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Drug-resistant Salmonella

Salmonellosis is one of the most common and widely distributed foodborne diseases. It constitutes a major public health burden and represents a significant cost in many countries. Millions of human cases are reported worldwide every year and the disease results in thousands of deaths. Salmonellosis is caused by the bacteria Salmonella. Today, there are over 2500 known types, or serotypes, of Salmonella.

In recent years problems related to Salmonella have increased significantly, both in terms of incidence and severity of cases of human salmonellosis. While some countries have managed to reverse the increasing incidence of human salmonellosis, new concerns have been identified. Since the beginning of the 1990s, strains of Salmonella which are resistant to a range of antimicrobials1, including first-choice agents for the treatment of humans, have emerged and are threatening to become a serious public health problem. This resistance results from the use of antimicrobials both in humans and animal husbandry. Multi-drug resistance to "critically important antimicrobials"2 are compounding the problems.

Salmonellosis

Salmonellosis in humans is generally contracted through the consumption of contaminated food of animal origin (mainly meat, poultry, eggs and milk), although many other foods, including green vegetables contaminated from manure, have been implicated in its transmission. The causative organisms pass through the food chain from primary production to households or food-service establishments and institutions.

A total of 2 501 different Salmonella serotypes have been identified up to 2004. While all serotypes can cause disease in humans, they are often classified according to their adaptation to animal hosts. A few serotypes have a limited host-spectrum (affect only one or a few animal species), for example Salmonella Typhi in primates; Salmonella Dublin in cattle; and Salmonella Choleraesuis in pigs. When these strains cause disease in humans, it is often invasive and can be life-threatening. Most serotypes, however, have a broad host-spectrum. Typically, such strains cause gastroenteritis, which is often uncomplicated and does not need treatment, but can be severe in the young, the elderly and patients with weakened immunity. This group features Salmonella Enteriditis and Salmonella Typhimurium, the two most important serotypes for salmonellosis transmitted from animals to humans.

The clinical course of human salmonellosis is usually characterized by acute onset of fever, abdominal pain, diarrhoea, nausea and sometimes vomiting. In some cases, particularly in the very young and in the elderly, the associated dehydration can become severe and life-threatening. In such cases, as well as in cases where Salmonella causes bloodstream infection, effective antimicrobials are essential drugs for treatment. Serious complications occur in a small proportion of cases. Although outbreaks usually attract media attention, studies indicate that more than 80% of all salmonellosis cases occur individually rather than as outbreaks.

Salmonellosis constitutes a major public health burden and represents a significant cost to society in many countries. Very few countries report data on economic cost of the disease. In the United States of America, an estimated 1.4 million non-typhoidal Salmonella infections, resulting in 168 000 visits to physicians, 15 000 hospitalizations and 580 deaths annually. Cost estimates per case of human salmonellosis range from approximately US$ 40 to US$ 4.6 million respectively for uncomplicated cases to cases ending with hospitalization and death. The total cost associated with Salmonella is estimated at US$ 3 billion annually in the United States3. In Denmark, the annual estimated cost of foodborne salmonellosis is US$ 15.5 million (2001) representing approximately 0.009% of GDP. A Salmonella control programme has been in place for several years in Denmark and the annual estimated cost of this control programme is US$ 14.1 million. It is estimated that this program saves US$ 25.5 million annually of Danish public expenditure. Data related to the cost of foodborne disease are generally not available from developing countries.

Treatment of salmonellosis in humans

The antimicrobials most widely regarded as optimal for the treatment of salmonellosis in adults is the group of fluoroquinolones. They are relatively inexpensive, well tolerated, have good oral absorption and are more rapidly and reliably effective than earlier drugs. Third-generation cephalosporins (which need to be given by injection) are widely used in children with serious infections, as quinolones are not generally recommended for this age group. The earlier drugs chloramphenicol, ampicillin and amoxicillin and trimethoprim-sulfamethoxazole are occasionally used as alternatives.

Epidemiology and transmission

In addition to acquiring infection from contaminated food, human cases have also occurred where individuals have had contact with infected animals, including domestic animals such as cats and dogs. Domestic animals probably acquire the infection in the same way as humans, i.e. through consumption of contaminated raw meat, poultry or poultry-derived products.

The evolution of specific Salmonella serotypes in intensive animal husbandry and subsequently in humans has been observed over the past three decades. S. Enteritidis caused the most recent epidemic, which peaked in humans in 1992 in many European countries. Its current slight decline sets the scene for re-emergence of S. Typhimurium as the most important serotype in human salmonellosis. Another possible scenario is that these two particular strains with epidemic potential will dominate in many countries in the foreseeable future.

