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616 PART 5: Infectious Disorders

The severity and duration of chemotherapy-associated mucositis cor- Clostridium Difficile–Associated Diarrhea: Diarrhea and enterocolitis
relate to some degree with the extent of preexisting dental plaque and due to the toxin elaborated by C difficile is not a rare problem among
periodontal disease. 314 neutropenic patients receiving broad-spectrum antibiotic therapy,
particularly those who are recipients of antibacterial agents that have
Clinical Approach: Herpetic infections of the oropharynx and esopha- high biliary excretion rates and are active against intestinal anaerobic
gus may be anticipated in patients with a history of herpetic stomatitis bacteria. The spectrum of clinical syndromes of Clostridium Difficile–
or in those with IgG antibodies to HSV, indicating infection in the associated diarrhea (CDAD) ranges from nuisance diarrhea (loose
past. Although typical discrete vesicular lesions on an erythematous watery stooling with no other symptoms) to severe enterocolitis
base may be observed in neutropenic patients, herpetic infections defined by ≥2 of the following: abdominal cramping, fever, leuko-
may also manifest as areas of painful ulceration over a diffusely cytosis with neutrophilia, hypoalbuminemia, CT-detected intestinal
erythematous base. Such lesions must be distinguished from a typi- mural thickening, and endoscopic documentation of pseudomembra-
cal presentation of oropharyngeal candidiasis or cytotoxic therapy– nous changes in the intestinal mucosal surface. The antibacterial
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induced mucositis. Pseudomembranous pharyngitis suggests yeast agents most commonly associated with CDAD include clindamycin,
infection. A thorough examination of the gingival and periodontal the penicillins, and the cephalosporins. These agents may produce
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tissues for focal areas of pain, erythema, swelling, and bleeding can diarrhea at rates of 5% to 25% independent of C difficile, however.
suggest the periodontium as a potential focus of infection (particu- Event rates for diarrhea may also be similar independent on route of
larly as a source of bacteremic infection) by viridans streptococci and administration. There is an association between CDAD and the admin-
oropharyngeal gram-negative anaerobic bacilli. 315 istration of antibacterial agents commonly used in febrile neutropenic
Laboratory aids include virus culture techniques, direct fungal stains, 262 321
direct electron microscopic examination for virus particles, cytologic patients such as the carbapenems and fluoroquinolones. High-
dose cytotoxic chemotherapy with agents such as methotrexate, pacli-
examination of cellular material from the base of the ulcer (eg, Tzanck taxel, or fluorouracil has also been linked to this complication. 322-324
preparation for the detection of multinucleated giant cells and intra- Risk factors include age older than 60 years, prolonged periods of
nuclear inclusions), or direct herpes simplex antigen detection tech- hospitalization, and exposure to antibacterial therapy. The prevalence
niques. The material from a specific lesion should be submitted to the of intestinal colonization with C difficile may be higher (20%-30%)
microbiology laboratory for culture and for direct examination. Routine among hospitalized patients compared to approximately 3% among
Gram stain can be helpful in demonstrating the presence of budding outpatients. Accordingly, this diagnosis must be considered when
yeasts and pseudohyphae suggestive of Candida species. A potassium older, hospitalized cancer patients who have received anticancer regi-
hydroxide mount (to digest extraneous unwanted cellular material) can mens containing such agents or who may have received recent anti-
also provide a clue to this diagnosis by demonstrating the presence of bacterial therapy develop abdominal pain in association with watery
these structures.
diarrhea with or without blood.
