InternalMed_Harrison

InternalMed_Harrison. with multiresistant bacteria, and recent use of β-lactam antibiotics. In PBP, a single organism is typically isolated; anaerobes are found less frequently in PBP than in secondary peritonitis, in which a mixed flora including anaerobes is the rule. In fact, if PBP is suspected and multiple organisms including anaerobes are recovered from the peritoneal fluid, the diagnosis must be reconsidered and a source of secondary peritonitis sought.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 159-2 Pneumoperitoneum. Free air under the diaphragm on an upright chest film suggests the presence of a bowel perfora-tion and associated peritonitis. (Image courtesy of Dr. John Braver; with permission.)


InternalMed_Harrison

InternalMed_Harrison. The diagnosis of PBP is not easy. It depends on the exclusion of a primary intraabdominal source of infection. Contrast-enhanced CT is useful in identifying an intraabdominal source for infection. It may be difficult to recover organisms from cultures of peritoneal fluid, presumably because the burden of organisms is low. However, the yield can be improved if 10 mL of peritoneal fluid is placed directly into a blood culture bottle. Because bacteremia frequently accompanies PBP, blood should be cultured simultaneously. To maximize the yield, culture samples should be collected prior to administration of antibiotics. No specific radiographic studies are helpful in the diagnosis of PBP. A plain film of the abdomen would be expected to show ascites. Chest and abdominal radiography should be performed in patients with abdominal pain to exclude free air, which signals a perforation (Fig. 159-2).


InternalMed_Harrison

InternalMed_Harrison. Treatment for PBP is directed at the isolate from blood or peritoneal fluid. Gram’s staining of peritoneal fluid often gives negative results in PBP. Therefore, until culture results become available, therapy should cover gram-negative aerobic bacilli and gram-positive cocci. Third-generation cephalosporins such as cefotaxime (2 g q8h, administered IV) provide reasonable initial coverage in moderately ill patients. Broad-spectrum antibiotics, such as penicillin/ β-lactamase inhibitor combinations (e.g., piperacillin/tazobactam, 3.375 g q6h IV for adults with normal renal function) or ceftriaxone (2 g q24h IV), are also options. Broader empirical coverage aimed at resistant hospital-acquired gram-negative bacteria (e.g., treatment with carbapenem) may be appropriate for nosocomially acquired PBP until culture results become available. Empirical coverage for anaerobes is not necessary. A mortality benefit from albumin (1.5 g/ kg of body weight within 6 h of detection and 1.0 g/kg on day


InternalMed_Harrison

InternalMed_Harrison. PBP until culture results become available. Empirical coverage for anaerobes is not necessary. A mortality benefit from albumin (1.5 g/ kg of body weight within 6 h of detection and 1.0 g/kg on day 3) has been demonstrated for patients who present with serum creatinine levels ≥1 mg/dL, blood urea nitrogen levels ≥30 mg/dL, or total bilirubin levels ≥4 mg/dL but not for patients who do not meet these criteria. After the infecting organism is identified, therapy should be narrowed to target the specific pathogen. Patients with PBP usually respond within 72 h to appropriate antibiotic therapy. Antimicrobial treatment can be administered for as little as 5 days if rapid improve-847 ment occurs and blood cultures are negative, but a course of up to 2 weeks may be required for patients with bacteremia and for those whose improvement is slow. Persistence of WBCs in the ascitic fluid after therapy should prompt a search for additional diagnoses.


InternalMed_Harrison

InternalMed_Harrison. Prevention • primary prevention Several observational studies and a meta-analysis raise the concern that proton pump inhibitor therapy may increase the risk of PBP. No prospective studies have yet addressed whether avoidance of such therapy may prevent PBP. Nonselective beta blockers may prevent secondary bacterial peritonitis. A 2012 guideline from the American Association for the Study of Liver Diseases recommends chronic antibiotic prophylaxis with a regimen described in the next section for patients who are at highest risk for PBP—that is, those with an ascitic-fluid total protein level <1.5 g/ dL along with impaired renal function (creatinine, ≥1.2 mg/dL; blood urea nitrogen, ≥25 mg/dL; or serum sodium, ≤130 mg/dL) and/or liver failure (Child-Pugh score, ≥9; and bilirubin, ≥3 mg/dL). A 7-day course of antibiotic prophylaxis is recommended for patients with cirrhosis and gastrointestinal bleeding.


InternalMed_Harrison

InternalMed_Harrison. secondary prevention PBP has a high rate of recurrence. Up to 70% of patients experience a recurrence within 1 year. Antibiotic prophylaxis is recommended for patients with a history of PBP to reduce this rate to <20% and improve short-term survival rates. Prophylactic regimens for adults with normal renal function include fluoroquinolones (ciprofloxacin, 750 mg weekly; norfloxacin, 400 mg/d) or trimethoprimsulfamethoxazole (one double-strength tablet daily). However, longterm administration of broad-spectrum antibiotics in this setting has been shown to increase the risk of severe staphylococcal infections.


InternalMed_Harrison

InternalMed_Harrison. Secondary peritonitis develops when bacteria contaminate the peritoneum as a result of spillage from an intraabdominal viscus. The organisms found almost always constitute a mixed flora in which facultative gram-negative bacilli and anaerobes predominate, especially when the contaminating source is colonic. Early in the course of infection, when the host response is directed toward containment, exudate containing fibrin and PMNs is found. Early death in this setting is attributable to gram-negative bacillary sepsis and to potent endotoxins circulating in the bloodstream (Chap. 325). Gram-negative bacilli, particularly


InternalMed_Harrison

InternalMed_Harrison. E. coli, are common bloodstream isolates, but Bacteroides fragilis bacteremia also occurs. The severity of abdominal pain and the clinical course depend on the inciting process. The organisms isolated from the peritoneum also vary with the source of the initial process and the normal flora at that site. Secondary peritonitis can result primarily from chemical irritation and/or bacterial contamination. For example, as long as the patient is not achlorhydric, a ruptured gastric ulcer will release low-pH gastric contents that will serve as a chemical irritant. The normal flora of the stomach comprises the same organisms found in the oropharynx but in lower numbers. Thus, the bacterial burden in a ruptured ulcer is negligible compared with that in a ruptured appendix. The normal flora of the colon below the ligament of Treitz contains ~1011 anaerobic organisms/g of feces but only 108 aerobes/g; therefore, anaerobic species account for 99.9% of the bacteria. Leakage of colonic contents (pH


InternalMed_Harrison

InternalMed_Harrison. below the ligament of Treitz contains ~1011 anaerobic organisms/g of feces but only 108 aerobes/g; therefore, anaerobic species account for 99.9% of the bacteria. Leakage of colonic contents (pH 7–8) does not cause significant chemical peritonitis, but infection is intense because of the heavy bacterial load.


InternalMed_Harrison

InternalMed_Harrison. Depending on the inciting event, local symptoms may occur in secondary peritonitis—for example, epigastric pain from a ruptured gastric ulcer. In appendicitis (Chap. 356), the initial presenting symptoms are often vague, with periumbilical discomfort and nausea followed in a number of hours by pain more localized to the right lower quadrant. Unusual locations of the appendix (including a retrocecal position) can complicate this presentation further. Once infection has spread to the peritoneal cavity, pain increases, particularly with infection involving the parietal peritoneum, which is innervated extensively. Patients usually lie motionless, often with knees drawn up to avoid stretching the nerve fibers of the peritoneal cavity. Coughing and sneezing, which increase pressure within the peritoneal cavity, are associated with sharp 848 pain. There may or may not be pain localized to the infected or diseased organ from which secondary peritonitis has arisen. Patients with secondary


InternalMed_Harrison

InternalMed_Harrison. peritoneal cavity, are associated with sharp 848 pain. There may or may not be pain localized to the infected or diseased organ from which secondary peritonitis has arisen. Patients with secondary peritonitis generally have abnormal findings on abdominal examination, with marked voluntary and involuntary guarding of the anterior abdominal musculature. Later findings include tenderness, especially rebound tenderness. In addition, there may be localized findings in the area of the inciting event. In general, patients are febrile, with marked leukocytosis and a left shift of the WBCs to band forms. While recovery of organisms from peritoneal fluid is easier in secondary than in primary peritonitis, a tap of the abdomen is rarely the procedure of choice in secondary peritonitis. An exception is in cases involving trauma, where the possibility of a hemoperitoneum may need to be excluded early. Emergent studies (such as abdominal CT) to find the source of peritoneal contamination should be


InternalMed_Harrison

InternalMed_Harrison. is in cases involving trauma, where the possibility of a hemoperitoneum may need to be excluded early. Emergent studies (such as abdominal CT) to find the source of peritoneal contamination should be undertaken if the patient is hemodynamically stable; unstable patients may require surgical intervention without prior imaging.


InternalMed_Harrison

InternalMed_Harrison. Treatment for secondary peritonitis includes early administration of antibiotics aimed particularly at aerobic gram-negative bacilli and anaerobes (see below). Mild to moderate disease can be treated with many drugs covering these organisms, including broad-spectrum penicillin/β-lactamase inhibitor combinations (e.g., ticarcillin/clavulanate, 3.1 g q4–6h IV), cefoxitin (2 g q4–6h IV), or a combination of either a fluoroquinolone (e.g., levofloxacin, 750 mg q24h IV) or a third-generation cephalosporin (e.g., ceftriaxone, 2 g q24h IV) plus metronidazole (500 mg q8h IV). Patients in intensive care units should receive imipenem (500 mg q6h IV), meropenem (1 g q8h IV), or combinations of drugs, such as ampicillin plus metronidazole plus ciprofloxacin. The role of enterococci and Candida species in mixed infections is controversial. Secondary peritonitis usually requires both surgical intervention to address the inciting process and antibiotics to treat early bacteremia, to decrease the


InternalMed_Harrison

InternalMed_Harrison. in mixed infections is controversial. Secondary peritonitis usually requires both surgical intervention to address the inciting process and antibiotics to treat early bacteremia, to decrease the incidence of abscess formation and wound infection, and to prevent distant spread of infection. Although surgery is rarely indicated in PBP in adults, it may be life-saving in secondary peritonitis. Recombinant human activated protein C (APC) was considered at one time for treatment of severe sepsis from causes including secondary peritonitis but was withdrawn from the market in 2011 after it was determined that the drug was associated with an increased risk of bleeding and that evidence for its beneficial effects was inadequate. Thus APC should not be used for sepsis or septic shock outside randomized clinical trials.


InternalMed_Harrison

InternalMed_Harrison. Peritonitis may develop as a complication of abdominal surgeries. These infections may be accompanied by localizing pain and/ or nonlocalizing signs or symptoms such as fever, malaise, anorexia, and toxicity. As a nosocomial infection, postoperative peritonitis may be associated with organisms such as staphylococci, components of the gram-negative hospital microflora, and the microbes that cause PBP and secondary peritonitis, as described above.


