|Bureau of Epidemiology|
|Bureau of Epidemiology||November 2000||Utah Department of Health|
Toxin Producing Escherichia coli
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Monthly Morbidity Summary
Enterohemorrhagic Escherichia coli (EHEC) has emerged as an increasingly problematic enteric pathogen associated with gastrointestinal disease. EHEC, also known as Shiga toxin producing E. coli (STEC) or verotoxin producing E. coli (VTEC), is distinguished from other classes of pathogenic E. coli primarily by its ability to produce one or more harmful exotoxins. These toxins are generally referred to as Shiga toxins 1 and 2. Nomenclature arose out of the discovery that the toxin produced by this class of E. coli was virtually indistinguishable in both structure and function to the Shiga toxin produced by Shigella dysenteriae type 1 (Stx) and could be neutralized by anti-Stx. Recognition of STEC as a distinct class of pathogenic E. coli resulted from epidemiological studies following two major outbreaks of hemorrhagic colitis in the early 1980s; both associated with STECs most recognized serotype, E. coli O157:H7. Since then, both O157 and several non-O157 STEC serotypes have been established as a major cause of bloody diarrhea and hemolytic-uremic syndrome (HUS) (1).
STEC produce disease by direct action of the Shiga toxin on certain cells. The toxin is believed to have a high affinity for receptors found on endothelial cells of blood vessels, smooth muscle cells, renal endothelial cells as well as red blood cells (which are the cells damaged in children and adults with HUS). Once bound, the toxin is internalized and inhibits intracellular protein synthesis invariably leading to cell death (2).
STEC appear to be implicated in three main types of illness including watery diarrhea, bloody diarrhea and HUS as a complication. The pathogen has an average incubation period of 3 to 4 days. Individuals most often present with bloody diarrhea however, symptoms may begin initially with watery diarrhea. Other findings include abdominal cramps and low fever. Abdominal pain with colic is common in young children and elderly patients. Vomiting may be present and is commonly associated with the presence of watery diarrhea. In the majority of cases, the diarrhea resolves without further complications in 4 to 10 days (1). Bloody diarrhea may progress to HUS, a life threatening complication of infection in 5-10% of those with STEC infections, affecting primarily young children and the elderly. HUS is characterized by acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia (3).
The primary reservoir for STEC is cattle, however, the organism has been isolated from a variety of animals including sheep, horses, goats, pigs, dogs, cats and deer. Transmission of the pathogen appears to occur via three principle routes including contaminated food and contaminated drinking or swimming water, person-to-person transmission and animal contact (4). Contamination of meat with STEC can occur from bovine feces during slaughter and meat processing. Not surprisingly, consumption of raw or undercooked meat, particularly ground beef, and unpasteurized milk, are the most commonly implicated foods. Cases have also been linked to the consumption of contaminated cheese, yogurt, cold cuts, lettuce, potatoes, seed sprouts and fresh-pressed apple juice (2).
The most commonly isolated STEC serotype in North America is E. coli O157:H7, however over 100 different STEC serotypes have been isolated from humans. The significance and public health impact of non-O157 STEC serotypes is less understood, partially due to differences and difficulties in screening methods. Many labs are only able to employ diagnostic tests such as culture on Sorbitol MacConkey agar (SMAC) which is unable to detect STEC serotypes other than O157. Subsequently, many stool samples containing non-O157 STEC organisms are never identified. Due to this limitation, the prevalence of non-O157 STEC in the population is presumably grossly underestimated. Frequently isolated non-O157 serotypes include O26, O91, O103, and O111. In several studies, non-O157 serotypes such as these have been the predominant cause of serious human disease (3).
Since September of 1997, two large laboratories in Utah, ARUP and the microbiology lab at Primary Children's Medical Center, have employed a commercial EHEC enzyme immunoassay (EIA), which is able to detect the presence of both Shiga toxins 1 and 2, allowing for the identification of both O157 and non-O157 STEC serotypes. All positive samples are then sent to the State Lab for confirmation. Positive samples are also sent to the Centers for Disease Control and Prevention (CDC) for further analysis and serotyping. Since 1998, when non-O157 STEC were first reported to the State, 67 non-O157 STEC have been identified and reported (Figure 1). This may represent only a fraction of the actual number of non-O157 cases, due to the inability of smaller laboratories to identify non-O157. Further, many health care providers fail to request that stool samples be screened for STEC serotypes other than O157. The CDC has recommended that specimens from patients with bloody diarrhea or HUS be tested for Shiga toxin, either initially or if stool cultures are negative for Shigella, Salmonella, Campylobacter, and E. coli O157 (5).
