I get asked frequently about the correlation between the use of antibiotics and the onset of hemolytic uremic syndrome (HUS) – that is, does the use of antibiotics with an E. coli O157:H7 infection cause a child who would not otherwise develop HUS to in fact develop it?
First, everyone knows that I am not a doctor. That being said, in nearly 18 years of representing families who have suffered through HUS, I have seen cases where children received no antibiotics and suffered HUS and I have seen the reverse.
In 2000 when Wong CS, Jelacic S, Habeeb RL, Watkins SL, Tarr PI., published “The risk of hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections” in the N Engl J Med 2000;342:1930-6, physicians (and lawyers) took notice. In pertinent part the article found:
In up to 15% of North American children infected with Escherichia coli O157:H7, hemolytic-uremic syndrome (HUS) develops because of systemic absorption of Shiga toxins produced by the organism. Although antibiotics have been shown in vitro to enhance release of these toxins from injured bacteria their effect on the development of HUS in people infected with E. coli O157:H7 is unknown.
In children with stool cultures positive for E. coli O157:H7, is antibiotic therapy associated with an increased risk of HUS, independent of the severity of the initial diarrheal illness?
The study’s criteria for HUS were met in 10 (14%) of the 71 subjects. HUS developed in 5 (56%) of 9 children who received antibiotic therapy and in 5 (8%) of 62 children who did not (p <% 0.001). Children who received antibiotic therapy were comparable to those who did not with respect to age, sex and the baseline clinical and laboratory features of their illness.
Multivariate analysis showed that the risk of HUS was associated significantly with what were considered to be 2 surrogate markers of disease severity: initial peripheral white blood cell count (p = 0.02) and time elapsed from the day of symptom onset to the day on which stool cultures were obtained (p = 0.008). Risk was directly proportional to the white blood cell count and inversely proportional to the interval between onset of illness and stool cultures. It was inferred from the latter finding that patients with more severe illness were evaluated earlier than those with less severe illness. The relative risk of HUS among the children who were given antibiotic therapy, when adjusted for these 2 variables, was 17.3 (95% confidence interval 2.2-137, p = 0.007).
Although this study is subject to the selection and confounding biases inherent in observational research, it offers compelling evidence of a link between antibiotic therapy and the development of HUS in diarrheal illness caused by E. coli O157:H7. The strength of the association and the biologically plausible effect of antibiotics on the amount of Shiga toxin available for absorption from the intestine support the inference of causality.
Although HUS develops in patients infected with E. coli O157:H7 with or without antibiotic treatment, it occurs much more frequently when antibiotics are given. The findings of this study strongly suggest that these drugs should be withheld in children with acute diarrheal illness until stool cultures confirm growth of an organism for which antibiotic therapy is indicated (e.g., Campylobacter pylori).
In JAMA in 2002 (Aug 28;288(8):996-1001) questions were raised by Safdar N, Said A, Gangnon RE, Maki DG. In part the comment found:
The use of antibiotics for treatment of Escherichia coli O157:H7 infection has become controversial since a recent small study found that it may increase the risk of hemolytic uremic syndrome (HUS). However, other larger studies have reported a protective effect or no association.
To determine whether antibiotic therapy for E coli O157:H7 enteritis increases the risk of HUS.
PubMed and MEDLINE computer searches were performed for studies published from January 1983 to February 2001 using the key words hemolytic uremic syndrome, risk factor, antibiotics, and Escherichia coli O157:H7. Reference lists of relevant publications were reviewed, and 12 experts in the field were contacted to identify additional reports. No language restrictions were applied to the search.
Studies were included if they reported a series of patients with documented E coli O157:H7 enteritis, some of whom developed HUS; had clear definitions of HUS; and had adequate data delineating the relationship between antibiotic therapy and the occurrence of HUS. Nine of the 26 identified studies fulfilled these criteria.
Two authors (N.S. and A.S.) independently reviewed each report identified by the searches and recorded predetermined information relevant to the inclusion criteria. A pooled odds ratio was calculated using a fixed-effects model, with assessment of heterogeneity among the studies.
The pooled odds ratio was 1.15 (95% confidence interval, 0.79-1.68), indicating that there does not appear to be an increased risk of HUS with antibiotic treatment of E coli O157:H7 enteritis. Incomplete reporting of data in individual studies precluded adjustment for severity of illness.
Our meta-analysis did not show a higher risk of HUS associated with antibiotic administration. A randomized trial of adequate power, with multiple distinct strains of E coli O157:H7 represented, is needed to conclusively determine whether antibiotic treatment of E coli O157:H7 enteritis increases the risk of HUS.
So, good readers, what is the answer to the question – “In E. coli O157:H7 cases, is antibiotic therapy associated with an increased risk of HUS, or not?