InternalMed_Harrison

InternalMed_Harrison. A third type of peritonitis arises in patients who are undergoing continuous ambulatory peritoneal dialysis (CAPD). Unlike PBP and secondary peritonitis, which are caused by endogenous bacteria, CAPD-associated peritonitis usually involves skin organisms. The pathogenesis of infection is similar to that of intravascular device– related infection, in which skin organisms migrate along the catheter, which both serves as an entry point and exerts the effects of a foreign body. Exit-site or tunnel infection may or may not accompany CAPD-associated peritonitis. Like PBP, CAPD-associated peritonitis is usually caused by a single organism. Peritonitis is, in fact, the most common reason for discontinuation of CAPD. Improvements in equipment design, especially the Y-set connector, have resulted in a decrease from one case of peritonitis per 9 months of CAPD to one case per 24 months.


InternalMed_Harrison

InternalMed_Harrison. The clinical presentation of CAPD peritonitis resembles that of secondary peritonitis in that diffuse pain and peritoneal signs are common. The dialysate is usually cloudy and contains >100 WBCs/μL, >50% of which are neutrophils. However, the number of cells depends in part on dwell time. According to a guideline from the International Society for Peritoneal Dialysis (2010), for patients undergoing automated peritoneal dialysis who present during their nighttime treatment and whose dwell time is much shorter than with CAPD, the clinician should use the percentage of PMNs rather than the absolute number of WBCs to diagnose peritonitis. As the normal peritoneum has very few PMNs, a proportion above 50% is strong evidence of peritonitis even if the absolute WBC count does not reach 100/μL. Meanwhile, patients undergoing automated peritoneal dialysis without a daytime exchange who present with abdominal pain may have no fluid to withdraw, in which case 1 L of dialysate should be infused


InternalMed_Harrison

InternalMed_Harrison. Meanwhile, patients undergoing automated peritoneal dialysis without a daytime exchange who present with abdominal pain may have no fluid to withdraw, in which case 1 L of dialysate should be infused and permitted to dwell a minimum of 1–2 h, then drained, examined for turbidity, and sent for cell count with differential and culture. The differential (with a shortened dwell time) may be more useful than the absolute WBC count. In equivocal cases or in patients with systemic or abdominal symptoms in whom the effluent appears clear, a second exchange is performed, with a dwell time of at least 2 h. Clinical judgment should guide initiation of therapy.


InternalMed_Harrison

InternalMed_Harrison. The most common organisms are Staphylococcus species, which accounted for ~45% of cases in one series. Historically, coagulasenegative staphylococcal species were identified most commonly in these infections, but these isolates have more recently been decreasing in frequency. Staphylococcus aureus is more often involved among patients who are nasal carriers of the organism than among those who are not, and this organism is the most common pathogen in overt exit-site infections. Gram-negative bacilli and fungi such as Candida species are also found. Vancomycin-resistant enterococci and vancomycinintermediate S. aureus have been reported to produce peritonitis in CAPD patients. The finding of more than one organism in dialysate culture should prompt evaluation for secondary peritonitis. As with PBP, culture of dialysate fluid in blood culture bottles improves the yield. To facilitate diagnosis, several hundred milliliters of removed dialysis fluid should be concentrated by


InternalMed_Harrison

InternalMed_Harrison. As with PBP, culture of dialysate fluid in blood culture bottles improves the yield. To facilitate diagnosis, several hundred milliliters of removed dialysis fluid should be concentrated by centrifugation before culture.


InternalMed_Harrison

InternalMed_Harrison. S. aureus, coagulase-negative Staphylococcus, and gram-negative bacilli until the results of cultures become available. Guidelines suggest that agents should be chosen on the basis of local experience with resistant organisms. In some centers, a first-generation cephalosporin such as cefazolin (for gram-positive bacteria) and a fluoroquinolone or a third-generation cephalosporin such as ceftazidime (for gram-negative bacteria) may be reasonable; in areas with high rates of infection with methicillin-resistant S. aureus, vancomycin should be used instead of cefazolin, and gram-negative coverage may need to be broadened—e.g., with an aminoglycoside, ceftazidime, cefepime, or carbapenem. Broad coverage including vancomycin should be particularly considered for toxic patients and for those with exit-site infections. Vancomycin should also be included in the regimen if the patient has a history of colonization or infection with methicillin-resistant S. aureus or has a history of severe


InternalMed_Harrison

InternalMed_Harrison. with exit-site infections. Vancomycin should also be included in the regimen if the patient has a history of colonization or infection with methicillin-resistant S. aureus or has a history of severe allergy to penicillins and cephalosporins. Loading doses are administered intraperitoneally; doses depend on the dialysis method and the patient’s renal function. Antibiotics are given either continuously (i.e., with each exchange) or intermittently (i.e., once daily, with the dose allowed to remain in the peritoneal cavity for at least 6 h). If the patient is severely ill, IV antibiotics should be added at doses appropriate for the patient’s degree of renal failure. The clinical response to an empirical treatment regimen should be rapid; if the patient has not responded after 48–96 h of treatment, new samples should be collected for cell counts and cultures, and catheter removal should be considered. For patients who lack exit-site or tunnel infection, the typical duration of antibiotic


InternalMed_Harrison

InternalMed_Harrison. new samples should be collected for cell counts and cultures, and catheter removal should be considered. For patients who lack exit-site or tunnel infection, the typical duration of antibiotic treatment is 14 days. For patients with exit-site or tunnel infection, catheter removal should be considered, and a longer duration of antibiotic therapy (up to 21 days) may be appropriate. In fungal infections, the catheter should be removed immediately.


InternalMed_Harrison

InternalMed_Harrison. See Chap. 202. Abscess formation is common in untreated peritonitis if overt gram-negative sepsis either does not develop or develops but is not fatal. In experimental models of abscess formation, mixed aerobic and anaerobic organisms have been implanted intraperitoneally. Without therapy directed at anaerobes, animals develop intraabdominal abscesses. As in humans, these experimental abscesses may stud the peritoneal cavity, lie within the omentum or mesentery, or even develop on the surface of or within viscera such as the liver.


InternalMed_Harrison

InternalMed_Harrison. Pathogenesis and Immunity There is often disagreement about whether an abscess represents a disease state or a host response. In a sense, it represents both: while an abscess is an infection in which viable infecting organisms and PMNs are contained in a fibrous capsule, it is also a process by which the host confines microbes to a limited space, thereby preventing further spread of infection. In any event, abscesses do cause significant symptoms, and patients with abscesses can be quite ill. Experimental work has helped to define both the host cells and the bacterial virulence factors responsible—most notably in the case of B. fragilis. This organism, although accounting for only 0.5% of the normal colonic flora, is the anaerobe most frequently isolated from intraabdominal infections, is especially prominent in abscesses, and is the most common anaerobic bloodstream isolate. On clinical grounds, therefore, B. fragilis appears to be uniquely virulent. Moreover, B. fragilis acts alone


InternalMed_Harrison

InternalMed_Harrison. especially prominent in abscesses, and is the most common anaerobic bloodstream isolate. On clinical grounds, therefore, B. fragilis appears to be uniquely virulent. Moreover, B. fragilis acts alone to cause abscesses in animal models of intraabdominal infection, whereas most other Bacteroides species must act synergistically with a facultative organism to induce abscess formation.


InternalMed_Harrison

InternalMed_Harrison. Of the several virulence factors identified in B. fragilis, one is critical: the capsular polysaccharide complex found on the bacterial surface. This complex comprises at least eight distinct surface polysaccharides. Structural analysis of these polysaccharides has shown an unusual motif of oppositely charged sugars. Polysaccharides having these zwitterionic characteristics, such as polysaccharide A, evoke a host response in the peritoneal cavity that localizes bacteria into abscesses. B. fragilis and polysaccharide A have been found to adhere to primary mesothelial cells in vitro; this adherence, in turn, stimulates the production of tumor necrosis factor α and intercellular adhesion molecule 1 by peritoneal macrophages. Although abscesses characteristically contain PMNs, the process of abscess induction depends on the stimulation of T lymphocytes by these unique zwitterionic polysaccharides. The stimulated CD4+ T lymphocytes secrete leukoattractant cytokines and chemokines. The


InternalMed_Harrison

InternalMed_Harrison. of abscess induction depends on the stimulation of T lymphocytes by these unique zwitterionic polysaccharides. The stimulated CD4+ T lymphocytes secrete leukoattractant cytokines and chemokines. The alternative pathway of complement and fibrinogen also participate in abscess formation.


InternalMed_Harrison

InternalMed_Harrison. While antibodies to the capsular polysaccharide complex enhance bloodstream clearance of B. fragilis, CD4+ T cells are critical in immunity to abscesses. When administered subcutaneously, B. fragilis polysaccharide A has immunomodulatory characteristics and stimulates CD4+ T regulatory cells via an interleukin 2–dependent mechanism to produce interleukin 10. Interleukin 10 downregulates the inflammatory response, thereby preventing abscess formation.


InternalMed_Harrison

InternalMed_Harrison. Clinical Presentation Of all intraabdominal abscesses, 74% are intra-peritoneal or retroperitoneal and are not visceral. Most intraperitoneal abscesses result from fecal spillage from a colonic source, such as an inflamed appendix. Abscesses can also arise from other processes. They usually form within weeks of the development of peritonitis and may be found in a variety of locations from omentum to mesentery, pelvis to psoas muscles, and subphrenic space to a visceral organ such as the liver, where they may develop either on the surface of the organ or within it. Periappendiceal and diverticular abscesses occur commonly. Diverticular abscesses are least likely to rupture. Infections of the female genital tract and pancreatitis are also among the more 849 common causative events. When abscesses occur in the female genital tract—either as a primary infection (e.g., tuboovarian abscess) or as an infection extending into the pelvic cavity or peritoneum—B. fragilis figures prominently


InternalMed_Harrison

InternalMed_Harrison. abscesses occur in the female genital tract—either as a primary infection (e.g., tuboovarian abscess) or as an infection extending into the pelvic cavity or peritoneum—B. fragilis figures prominently among the organisms isolated. B. fragilis is not found in large numbers in the normal vaginal flora. For example, it is encountered less commonly in pelvic inflammatory disease and endometritis without an associated abscess. In pancreatitis with leakage of damaging pancreatic enzymes, inflammation is prominent. Therefore, clinical findings such as fever, leukocytosis, and even abdominal pain do not distinguish pancreatitis itself from complications such as pancreatic pseudocyst, pancreatic abscess (Chap. 371), or intraabdominal collections of pus. Especially in cases of necrotizing pancreatitis, in which the incidence of local pancreatic infection may be as high as 30%, needle aspiration under CT guidance is performed to sample fluid for culture. Many centers prescribe preemptive


