October 2004 • Volume 39 • Number 10

Case Reports

Severe ciprofloxacin-associated pseudomembranous colitis in an eight-year-old child

Carlos A. Angel a, b, c, d * [MEDLINE LOOKUP]

Justtin Green a, b, c, d [MEDLINE LOOKUP]

Leonard Swischuk a, b, c, d [MEDLINE LOOKUP]

Janak Patel a, b, c, d [MEDLINE LOOKUP]

Abstract

Clostridium difficile is the principal cause of antibiotic-associated diarrhea and pseudomembranous enterocolitis in children. A case of severe pseudomembranous colitis developing in an 8-year-old child who had received oral ciprofloxacin therapy as part of an investigational protocol is presented. The safety and efficacy of fluoroquinolones in children has not yet been established. Use of these antibiotics in children outside investigational protocols ("off-label" use) as oral antipseudomonas agents is discouraged.

CLOSTRIDIUM DIFFICILE infection is the principal cause of nosocomial, antibiotic-associated diarrhea and pseudomembranous colitis.1 Although infections in children by this microorganism are known to be associated with a variety of antibiotics, particularly, clindamycin, lincomycin, amoxicillin, and cephalosporins, there are no reports in the pediatric literature of ciprofloxacin-associated pseudomembranous colitis. The use of ciprofloxacin, a fluoroquinolone with broad-spectrum activity against Gram-positive and Gram-negative bacteria especially effective against Pseudomonas aeruginosa, is becoming more widespread in the pediatric population, either for "off-label" use as an oral antipseudomonas agent or as an investigational drug in clinical trials. Several groups of patients susceptible to pseudomonas infections currently often receive ciprofloxacin therapy. These include children with cystic fibrosis, chronic otorrhea, osteochondritis from nail wounds in the feet, severe burns, and patients with neurogenic bladders and complicated recurrent urinary tract infections. We report a case of severe pseudomembranous colitis in an 8-year-old child who received ciprofloxacin treatment as part of an IRB-approved clinical trial at our institution.

Case report

The patient is a 9-year-old boy born at 23 weeks’ gestation with sacral agenesis and neurogenic bladder. At 3 years of age this child presented with his first urinary tract infection and had left vesicoureteral reflux diagnosed, which, after an initial trial of medical management, was treated with ureteral reimplantation. The patient was first seen by us at 8 years of age after an episode of acute pyelonephritis. At that time, clean-intermittent catheterization, anticholinergics, and antibiotic prophylaxis with trimethoprim-sulfamethoxazole were instituted for management of his neurogenic bladder and newly diagnosed grade III right vesicoureteral reflux. In addition, a bowel management program with enemas and suppositories was begun. Over the course of the next 4 months, the patient experienced 2 breakthrough, febrile, urinary tract infections, the first one caused by Escherichia coli, which responded to intravenous cefotaxime, and the second one caused by Klebsiella pneumoniae, which was initially treated with intravenous cefotaxime. However, once the sensitivities became available, the patient was enrolled on an institutional IRB-approved clinical trial with oral ciprofloxacin (250 mg twice a day for 10 days). The child was scheduled for right ureteral reimplantation 2 weeks later. After an uneventful operation, the patient was discharged on the second postoperative day in good condition. Six days later, this child was brought to the emergency department with severe abdominal pain and distension. The mother mentioned that before the ureteral reimplant he was having loose stools, which she failed to report, and after the operation he stopped having stools despite his usual regimen of enemas and suppositories. In the emergency room, the patient passed a large amount of bloody mucus per rectum. The patient was found to have an elevated white cell count (17,000) and hyponatremia (serum Na, 125 meq/dL). After admission and fluid resuscitation, an acute abdominal series showed severe "thumbprinting" of the intestine, suggestive of pseudomembranous colitis (Fig 1). This was confirmed with a positive enzyme immunoassay for C difficile toxin. Because of progressive abdominal distension, clinical deterioration, and severe hyponatremia, treatment was started with oral vancomycin and lactobacillus, intravenous metronidazole, and cefepime. Cefepime was continued for 72 hours to prevent secondary Gram-negative bacteremia. Abdominal distension progressed, and the possibility of toxic megacolon was contemplated. Computed tomography on the third day of admission showed ascites (serum albumin was 1.9 mg/dL) and diffusely thickened, markedly edematous loops of colon consistent with pseudomembranous colitis (Fig 2). Findings during the patient’s abdominal examinations began to improve, and on hospital-day 8 he was tolerating clear liquids by mouth, and his urine culture was clear; amphotericin B bladder washes were discontinued at this point. Diet was advanced slowly. On day 11 of antibiotic therapy, enzyme immunoassay for C difficile toxin was negative. A 14-day course of intravenous and oral antibiotics was completed. After 16 days of hospitalization, the patient was discharged on oral vancomycin (180 mg 3 times a day for 12 days), anticholinergics, clean-intermittent catheterizations, no urinary antibiotic prophylaxis, and no enemas. There have been no recurrences of colitis or diarrhea on follow-up of 16 months.

