacterial cultures from the bile and surgical sites of patients with acute and its sensitivity and specificity for detection of this condition are not cholecystitis and acute cholangitis typically yield constituents of the known.179,180 CT findings associated with acute cholecystitis include normal intestinal microbiota (Table 75.5).174,184 These include gram- gallstones, particularly within the cystic duct; gallbladder distention negative bacilli such as E. coli, Klebsiella spp., and Enterobacterr spp. 1044

TABLE 75.6 Recommended Agents and Regimens for Empirical Treatment of Acute Biliary Infections TYPE OF INFECTION FOR MILD TO MODERATELY SEVERE INFECTION FOR HIGHLY SEVERE INFECTION s Community-acquired acute Cephalosporin-based therapy (cefazolin,a cefuroxime,a or Imipenem-cilastatin, meropenem, doripenem, piperacillin-tazobactam, cholecystitis ceftriaxone) or cefepime plus metronidazole Acute cholangitis following Imipenem-cilastatin, meropenem, doripenem, piperacillin- Imipenem-cilastatin, meropenem, doripenem, piperacillin-tazobactam, ndrome b y biliary-enteric anastomosis tazobactam, cefepime plus metronidazole, ciprofloxacin plus or cefepime plus metronidazole metronidazole, levofloxacinb plus metronidazole, or moxifloxacinb Health care–associated Imipenem-cilastatin, meropenem, doripenem, piperacillin- Imipenem-cilastatin, meropenem, doripenem, piperacillin-tazobactam, biliary infection tazobactam, cefepime plus metronidazole, ciprofloxacinb plus or cefepime plus metronidazole metronidazole, levofloxacinb plus metronidazole, or moxifloxacinb Vancomycinc added to each regimen c or Clinical S Vancomycin added to each regimen j aLocal antimicrobial susceptibility profiles and, if available, isolate susceptibility should be reviewed. Ma b

I Addition of metronidazole is necessary due to increasing resistance of Bacteroides to fluoroquinolones other than moxifloxacin. Local antimicrobial susceptibility profiles and, if available, isolate susceptibility should be reviewed due to increasing resistance of Escherichia coli to fluoroquinolones. cLinezolid or daptomycin may be considered in cases where vancomycin-resistant Enterococcus (VRE) is known to be colonizing the patient, if previous treatment included art I

P vancomycin, and/or if VRE is common in the community. Modified from Solomkin JS, Mazuski JE, Bradley JS, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:133–164; and Gomi H, Solomkin JS, Schlossberg D, et al. Tokyo Guidelines 2018: antimicrobial therapy for acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2018;25:3–16.

Anaerobes, most frequently Bacteroides spp., Fusobacterium spp., and Acute Cholecystitis clostridia, are recovered less frequently but are isolated more often from The role of antibiotics in acute cholecystitis has not been well established. patients with prior biliary tract surgical procedures and those with Many cases of acute cholecystitis remit spontaneously, and retrospective biliary-intestinal anastomoses. Finally, enterococci are not uncommonly studies of patients with uncomplicated cholecystitis have failed to found in infected bile, usually in association with other organisms.185 demonstrate reduced complications such as pericolic abscess or perfora- Parasites that infect the biliary tree include Clonorchis sinensis, tion with antibiotic administration.193,194 In addition, two recent prospec- Opisthorchis felineus, Opisthorchis viverrini, and Fasciola hepatica.186 tive, randomized controlled trials of patients with mild-to-moderate These organisms are prevalent in regions of Asia and can cause acute acute cholecystitis managed with early cholecystectomy demonstrated and relapsing cholangitis with associated stricture and stone formation. no increase in complications when postoperative antibiotics were Clonorchis and Opisthorchis infection can lead to the development of withheld, but neither study reached the primary end point of noninferior- carcinoma of the biliary tract. Ascaris lumbricoides, a more cosmopolitan ity.195,196 Similarly, a recent review of published studies concluded that parasite, occasionally obstructs the biliary tree, resulting in acute there was no clear indication that antibiotics are beneficial for patients cholangitis.187 Echinococcal disease can cause biliary obstruction due with acute cholecystitis who were treated conservatively or with delayed to mass effect. Parasites that complicate HIV disease may also invade cholecystectomy, although the level of evidence was low.197 In summary, the biliary tree (see discussion following). the data suggest that antibiotics can be safely discontinued within 24 hours after cholecystectomy for acute uncomplicated cholecystitis, as AIDS Cholangiopathy (AIDS-Related long as there is no evidence of infection outside the gallbladder wall.193 Sclerosing Cholangitis) Antibiotics are clearly indicated for patients with complications of Biliary tract disease is a complication of advanced HIV infection188 cholecystitis, such as gangrenous cholecystitis or perforation. Guidelines (discussed in Chapter 125). In the era of potent antiretroviral therapy, recommend a total of 4 to 7 days of therapy once source control is AIDS cholangiopathy is now a rare clinical entity.189 Although it is obtained and anatomic issues have been addressed, although longer possible that this condition is caused by infection of the biliary tract courses of treatment may be necessary for complications such as pyogenic with HIV per se, more likely it results from opportunistic infection of liver abscess.174,175 Antibiotics directed against the enteric flora (as the biliary system. The pathologic findings of AIDS cholangiopathy described earlier) should also be given to patients who are debilitated, include stenosis of the distal common bile duct and irregularities of severely ill, elderly, immunocompromised, or jaundiced (Table 75.6).174,175 the intrahepatic and extrahepatic bile ducts.190 The most common Despite the relatively frequent isolation of enterococci from bile cultures, pathogen associated with cholangitis in HIV is Cryptosporidium. After successful treatment of community-acquired cholecystitis typically does an outbreak of cryptosporidiosis in Milwaukee, Wisconsin, in 1995, not require antimicrobial therapy against enterococci.174,175,185 This finding 29% of patients with HIV infection and intestinal cryptosporidiosis may be a result of the low pathogenic potential of enterococci in this developed cholangiopathy as well.191 Cytomegalovirus is also a major setting; elimination of other pathogens effectively treats the infection cause of AIDS-related cholangitis, having been described in up to 42% even in the setting of persistent enterococcal contamination. However, of patients. Other pathogens associated with AIDS cholangiopathy enterococci may be important pathogens in high-risk patients, such as include Enterocytozoon bieneusi, Cystoisospora belli, and Mycobacterium liver transplant recipients; in these cases, treatment that also targets avium-intracellulare. The clinical manifestations of biliary tract disease enterococci may be indicated.174,175 Institutional drug resistance patterns do not differ markedly from those in non–HIV-infected individuals should be considered when selecting an initial antimicrobial regimen and include right upper quadrant pain and fever. Diagnosis is usually for health care–associated severe cholecystitis. Use of an agent active made by characteristic findings on ultrasound, with dilatation of the against gram-negative anaerobes, such as metronidazole, is not required common bile duct observed in approximately two-thirds of cases. for community-acquired cholecystitis, unless a biliary-enteric anastomosis Endoscopic retrograde cholangiopancreatography (ERCP) demonstrates is present.174,175 dilatation and irregularities of the ducts and has become the gold standard In the presence of suspected gangrene or perforation, immediate for the diagnosis.192 It is also useful in treatment; sphincterotomy provides surgery is indicated. Ideally, this includes cholecystectomy with intra- symptomatic benefit for many patients. operative cholangiogram. Alternatively, in unstable patients, cholecys- totomy (percutaneous drainage of the biliary system with removal of Therapy obstructing stones) may be performed as a temporizing measure.198 Because biliary disease results most commonly from obstruction of the This procedure can be performed under local anesthesia and at the bile ducts, definitive treatment involves removal of the obstruction or bedside in critically ill patients and can be lifesaving. In some circum- the infected material. This can be accomplished surgically, percutaneously, stances, further surgery may not be required. or endoscopically (i.e., by ERCP).163 Antibiotics and other supportive In the absence of severe complications, the timing of definitive surgical measures are considered temporizing. intervention in the management of acute cholecystitis is the subject of 1045 some debate. Traditionally, in the group of patients who are stable and health care–associated disease should be influenced by local nosocomial respond to conservative management, surgery has been delayed for 6 to resistance patterns, as well as the patient’s prior antibiotic exposures 12 weeks. However, several studies have shown that patients who undergo and known microbial colonization.174,175 Although anaerobes are only Cha early surgical intervention (most often laparoscopic cholecystectomy) infrequently cultured from bile in acute cholangitis, the addition of

