A Pediatric Case of Antibiotic-Associated Hemorrhagic Colitis Caused by Klebsiella Oxytoca.

Klebsiella oxytoca is a gram-negative member of the human fecal microbiota, which is detected in the intestine of about 1.6% to 9% of healthy subjects and thus considered to be a commensal member of the enteric microflora.[1] Recently, K. oxytoca has been recognized as the causative organism of antibiotic-associated hemorrhagic colitis (AAHC) after the use of antibiotics, whereas some studies have shown that K. oxytoca is not associated with nonhemorrhagic antibiotic-associated diarrhea.[2,3] The characteristics of AAHC are sudden onset of bloody diarrhea and abdominal cramps after penicillin therapy that is considered to be critical for triggering dysbiosis as K. oxytoca exhibits a natural resistance to penicillins.[4]

Here we describe a pediatric case of AAHC who initially presented with acute abdominal pain and bloody diarrhea after taking an antibiotic for traumatic dental injury. In addition, we conduct a literature review of previously reported cases of AAHC to clarify the characteristics from a clinical point of view.

Case Report

A previously healthy 14-year-old Japanese girl was admitted to our hospital with acute severe abdominal pain and frequent bloody diarrhea. She had been treated with 0.75 g oral amoxicillin (AMPC) daily without probiotics since she accidentally lost her teeth 3 days before the admission. She remained afebrile, and the positive findings on physical examination were limited to the abdomen: severe tenderness in the umbilical region without rebound and absent bowel sound. Laboratory examination was normal except for slightly elevated values of white blood cell count (12 400/µL) and C-reactive protein (0.95 mg/dL). An X-ray of the abdomen revealed distension of the small intestine, and ultrasound study demonstrated thickening of the colon walls. Based on the physical examination, laboratory findings, and imaging studies, acute infectious enteritis was initially suspected. The fact that she did not have high fever and that white blood cell count and C-reactive protein level were not highly elevated suggested that severe bacterial infection was less likely, so symptomatic treatment including fluid and diet therapy was administered with discontinuation of AMPC. On the third day of hospitalization, the results of stool bacterial analysis collected on admission were established: Clostridium difficile toxin A and B were not detected by the cytotoxin assay, nor was C. difficile itself isolated from the anaerobic stool culture. None of the intestinal pathogens such as Salmonella, Shigella, Vibrio, Campylobacter, Yersinia, and pathogenic Escherichia Coli were isolated either, but pure growth of K. oxytoca was yielded from the aerobic stool culture (Figure 1). The diagnosis of AAHC caused by K. oxytoca was made on the basis of the history of AMPC medication and the result of stool culture. Her condition gradually improved with the resolution of bloody diarrhea and abdominal cramps. She was discharged on the fifth day of hospitalization, and no recurrence of symptoms was observed thereafter.

Figure 1.

Stool culture yielded pure growth of Klebsiella oxytoca on MacConkey agar plate.

Discussion

We presented a pediatric case of AAHC caused by K. oxytoca who initially had acute abdominal pain and bloody diarrhea after taking AMPC, which then resolved spontaneously after cessation of AMPC. For the sake of comparison, we summarized the previously reported cases of AAHC (Table 1).[2,3,5-9] Of note, all cases of AAHC described to date suddenly developed bloody diarrhea and severe abdominal cramps approximately 4 to 10 days after taking penicillin derivatives. Symptoms resolved within 3 days after cessation of antibiotic therapy. It is also noteworthy that, in addition to adults, school-age children and adolescents have been affected with AAHC. In this context, narrow-spectrum antibiotics are widely prescribed for the treatment of common pediatric conditions such as upper respiratory tract infections or acute otitis media in the pediatric outpatient clinic, despite the fact that such conditions are often self-limiting viral infections and thus not benefitting from antibiotic therapy. Therefore, it is reasonably assumed that pediatric patients predominantly develop AAHC following administration of narrow-spectrum antibiotics. In fact, there have been a limited number of reports of AAHC by K. oxytoca probably because the symptoms are rather common and nonspecific, leading to underdiagnosis or misdiagnosis. Thus, it is speculated that the prevalence of AAHC would be underestimated and that there would be much more unreported pediatric and adult cases. Given that only withdrawal of the causative antibiotic treatment can usually result in the improvement of the symptoms and that more invasive management such as endoscopy is not the requisite for the diagnosis, it is important to keep this disease in mind as a possible differential diagnosis of acute bloody diarrhea. In this regard, taking a history of antibiotics medication would be beneficial for the diagnosis.

Table 1.

Clinical Features of Previously Reported AAHC Cases.

	This Case	Pediatric Cases (n = 6)	Adult Cases (n = 20)
Age (years)	14	6-14 (median = 11.5)	22-74 (median = 40)
Gender	Female	Females = 3, males = 3	Females = 10, males = 10
Antibiotics triggering AAHC (no. of cases)	AMPC	AMPC (4)	SBT/ABPC (10)
		AMPC/CVA (1)	AMPC (4)
		ABPC (1)	AMPC/CVA (4)
			AMPC + CAM (1)
			AMPC + MNZ (1)
Indication of antibiotics	Dental procedure	Upper respiratory tract infection	Sinusitis
		Urinary tract infection	Bronchitis
		Epididymitis	Tonsillitis
			Dental procedure
Time to onset (days)	4	3-12 (median = 6.5)	1-14 (median = 4.2)
Symptoms	Hemorrhagic diarrhea	Hemorrhagic diarrhea	Hemorrhagic diarrhea
	Severe abdominal pain	Severe abdominal pain	Severe abdominal pain
Time to recovery (days)	3	2-5 (median = 3.3)	2-7 (median = 2.8)
References		Refs 3-5	Refs 2, 6-8

Abbreviations: AAHC, antibiotic-associated hemorrhagic colitis; AMPC, amoxicillin; ABPC, ampicillin; SBT/ABPC, sulbactam/ampicillin; AMPC/CVA, amoxicillin/clavulanate; CAM, clarithromycin; MNZ, metronidazole.

Preventive measures for AAHC remain to be investigated. The cytotoxin-producing K. oxytoca strains present at least temporarily in the colon of healthy individuals are the causative organism of AAHC. Following therapy with penicillin derivatives, toxigenic K. oxytoca can selectively overgrow as microbial substitution, because Klebsiella is usually resistant to penicillins due to production of β-lactamase.[2] Based on the above-mentioned notion, taking probiotics is thought to be a good candidate for prevention. Although no reports have examined the prophylactic effect of probiotics against AAHC thus far, some trials in children receiving antibiotics have been performed to assess the efficacy of probiotics used for the prevention of antibiotic-associated diarrhea, demonstrating a dose-dependent benefit from probiotics.[10,11] Further investigations are needed to precisely evaluate the effect of probiotics against AAHC; nonetheless, taking probiotics such as live antibiotic-resistant Lactobacilli when using penicillin derivatives would be worth consideration even at this time point.

In summary, we present a 14-year-old girl with AAHC caused by K. oxytoca. AAHC is possibly misdiagnosed due to its nonspecific symptoms. Pediatricians should keep this disease in mind when seeing patients with bloody diarrhea and abdominal cramp after starting penicillin treatment.