Discussion

Clostridium difficile is the principal cause of antibiotic-associated colitis and diarrhea in adults and children. Colitis is mediated by 2 potent exotoxins produced by this organism: (1) toxin A, an enterotoxin that induces increased fluid secretion and elicits an acute intestinal mucosal inflammatory response with granulocyte infiltration, epithelial cell necrosis, ulceration, and hemorrhagic edema and (2) toxin B, a powerful cytotoxin. Toxin A seems to be the principal mediator of intestinal disease.1,2 The spectrum of the disease ranges from asymptomatic carrier state to life-threatening pseudomembranous colitis and toxic megacolon. Approximately 25% to 65% of children less than 1 year of age are colonized with C difficile, whereas only 1% to 10% are colonized after 1 year.3 In vitro, a variety of aerobic and anaerobic microorganisms such as Lactobacillus species, Bacteroides species, group D enterococcus, and others may inhibit the growth of C difficile.2 Pathogenesis of pseudomembranous colitis results from antibiotic suppression of the natural microflora of the colon, which creates an environment favorable for C difficile proliferation.

Harmon et al4 reported a case in which pseudomembranous colitis with perforation developed in a breast-fed infant whose mother was taking oral ciprofloxacin. Although initially there was some controversy as to whether ciprofloxacin could be used to treat pseudomembranous colitis or traveler’s diarrhea in adults, it soon became evident that, as with many other antibiotics, the use of this compound could be associated with C difficile colitis.5 There is no reason to believe that this should not be the case in children because the bacteriology and antibiotic susceptibility of C difficile is the same in children as in adults. Although, in our case, a strict cause and effect relationship between ciprofloxacin therapy and pseudomembranous colitis cannot be clearly established because this patient had received other antibiotics known to cause pseudomembranous colitis, the time association between the onset of symptoms and therapy with ciprofloxacin is highly suggestive that this was the case. There are, currently, several clinical trials designed to answer questions about the safety and efficacy of fluoroquinolones in children. Until these questions are answered, a word of caution is in order for off-label use of these antibiotics in children.

References

1. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises: Case 6-1993. A 31-month-old girl with fever, diarrhea, abdominal distention, and edema. N Engl J Med 1994;330:420-426. MEDLINE

2. Devenyi AG. Antibiotic-induced colitis. Semin Pediatr Surg 1995;4:215-220. MEDLINE

3. Mitchell DK, Van R, Mason EH. Prospective study of toxigenic Clostridium difficile in children given amoxicillin/clavulanate for otitis media. Pediatr Infect Dis J 1996;15:514-519. MEDLINE

4. Harmon T, Burkhart G, Applebaum H. Perforated pseudomembranous colitis in the breast-fed infant. J Pediatr Surg 1992;27:744-746. MEDLINE

5. Cain DB, O’Connor ME. Pseudomembranous colitis associated with ciprofloxacin. Lancet 1990;336:946. MEDLINE

Publishing and Reprint Information

aDepartment of Surgery (Pediatric Surgery), The University of Texas Medical Branch, Galveston, TX, USA

bDepartment of Urology, The University of Texas Medical Branch, Galveston, TX, USA

cDepartment of Radiology (Pediatric Radiology), The University of Texas Medical Branch, Galveston, TX, USA

dDepartment of Pediatrics (Pediatric Infectious Diseases), The University of Texas Medical Branch, Galveston, TX, USA

*Address reprint request to Carlos A. Angel, MD, Associate Professor of Surgery and Pediatrics, Section of Pediatric Surgery, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555-0353 USA

Copyright © 2004 by Elsevier Inc.

doi: 10.1016/j.jpedsurg.2004.06.028