Management: The morbidity associated with oropharyngeal or esoph- The emergence of a hypervirulent (NAP1/B1/027) strain of C difficile
ageal mucositis can be life threatening, particularly when local pain that produces toxins A and B at concentrations 16- to 23-fold higher
interferes with adequate nutritional intake. Pain control becomes a high than the wild-type strains is associated with more severe clinical disease
priority. Topical anesthetics such as lidocaine in a 2% water-soluble gel and a higher risk for treatment failure. Such infections may also occur in
or 5% water-insoluble ointment has been used widely with inconsis- lower risk patients who have not received antibiotic therapy.
tent success. Continuous intravenous morphine infusions have been Treatment has been based on the administration of oral metro-
successful for symptom control among HSCT recipients with cytotoxic nidazole (500 mg thrice daily or 250 mg four times daily) for mild-
therapy–induced mucositis or acute oral graft-versus-host disease. to-moderate cases or oral vancomycin (125 mg four times daily) for
325
Herpetic mucositis involving the oropharynx or esophagus should moderate-to-severe cases over a 10-day course. Clinical response is
be treated with acyclovir. Intravenous acyclovir (250 mg/m q8h) defined by resolution of the diarrhea (three or fewer unformed stools
2
may be administered for severe cases until oral administration per 24 hours over 2 consecutive days). Overall, cure rates of 90%
(200 mg q4 h) can be tolerated for a total course of 7 days. Pseudo- are common; however, those with severe disease have lower rates of
membranous candidiasis involving the oropharynx or esophagus may response, 86% among those with severe disease compared to 94% among
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be treated with various approaches. Topical therapy with oral nystatin those with mild disease. The median times to response have been 60 to
suspension remains a popular first-line approach. Many physicians 120 hours in clinical trials. Those with severe disease respond less well
prefer to prescribe orally absorbed azole antifungal agents such as flu- to metronidazole (76%) as compared to vancomycin (97%). Similarly,
conazole (50-400 mg daily). Invasive candidal esophagitis should be relapse rates for those with severe disease receiving metronidazole are
treated with intravenous amphotericin B to a cumulative dose of 500 higher (21%) than for those receiving vancomycin (10%). Relapse rates
to 1500 mg (approximately 5-15 mg/kg); oropharyngeal candidiasis among patients with the hypervirulent strain of C difficile are higher
has been treated successfully with cumulative doses of about 500 mg among vancomycin recipients (14%-36%).
(5 mg/kg). Necrotizing polymicrobial anaerobic mucositis responds Typhlitis and neutropenic Enterocolitis: Typhlitis, also called neutrope-
well to metronidazole (500 mg PO or IV q8h). 224 nic enterocolitis, necrotizing enterocolitis, or ileocecal syndrome, is a
Evidence is accumulating that much of the extramorbidity caused by serious, potentially life-threatening infection of the bowel wall seen
these infections superimposed on chemotherapy-induced mucositis can be in up to 32% of patients undergoing remission-induction therapy for
reduced by the prophylactic use of antiviral agents such as acyclovir among acute leukemia. 326-329 The pathological process includes diffuse dila-
HSV-seropositive individuals, antiseptics such as chlorhexidine, 317 tion and edema of the bowel wall, with varying degrees of mucosal
316
and antifungal agents such as oral azoles. Further work is required to and submucosal hemorrhage, and ulceration. The cecum appears
318
330
determine optimal doses and routes of administration for these agents. to be favored for the development of this syndrome, possibly related
■ ENTERIC INFECTIONS to its relatively tenuous blood supply. Bacterial invasion through
an ischemic gut wall in the setting of neutropenia and cytotoxic
Invasive enteric bacterial infections of the gut due to Salmonella or therapy–induced mucosal surface damage is the probable pathogen-
Shigella species are relatively uncommon in neutropenic patients. Two esis. 328,329 The syndrome presents a spectrum of severity from mild
clinical entities must be considered in febrile neutropenic patients with self-limiting cecal inflammation to fulminant bowel wall necrosis
abdominal pain and diarrhea: toxigenic enterocolitis from the toxin with perforation. The clinical syndrome is typically characterized by a
elaborated from an overgrowth of Clostridium difficile and neutropenic triad of diarrhea, abdominal pain, and fever in the setting of cytotoxic
enterocolitis (typhlitis). therapy–induced neutropenia. 330,331 Abdominal distention, nausea,

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