InternalMed_Harrison

InternalMed_Harrison. in which the incidence of local pancreatic infection may be as high as 30%, needle aspiration under CT guidance is performed to sample fluid for culture. Many centers prescribe preemptive antibiotics for patients with necrotizing pancreatitis. Imipenem is frequently used for this purpose because it reaches high tissue levels in the pancreas (although it is not unique in this regard). Recent randomized controlled studies have not demonstrated a benefit from this practice, and some guidelines no longer recommend preemptive antibiotics for patients with acute pancreatitis. If needle aspiration yields infected fluid in the setting of acute necrotizing pancreatitis, antibiotic treatment is appropriate in conjunction with surgical and/or percutaneous drainage of infected material. Infected pseudocysts that occur remotely from acute pancreatitis are unlikely to be associated with significant amounts of necrotic tissue and may be treated with either surgical or percutaneous catheter drainage


InternalMed_Harrison

InternalMed_Harrison. that occur remotely from acute pancreatitis are unlikely to be associated with significant amounts of necrotic tissue and may be treated with either surgical or percutaneous catheter drainage in conjunction with appropriate antibiotic therapy. Diagnosis Scanning procedures have considerably facilitated the diagnosis of intraabdominal abscesses. Abdominal CT probably has the highest yield, although ultrasonography is particularly useful for the right upper quadrant, kidneys, and pelvis. Both indium-labeled WBCs and gallium tend to localize in abscesses and may be useful in finding a collection. Because gallium is taken up in the bowel, indium-labeled WBCs may have a slightly greater yield for abscesses near the bowel. Neither indium-labeled WBC nor gallium scans serve as a basis for a definitive diagnosis, however; both need to be followed by other, more specific studies, such as CT, if an area of possible abnormality is identified. Abscesses contiguous with or contained within


InternalMed_Harrison

InternalMed_Harrison. a definitive diagnosis, however; both need to be followed by other, more specific studies, such as CT, if an area of possible abnormality is identified. Abscesses contiguous with or contained within diverticula are particularly difficult to diagnose with scanning procedures. Although barium should not be injected if a perforation is suspected, a barium enema occasionally may detect a diverticular abscess not diagnosed by other procedures. If one study is negative, a second study sometimes reveals a collection. Although exploratory laparotomy has been less commonly used since the advent of CT, this procedure still must be undertaken on occasion if an abscess is strongly suspected on clinical grounds.


InternalMed_Harrison

InternalMed_Harrison. An algorithm for the management of patients with intraabdominal (including intraperitoneal) abscesses by percutaneous drainage is presented in Fig. 159-3. The treatment of intraabdominal infections involves the determination of the initial focus of infection, the administration of broad-spectrum antibiotics targeting the organisms involved, and the performance of a drainage procedure if one or more definitive abscesses have formed. Antimicrobial therapy, in general, is adjunctive to drainage and/or surgical correction of an underlying lesion or process in intraabdominal abscesses. Unlike the intraabdominal abscesses resulting from most causes, for which drainage of some kind is generally required, abscesses associated with diverticulitis usually wall off locally after rupture of a diverticulum, so that surgical intervention is not routinely required.


InternalMed_Harrison

InternalMed_Harrison. A number of agents exhibit excellent activity against aerobic gram-negative bacilli. Because death in intraabdominal sepsis is linked to gram-negative bacteremia, empirical therapy for intra-abdominal infection always needs to include adequate coverage of gram-negative aerobic, facultative, and anaerobic organisms. Even 850 Percutaneous drainage No improvement by 48 h Defervescence by 24–48 h Drain out when criteria for catheter removal satisfied Repeat CT scan with dilute Hypaque injection into cavity and attempt further drainage No drainage or no improvement Successful drainage and defervescence Surgery FIGURE 159-3 Algorithm for the management of patients with intraabdominal abscesses using percutaneous drainage. Antimicrobial therapy should be administered concomitantly.


InternalMed_Harrison

InternalMed_Harrison. FIGURE 159-3 Algorithm for the management of patients with intraabdominal abscesses using percutaneous drainage. Antimicrobial therapy should be administered concomitantly. (Reprinted with permission from B Lorber [ed]: Atlas of Infectious Diseases, vol VII: Intra-abdominal Infections, Hepatitis, and Gastroenteritis. Philadelphia, Current Medicine, 1996, p 1.30, as adapted from OD Rotstein, RL Simmons, in SL Gorbach et al [eds]: Infectious Diseases. Philadelphia, Saunders, 1992, p 668.) if anaerobes are not cultured from clinical specimens, they still must be covered by the therapeutic regimen. Empirical antibiotic therapy should be the same as that discussed above for secondary peritonitis.


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InternalMed_Harrison. VISCERAL ABSCESSES Liver Abscesses The liver is the organ most subject to the development of abscesses. In one study of 540 intraabdominal abscesses, 26% were visceral. Liver abscesses made up 13% of the total number, or 48% of all visceral abscesses. Liver abscesses may be solitary or multiple; they may arise from hematogenous spread of bacteria or from local spread from contiguous sites of infection within the peritoneal cavity. In the past, appendicitis with rupture and subsequent spread of infection was the most common source for a liver abscess. Currently, associated disease of the biliary tract is most common. Pylephlebitis (suppurative thrombosis of the portal vein), usually arising from infection in the pelvis but sometimes from infection elsewhere in the peritoneal cavity, is another common source for bacterial seeding of the liver.


InternalMed_Harrison

InternalMed_Harrison. Fever is the most common presenting sign of liver abscess. Some patients, particularly those with associated disease of the biliary tract, have symptoms and signs localized to the right upper quadrant, including pain, guarding, punch tenderness, and even rebound tenderness. Nonspecific symptoms, such as chills, anorexia, weight loss, nausea, and vomiting, may also develop. Only 50% of patients with liver abscesses, however, have hepatomegaly, right-upper-quadrant tenderness, or jaundice; thus, one-half of patients have no symptoms or signs to direct attention to the liver. Fever of unknown origin may be the only manifestation of liver abscess, especially in the elderly. Diagnostic studies of the abdomen, especially the right upper quadrant, should be a part of any workup for fever of unknown origin. The single most reliable laboratory finding is an elevated serum concentration of alkaline phosphatase, which is documented in 70% of patients with liver abscesses. Other tests of liver


InternalMed_Harrison

InternalMed_Harrison. origin. The single most reliable laboratory finding is an elevated serum concentration of alkaline phosphatase, which is documented in 70% of patients with liver abscesses. Other tests of liver function may yield normal results, but 50% of patients have elevated serum levels of bilirubin, and 48% have elevated concentrations of aspartate aminotransferase. Other laboratory findings include leukocytosis in 77% of patients, anemia (usually normochromic, normocytic) in 50%, and hypoalbuminemia in 33%. Concomitant bacteremia is found in one-third to one-half of patients. A liver abscess is sometimes suggested by chest radiography, especially if a new elevation of the right hemidiaphragm is seen; other suggestive findings include a right basilar infiltrate and a right pleural effusion.


InternalMed_Harrison

InternalMed_Harrison. Imaging studies are the most reliable methods for diagnosing liver abscesses. These studies include ultrasonography, CT (Fig. 159-4), indium-labeled WBC or gallium scan, and MRI. More than one such FIGURE 159-4 Multilocular liver abscess on CT scan. Multiple or multilocular abscesses are more common than solitary abscesses. (Reprinted with permission from B Lorber [ed]: Atlas of Infectious Diseases, vol VII: Intra-abdominal Infections, Hepatitis, and Gastroenteritis. Philadelphia, Current Medicine, 1996, Fig. 1.22.) study may be required.


InternalMed_Harrison

InternalMed_Harrison. Organisms recovered from liver abscesses vary with the source. In liver infection arising from the biliary tree, enteric gram-negative aerobic bacilli and enterococci are common isolates. Klebsiella pneumoniae liver abscess has been well described in Southeast Asia for more than 20 years and has become an emerging syndrome in North America and elsewhere. These community-acquired infections have been linked to a virulent hypermucoviscous K. pneumoniae phenotype and to a specific genotype. The typical syndrome includes liver abscess, bacteremia, and metastatic infection. Ampicillin/amoxicillin therapy started within the previous 30 days has been associated with increased risk for this syndrome, presumably because of selection for the causative strain. Unless previous surgery has been performed, anaerobes are not generally involved in liver abscesses arising from biliary infections. In contrast, in liver abscesses arising from pelvic and other intraperitoneal sources, a mixed flora


InternalMed_Harrison

InternalMed_Harrison. anaerobes are not generally involved in liver abscesses arising from biliary infections. In contrast, in liver abscesses arising from pelvic and other intraperitoneal sources, a mixed flora including both aerobic and anaerobic species is common; B. fragilis is the species most frequently isolated. With hematogenous spread of infection, usually only a single organism is encountered; this species may be S. aureus or a streptococcal species such as one in the Streptococcus milleri group. Results of cultures obtained from drain sites are not reliable for defining the etiology of infections. Liver abscesses may also be caused by Candida species; such abscesses usually follow fungemia in patients receiving chemotherapy for cancer and often present when PMNs return after a period of neutropenia. Amebic liver abscesses are not an uncommon problem (Chap. 247). Amebic serologic testing gives positive results in >95% of cases. In addition, polymerase chain reaction (PCR) testing has been used in


InternalMed_Harrison

InternalMed_Harrison. Amebic liver abscesses are not an uncommon problem (Chap. 247). Amebic serologic testing gives positive results in >95% of cases. In addition, polymerase chain reaction (PCR) testing has been used in recent years. Negative results from these studies help to exclude this diagnosis.


InternalMed_Harrison

InternalMed_Harrison. (Fig. 159-3) Drainage is the mainstay of therapy for intraabdominal abscesses, including liver abscesses; the approach can be either percutaneous (with a pigtail catheter kept in place or possibly with a device that can perform pulse lavage to fragment and evacuate the semisolid contents of a liver abscess) or surgical. However, there is growing interest in medical management alone for pyogenic liver abscesses. The drugs used for empirical therapy include the same ones used in intraabdominal sepsis and secondary bacterial peritonitis. Usually, blood cultures and a diagnostic aspirate of abscess contents should be obtained before the initiation of empirical therapy, with antibiotic choices adjusted when the results of Gram’s staining and culture become available. Cases treated without definitive drainage generally require longer courses of antibiotic therapy. When percutaneous drainage was compared with open surgical drainage, the average length of hospital stay for the former was


InternalMed_Harrison

InternalMed_Harrison. definitive drainage generally require longer courses of antibiotic therapy. When percutaneous drainage was compared with open surgical drainage, the average length of hospital stay for the former was almost twice that for the latter, although both the time required for fever to resolve and the mortality rate were the same for the two procedures. The mortality rate was appreciable despite treatment, averaging 15%. Several factors predict the failure of percutaneous drainage and therefore may favor primary surgical intervention. These factors include the presence of multiple, sizable abscesses; viscous abscess contents that tend to plug the catheter; associated disease (e.g., disease of the biliary tract) requiring surgery; the presence of yeast; communication with an untreated obstructed biliary tree; or the lack of a clinical response to percutaneous drainage in 4–7 days.


