Traveling Children and E. coli O157:H7
Abstract & Commentary
Synopsis: Children with diarrhea due to E. coli O157:H7 who received antibiotics were more likely to develop hemolytic-uremic syndrome than those who did not receive antibiotics. Nonetheless, presumptive use of antimicrobials for travelers’ diarrhea still seems appropriate.
Source: Wong CS, et al. The risk of hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med 2000;342:1930-1936 (pre-publication electronic posting May 23, 2000).
Investigators at the university of washington prospectively evaluated 71 children younger than 10 years old who had diarrhea caused by E. coli O157:H7. Medical therapy was noted, and daily laboratory tests (blood count, renal function tests) were done until the episode of illness resolved (or until hemolytic-uremic syndrome [HUS] developed). Ten children (14%) developed HUS; seven required transfusions of blood products, four required dialysis, and all survived. The frequency of HUS did not relate to gender, fever, or initial renal function but was associated both with higher initial white blood cell counts and with antibiotic use. Children who received antibiotics seemed to have similar degrees of illness to those who did not. Five of nine (56%) antibiotic-treated children (3 with cephalosporins, 2 with cotrimoxazole) developed HUS, and only five of 62 (8%; P < 0.001) children who did not receive antibiotics developed HUS. The E. coli O157:H7 strains isolated were susceptible to the antibiotics used. It was concluded that antibiotic therapy for children with E. coli O157:H7 markedly increases the risk of HUS.
Comment by holenarasipur r. Vikram, MD, John c. Christenson, MD, & Philip R. Fischer, MD, DTM&H
The finding that antibiotic use increases the risk of HUS has direct implications for the management of children with bloody diarrhea. The importance of this finding is indicated by the decision of the New England Journal of Medicine editors to prepublish this paper electronically rather than delaying dissemination of the data for an additional month until the printed version would come out.
E. coli O157:H7 was identified as a human pathogen in the early 1980s. Most food-borne outbreaks have been traced to cattle, either in the form of ground beef or raw milk. In recent years, fruits, vegetables, and sprouts have accounted for a growing number of outbreaks. Person-to-person transmission in day-care and chronic-care facilities, and drinking and swimming in unchlorinated water are important considerations in selected situations. Like Shigella, E. coli O157:H7 produces Shiga toxin, which seems to play a role in intestinal invasion, in bloody diarrhea, and binding to endothelial cells in the kidneys. Within the renal vasculature, toxin triggers a cascade of events in which children develop microangiopathic hemolytic anemia, thrombocytopenia, and uremia. The majority of children with E. coli O157:H7 infection do not develop HUS, but some of those who do have either fatal courses or long-term complications.
Several different bacteria in addition to E. coli O157:H7 and Shigella can produce toxins that lead to HUS. Nonetheless, it is not clear what predisposes just some of the children with these infections to develop HUS. Selected factors reported to increase the risk of developing HUS among patients with E. coli O157:H7 infection include: use of antimotility agents, bloody diarrhea, fever, vomiting, elevated serum leukocyte count, extremes of age, and female gender.1 Antibiotic treatment has been considered a possible risk factor for several years.2 With Shigella, antibiotics seem to favorably affect the course of the diarrheal illness, but this is not the case with E. coli O157:H7.2 When shigellosis is treated with antibiotics to which the organisms are resistant, HUS is more common.3,4 Similarly, subtherapeutic concentrations of antibiotics in a laboratory setting stimulate E. coli O157:H7 to produce more toxins.5 Some studies, however, have shown that antibiotics have either no effect or a protective influence on outcomes in children with E. coli O157:H7 diarrhea.6-10 In a recent study involving a large outbreak of E. coli O157:H7 infection in Japanese schools, fosfomycin administered before the third day of illness was protective against HUS. However, a control group who did not receive antibiotics was lacking.11 The new, prospectively-acquired data from Washington tilt the balance of conflicting evidence toward a significant risk with the use of antibiotics, even those to which the organisms are susceptible, in children with E. coli O157:H7-induced diarrhea.
Can these results be extrapolated to adults with E. coli O157:H7 infection? Patients 50-59 years of age have been identified as having the second highest age-specific isolation rates after children for E. coli O157:H7 from stool specimens.12 However, the proportion of adults that go on to develop HUS (or the related thrombotic thrombocytopenic purpura) is unknown. Given the lack of any data in adults regarding the risk of precipitation of HUS with antibiotics, it is reasonable to avoid antibiotics in adults with E. coli O157:H7 infection. If a stool specimen can be sent promptly to the laboratory after the onset of bloody diarrhea, antibiotics can be avoided until the pathogen, if any, is identified.
How do these results relate to traveling children who develop diarrhea? Travel medicine practitioners often prescribe antibiotics for presumptive use in the event of a severe diarrheal illness. Should antibiotics be withheld from children with bloody diarrhea until results of specific E. coli O157:H7 testing are available?
Lacking definitive data to suggest a firm answer to these questions, several points can direct a reasoned response. First, E. coli O157:H7 is mostly associated with areas where there are large numbers of cattle. HUS associated with E. coli is mostly reported from developed countries, not from areas where travelers’ diarrhea is common. Second, results of reliable testing for E. coli O157:H7 toxin, antigen, and/or culture will not be immediately available at many travel destinations. Third, while awaiting culture results, antibiotics can help children with bloody diarrhea due to Shigella as well as travelers with non-bloody diarrhea due to non-O157:H7 enterotoxigenic E. coli.
With all this in mind, what should we do? First, we should fortify our promotion of food and water hygiene to prevent diarrhea in travelers, and we should continue to advise good oral hydration to treat children with diarrhea. Second, in areas such as North America where E. coli O157:H7 is increasingly common and where reliable labs are available, we should do prompt and specific pathogen isolation and testing before initiating antibiotic therapy for children with bloody diarrhea. Many laboratories in the United States test only bloody stools for the presence of E. coli O157:H7. Unfortunately, up to a third of isolates can originate from nonbloody stools.12 Supplementing the presence of visible blood in the specimen with a patient history of bloody diarrhea can increase the sensitivity of detection of E. coli O157:H7 in the stool to more than 90%.12 In children with whom one is concerned about HUS, specific testing for toxin might also be useful since organisms other than E. coli O157:H7 and Shigella can produce toxins that lead to HUS. Third, for travelers to developing countries, we can still provide an antibiotic (cotrimoxazole or azithromycin; ciprofloxacin probably safe but not FDA-approved for use in children) for use in cases of severe travelers’ diarrhea. Recommendations might change as more data become available about the epidemiology of E. coli O157:H7 in developing countries and about risks associated with antibiotic use in children with diarrhea. (Dr. Vikram is a Fellow in Infectious Diseases at Yale University and Dr. Christenson is Professor of Pediatrics and Chief of Pediatric Infectious Diseases at the University of Utah.)
References
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