Background Children with gastrointestinal infections causedby Escherichia coli O157:H7 are at risk for the hemolytic–uremicsyndrome. Whether antibiotics alter this risk is unknown.
Methods We conducted a prospective cohort study of 71 childrenyounger than 10 years of age who had diarrhea caused by E. coliO157:H7 to assess whether antibiotic treatment in these childrenaffects the risk of the hemolytic–uremic syndrome andto assess the influence of confounding factors on this outcome.Estimates of relative risks were adjusted for possible confoundingeffects with the use of logistic-regression analysis.
Results Among the 71 children, 9 (13 percent) received antibioticsand the hemolytic–uremic syndrome developed in 10 (14percent). Five of these 10 children had received antibiotics.Factors significantly associated with the hemolytic–uremicsyndrome were a higher initial white-cell count (relative risk,1.3; 95 percent confidence interval, 1.1 to 1.5), evaluationwith stool culture soon after the onset of illness (relativerisk, 0.3; 95 percent confidence interval, 0.2 to 0.8), andtreatment with antibiotics (relative risk, 14.3; 95 percentconfidence interval, 2.9 to 70.7). The clinical and laboratorycharacteristics of the 9 children who received antibiotics andthe 62 who did not receive antibiotics were similar. In a multivariateanalysis that was adjusted for the initial white-cell countand the day of illness on which stool was obtained for culture,antibiotic administration remained a risk factor for the developmentof the hemolytic–uremic syndrome (relative risk, 17.3;95 percent confidence interval, 2.2 to 137).
Conclusions Antibiotic treatment of children with E. coli O157:H7infection increases the risk of the hemolytic–uremic syndrome.
Escherichia coli O157:H7 causes sporadic and epidemic gastrointestinalinfections worldwide. In approximately 15 percent of the childrenin North America who are infected with E. coli O157:H7, thehemolytic–uremic syndrome develops soon after the onsetof diarrhea.1,2,3,4 This syndrome is characterized by thrombocytopenia,hemolytic anemia, and nephropathy and is believed to be causedby Shiga toxins elaborated by E. coli O157:H7 or other infectingE. coli that have been absorbed into the systemic circulation.5
Treatment with antibiotics does not ameliorate E. coli O157:H7infections,1,6,7 and in some studies, it has been associatedwith worse clinical outcomes.8,9,10 In one prospective, randomized,controlled trial, antibiotic treatment was neither harmful norbeneficial, but treatment was administered late in the courseof illness.11 In a child infected with E. coli O157:H7 who wastreated with antibiotics before the onset of diarrhea, fecalshedding of the organisms ceased, but the treatment did notprevent the hemolytic–uremic syndrome.12
When analyzing the role of antibiotic administration as a riskfactor for the development of the hemolytic–uremic syndromein children infected with E. coli O157:H7, it is important toconsider that the severity of illness might confound the associationwith antibiotic treatment. For example, antibiotics might beadministered to more severely ill infected children in whomthe hemolytic–uremic syndrome is destined to develop independentlyof antibiotic treatment. We therefore examined data from a prospectivecohort study to determine whether antibiotic treatment altersthe risk of the hemolytic–uremic syndrome among childreninfected with E. coli O157:H7.
Methods
A network of 47 cooperating laboratories in Washington, Oregon,Idaho, and Wyoming prospectively identified 73 children youngerthan 10 years of age who had E. coli O157:H7 infections betweenApril 1, 1997, and August 31, 1999. These children were identifiedon the basis of stool cultures done on sorbitol–MacConkeyagar to detect this pathogen.13 One of the investigators wascontacted immediately by telephone after the identificationof each infected child by the laboratory. This investigatorthen immediately telephoned the child's physician seeking permissionto approach the child's family about participation in the study.Written informed consent was obtained from the parents or guardiansof each child, and, if appropriate, assent was obtained fromthe child. The study was approved by the institutional reviewboard at each participating hospital. Only the 71 children whosestool cultures were obtained within the first seven days afterthe onset of illness (the first day of diarrhea was consideredto be the first day of illness) were included in the analysis.
A standardized questionnaire was administered to the caregiversof each enrolled child within two days after enrollment. Questionswere included about the child's sex, age, and race or ethnicgroup; the duration of symptoms and signs; the presence or absenceof visible blood in the stool, vomiting, and fever; and thenames of prescription and nonprescription medications takenduring the illness. Prescription medications were administeredat the discretion of each child's primary care, inpatient, oremergency department physician. Nonprescription medicationswere administered on the recommendation of each patient's treatingphysician or on the basis of the caregiver's decision. Onlymedications taken on or before the seventh day of illness wereconsidered. Medications administered after the hemolytic–uremicsyndrome was diagnosed were not analyzed. Medications were classifiedas antibiotics; antimotility drugs (if they inhibited intestinalperistalsis), including opioid narcotics; acetaminophen; andnonsteroidal antiinflammatory drugs.
