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Escherichia Coli O157:H7 Foodborne Illness and the Usefulness of the Critical Path in FDA’s Work to Combat It

by Richard Arkin, J.D., Assistant Editor
FDA Veterinarian Newsletter January / February 2008 Volume XXIII, No I

Under the Food and Drug Administration’s Critical Path Initiative, the Center for Veterinary Medicine is working as part of a joint effort of industry and government agencies to identify key problems and develop targeted solutions to reduce or eliminate Escherichia coli O157:H7 in or on cattle going to slaughter.

E. coli O157:H7 is a strain of the commonly found bacterium that has emerged as a significant cause of foodborne ill-ness in the United States. E. coli strains are commonly found in the lower intestines of healthy humans and other warm blooded animals, such as mammals and birds. Most strains are harmless and are part of normal gut flora. They benefit their hosts by producing vitamin K3 or blocking the growth of pathogenic bacteria in the intestine.

E. coli O157:H7 (the letters and numbers in the name refer to the specific markers found on organisms surfaces that distinguish this strain from others) is just one of hundreds of E. coli strains. E. coli O157:H7 is not pathogenic in cattle and is readily carried in the intestinal tract of healthy animals. Unlike most other strains, however, this one produces a toxin that can cause a severe infection in humans, resulting in serious food poisoning. It is enterohemorrhagic in humans, which means it can cause bloody diarrhea, which occasionally leads to kidney failure, particularly in children, the elderly, and those who are immuno-compromised.

The E. coli Coalition

In 2006, CVM and the National Cattlemen’s Beef Association (NCBA), a cattle producers’ organization, joined together to form the E. coli Coalition. Additional members—the U.S. Department of Agriculture (USDA), the American Meat Insti-tute (AMI), and the Animal Health Institute (AHI)—have since joined.

The coalition has identified four areas of focus as part of its “Farm to Fork” approach:

  • Pre-harvest interventions (on the farm)
  • Transport (from the farm to arrival at the slaughter plant)
  • Post-harvest (from the slaughter plant to the finished/packaged product)
  • Environmental impact

CVM is working with other members of the group on the pre-harvest frame, trying to identify therapeutic interventions to reduce or eliminate E. coli O157:H7 in or on cattle presented for slaughter. FDA is collaborating with USDA’s Animal and Plant Health Inspection Service’s Center for Veterinary Biologics, NCBA, and AHI on establishing standards for product effectiveness. These standards will utilize tools available under FDA’s Critical Path Initiative, while still being acceptable under FDA’s authorizing statutes.

Most E. coli illness in the United States has been associated with eating undercooked, contaminated ground beef. The number of E. coli organisms required to cause disease in humans is not known; it is suspected to be small. Meat becomes contaminated by E. coli from cattle intestines during slaughter and the E. coli organisms can be thoroughly mixed into beef when it is ground. Contaminated beef generally looks and smells normal.

E. coli illness can also occur because bacteria present on a cow’s udder or on equipment gets into raw milk consumed without pasteurization.

Consumers can prevent E. coli O157:H7 infection by thoroughly cooking ground beef, avoiding unpasteurized milk, us-ing safe food preparation techniques, and washing hands frequently and carefully.

E. coli O157:H7 was first recognized as a pathogen as a result of an outbreak of unusual gastrointestinal illness in 1982. The illness was similar to other outbreaks in the United States and Japan, and this incident was traced to contami-nated hamburger. The O157:H7 serotype of E. coli was recognized by the Centers for Disease Control and Prevention (CDC) as the causative agent of the illness in two separate outbreaks of hemorrhagic colitis in Michigan and Oregon in 1982. This serotype was then rare, having been first isolated in 1975.

Because the organism is common in the intestines of healthy cattle, preventive measures on cattle farms and during meat processing are being investigated by Coalition members.

NCBA, along with AMI, AHI, and other trade groups, has been working on a number of control point interventions to re-solve the specific problem of E. coli O157:H7. FDA is aware that the NCBA and other groups are diligently searching for on-farm interventions by funding research to identify therapeutic interventions. The agency has concluded, however, that no single intervention is likely to eliminate the E. coli 0157:H7 problem.