InternalMed_Harrison

InternalMed_Harrison. Treatment of candidal liver abscesses often entails initial administration of amphotericin B or liposomal amphotericin, with subsequent fluconazole therapy (Chap. 240). In some cases, therapy with fluconazole alone (6 mg/kg daily) may be used—e.g., in clinically stable patients whose infecting isolate is susceptible to this drug.


InternalMed_Harrison

InternalMed_Harrison. Splenic Abscesses Splenic abscesses are much less common than liver abscesses. The incidence of splenic abscesses has ranged from 0.14% to 0.7% in various autopsy series. The clinical setting and the organisms isolated usually differ from those for liver abscesses. The degree of clinical suspicion for splenic abscess needs to be high because this condition is frequently fatal if left untreated. Even in the most recently published series, diagnosis was made only at autopsy in 37% of cases. Although splenic abscesses may arise occasionally from contiguous spread of infection or from direct trauma to the spleen, hematogenous spread of infection is more common. Bacterial endocarditis is the most common associated infection (Chap. 155). Splenic abscesses can develop in patients who have received extensive immunosuppressive therapy (particularly those with malignancy involving the spleen) and in patients with hemoglobinopathies or other hematologic disorders (especially sickle cell anemia).


InternalMed_Harrison

InternalMed_Harrison. Although ~50% of patients with splenic abscesses have abdominal pain, the pain is localized to the left upper quadrant in only one-half of these cases. Splenomegaly is found in ~50% of cases. Fever and leukocytosis are generally present; the development of fever preceded diagnosis by an average of 20 days in one series. Left-sided chest findings may include abnormalities to auscultation, and chest radiographic findings may include an infiltrate or a left-sided pleural effusion. CT scan of the abdomen has been the most sensitive diagnostic tool. Ultrasonography can yield the diagnosis but is less sensitive. Liver-spleen scan or gallium scan may also be useful. Streptococcal species are the most common bacterial isolates from splenic abscesses, followed by S. aureus—presumably reflecting the associated endocarditis. An increase in the prevalence of gram-negative aerobic isolates from splenic abscesses has been reported; these organisms often derive from a urinary tract focus, with


InternalMed_Harrison

InternalMed_Harrison. the associated endocarditis. An increase in the prevalence of gram-negative aerobic isolates from splenic abscesses has been reported; these organisms often derive from a urinary tract focus, with associated bacteremia, or from another intraabdominal source. Salmonella species are seen fairly commonly, especially in patients with sickle cell hemoglobinopathy. Anaerobic species accounted for only 5% of isolates in the largest collected series, but the reporting of a number of “sterile abscesses” may indicate that optimal techniques for the isolation of anaerobes were not used.


InternalMed_Harrison

InternalMed_Harrison. Because of the high mortality figures reported for splenic abscesses, splenectomy with adjunctive antibiotics has traditionally been considered standard treatment and remains the best approach for complex, multilocular abscesses or multiple abscesses. However, percutaneous drainage has worked well for single, small (<3-cm) abscesses in some studies and may also be useful for patients with high surgical risk. Patients undergoing splenectomy should be vaccinated against encapsulated organisms (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis). The most important factor in successful treatment of splenic abscesses is early diagnosis.


InternalMed_Harrison

InternalMed_Harrison. Perinephric and Renal Abscesses Perinephric and renal abscesses are 851 not common. The former accounted for only ~0.02% of hospital admissions and the latter for ~0.2% in Altemeier’s series of 540 intraabdominal abscesses. Before antibiotics became available, most renal and perinephric abscesses were hematogenous in origin, usually complicating prolonged bacteremia, with S. aureus most commonly recovered. Now, in contrast, >75% of perinephric and renal abscesses arise from a urinary tract infection. Infection ascends from the bladder to the kidney, with pyelonephritis preceding abscess development. Bacteria may directly invade the renal parenchyma from medulla to cortex. Local vascular channels within the kidney may also facilitate the transport of organisms. Areas of abscess developing within the parenchyma may rupture into the perinephric space. The kidneys and adrenal glands are surrounded by a layer of perirenal fat that, in turn, is surrounded by Gerota’s fascia, which extends


InternalMed_Harrison

InternalMed_Harrison. within the parenchyma may rupture into the perinephric space. The kidneys and adrenal glands are surrounded by a layer of perirenal fat that, in turn, is surrounded by Gerota’s fascia, which extends superiorly to the diaphragm and inferiorly to the pelvic fat. Abscesses extending into the perinephric space may track through Gerota’s fascia into the psoas or transversalis muscles, into the anterior peritoneal cavity, superiorly to the subdiaphragmatic space, or inferiorly to the pelvis. Of the risk factors that have been associated with the development of perinephric abscesses, the most important is concomitant nephrolithiasis obstructing urinary flow. Of patients with perinephric abscess, 20–60% have renal stones. Other structural abnormalities of the urinary tract, prior urologic surgery, trauma, and diabetes mellitus have also been identified as risk factors.


InternalMed_Harrison

InternalMed_Harrison. The organisms most frequently encountered in perinephric and renal abscesses are E. coli, Proteus species, and Klebsiella species. E. coli, the aerobic species most commonly found in the colonic flora, seems to have unique virulence properties in the urinary tract, including factors promoting adherence to uroepithelial cells. The urease of Proteus species splits urea, thereby creating a more alkaline and more hospitable environment for bacterial proliferation. Proteus species are frequently found in association with large struvite stones caused by the precipitation of magnesium ammonium sulfate in an alkaline environment. These stones serve as a nidus for recurrent urinary tract infection. Although a single bacterial species is usually recovered from a perinephric or renal abscess, multiple species may also be found. If a urine culture is not contaminated with periurethral flora and is found to contain more than one organism, a perinephric abscess or renal abscess should be considered


InternalMed_Harrison

InternalMed_Harrison. species may also be found. If a urine culture is not contaminated with periurethral flora and is found to contain more than one organism, a perinephric abscess or renal abscess should be considered in the differential diagnosis. Urine cultures may also be polymicrobial in cases of bladder diverticulum.


InternalMed_Harrison

InternalMed_Harrison. Candida species can cause renal abscesses. This fungus may spread to the kidney hematogenously or by ascension from the bladder. The hallmark of the latter route of infection is ureteral obstruction with large fungal balls.


InternalMed_Harrison

InternalMed_Harrison. The presentation of perinephric and renal abscesses is quite nonspecific. Flank pain and abdominal pain are common. At least 50% of patients are febrile. Pain may be referred to the groin or leg, particularly with extension of infection. The diagnosis of perinephric abscess, like that of splenic abscess, is frequently delayed, and the mortality rate in some series is appreciable, although lower than in the past. Perinephric or renal abscess should be most seriously considered when a patient presents with symptoms and signs of pyelonephritis and remains febrile after 4 or 5 days of treatment. Moreover, when a urine culture yields a polymicrobial flora, when a patient is known to have renal stones, or when fever and pyuria coexist with a sterile urine culture, these diagnoses should be entertained.


InternalMed_Harrison

InternalMed_Harrison. Renal ultrasonography and abdominal CT are the most useful diagnostic modalities. If a renal or perinephric abscess is diagnosed, nephrolithiasis should be excluded, especially when a high urinary pH suggests the presence of a urea-splitting organism. Treatment for perinephric and renal abscesses, like that for other intraabdominal abscesses, includes drainage of pus and antibiotic therapy directed at the organism(s) recovered. For perinephric abscesses, percutaneous drainage is usually successful.


InternalMed_Harrison

InternalMed_Harrison. 852 Psoas Abscesses The psoas muscle is another location in which abscesses are encountered. Psoas abscesses may arise from a hematogenous source, by contiguous spread from an intraabdominal or pelvic process, or by contiguous spread from nearby bony structures (e.g., vertebral bodies). Associated osteomyelitis due to spread from bone to muscle or from muscle to bone is common in psoas abscesses. When Pott’s disease was common, Mycobacterium tuberculosis was a frequent cause of psoas abscess. Currently, either S. aureus or a mixture of enteric organisms including aerobic and anaerobic gram-negative bacilli is usually isolated from psoas abscesses in the United States.


InternalMed_Harrison

InternalMed_Harrison. S. aureus is most likely to be isolated when a psoas abscess arises from hematogenous spread or a contiguous focus of osteomyelitis; a mixed enteric flora is the most likely etiology when the abscess has an intra-abdominal or pelvic source. Patients with psoas abscesses frequently present with fever, lower abdominal or back pain, or pain referred to the hip or knee. CT is the most useful diagnostic technique. Treatment includes surgical drainage and the administration of an antibiotic regimen directed at the inciting organism(s). Pancreatic Abscesses See Chap. 371. The substantial contributions of Dori F. Zaleznik, MD, to this chapter in previous editions are gratefully acknowledged. PART 8 Acute Infectious Diarrheal Diseases and Bacterial food Poisoning Regina C. LaRocque, Edward T. Ryan, Stephen B. Calderwood 160


InternalMed_Harrison

InternalMed_Harrison. PART 8 Acute Infectious Diarrheal Diseases and Bacterial food Poisoning Regina C. LaRocque, Edward T. Ryan, Stephen B. Calderwood 160 Acute diarrheal disease is a leading cause of illness globally and is associated with an estimated 1.4 million deaths per year. Among children <5 years of age, diarrheal disease is second only to lower respiratory infection as the most common infectious cause of death. The incidence rate of diarrheal disease among children in lowand middle-income countries is estimated to be 2.9 episodes per child per year, for a total of 1.7 billion episodes annually. The morbidity from diarrhea is also significant. Recurrent intestinal infections are associated with physical and mental stunting, wasting, micronutrient deficiencies, and malnutrition. In short, diarrheal disease is a driving factor in global morbidity and mortality.


InternalMed_Harrison

InternalMed_Harrison. The wide range of clinical manifestations of acute gastrointestinal illnesses is matched by the wide variety of infectious agents involved, including viruses, bacteria, and parasites (Table 160-1). This chapter discusses factors that enable gastrointestinal pathogens to cause disease, reviews host defense mechanisms, and delineates an approach to the evaluation and treatment of patients presenting with acute diarrhea. Individual organisms causing acute gastrointestinal illnesses are discussed in detail in subsequent chapters. Enteric pathogens have developed a variety of tactics to overcome host defenses. Understanding the virulence factors employed by these organisms is important in the diagnosis and treatment of clinical disease.


InternalMed_Harrison

InternalMed_Harrison. The number of microorganisms that must be ingested to cause disease varies considerably from species to species. For Shigella, enterohemorrhagic Escherichia coli, Giardia lamblia, or Entamoeba, as few as 10–100 bacteria or cysts can produce infection, while 105−108 Vibrio cholerae organisms must be ingested to cause disease. The infective dose of Salmonella varies widely, depending on the species, host, and food vehicle. The ability of organisms to overcome host defenses has important implications for transmission; Shigella, enterohemorrhagic E. coli, Entamoeba, and Giardia can spread by person-to-person contact, whereas under some circumstances Salmonella may have to grow in food for several hours before reaching an effective infectious dose.