The administration of all reported prescription drugs was verifiedby the medical provider who prescribed them or by inspectingthe child's medical record. Isolates of E. coli O157:H7 weresent to the Children's Hospital and Regional Medical Centerin Seattle for determinations of their susceptibility to theantibiotics administered to the children. The disk-diffusiontechnique was used for susceptibility testing.14
To reduce concern about observer error and the ability to validatetemperature measurements, the analysis included only the initialtemperature determinations for children evaluated at Children'sHospital and Regional Medical Center in Seattle. The laboratorydata that were analyzed consisted of white-cell counts and serumurea nitrogen and creatinine concentrations. Only the initiallaboratory test result for each child was analyzed as a potentialrisk factor for the development of the hemolytic–uremicsyndrome.
Daily blood counts and renal-function tests were performed inall infected children until the hemolytic–uremic syndromedeveloped and resolved or until the diarrhea resolved and thehemolytic–uremic syndrome clearly did not develop. Thehemolytic–uremic syndrome was defined as hemolytic anemia(a hematocrit below 30 percent, with evidence of the destructionof erythrocytes on a peripheral-blood smear), thrombocytopenia(a platelet count of less than 150,000 per cubic millimeter),and renal insufficiency (a serum creatinine concentration thatexceeded the upper limit of the normal range for age).
On the basis of previous studies in Washington of children infectedwith E. coli O157:H7,1,2 the period of risk for the hemolytic–uremicsyndrome was considered to be 14 days from the onset of diarrheaamong children with a positive culture for E. coli O157:H7,and this represented the period of clinical observation. Theincidence of the hemolytic–uremic syndrome was expressedin terms of the risk of development of the syndrome for an individualchild during these 14 days. Children with the syndrome werecategorized as having oligoanuria if they excreted less than0.5 ml of urine per kilogram of body weight per hour for 48or more hours during the course of the syndrome. Medical recordswere reviewed to verify the fulfillment of the classificationcriteria.
Differences between the children who were treated with antibioticsand those who were not were analyzed with the use of independent-samplet-tests for continuous variables and Fisher's exact or chi-squaretests for categorical variables and with use of univariate logisticregression for linear trend.15 Multivariate logistic-regressionanalysis was used to examine the risk of the hemolytic–uremicsyndrome after adjustment for the initial white-cell count andthe day of illness on which the initial stool culture was obtainedfor analysis.15 These factors were chosen because they wereassociated with the risk of the hemolytic–uremic syndrome.1,8The day of submission of the stool sample was the most commonpoint in the illness at which antibiotics were prescribed forthe children in this study.
The association between the exposure to medication during thediarrheal phase of infection and the subsequent developmentof the hemolytic–uremic syndrome was estimated by oddsratios and reported as the relative risk. Demographic factors,the presence or absence of specific symptoms, the duration ofthe diarrhea before the laboratory assessments and the administrationof antibiotics, and initial laboratory values were studied todetermine whether these factors confounded the association betweenexposure to medication and the development of the hemolytic–uremicsyndrome. We selected the variables that were significantlyassociated with the hemolytic–uremic syndrome, and werea priori considered to be potential confounders, to yield themost parsimonious model. After adjustment, the final modelswere interpreted as the adjusted relative risk of the hemolytic–uremicsyndrome among children infected with E. coli O157:H7. Adjustedrelative risks and their 95 percent confidence intervals werecalculated from the logistic-regression coefficients and theirstandard errors. Results are reported as adjusted relative riskswith 95 percent confidence intervals. All P values are two-tailed.Computations were performed with use of Intercooled Stata software(version 6.0 for Windows, Stata, College Station, Tex.).
Results
The hemolytic–uremic syndrome developed in 10 of the 71children with E. coli O157:H7 infection (14 percent). Four ofthese 10 children were classified as having oligoanuria, andeach of these 4 required dialysis. Seven children required erythrocytetransfusions, platelet transfusions, or both. None of the childrendied during hospitalization. The incidence of the hemolytic–uremicsyndrome according to the children's characteristics is summarizedin Table 1.
Table 1. Frequency of the Hemolytic–Uremic Syndrome According to the Characteristics of 71 Children Infected with Escherichia coli O157:H7.
