Clostridium Difficile Colitis Associated with Infant Botulism: Near-Fatal Case

367 Clostridium difficile Colitis Associated with Infant Botulism: Near-Fatal Case Analogous to Hirschsprung’s Enterocolitis Robert Schechter, Bradley Peterson, James McGee, From the Infant Botulism Treatment and Prevention Program, Division Olajire Idowu, and John Bradley of Communicable Disease Control, California Department of Health Services, Berkeley; Children’s Hospital Oakland, Oakland; and Children’s Hospital San Diego, San Diego, California We present the first five reported cases of Clostridium difficile–associated diarrhea (CDAD) in children with infant botulism caused by Clostridium botulinum. We compare two fulminant cases of colitis in children with colonic stasis, the first caused by infant botulism and the second caused by Hirschsprung’s disease. In both children, colitis was accompanied by hypovolemia, hypotension, profuse ascites, pulmonary effusion, restrictive pulmonary disease, and femoral-caval thrombosis. Laboratory findings included pronounced leukocytosis, hypoalbuminemia, hyponatremia, coagulopathy, and, when examined in the child with infant botulism, detection of C. difficile toxin in ascites. CDAD recurred in both children, even though difficile cytotoxin was undetectable in stool after prolonged initial therapy. Four children who had both infant botulism and milder CDAD also are described. Colonic stasis, whether acquired, as in infant botulism, or congenital, as in Hirsch- sprung’s disease, may contribute to the susceptibility to and the severity of CDAD. The clostridia are diverse bacteria affiliated by their ability to Case Reports form spores and to survive anaerobically. They cause disease through extracellular peptide toxins, such as the neurotoxins of Fulminant CDAD (Toxic Megacolon) Associated with Colonic Stasis Clostridium botulinum and toxins A and B produced by Clos- tridium difficile. Of these two species, C. difficile is more Case 1. The initial phase of illness was typical of moder- familiar to clinicians as an agent of antibiotic-associated diar- ately severe infant botulism. The patient was a thriving rhea. This manifestation is but one point on a spectrum of 5-month-old white girl whose diet was breast milk, rice cereal, gastrointestinal disease. Up to a majority of formula-fed infants and fruit. She had soft, daily bowel movements. One month are asymptomatically colonized with C. difficile [1]. Whether before onset, her family had relocated temporarily from New colonization causes a silent protein-losing enteropathy is dis- England to a residence near heavy construction with soil dis- puted [2, 3]. C. difficile–associated diarrhea (CDAD) ranges ruption in southern California, where her father had a work from mild diarrhea to severe pseudomembranous colitis. Tox- assignment. She developed less frequent bowel movements, a igenic C. difficile has been detected in infants with lethal progressive inability to nurse, and weakness of cry, neck, and Hirschsprung’s enterocolitis [4–6], the primary cause of death facial expression over 2 days (figure 1). She was admitted to in Hirschsprung’s disease. the regional children’s hospital for evaluation of suspected Presented here are the first five reported cases of CDAD in sepsis vs. abdominal obstruction. those paralyzed with infant botulism, a rare illness caused by A diagnosis of infant botulism subsequently was considered, intestinal colonization with C. botulinum. We focus on parallel and she was infused on hospital day 2 with human botulism cases of fulminant C. difficile colitis in two children with immune globulin [7]. The state public health laboratory de- colonic stasis, the first caused by infant botulism and the tected botulinum toxin type A and type A C. botulinum in her second by Hirschsprung’s disease. We also describe four chil- feces from hospital day 2. She required mechanical ventilation dren who had both infant botulism and milder CDAD and for respiratory paralysis during hospital days 3–13. She re- reexamine an infant who was ill with colitis consistent with ceived ceftriaxone on hospital days 0–3 to treat suspected CDAD before testing for C. difficile was available. sepsis and then cefotaxime, cefazolin sodium, and ceftazidime on hospital days 8–18 because of fever and tracheal aspirates that yielded Pseudomonas aeruginosa, Branhamella catarrha- lis, and Staphylococcus aureus. By hospital day 21, she had regained much of her strength and tone, although feeding Received 27 July 1998; revised 29 March 1999. Reprints or correspondence: Dr. Robert Schechter, California Department of weakness and infrequent bowel movements persisted. Health Services, 2151 Berkeley Way, Room 716, Berkeley, California 94704 Her illness was then protracted by near-fatal pseudomem- ([email protected]). branous colitis. On hospital day 22, she began with fever, Clinical Infectious Diseases 1999;29:367–74 emesis, and watery stools from which leukocytes, heme, and © 1999 by the Infectious Diseases Society of America. All rights reserved. 