Critical Path Initiative

Under FDA’s Critical Path Initiative, developed to facilitate the evaluation and approval process, FDA and CVM are also working to combat the problem by research and by speeding evaluation and approval of therapeutic interventions for E. coli O157:H7.

FDA knows that the current medical product development path has become increasingly challenging, inefficient, and costly, and that costs of product development have soared over the last decade or so. The Agency also recognizes that the increasing costs and growing difficulties of medical product development lead to stagnation and decline in innovation, which could mean that the biomedical revolution of recent years might not deliver on its promise of better health.

At FDA, the Critical Path Initiative is seen as a way to identify and prioritize the most pressing development problems and the areas that provide the greatest opportunities for rapid improvement and public health benefits. It is FDA’s man-agement tool for the scientific process by which a potential human or animal drug, biological product, or medical device is transformed from discovery or “proof concept” into a medical product.

The Critical Path Initiative allows the Agency flexibility in mapping out the regulatory path to market for new and innova-tive therapeutics. It utilizes the newest scientific tests and tools to predict whether a product candidate will be safe and effective. These tools can predict which product candidates do not hold promise early in the development process, thereby allowing sponsors to direct resources to products more likely to meet safety and efficacy requirements.

Through the Critical Path, FDA brings national focus to current product development issues, serving as a hub for prob-lem identification and information exchange. FDA encourages use of Critical Path tools by accepting the results of the new tools as valid proof in product review (including updated science-based standards and guidances). FDA also serves as the catalyst to initiate projects and collaborations to help modernize the Critical Path.

One of the key areas of focus for the Critical Path at FDA is bringing to market products to address urgent public health needs. As part of this process, FDA is interested in working with sponsors to identify and bring to market interventions. A therapeutic intervention just prior to slaughter, in conjunction with other risk management interventions during the slaugh-ter and processing of beef, would reduce the exposure of humans to E. coli O157:H7. This reduction would be an oppor-tunity for a direct public health benefit through the Critical Path, so the E. coli initiative has given CVM an identified project under the Critical Path at FDA, as well as giving the Center a clearly defined role in efforts to reduce E. coli O157:H7.

CVM sees the Critical Path as a mechanism for expedited review of potentially approvable products, while products that cause human food safety, target animal safety, environmental or resistance concerns will not qualify for Critical Path ex-pedited review.

CVM wants to learn about research involved in new technologies to address the E. coli O157:H7 problem and is inter-ested in working with sponsors of animal drugs in a cooperative approach to finding new therapeutic interventions.

The Center wants to allow those technologies to come to market that have the most chance of becoming therapeutic in-terventions to eliminate E. coli O157:H7 prior to slaughter and thus reduce or eliminate foodborne illness caused by this bacterium. The Critical Path is an important element in achieving this goal.

Escherichia coli O157:H7 and Disease

The Centers for Disease Control and Prevention (CDC) has recognized four classes of enterovirulent Escherichia coli that cause gastroenteritis in humans. CDC refers to these as the EEC Group. Among these is the enterohemorrhagic strain designated E. coli O157:H7.

E. coli normally is present in the intestines of all animals, including humans. When certain culture methods are used in the laboratory, E. coli is the predominant species found in feces. E. coli usually serves a useful function in the body by synthesizing vitamins and suppressing the growth of harmful bacterial species.

Some varieties of E. coli strains are capable of causing human illness by several different mechanisms. The O157:H7 serotype of E. coli is a rare strain that produces large quantities of one or more potent toxins that cause severe damage to the intestinal lining. These toxins are closely related or identical to the toxin produced by Shigella dysenteriae, one of the causes of dysentery.

E. coli O157:H7 causes the acute disease called hemorrhagic colitis. The illness is characterized by severe abdominal cramping and pain, as well as watery diarrhea that usually becomes very bloody. Vomiting sometimes also occurs. Gen-erally, there is either no fever or a low-grade fever.