There were no significant differences in the frequency of thehemolytic–uremic syndrome with respect to sex and thepresence or absence of bloody diarrhea, caregivers' reportsof fever, and vomiting. Nor was the frequency significantlyrelated to the initial serum urea nitrogen or creatinine concentrationor, for the subgroup of children evaluated at Children's Hospitaland Regional Medical Center, the initial temperature. However,the frequency of the syndrome was significantly related to theinitial white-cell count (P=0.005), with a rate of 0 percentamong children with an initial count of 3200 to 8700 per cubicmillimeter, a rate of 6 percent among those with an initialcount of 8800 to 11,800 per cubic millimeter, a rate of 17 percentamong those with an initial count of 11,900 to 14,200 per cubicmillimeter, and a rate of 35 percent among those with an initialcount of 14,300 to 24,600 per cubic millimeter. In addition,the frequency of the syndrome was higher among children whohad laboratory studies soon after the onset of illness (accordingto the day of illness on which the stool was obtained for culture,the day on which the culture was positive, and the day on whichthe initial white-cell count was obtained) and among those whowere treated with antibiotics.
The hemolytic–uremic syndrome developed in 5 of the 9children given antibiotics (56 percent), as compared with 5of the 62 children who were not given antibiotics (8 percent,P<0.001). The characteristics of the children who were givenantibiotics and those who were not were similar (Table 2).
Table 2. Characteristics of Children Infected with Escherichia coli O157:H7 According to Whether They Were Treated with Antibiotics.
We used logistic-regression analysis to assess demographic variables,symptoms, laboratory values, and medication use as potentialrisk factors for the hemolytic–uremic syndrome (Table 3).The initial white-cell count and the day of the initialstool culture — two surrogates for the severity of illness— were independently associated with the development ofthe syndrome. In the logistic-regression analysis of both factors,the initial white-cell count remained significantly associatedwith the hemolytic–uremic syndrome (P=0.02), with riskbeing proportional to the white-cell count. Also, the intervalfrom the onset of diarrhea to the day on which the initial stoolculture was obtained remained strongly associated with the riskof the hemolytic–uremic syndrome (P= 0.008), with therisk being inversely proportional to the number of days in thisinterval.
Table 3. Relative Risk of the Hemolytic–Uremic Syndrome among Children Infected with Escherichia coli O157:H7.
Multivariate analysis, adjusted for the day on which the initialstool culture was obtained and the initial white-cell count,showed that children treated with antibiotics had a higher riskof the hemolytic–uremic syndrome than did children whodid not receive antibiotics (adjusted relative risk, 17.3; 95percent confidence interval, 2.2 to 137; P=0.007). Among thechildren who received antibiotics within the first three daysafter the onset of illness, the risk of the syndrome was increasedin the univariate analysis (relative risk, 15.0; 95 percentconfidence interval, 1.3 to 174; P=0.03) and after adjustmentfor the day on which the initial stool culture was obtainedand the initial white-cell count in the multivariate analysis(adjusted relative risk, 32.3; 95 percent confidence interval,1.4 to 737; P=0.03). Adjustment for other base-line covariatesdid not affect the significance of the association between antibiotictreatment and the development of the hemolytic–uremicsyndrome (data not shown).
Of the 10 children in whom the hemolytic–uremic syndromedeveloped, 2 were treated with trimethoprim–sulfamethoxazoleand 3 were treated with cephalosporins. Among the four antibiotic-treatedchildren in whom the syndrome did not develop, one receivedtrimethoprim–sulfamethoxazole, one a cephalosporin, andtwo amoxicillin. The relative risk of the hemolytic–uremicsyndrome as a function of the class of antibiotic used, afteradjustment for the initial white-cell count, was 17.7 for trimethoprim–sulfamethoxazole(95 percent confidence interval, 1.2 to 261; P=0.04) and 13.4for ß-lactam antibiotics (95 percent confidence interval,1.9 to 96; P=0.01). In each case, all E. coli O157:H7 strainsisolated from the nine children who received antibiotics weresusceptible to the drug taken by the child from whom the organismswere recovered.
Discussion
This prospective cohort study demonstrates that among childreninfected with E. coli O157:H7, the hemolytic–uremic syndromedeveloped more often in those who were given antibiotics thanin those who were not. We were unable to identify any characteristicsthat differentiated children who received antibiotics from thosewho did not.
Our data confirm that administering sulfa-containing antibioticsto children infected with E. coli O157:H7 increases their riskof the hemolytic–uremic syndrome8,9 and indicate thatß-lactam antibiotics are associated with a similardegree of risk. An extensive analysis of the E. coli O157:H7outbreak in Sakai City, Japan, suggested that treatment withfosfomycin was associated with a significantly decreased riskof the hemolytic–uremic syndrome,16 but only for childrenwho received the drug on the second day, but not on other days,of their illness. Also, fosfomycin was compared only with otherantibiotics, not with the absence of treatment with antibiotics,because as in other reports describing this outbreak,16,17,18,19,20,21,22,23,24,25almost all children received antibiotics.