InternalMed_Harrison

InternalMed_Harrison. Many organisms must adhere to the gastrointestinal mucosa as an initial step in the pathogenic process; thus, organisms that can compete with the normal bowel flora and colonize the mucosa have an important advantage in causing disease. Specific cell-surface proteins involved in attachment of bacteria to intestinal cells are important virulence determinants. V. cholerae, for example, adheres to the brush border of small-intestinal enterocytes via specific surface adhesins, including the toxin-coregulated pilus and other accessory colonization factors. Enterotoxigenic E. coli, which causes watery diarrhea, produces an adherence protein called colonization factor antigen that is necessary for colonization of the upper small intestine by the organism prior to the production of enterotoxin. Enteropathogenic E. coli, an agent of diarrhea in young children, and enterohemorrhagic E. coli, which causes hemorrhagic colitis and the hemolytic-uremic syndrome, produce virulence determinants that


InternalMed_Harrison

InternalMed_Harrison. E. coli, an agent of diarrhea in young children, and enterohemorrhagic E. coli, which causes hemorrhagic colitis and the hemolytic-uremic syndrome, produce virulence determinants that allow these organisms to attach to and efface the brush border of the intestinal epithelium.


InternalMed_Harrison

InternalMed_Harrison. The production of one or more exotoxins is important in the pathogenesis of numerous enteric organisms. Such toxins include enterotoxins, which cause watery diarrhea by acting directly on secretory mechanisms Mechanism Location Illness Stool Findings Examples of Pathogens Involved Vibrio cholerae, enterotoxigenic Escherichia coli (LT and/or ST), enteroaggregative E. coli, Clostridium perfringens, Bacillus cereus, Staphylococcus aureus, Aeromonas hydrophila, Plesiomonas shigelloides, rotavirus, norovirus, enteric adenoviruses, Giardia lamblia, Cryptosporidium spp., Cyclospora spp., microsporidia Shigella spp., Salmonella spp., Campylobacter jejuni, enterohemorrhagic E. coli, enteroinvasive E. coli, Yersinia enterocolitica, Listeria monocytogenes, Vibrio parahaemolyticus, Clostridium difficile, A. hydrophila, P. shigelloides, Entamoeba histolytica, Klebsiella oxytoca Salmonella typhi, Y. enterocolitica Abbreviations: LT, heat-labile enterotoxin; ST, heat-stable enterotoxin.


InternalMed_Harrison

InternalMed_Harrison. Salmonella typhi, Y. enterocolitica Abbreviations: LT, heat-labile enterotoxin; ST, heat-stable enterotoxin. in the intestinal mucosa; cytotoxins, which cause destruction of mucosal cells and associated inflammatory diarrhea; and neurotoxins, which act directly on the central or peripheral nervous system.


InternalMed_Harrison

InternalMed_Harrison. in the intestinal mucosa; cytotoxins, which cause destruction of mucosal cells and associated inflammatory diarrhea; and neurotoxins, which act directly on the central or peripheral nervous system. The prototypical enterotoxin is cholera toxin, a heterodimeric protein composed of one A and five B subunits. The A subunit contains the enzymatic activity of the toxin, while the B subunit pentamer binds holotoxin to the enterocyte surface receptor, the ganglioside GM1. After the binding of holotoxin, a fragment of the A subunit is translocated across the eukaryotic cell membrane into the cytoplasm, where it catalyzes the adenosine diphosphate ribosylation of a guanosine triphosphate–binding protein and causes persistent activation of adenylate cyclase. The end result is an increase of cyclic adenosine monophosphate in the intestinal mucosa, which increases Cl– secretion and decreases Na+ absorption, leading to a loss of fluid and the production of diarrhea.


InternalMed_Harrison

InternalMed_Harrison. Enterotoxigenic strains of E. coli may produce a protein called heat-labile enterotoxin (LT) that is similar to cholera toxin and causes secretory diarrhea by the same mechanism. Alternatively, enterotoxigenic strains of E. coli may produce heat-stable enterotoxin (ST), one form of which causes diarrhea by activation of guanylate cyclase and elevation of intracellular cyclic guanosine monophosphate. Some enterotoxigenic strains of E. coli produce both LT and ST. Bacterial cytotoxins, in contrast, destroy intestinal mucosal cells and produce the syndrome of dysentery, with bloody stools containing inflammatory cells. Enteric pathogens that produce such cytotoxins include Shigella dysenteriae type 1, Vibrio parahaemolyticus, and Clostridium difficile. S. dysenteriae type 1 and Shiga toxin–producing strains of E. coli produce potent cytotoxins and have been associated with outbreaks of hemorrhagic colitis and hemolytic-uremic syndrome.


InternalMed_Harrison

InternalMed_Harrison. Neurotoxins are usually produced by bacteria outside the host and therefore cause symptoms soon after ingestion. Included are the staphylococcal and Bacillus cereus toxins, which act on the central nervous system to produce vomiting.


InternalMed_Harrison

InternalMed_Harrison. Dysentery may result not only from the production of cytotoxins but also from bacterial invasion and destruction of intestinal mucosal cells. Infections due to Shigella and enteroinvasive E. coli are characterized by the organisms’ invasion of mucosal epithelial cells, intraepithelial multiplication, and subsequent spread to adjacent cells. Salmonella causes inflammatory diarrhea by invasion of the bowel mucosa but generally is not associated with the destruction of enterocytes or the full clinical syndrome of dysentery. Salmonella typhi and Yersinia enterocolitica can penetrate intact intestinal mucosa, multiply intracellularly in Peyer’s patches and intestinal lymph nodes, and then disseminate through the bloodstream to cause enteric fever, a syndrome characterized by fever, headache, relative bradycardia, abdominal pain, splenomegaly, and leukopenia.


InternalMed_Harrison

InternalMed_Harrison. Given the enormous number of microorganisms ingested with every meal, the normal host must combat a constant influx of potential enteric pathogens. Studies of infections in patients with alterations in defense mechanisms have led to a greater understanding of the variety of ways in which the normal host can protect itself against disease.


InternalMed_Harrison

InternalMed_Harrison. The large numbers of bacteria that normally inhabit the intestine (the intestinal microbiota) act as an important host defense mechanism, preventing colonization by potential enteric pathogens. Persons with fewer intestinal bacteria, such as infants who have not yet developed normal enteric colonization or patients receiving antibiotics, are at significantly greater risk of developing infections with enteric pathogens. The composition of the intestinal microbiota is as important as the number of organisms present. More than 99% of the normal colonic microbiota is made up of anaerobic bacteria, and the acidic pH and volatile fatty acids produced by these organisms appear to be critical elements in resistance to colonization.


InternalMed_Harrison

InternalMed_Harrison. The acidic pH of the stomach is an important barrier to enteric pathogens, and an increased frequency of infections due to Salmonella, G. lamblia, and a variety of helminths has been reported among patients who have undergone gastric surgery or are achlorhydric for some other reason. Neutralization of gastric acid with antacids, proton pump inhibitors, or H2 blockers—a common practice in the management of hospitalized patients—similarly increases the risk of enteric colonization. In addition, some microorganisms can survive the extreme acidity of the gastric environment; rotavirus, for example, is highly stable to acidity.


InternalMed_Harrison

InternalMed_Harrison. Normal peristalsis is the major mechanism for clearance of bacteria from the proximal small intestine. When intestinal motility is impaired (e.g., by treatment with opiates or other antimotility drugs, anatomic abnormalities, or hypomotility states), the frequency of bacterial overgrowth and infection of the small bowel with enteric pathogens is increased. Some patients whose treatment for Shigella infection consists of diphenoxylate hydrochloride with atropine (Lomotil) experience prolonged fever and shedding of organisms, while patients treated with opiates for mild Salmonella gastroenteritis have a higher frequency of bacteremia than those not treated with opiates.


InternalMed_Harrison

InternalMed_Harrison. Both cellular immune responses and antibody production play important roles in protection from enteric infections. Humoral immunity to enteric pathogens consists of systemic IgG and IgM as well as secretory IgA. The mucosal immune system may be the first line of defense against many gastrointestinal pathogens. The binding of bacterial antigens to the luminal surface of M cells in the distal small bowel and the subsequent presentation of antigens to subepithelial lymphoid tissue lead to the proliferation of sensitized lymphocytes. These lymphocytes circulate and populate all of the mucosal tissues of the body as IgAsecreting plasma cells.


InternalMed_Harrison

InternalMed_Harrison. Host genetic variation influences susceptibility to diarrheal diseases. People with blood group O show increased susceptibility to disease due to V. cholerae, Shigella, E. coli O157, and norovirus. Polymorphisms in genes encoding inflammatory mediators have been associated with the outcome of infection with enteroaggregative E. coli, enterotoxin-producing E. coli, Salmonella, C. difficile, and V. cholerae. APPROACH TO THE PATIENT: The approach to the patient with possible infectious diarrhea or bacterial food poisoning is shown in Fig. 160-1. The answers to questions with high discriminating value can quickly narrow the range of potential causes of diarrhea and help determine whether treatment is needed. Important elements of the narrative history are detailed in Fig. 160-1.


InternalMed_Harrison

InternalMed_Harrison. The examination of patients for signs of dehydration provides essential information about the severity of the diarrheal illness and the need for rapid therapy. Mild dehydration is indicated by thirst, dry mouth, decreased axillary sweat, decreased urine output, and slight weight loss. Signs of moderate dehydration include an orthostatic fall in blood pressure, skin tenting, and sunken eyes (or, in infants, a sunken fontanelle). Signs of severe dehydration include lethargy, obtundation, feeble pulse, hypotension, and frank shock. After the severity of illness is assessed, the clinician must distinguish between inflammatory and noninflammatory disease. Using the history and epidemiologic features of the case as guides, the clinician Resolution Continued illness Assess: Duration (>1 day) Severity (see text) Symptomatic therapy Oral rehydration therapy (see Table 160-5) Diarrhea, Nausea, or Vomiting No


InternalMed_Harrison

InternalMed_Harrison. Resolution Continued illness Assess: Duration (>1 day) Severity (see text) Symptomatic therapy Oral rehydration therapy (see Table 160-5) Diarrhea, Nausea, or Vomiting No Obtain stool to be examined for WBCs (and, if >10 days, for parasites) Continue symptomatic therapy (Table 160-5); further evaluation if no resolution Specific antiparasitic therapy Culture for: Shigella, Salmonella, C. jejuni Consider: C.difficile cytotoxin Noninflammatory (no WBCs; see Table 160-1) Inflammatory (WBCs; see Table 160-1) Examine stool for parasites Consider: Empirical antimicrobial therapy (Table 160-5) FIGURE 160-1 Clinical algorithm for the approach to patients with community-acquired infectious diarrhea or bacterial food poisoning.