Consensus on treatment recommendations for STEC infections has been problematic. The majority of studies regarding the efficacy of antibiotic therapy have been unable to conclude their benefit in preventing the progression of STEC infection from diarrhea or bloody diarrhea to HUS. Further, in vitro studies have implicated numerous antibiotics as risk factors in the development of HUS (6, 7).
A recently published study (6) reported that treatment with bacteriophage-inducing antibiotics, including all quinolones, trimethoprim, furazolidone and Mitomycin C, resulted in a dramatic increase in in vitro Shiga toxin production. The study found that as a group, the only antibiotics that failed to induce Shiga toxin production were the agents that inhibit prokaryotic translation, which include Erythromycin and Doxycycline. Fosfomycin was also found to have no affect on in vitro Shiga toxin production. A recently published animal study (7) reported similar results suggesting that treatment of human STEC infection with bacteriophage-inducing antibiotics, such as fluoroquinolones, may have significant adverse clinical consequences.
There have been no large prospective randomized controlled studies evaluating the efficacy of antibiotics on the treatment of humans with STEC infections. A small prospective placebo-controlled study evaluating the effect of trimethoprim-sulfamethoxazole in children with lab-confirmed E. coli O157:H7, indicated no statistically significant effect of treatment on progression of symptoms or the incidence of HUS (8). A few small retrospective studies have reported antibiotic treatment to be a risk factor in the progression of STEC infection to more serious illness (9-11). In contrast, a large retrospective study in Japan following an outbreak of E. coli O157:H7 concluded that early treatment with fosfomycin was associated with a reduced risk of progression from bloody diarrhea to HUS (12). Fosfomycin was however one of the antibiotics found to have no in vitro affect on bacterial Shiga toxin production. The CDC has stated that there is no evidence that antibiotics improve the course of disease, and it is thought that treatment with some antibiotics may precipitate kidney complications. They also stated that antidiarrheal agents, such as loperamide (Imodium), should be avoided (13).
Due to the discordant results of some in vivo and in vitro studies relating to the effect of antibiotics on individuals infected with STEC, their use should be avoided until definitive data about antibiotic use becomes available. Studies have also suggested that antimotility agents may pose additional risk to STEC infected patients and should also be avoided in the treatment of STEC associated diarrhea (3, 10, 13). Treatment options for STEC infection are fairly limited and for the most part include supportive care, including maintaining hydration. In addition, in severe cases, patients, especially young children, should be closely monitored for the development of HUS.
It is clear that both O157 and non-O157 STEC infections pose a real and certain public health hazard. However, far too little attention has been given to the epidemiological seriousness of non-O157 STEC, even though prevalence studies indicate that it is not uncommon. Australian studies have reported that STEC serotype O111:nm is the most frequent cause of serious STEC associated human disease and a U.S. study of over 3,289 diarrheal samples found that non-0157 STEC was more prevalent than O157 STEC (14). In June 2000, the Council of State and Territorial Epidemiologists (CSTE) adopted a position statement recommending inclusion of all STEC that cause human illness as reportable through the National Public Health Surveillance System, indicating formal recognition of the reality and severity of the public health impact that STEC pose (5).
It is critical that a collaborative effort between Utah's public health agencies and patient care providers be maintained in order to better understand and address the impact that both O157 and non-O157 STEC organisms have on Utah's populations. In order to accurately determine the prevalence of non-O157 STEC in Utah, testing methods that are able to identify these pathogens need to be more readily utilized. In the absence of other enteric pathogens, it is recommended that laboratories lacking the capability to identify non-O157 STEC should send samples to a reference laboratory that is able to identify non-O157 STEC. Further, patient care providers should consider non-0157 STEC as a possible cause of bloody diarrhea and HUS in patients.
References available upon request.
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The Epidemiology Newsletter is published monthly by the Utah Department of Health, Division of Epidemiology and Laboratory Services, Bureau of Epidemiology, to disseminate epidemiologic information to the health care professional and the general public.
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Rod Betit, Executive Director, Utah Department of Health