According to CDC, all people are believed to be susceptible to hemorrhagic colitis, but young children and the elderly appear to progress to more serious symptoms more frequently. Some victims, particularly the very young, have developed the hemolytic uremic syndrome (HUS), characterized by renal failure and hemolytic anemia. HUS, which can result in permanent loss of kidney function, can affect as many as 15 percent of hemorrhagic colitis victims. HUS, plus two other symptoms, fever and neurologic symptoms, constitutes thrombotic thrombocytopenic purpura (TTP), which can be found in some elderly victims. TTP can have a mortality rate in the elderly as high as 50 percent.

According to CDC, outbreak data and the known ability of the organism to be passed from person to person in nursing homes, day-care centers, and other personal care facilities, indicate that the presence of as few as 10 organisms could result in disease.

Hemorrhagic colitis is diagnosed by laboratory isolation of the causative agent in diarrheal stools. Confirmation can come from isolation of E. coli of the same serotype from the food believed to have caused the illness.

CDC reports that hemorrhagic colitis infections are not commonly identified, but that actual reported cases may not re-flect the true frequency of the disease. CDC says that E. coli O157:H7 is thought to be the second most common cause of bacterial diarrhea (Salmonella is the most common cause) in the Pacific Northwest States. Victims with the most severe cases, who have profuse, visible blood in their diarrhea, probably seek medical attention. However, CDC believes that less severe cases in which blood may be less visible, or may not be present at all, are probably more numerous.

How the Consumer Can Fight Foodborne Illness

The Centers for Disease Control and Prevention (CDC) recommendations for prevention of an infection caused by Escherichia coli O157:H7 include:

  • Cook all ground beef or hamburger thoroughly. Make sure that the cooked meat is gray or brown throughout (not pink), any juices run clear, and the inside is hot.
  • The temperature of the meat should reach a minimum of 160 degrees F, as measured with a digital instant-read meat thermometer.
  • If you are served an undercooked hamburger in a restaurant, send it back.
  • Consume only pasteurized milk and milk products. Avoid raw milk.
  • Consume only pasteurized juices and ciders.
  • Make sure that infected persons, especially children, wash their hands carefully and frequently with soap and water to reduce the risk of spreading the infection.
  • Drink municipal water that has been treated with adequate levels of chlorine, or other effective disinfectants.
  • Avoid swallowing lake or pool water while swimming.
  • Wash hands thoroughly after using the toilet.
  • People with diarrhea should not:
    • swim in public pools or lakes
    • bathe with others
    • prepare food for others.

Using FoodNet for Surveillance of E. coli bacteria

An estimated 73,000 cases of infection and 61 deaths occur each year in the United States from Escherichia coli O157:H7, and this strain has been responsible for a number of costly product recalls. As a result, FDA has become part of a multi-agency foodborne surveillance initiative, the Foodborne Diseases Active Surveillance Network (FoodNet), to pro-tect human health by combating E. coli O157:H7.

The other agencies involved are the Centers for Disease Control and Prevention (CDC), the U.S. Department of Agri-culture’s (USDA’s) Food and Nutrition Service and the Center for Veterinary Biologics.

FoodNet, described in detail last year in Volume XXII No. VI of FDA Veterinarian, is a collaborative project of the FDA, CDC, USDA, and State public health laboratories. The project consists of active surveillance for foodborne diseases and related studies designed to help public health officials better understand the epidemiology of foodborne diseases in the United States.

FoodNet sites around the country employ a sampling scheme in which at least one grocery store each month is visited. Personnel from each site purchase 10 packages each of retail chicken breasts, pork chops, ground turkey, and ground beef from the retail outlets.

At each of 10 State public health laboratories, a “rinse” (liquid sample for laboratory analysis) is produced using stan-dardized methods from each meat sample for the presence of Salmonella and Campylobacter. The rinses are produced using procedures adapted from the FDA’s Bacteriological Analytical Manual, which presents the agency’s preferred labo-ratory procedures for microbiological analyses of foods and cosmetics.

Isolates are sent to the Office of Research at the Center for Veterinary Medicine’s laboratories for identification, antim-icrobial susceptibility testing, and genetic studies. In addition, four sites (Georgia, Maryland, Oregon, and Tennessee) cul-ture the rinses for E. coli and Enterococcus and send the isolates on to CVM.