InternalMed_Harrison

InternalMed_Harrison. Key to superscripts: 1. Diarrhea lasting >2 weeks is generally defined as chronic; in such cases, many of the causes of acute diarrhea are much less likely, and a new spectrum of causes needs to be considered. 2. Fever often implies invasive disease, although fever and diarrhea may also result from infection outside the gastrointestinal tract, as in malaria. 3. Stools that contain blood or mucus indicate ulceration of the large bowel. Bloody stools without fecal leukocytes should alert the laboratory to the possibility of infection with Shiga toxin–producing enterohemorrhagic Escherichia coli. Bulky white stools suggest a small-intestinal process that is causing malabsorption. Profuse “rice-water” stools suggest cholera or a similar toxigenic process. 4. Frequent stools over a given period can provide the first warning of impending dehydration. 5. Abdominal pain may be most severe in inflammatory processes like those due to Shigella, Campylobacter, and necrotizing toxins. Painful


InternalMed_Harrison

InternalMed_Harrison. can provide the first warning of impending dehydration. 5. Abdominal pain may be most severe in inflammatory processes like those due to Shigella, Campylobacter, and necrotizing toxins. Painful abdominal muscle cramps, caused by electrolyte loss, can develop in severe cases of cholera. Bloating is common in giardiasis. An appendicitis-like syndrome should prompt a culture for Yersinia enterocolitica with cold enrichment. 6. Tenesmus (painful rectal spasms with a strong urge to defecate but little passage of stool) may be a feature of cases with proctitis, as in shigellosis or amebiasis. 7. Vomiting implies an acute infection (e.g., a toxin-mediated illness or food poisoning) but can also be prominent in a variety of systemic illnesses (e.g., malaria) and in intestinal obstruction. 8. Asking patients whether anyone else they know is sick is a more efficient means of identifying a common source than is constructing a list of recently eaten foods. If a common source seems likely,


InternalMed_Harrison

InternalMed_Harrison. 8. Asking patients whether anyone else they know is sick is a more efficient means of identifying a common source than is constructing a list of recently eaten foods. If a common source seems likely, specific foods can be investigated. See text for a discussion of bacterial food poisoning. 9. Current antibiotic therapy or a recent history of treatment suggests Clostridium difficile diarrhea (Chap. 161). Stop antibiotic treatment if possible and consider tests for C. difficile toxins. Antibiotic use may increase the risk of chronic intestinal carriage following salmonellosis. 10. See text (and Chap. 149) for a discussion of traveler’s diarrhea.


InternalMed_Harrison

InternalMed_Harrison. (After TS Steiner, RL Guerrant: Principles and syndromes of enteric infection, in Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, 7th ed, GL Mandell et al [eds]. Philadelphia, Churchill Livingstone, 2010, pp 1335–1351; RL Guerrant, DA Bobak: N Engl J Med 325:327, 1991; with permission.) can then rapidly evaluate the need for further efforts to define a specific etiology and for therapeutic intervention. Examination of a stool sample may supplement the narrative history. Grossly bloody or mucoid stool suggests an inflammatory process. A test for fecal leukocytes (preparation of a thin smear of stool on a glass slide, addition of a drop of methylene blue, and examination of the wet mount) can suggest inflammatory disease in patients with diarrhea, although the predictive value of this test is still debated. A test for fecal lactoferrin, which is a marker of fecal leukocytes, is more sensitive and is available in latex agglutination and enzyme-linked


InternalMed_Harrison

InternalMed_Harrison. the predictive value of this test is still debated. A test for fecal lactoferrin, which is a marker of fecal leukocytes, is more sensitive and is available in latex agglutination and enzyme-linked immunosorbent assay formats. Causes of acute infectious diarrhea, categorized as inflammatory and noninflammatory, are listed in Table 160-1.


InternalMed_Harrison

InternalMed_Harrison. Chronic complications may follow the resolution of an acute diarrheal episode. The clinician should inquire about prior diarrheal illness if the conditions listed in Table 160-2 are observed. Chronic diarrhea Occurs in ~1% of travelers with acute diarrhea • Protozoa account for ~1/3 of cases Initial presentation or May be precipitated by traveler’s diarrhea exacerbation of inflammatory bowel disease Irritable bowel syndrome Occurs in ~10% of travelers with traveler’s diarrhea Reactive arthritis Particularly likely after infection with invasive organisms (Shigella, Salmonella, Campylobacter, Yersinia) Hemolytic-uremic syndrome Follows infection with Shiga toxin– (hemolytic anemia, producing bacteria (Shigella dysenteriae type thrombocytopenia, and renal 1 and enterohemorrhagic Escherichia coli) failure) Of the several million people who travel from temperate industrialized countries to tropical regions of Asia, Africa, and


InternalMed_Harrison

InternalMed_Harrison. Of the several million people who travel from temperate industrialized countries to tropical regions of Asia, Africa, and Central and South America each year, 20–50% experience a sudden onset of abdominal cramps, anorexia, and watery diarrhea; thus traveler’s diarrhea is the most common travel-related infectious illness (Chap. 149). The time of onset is usually 3 days to 2 weeks after the traveler’s arrival in a resource-poor area; most cases begin within the first 3–5 days. The illness is generally self-limited, lasting 1–5 days. The high rate of diarrhea among travelers to underdeveloped areas is related to the ingestion of contaminated food or water.


InternalMed_Harrison

InternalMed_Harrison. The organisms that cause traveler’s diarrhea vary considerably with location (Table 160-3), as does the pattern of antimicrobial resistance. In all areas, enterotoxigenic and enteroaggregative strains of E. coli are the most common isolates from persons with the classic secretory traveler’s diarrhea syndrome. Infection with Campylobacter jejuni is especially common in areas of Asia. Closed and semi-closed communities, including day-care centers, schools, residential facilities, and cruise ships, are important settings for outbreaks of enteric infections. Norovirus, which is highly contagious and robust in surviving on surfaces, is the most common etiologic agent associated with outbreaks of acute gastroenteritis. Other common organisms, often spread by fecal-oral contact in such communities, are Shigella,


InternalMed_Harrison

InternalMed_Harrison. C. jejuni, and Cryptosporidium. Rotavirus is rarely a cause of pediatric diarrheal outbreaks in the United States since rotavirus vaccination was broadly recommended in 2006. Similarly, hospitals are sites in which enteric infections are concentrated. Diarrhea is one of the most common manifestations of nosocomial infections. C. difficile is the predominant cause of nosocomial diarrhea among adults in the United States, and outbreaks of norovirus infection are common in health care settings. Klebsiella oxytoca has been identified as a cause of antibiotic-associated hemorrhagic colitis. Enteropathogenic E. coli has been associated with outbreaks of diarrhea in nurseries for newborns. One-third of elderly patients in chronic-care institutions develop a significant diarrheal illness each year; more than one-half of these cases are caused by cytotoxin-producing C. difficile. Antimicrobial therapy can predispose to pseudomembranous colitis by altering the normal colonic flora and allowing


InternalMed_Harrison

InternalMed_Harrison. more than one-half of these cases are caused by cytotoxin-producing C. difficile. Antimicrobial therapy can predispose to pseudomembranous colitis by altering the normal colonic flora and allowing the multiplication of C. difficile (Chap. 161).


InternalMed_Harrison

InternalMed_Harrison. aFor etiologic agents, see Table 160-4. Source: After DR Hill et al: The practice of travel medicine: Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43:1499, 2006. Globally, most morbidity and mortality from enteric pathogens involves children <5 years of age. Breast-fed infants are protected from contaminated food and water and derive some protection from maternal antibodies, but their risk of infection rises dramatically when they begin to eat solid foods. Exposure to rotavirus is universal, with most children experiencing their first infection in the first or second year of life if not vaccinated. Older children and adults are more commonly infected with norovirus. Other organisms with higher attack rates among children than among adults include enterotoxigenic, enteropathogenic, and enterohemorrhagic E. coli; Shigella; C. jejuni; and G. lamblia.


InternalMed_Harrison

InternalMed_Harrison. Immunocompromised hosts are at elevated risk of acute and chronic infectious diarrhea. Individuals with defects in cell-mediated immunity (including those with AIDS) are at particularly high risk of invasive enteropathies, including salmonellosis, listeriosis, and cryptosporidiosis. Individuals with hypogammaglobulinemia are at particular risk of C. difficile colitis and giardiasis. Patients with cancer are more likely to develop C. difficile infection as a result of chemotherapy and frequent hospitalizations. Infectious diarrhea can be life-threatening in immunocompromised hosts, with complications including bacteremia and metastatic seeding of infection. Furthermore, dehydration may compromise renal function and increase the toxicity of immunosuppressive drugs.


InternalMed_Harrison

InternalMed_Harrison. If the history and the stool examination indicate a noninflammatory etiology of diarrhea and there is evidence of a common-source outbreak, questions concerning the ingestion of specific foods and the time of onset of the diarrhea after a meal can provide clues to the bacterial cause of the illness. Potential causes of bacterial food poisoning are shown in Table 160-4.


InternalMed_Harrison

InternalMed_Harrison. Bacterial disease caused by an enterotoxin elaborated outside the host, such as that due to Staphylococcus aureus or B. cereus, has the shortest incubation period (1–6 h) and generally lasts <12 h. Most cases of staphylococcal food poisoning are caused by contamination from infected human carriers. Staphylococci can multiply at a wide range of temperatures; thus, if food is left to cool slowly and remains at room temperature after cooking, the organisms will have the opportunity to form enterotoxin. Outbreaks following picnics where potato salad, mayonnaise, and cream pastries have been served offer classic examples of staphylococcal food poisoning. Diarrhea, nausea, vomiting, and abdominal cramping are common, while fever is less so.


InternalMed_Harrison

InternalMed_Harrison. B. cereus can produce either a syndrome with a short incubation period—the emetic form, mediated by a staphylococcal type of enterotoxin—or one with a longer incubation period (8–16 h)—the diarrheal form, caused by an enterotoxin resembling E. coli LT, in which diarrhea and abdominal cramps are characteristic but vomiting is uncommon. The emetic form of B. cereus food poisoning is associated with contaminated fried rice; the organism is common in uncooked rice, and its heat-resistant spores survive boiling. If cooked rice is not refrigerated, the spores can germinate and produce toxin. Frying before serving may not destroy the preformed, heat-stable toxin.


InternalMed_Harrison

InternalMed_Harrison. Food poisoning due to Clostridium perfringens also has a slightly longer incubation period (8–14 h) and results from the survival of heat-resistant spores in inadequately cooked meat, poultry, or legumes. After ingestion, toxin is produced in the intestinal tract, causing moderately severe abdominal cramps and diarrhea; vomiting is rare, as is fever. The illness is self-limited, rarely lasting >24 h. Not all food poisoning has a bacterial cause. Nonbacterial agents of short-incubation food poisoning include capsaicin, which is found in hot peppers, and a variety of toxins found in fish and shellfish (Chap. 474).