We noticed an inverse relation between the risk of the hemolytic–uremicsyndrome and the length of the interval between the onset ofdiarrhea and the day on which the initial stool culture wasobtained. This inverse relation could represent the presenceof a more fulminant course that prompted earlier evaluationand therefore reflected more severe extraintestinal injury ininfected children who were at greater risk for the syndromewhether or not antibiotics were prescribed. However, multivariateanalysis did not diminish the risk associated with antibioticadministration when this factor was considered.
We did not find an association between the reported presenceof fever and the risk of the hemolytic–uremic syndrome,as has been found in some studies.8,16 However, prehospitalizationtemperatures were determined by a variety of caregivers, usingdifferent instruments and techniques. Moreover, of the 18 childrenwho were evaluated at Children's Hospital and Regional MedicalCenter, only 1 had a temperature exceeding 38.0°C on initialevaluation, and the hemolytic–uremic syndrome did notdevelop in this child. Also, despite the absence of an associationbetween treatment with antimotility drugs or opioid narcoticsand the risk of the hemolytic–uremic syndrome, we recommendagainst the use of these drugs in children with acute diarrhea,because of their reported association with complications ofE. coli O157:H7 infection and with the prolongation of symptoms.1,24,26,27,28
Our data may have been confounded by selection bias, becausewe studied only children whose stools yielded E. coli O157:H7as identified by our surveillance network. However, we are unableto assess the effect of antibiotic treatment in children infectedwith this pathogen whose illness was not diagnosed by our systemof participating laboratories.
There are considerable data to support an association betweenthe hemolytic–uremic syndrome and enteric infection withShiga-toxin–producing bacteria.2,5 Cytotoxin, presumablyShiga toxin, has been found in the stools of patients with bothE. coli O157:H7 infection and the hemolytic–uremic syndrome.5,29In in vitro experiments, exposure to various antibiotics causesE. coli to release Shiga toxin.30,31,32,33 Antibiotics mightincrease the risk of the hemolytic–uremic syndrome bycausing the release of Shiga toxin from injured bacteria inthe intestine, making the toxin more available for absorption.
An observational study cannot completely eliminate other potentialbiases with respect to the association of antibiotics and therisk of the hemolytic–uremic syndrome, but our analysishas several strengths in comparison with previous attempts toassess the risks or benefits of antibiotic treatment of E. coliO157:H7 infections. Children's caregivers were questioned prospectivelyduring the acute illness, reducing problems with recall thatmay occur when interviews are performed weeks or months afterinfection. Such a bias might pertain especially to the use ofnonprescription drugs. Also, our study addressed the use ofantibiotics in children infected with a variety of strains ofE. coli O157:H7 and was not limited to children infected withthe same strain, as is the case in analyses of outbreaks.1,6,8,10,16,17,18,19,20,21,22Thus, our data are broadly applicable to clinical practice,where physicians encounter children infected with one of manysubtypes of this pathogen. Indeed, the variability among E.coli O157:H7 strains in the antibiotic-induced release of Shigatoxin30 also suggests that conclusions from analyses of outbreaksmay not be easily generalizable.
The association between antibiotic treatment and the developmentof the hemoltyic–uremic syndrome in children with E. coliO157:H7 infections is strong and plausible. We therefore recommendagainst giving antibiotics to children who may be infected withE. coli O157:H7 until the results of a stool culture indicatethat the pathogen responsible is one that is appropriately treatedby an antibiotic. Even if the small advantage associated withempirical fluoroquinolone therapy in some adults with acutediarrhea34,35,36 holds true for children, we believe that therisk of administering antibiotics to children who might be infectedwith pathogens for which antibiotics are contraindicated (i.e.,E. coli O157:H7) exceeds the potential benefit. However, itis important to remember that the hemolytic–uremic syndromecan occur even in infected children who have not been treatedwith antibiotics. Therefore, we believe that the hemolytic–uremicsyndrome is best prevented by avoiding primary infection.
Supported by a grant (1RO1DK52081) from the National Institutesof Health.
We are indebted to Christine A. Merrikin and Kaye Green forexpert secretarial assistance, to Dr. Yukiko Ikeda and Dr. Dong-KiLee for translating Japanese studies, and to participating patients,families, microbiologists and other laboratorians, nurses, andphysicians for providing data used in the study.
Source Information
From Children's Hospital and Regional Medical Center and the University of Washington School of Medicine, Seattle. Presented in part at the 35th United States–Japan Cholera and Related Diarrheal Diseases Conference, Baltimore, December 3–5, 1999.
Address reprint requests to Dr. Tarr at the Division of Gastroenterology, CH-24, Children's Hospital and Regional Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105, or at tarr{at}u.washington.edu.
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