1058–4838/99/2902–0028$03.00 rotavirus antigen were not detected. Diarrhea subsided within 368 Schechter et al. CID 1999;29 (August) Figure 1. Timing of illness for case 1: fulminant Clostridium difficile–associated diarrhea associated with infant botulism. DC 5 discharge from hospital; 15detected in laboratory testing; 25not detected in laboratory testing. 36 hours, but her serum sodium level decreased to 124 mmol/L, The evacuated stool contained tan and green pseudomem- while her potassium level was 5.3 mmol/L. Over hospital day branes consisting of mucopurulent exudate and fibrin. Culture 23, she became lethargic with abdominal distention, emesis, of stool and pseudomembranes yielded the following organ- and heme found in her stools. She returned to the intensive care isms: P. aeruginosa at 41 growth; Streptococcus faecalis, 31; unit on hospital day 24 with extreme abdominal distention, C. difficile, 11. Rotavirus antigen was not detected. Cytotox- anasarca, poor perfusion, hypotension, hemorrhage from the icity of stool diluted to 1:12 was neutralized by C. difficile sites of arterial cannulation and nasogastric tube placement, antitoxin (Bartels, Issaquah, WA) after a standard 1:3 dilution respiratory distress, and tongue thrusting as suspected seizure remained cytotoxic. Neutralizable C. difficile toxicity was de- activity. tectable to 500 LD50 by means of mouse bioassay. Cultures of Blood analyses revealed the following: WBC count, blood, urine, CSF, and peritoneal fluid showed no bacterial or 37,000/mm3, with 63% neutrophils, including 37% band forms; fungal growth. When peritoneal fluid was tested, C. difficile serum albumin, 1.8 g/dL; and serum total protein, 2.8 g/dL. toxin was detected by cytotoxicity assay, but C. difficile did not During laparotomy on hospital day 24, .1L(.15% of body grow on culture. Reevaluation of archived feces obtained on weight at admission) of slightly cloudy ascites was evacuated. hospital day 2 by culture and toxin assay found no evidence of Although her small intestine and proximal colon appeared C. difficile or its toxins, consistent with C. difficile colonization normal, her colon was dilated and hyperemic discretely from occurring during hospitalization. the midtransverse colon to rectum. There was no visible ne- Treatment for C. difficile included vancomycin given by crosis or perforation, and no bowel was resected. The colon nasointestinal and rectal tube on hospital days 24–27 and was milked gently to evacuate stool and then lavaged with intravenous metronidazole on hospital days 24–45. She also warm saline and kanamycin. A rectal tube was placed for received ampicillin, gentamicin, imipenem, and fluconazole for decompression and infusion of vancomycin. P. aeruginosa, Candida parapsilosis, and other organisms iso- CID 1999;29 (August) C. difficile and Infant Botulism 369 lated from cultures of stool and respiratory secretions. The At age 15 months, he was admitted after 2 days of poor correction of shock required infusions of multiple vasopressors feeding, abdominal distention, and not defecating. He had and albumin. Immunoglobulin was given intravenously at completed a course of treatment with erythromycin and sul- 1,200 mg/kg, both as colloid and in the attempt to neutralize fisoxazole for pneumonia 3 weeks previously. His vital signs C. difficile toxins. The patient again required mechanical ven- were normal; his abdomen was tender, with mucoid stool tilation during hospital days 24–39 for bilateral pleural effu- palpated in the rectal vault. His WBC count was 26,000/mm3, sions and atelectasis. with 85% neutrophils, including 54% band forms. Culture of Coagulopathy was confirmed as a cause of hemorrhage; her stool yielded normal flora, and blood and urine cultures showed hemoglobin level fell to 7.3 g/dL, her platelet count to no bacterial growth. An abdominal radiograph displayed dis- 25,000/mL, and her fibrinogen level to 113 mg/dL, and pro- tended loops of bowel and multiple air-fluid levels. A rectal thrombin time was elevated to 18.9 seconds and activated tube was placed for decompression, enteral feedings were partial thromboplastin time to 98 seconds. Over 10 days, she withheld, and treatment with intravenous ampicillin, gentami- required 14 units of platelets, 10 units of cryoprecipitate, 200 cin, and clindamycin was initiated. mL/kg fresh frozen plasma, and 85 mL/kg packed RBCs. On hospital day 2, half-strength formula feedings were be- Computed tomographs taken on hospital day 33 and 75 dis- gun, and within 5 hours, the child’s abdomen became mas- played a thrombus extending from the

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