InternalMed_Harrison

InternalMed_Harrison. Many cases of noninflammatory diarrhea are self-limited or can be treated empirically, and in these instances the clinician may not need to determine a specific etiology. Potentially pathogenic E. coli cannot be distinguished from normal fecal flora by routine culture, and tests to detect enterotoxins are not available in most clinical laboratories. In situations in which cholera is a concern, stool should be cultured on selective media such as thiosulfate–citrate–bile salts–sucrose (TCBS) or tellurite-taurocholate-gelatin (TTG) agar. A latex agglutination test has made the rapid detection of rotavirus in stool practical for many laboratories, while reverse-transcriptase polymerase chain reaction (PCR) and specific antigen enzyme immunoassays have been developed for the identification of norovirus. Stool specimens should be examined by immunofluorescence-based rapid assays or (less sensitive) standard microscopy for Giardia cysts or Cryptosporidium if the level of clinical suspicion


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InternalMed_Harrison. norovirus. Stool specimens should be examined by immunofluorescence-based rapid assays or (less sensitive) standard microscopy for Giardia cysts or Cryptosporidium if the level of clinical suspicion regarding the involvement of these organisms is high.


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InternalMed_Harrison. All patients with fever and evidence of inflammatory disease acquired outside the hospital should have stool cultured for Salmonella, Shigella, and Campylobacter. Salmonella and Shigella can be selected on MacConkey agar as non-lactose-fermenting (colorless) colonies or can be grown on Salmonella-Shigella agar or in selenite enrichment broth, both of which inhibit most organisms except these pathogens. Evaluation of nosocomial diarrhea should initially focus on C. difficile; stool culture for other pathogens in this setting has an extremely low yield and is not cost-effective. Toxins A and B produced by pathogenic strains of C. difficile can be detected by rapid enzyme immunoassays, latex agglutination tests, or PCR (Chap. 161). Isolation of C. jejuni requires inoculation of fresh stool onto selective growth medium and incubation at 42°C in a microaerophilic atmosphere. In many laboratories in the United States, E. coli O157:H7 is among the most common pathogens isolated from visibly


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InternalMed_Harrison. selective growth medium and incubation at 42°C in a microaerophilic atmosphere. In many laboratories in the United States, E. coli O157:H7 is among the most common pathogens isolated from visibly bloody stools. Strains of this enterohemorrhagic serotype can be identified in specialized laboratories by serotyping but also can be identified presumptively in hospital laboratories as lactose-fermenting, indole-positive colonies of sorbitol nonfermenters (white colonies) on sorbitol MacConkey plates. If the clinical presentation suggests the possibility of intestinal amebiasis, stool should be examined by a rapid antigen detection assay or by (less sensitive and less specific) microscopy.


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InternalMed_Harrison. In many cases, a specific diagnosis is not necessary or not available to guide treatment. The clinician can proceed with the information obtained from the history, stool examination, and evaluation of dehydration severity. Empirical regimens for the treatment of traveler’s diarrhea are listed in Table 160-5.


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InternalMed_Harrison. The mainstay of treatment is adequate rehydration. The treatment of cholera and other dehydrating diarrheal diseases was revolutionized by the promotion of oral rehydration solution (ORS), the efficacy of which depends on the fact that glucose-facilitated absorption of sodium and water in the small intestine remains intact in the presence of cholera toxin. The use of ORS has reduced mortality rates for cholera from >50% (in untreated cases) to <1%. A number of ORS formulas have been used. Initial preparations were based on the treatment of patients with cholera and included a solution containing 3.5 g of sodium chloride, 2.5 g of sodium bicarbonate (or 2.9 g of sodium citrate), 1.5 g of potassium chloride, and 20 g of glucose (or 40 g of sucrose) per liter of water. Such a preparation can still be used for the treatment of severe cholera. Many causes of secretory diarrhea, however, are associated with less electrolyte loss than occurs in cholera. Beginning in 2002, the World Health


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InternalMed_Harrison. still be used for the treatment of severe cholera. Many causes of secretory diarrhea, however, are associated with less electrolyte loss than occurs in cholera. Beginning in 2002, the World Health Organization recommended a “reduced-osmolarity/reduced-salt” ORS that is better tolerated and more effective than classic ORS. This preparation contains 2.6 g of sodium chloride, 2.9 g of trisodium citrate, 1.5 g of potassium chloride, and 13.5 g of glucose (or 27 g of sucrose) per liter of water. ORS formulations containing rice or cereal as the carbohydrate source may be even more effective than glucose-based solutions. Patients who are severely dehydrated or in whom vomiting precludes the use of oral therapy should receive IV solutions such as Ringer’s lactate.


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InternalMed_Harrison. Although most secretory forms of traveler’s diarrhea (usually due to enterotoxigenic or enteroaggregative E. coli or to Campylobacter) can be treated effectively with rehydration, bismuth subsalicylate, Watery diarrhea (no blood in stool, Oral fluids (oral rehydration solution, no fever), 1 or 2 unformed stools Pedialyte, Lytren, or flavored mineral per day without distressing enteric water) and saltine crackers symptoms Watery diarrhea (no blood in stool, Bismuth subsalicylate (for adults): no fever), 1 or 2 unformed stools per 30 mL or 2 tablets (262 mg/tablet) day with distressing enteric every 30 min for 8 doses; or symptoms loperamideb: 4 mg initially followed by 2 mg after passage of each unformed stool, not to exceed Watery diarrhea (no blood in stool, Antibacterial drugc plus (for adults) no distressing abdominal pain, no loperamideb (see dose above) fever), >2 unformed stools per day Dysentery (passage of bloody stools) Antibacterial drugc or fever (>37.8°C)


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InternalMed_Harrison. Dysentery (passage of bloody stools) Antibacterial drugc or fever (>37.8°C) Vomiting, minimal diarrhea Bismuth subsalicylate (for adults; see dose above) rehydration solution, Pedialyte, Lytren); continue feeding, especially attention for moderate dehydration, fever lasting >24 h, bloody stools, or aAll patients should take oral fluids (Pedialyte, Lytren, or flavored mineral water) plus saltine crackers. If diarrhea becomes moderate or severe, if fever persists, or if bloody stools or dehydration develops, the patient should seek medical attention. bLoperamide should not be used by patients with fever or dysentery; its use may prolong diarrhea in patients with infection due to Shigella or other invasive organisms. cThe recommended antibacterial drugs are as follows: If the level of suspicion is low for fluoroquinolone-resistant Campylobacter:


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InternalMed_Harrison. If the level of suspicion is low for fluoroquinolone-resistant Campylobacter: Adults: (1) A fluoroquinolone such as ciprofloxacin, 750 mg as a single dose or 500 mg bid for 3 days; levofloxacin, 500 mg as a single dose or 500 mg qd for 3 days; or norfloxacin, 800 mg as a single dose or 400 mg bid for 3 days. (2) Azithromycin, 1000 mg as a single dose or 500 mg qd for 3 days. (3) Rifaximin, 200 mg tid or 400 mg bid for 3 days (not recommended for use in dysentery). Children: Azithromycin, 10 mg/kg on day 1, 5 mg/kg on days 2 and 3 if diarrhea persists. If fluoroquinolone-resistant Campylobacter is suspected (for example, following travel to Southeast Asia): Adults: Azithromycin (at above dose for adults). Children: other areas (see above). Source: Diseases Society of America. Clin Infect Dis 43:1499, 2006. be treated empirically with an antimicrobial agent (e.g.,


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InternalMed_Harrison. Source: Diseases Society of America. Clin Infect Dis 43:1499, 2006. be treated empirically with an antimicrobial agent (e.g., Individuals Individuals with Campylobacter infection often benefit from antimicrobial treatment as well. Because of widespread resistance of Campylobacter to fluoroquinolones, especially in parts of Asia, a macrolide antibiotic such as erythromycin or azithromycin may be preferred for this infection.


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InternalMed_Harrison. Treatment of salmonellosis must be tailored to the individual patient. Since administration of antimicrobial agents often prolongs intestinal colonization with Salmonella, these drugs are usually reserved for individuals at high risk of complications from disseminated salmonellosis, such as young children, patients with prosthetic devices, elderly patients, and immunocompromised persons. Antimicrobial agents should not be administered to individuals (especially children) in whom enterohemorrhagic E. coli infection is 857 suspected. Laboratory studies of enterohemorrhagic E. coli strains have demonstrated that a number of antibiotics induce replication of Shiga toxin–producing lambdoid bacteriophages, thereby significantly increasing toxin production by these strains. Clinical studies have supported these laboratory results, and antibiotics may increase by twentyfold the risk of hemolytic-uremic syndrome and renal failure during enterohemorrhagic E. coli infection. A clinical clue in


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InternalMed_Harrison. supported these laboratory results, and antibiotics may increase by twentyfold the risk of hemolytic-uremic syndrome and renal failure during enterohemorrhagic E. coli infection. A clinical clue in the diagnosis of the latter infection is bloody diarrhea with low fever or none at all.


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InternalMed_Harrison. Improvements in hygiene to limit fecal-oral spread of enteric pathogens will be necessary if the prevalence of diarrheal diseases is to be significantly reduced in developing countries. Travelers can reduce their risk of diarrhea by eating only hot, freshly cooked food; by avoiding raw vegetables, salads, and unpeeled fruit; and by drinking only boiled or treated water and avoiding ice. Historically, few travelers to tourist destinations adhere to these dietary restrictions. Bismuth subsalicylate is an inexpensive agent for the prophylaxis of traveler’s diarrhea; it is taken at a dosage of 2 tablets (525 mg) four times a day. Treatment appears to be effective and safe for up to 3 weeks, but adverse events such as temporary darkening of the tongue and tinnitus can occur. A meta-analysis suggests that probiotics may lessen the likelihood of traveler’s diarrhea by ~15%. Prophylactic antimicrobial agents, although effective, are not generally recommended for the prevention of traveler’s


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InternalMed_Harrison. that probiotics may lessen the likelihood of traveler’s diarrhea by ~15%. Prophylactic antimicrobial agents, although effective, are not generally recommended for the prevention of traveler’s diarrhea except when travelers are immunosuppressed or have other underlying illnesses that place them at high risk for morbidity from gastrointestinal infection. The risk of side effects and the possibility of developing an infection with a drug-resistant organism or with more harmful, invasive bacteria make it more reasonable to institute an empirical short course of treatment if symptoms develop. If prophylaxis is indicated, the nonabsorbed antibiotic rifaximin can be considered.