have a lower complication rate, a shorter hospital stay, and, if laparoscopic metronidazole to empirical third- or fourth-generation cephalosporin- p cholecystectomy is performed, a lower requirement for conversion to an based regimens is advisable (see Table 75.6).174,175 Like severe acute ter 75 open procedure, compared with patients undergoing delayed surgery.199,200 cholecystitis, acute cholangitis is treated for a total of 4 to 7 days once

Several recent meta-analyses of randomized controlled trials found early source control is obtained and anatomic problems have resolved, although Abscess, Cholangitis, Cholecystitis Infections of the Liver and Biliary System (Liver surgery to be as safe and effective as delayed surgery and associated longer courses of treatment may be necessary due to complications such with lower hospital costs, fewer work days lost, and lower risk of wound as pyogenic liver abscess or gram-positive bacteremia.174 infection.201–203 For patients with high surgical risk and those who are Drainage of the biliary tract may be accomplished surgically, endo- unstable, delayed surgery may still be preferable. scopically, or percutaneously. ERCP has, to a large extent, supplanted open surgical procedures in the management of acute cholangitis and Acute Cholangitis is successful in more than 90% of cases.204,205 (Paradoxically, ERCP Acute cholangitis remains a disease with substantial mortality, and is not infrequently the cause of acute cholangitis when it is used in therapy should include antibiotics and supportive measures along an attempt to decompress an obstructed but not frankly infected bile with decompression/drainage of the biliary system for cases that do duct.206) ERCP is generally thought to have a lower morbidity rate not respond promptly to conservative therapy. A variety of antibiotic than open surgery, and it is more likely to offer definitive treatment regimens have been used in the management of acute cholangitis (see (e.g., by removal of an impacted gallstone) than percutaneous biliary Table 75.6).172,174,175 Empirical coverage should be directed against drainage. Some cases of acute cholangitis will respond to conserva- enteric gram-negative bacilli. A β-lactam–β-lactamase inhibitor such tive therapy with drainage deferred until 24 to 48 hours to monitor as piperacillin-tazobactam is appropriate initial empirical therapy.174 response.207,208 Cephalosporins, carbapenems, and fluoroquinolones have also proved Treatment of parasitic infections affecting the biliary tree is covered efficacious.172,174,176 Selection of empirical antibiotic therapy in cases of in Chapters 287, 289, and 290.

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Clin Infect Dis. factors for acute suppurative cholangitis caused by 285–289. 2018;66:1427–1434. common bile duct stones? Gut Liver. 2010;4:363. Chapter 75 Infections of the Liver and Biliary System (Liver Abscess, Cholangitis, Cholecystitis)

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