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InternalMed_Harrison. The possibility of exerting a major impact on the worldwide morbidity and mortality associated with diarrheal diseases has led to intense efforts to develop effective vaccines against the common bacterial and viral enteric pathogens. An effective rotavirus vaccine is currently available. Vaccines against S. typhi and V. cholerae also are available, although the protection they offer is incomplete and/or short lived. At present, there is no effective commercially available vaccine against Shigella, enterotoxigenic E. coli, Campylobacter, nontyphoidal Clostridium difficile Infection, 161 Including Pseudomembranous Colitis Dale N. Gerding, Stuart Johnson


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InternalMed_Harrison. Clostridium difficile Infection, 161 Including Pseudomembranous Colitis Dale N. Gerding, Stuart Johnson Clostridium difficile infection (CDI) is a unique colonic disease that is acquired most often in association with antimicrobial use and the consequent disruption of the normal colonic microbiota. The most commonly diagnosed diarrheal illness acquired in the hospital, CDI results from the ingestion of spores of C. difficile that vegetate, multiply, and secrete toxins, causing diarrhea and pseudomembranous colitis (PMC) in the most severe cases. C. difficile is an obligately anaerobic, gram-positive, spore-forming bacillus whose spores are found widely in nature, particularly in the environment of hospitals and chronic-care facilities. CDI occurs


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InternalMed_Harrison. Clostridium difficile Infection, Including Pseudomembranous Colitis 858 frequently in hospitals and nursing homes (or shortly after discharge from these facilities) where the level of antimicrobial use is high and the environment is contaminated by C. difficile spores. Clindamycin, ampicillin, and cephalosporins were the first antibiotics associated with CDI. The secondand third-generation cephalosporins, particularly cefotaxime, ceftriaxone, cefuroxime, and ceftazidime, are frequently responsible for this condition, and the fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) are the most recent drug class to be implicated in hospital outbreaks. Penicillin/ β-lactamase-inhibitor combinations such as ticarcillin/clavulanate and piperacillin/tazobactam pose significantly less risk. However, all antibiotics, including vancomycin and metronidazole (the agents most commonly used to treat CDI), carry a risk of subsequent CDI. Rare cases are reported in patients without prior


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InternalMed_Harrison. risk. However, all antibiotics, including vancomycin and metronidazole (the agents most commonly used to treat CDI), carry a risk of subsequent CDI. Rare cases are reported in patients without prior antibiotic exposure.


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InternalMed_Harrison. C. difficile is acquired exogenously—most frequently in the hospital or nursing home, but also possibly in the outpatient setting—and is carried in the stool of both symptomatic and asymptomatic patients. The rate of fecal colonization is often ≥20% among adult patients hospitalized for >1 week; in contrast, the rate is 1–3% among community residents. Community-onset CDI without recent hospitalization, nursing home residence, or outpatient health-care contact probably accounts for ≤10% of all cases. The risk of C. difficile acquisition increases in proportion to the length of hospital stay. Asymptomatic fecal carriage of C. difficile in healthy neonates is very common, with repeated colonization by multiple strains in infants (<1 year old), but associated disease in these infants is extremely rare if it occurs at all. Spores of C. difficile are found on environmental surfaces (where the organism can persist for months) and on the hands of hospital personnel who fail to practice good


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InternalMed_Harrison. rare if it occurs at all. Spores of C. difficile are found on environmental surfaces (where the organism can persist for months) and on the hands of hospital personnel who fail to practice good hand hygiene. Hospital epidemics of CDI have been attributed to a single C. difficile strain and to multiple strains present simultaneously. Other identified risk factors for CDI include older age, greater severity of underlying illness, gastrointestinal surgery, use of electronic rectal thermometers, enteral tube feeding, and antacid treatment. Use of proton pump inhibitors may be a risk factor, but this risk is probably modest, and no firm data have implicated these agents in patients who are not already receiving antibiotics.


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InternalMed_Harrison. Spores of toxigenic C. difficile are ingested, survive gastric acidity, germinate in the small bowel, and colonize the lower intestinal tract, where they elaborate two large toxins: toxin A (an enterotoxin) and toxin B (a cytotoxin). These toxins initiate processes resulting in the disruption of epithelial-cell barrier function, diarrhea, and pseudo-membrane formation. Toxin A is a potent neutrophil chemoattractant, and both toxins glucosylate the guanosine triphosphate (GTP)–binding proteins of the Rho subfamily that regulate the actin cell cytoskeleton. Data from studies using molecular disruption of toxin genes in isogenic mutants suggest that toxin B is the more important virulence factor. This possibility, if confirmed, might account for the occurrence of clinical disease caused by toxin A–negative strains. Disruption of the cytoskeleton results in loss of cell shape, adherence, and tight junctions, with consequent fluid leakage. A third toxin, binary toxin CDT, was previously


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InternalMed_Harrison. toxin A–negative strains. Disruption of the cytoskeleton results in loss of cell shape, adherence, and tight junctions, with consequent fluid leakage. A third toxin, binary toxin CDT, was previously found in only ~6% of strains but is present in all isolates of the widely recognized epidemic NAP1/BI/027 strain (see “Global Considerations,” below); this toxin is related to C. perfringens iota toxin. Its role in the pathogenesis of CDI has not yet been defined.


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InternalMed_Harrison. The pseudomembranes of PMC are confined to the colonic mucosa and initially appear as 1to 2-mm whitish-yellow plaques. The intervening mucosa appears unremarkable, but, as the disease progresses, the pseudomembranes coalesce to form larger plaques and become confluent over the entire colon wall (Fig. 161-1). The whole colon is usually involved, but 10% of patients have rectal sparing. Viewed microscopically, the pseudomembranes have a mucosal attachment point and contain necrotic leukocytes, fibrin, mucus, and cellular debris. The epithelium is eroded and necrotic in focal areas, with neutrophil infiltration of the mucosa.


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InternalMed_Harrison. Patients colonized with C. difficile were initially thought to be at high risk for CDI. However, four prospective studies have shown that colonized patients who have not previously had CDI actually have a decreased risk of CDI. At least three events are proposed as essential for the development of CDI (Fig. 161-2). Exposure to antimicrobial agents is the first event and establishes susceptibility to C. difficile infection, most likely through disruption of the normal gastrointestinal microbiota. The second event is exposure to toxigenic C. difficile. Given that the majority of patients do not develop CDI after the first two events, a third event is clearly essential for its occurrence. Candidate third events include exposure to a C. difficile strain of particular virulence, exposure to antimicrobial agents especially likely


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InternalMed_Harrison. FIGURE 161-1 Autopsy specimen showing confluent pseudo-membranes covering the cecum of a patient with pseudomembra-nous colitis. Note the sparing of the terminal ileum (arrow). Pathogenesis model for C. difficile enteric disease Antimicrobial(s) Hospitalization CDI Asymptomatic C. difficile colonization Acquisition of a toxigenic strain of C. difficile and failure to mount an anamnestic toxin A antibody response result in CDI. C. difficile acquisition C. difficile acquisition


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InternalMed_Harrison. FIGURE 161-2 Pathogenesis model for hospital-acquired Clostridium difficile infection (CDI). At least three events are integral to C. difficile pathogenesis: (1) Exposure to antibiotics establishes susceptibility to infection. (2) Once susceptible, the patient may acquire nontoxigenic (nonpathogenic) or toxigenic strains of C. difficile as a second event. (3) Acquisition of toxigenic C. difficile may be followed by asymptomatic colonization or CDI, depending on one or more additional events (e.g., an inadequate host anamnestic IgG response to C. difficile toxin A).


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InternalMed_Harrison. to cause CDI, and an inadequate host immune response. The host anamnestic serum IgG antibody response to toxin A of C. difficile is the most likely third event that determines which patients develop diarrhea and which patients remain asymptomatic. In all probability, the majority of people first develop antibody to C. difficile toxins when colonized asymptomatically during the first year of life or after CDI in childhood. Infants are thought not to develop symptomatic CDI because they lack suitable mucosal toxin receptors that develop later in life. In adulthood, serum levels of IgG antibody to toxin A increase more in response to infection in individuals who become asymptomatic carriers than in those who develop CDI. For persons who develop CDI, development of increasing levels of antitoxin A during treatment correlates with a lower risk of recurrence of CDI. A clinical trial using monoclonal antibodies to both toxin A and toxin B in addition to standard therapy showed rates of


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InternalMed_Harrison. A during treatment correlates with a lower risk of recurrence of CDI. A clinical trial using monoclonal antibodies to both toxin A and toxin B in addition to standard therapy showed rates of recurrence significantly lower than those obtained with placebo plus standard therapy.


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InternalMed_Harrison. Rates and severity of CDI in the United States, Canada, and Europe increased markedly after the year 2000. Rates in U.S.


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InternalMed_Harrison. hospitals tripled between 2000 and 2005. In 2005, hospitals in Montreal, Quebec, reported rates four times higher than the 1997 baseline, with directly attributable mortality of 6.9% (increased from 1.5%). An epidemic strain, variously known as toxinotype III, REA type BI, polymerase chain reaction (PCR) ribotype 027, and pulsed-field type NAP1 and thus collectively designated NAP1/BI/027, is thought to account for much of the increase in incidence and has been found in North America, Europe, and Asia. It is now recognized that two clones of NAP1/BI/027 originated in the United States and Canada and spread to the United Kingdom, Europe, and Asia. The epidemic organism is characterized by (1) an ability to produce 16–23 times as much toxin A and toxin B as control strains in vitro; (2) the presence of a third toxin (binary toxin CDT); and (3) high-level resistance to all fluoroquinolones. New strains have been and probably will continue to be implicated in outbreaks, including a strain


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InternalMed_Harrison. presence of a third toxin (binary toxin CDT); and (3) high-level resistance to all fluoroquinolones. New strains have been and probably will continue to be implicated in outbreaks, including a strain (toxinotype V, ribotype 078) commonly found in food animals that also carries binary toxin and has been associated with high mortality risk in human infections. In the past 5 years, rates of CDI in the United Kingdom have markedly decreased, and the frequency of the NAP1/BI/027 strain in the countries of the European Union has likewise decreased. However, there has been no evidence of decreased rates of CDI or a decreased incidence of NAP1/BI/027 in North America; the latter strain still causes 25–35% of all CDIs in most regions of the United States.


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InternalMed_Harrison. Diarrhea is the most common manifestation caused by C. difficile. Stools are almost never grossly bloody and range from soft and unformed to watery or mucoid in consistency, with a characteristic odor. Patients may have as many as 20 bowel movements per day. Clinical and laboratory findings include fever in 28% of cases, abdomi-859 nal pain in 22%, and leukocytosis in 50%. When adynamic ileus (which is seen on x-ray in ~20% of cases) results in cessation of stool passage, the diagnosis of CDI is frequently overlooked. A clue to the presence of unsuspected CDI in these patients is unexplained leukocytosis, with ≥15,000 white blood cells (WBCs)/μL. Such patients are at high risk for complications of C. difficile infection, particularly toxic megacolon and sepsis.