Emergence of Salmonella resistant to medically important antimicrobials

While resistance to the fluoroquinolones often emerges as a result of mutations in the bacterial genome (DNA), resistance to other antimicrobials often spread by transfer of DNA between bacterial strains. In some cases multidrug-resistance (resistance to multiple antimicrobials in the same bacterial strain) is transferred through one coherent piece of DNA (often called a plasmid).

When fluoroquinolones were first licensed for human therapy, no immediate rise in Salmonella resistance was observed. In contrast, when fluoroquinolones were subsequently licensed for use in food animals, the rates of fluoroquinolone-resistant Salmonella in animals and food, and then subsequently in human infections, rapidly increased in several countries4.

Multidrug-resistant (MDR) strains of Salmonella are now encountered frequently and the rates of multidrug-resistance have increased considerably in recent years. Even worse, some variants of Salmonella have developed multidrug-resistance as an integral part of the genetic material of the organism, and are therefore likely to retain their drug-resistant genes even when antimicrobial drugs are no longer used, a situation where other resistant strains would typically lose their resistance.

Drug-resistant Salmonella emerge in response to antimicrobial usage in food animals. Selective pressure from the use of antimicrobials is a major driving force behind the emergence of resistance, but other factors also need to be taken into consideration. For example, some Salmonella serotypes are more prone to develop resistance than others. Furthermore, major shifts in the occurrence of Salmonella serotypes in food animal and humans are regularly seen. A recent example is the global spread of a multidrug-resistant S. Typhimurium phage type DT104 in animals and humans. While the spread of DT104 may have been facilitated by the use of antimicrobials, international and national trade of infected animals is thought to play a major role in international spread.

The emergence of MDR Salmonella strains with resistance to fluoroquinolones and third-generation cephalosporins is a serious development, which results in severe limitation of the possibilities for effective treatment of human infections.

Human health consequences of drug-resistant Salmonella following non-human use of antimicrobial agents

Recent studies provide increasing evidence of adverse human health consequences due to the occurrence of resistant microorganisms. These consequences can be divided into two categories: (1) infections that would otherwise not have occurred; and (2) increased frequency of treatment failures and increased severity of infections.

Infections that would otherwise not have occurred

Infections that would otherwise not have occurred. Use of antimicrobial agents in humans and animals affect the intestinal tract, placing those concerned at increased risk of certain infections. For example people treated using antimicrobial drugs for unrelated reasons, such as treatment of an upper respiratory tract infection, are at increased risk of infection with Salmonella that are resistant to the antimicrobial agent. This increased risk can be expressed in the form of an attributable fraction, which is defined as the proportion of Salmonella infections that would not have occurred if the Salmonella were not resistant (or if the person had not been taking the antimicrobial agent for the unrelated reason). In a recent review of the attributable fraction of the over one million cases of Salmonella infection each year in the United States, it was estimated that antimicrobial resistance in Salmonella may result in about 30 000 additional Salmonella infections leading to about 300 hospitalizations and 10 deaths.

In addition antimicrobial agents used in animals can result in increased transmission of resistant microorganisms between animals, and therefore will result in increased transmission of such microorganisms to humans through food.

Increased frequency of treatment failure and increased severity of infection may be manifested by prolonged duration of illness, increased frequency of bloodstream infections, increased hospitalization, or increased mortality. The association between an increased relative frequency of antimicrobial-resistant Salmonella and an increased frequency of hospitalization has been demonstrated for salmonellosis in several studies. Similarly, persons with infections caused by antimicrobial-resistant Salmonella have been found to be more likely to have bloodstream infection or die within 90 days following specimen collection than control groups with susceptible infections.

A Danish study found that although persons with susceptible Salmonella infections had a higher mortality than the general population, persons with resistant Salmonella infections had an even higher mortality. The death rate for persons with multidrug-resistant infections was estimated to be 10 times higher in the two years following specimen collection than for the general population.

Increased frequency of treatment failure and increased severity of infection

The emergence of Salmonella strains that are resistant to commonly used antimicrobials should be particularly noted by clinicians, microbiologists and those responsible for the control of communicable diseases, as well as the food producers including the food industry. Control of drug-resistant Salmonella is most efficiently achieved through the reduction of antimicrobial use. Prudent usage in food animals should be combined with good husbandry, good abattoir practice and good hygiene at all stages in the food production chain, from processing plants to kitchens and food service establishments. These combined efforts should reduce the numbers of the relevant strains in food animals and lower the risk of contamination by resistant Salmonella at all stages in the food production chain.

While activities addressing the occurrence of antimicrobial resistance in foodborne microorganisms are ongoing, the magnitude of the problem is largely unknown in many countries. International collaborative efforts, including efforts in support of surveillance and risk assessment, need to be increased. Countries can join WHO's Global Salm-Surv programme5 to develop their capacities to detect antibiotic-resistant pathogens, including Salmonella, in human, animals and food.

Although some countries have succeeded in reducing the frequency of Salmonella in poultry dramatically it is unlikely that the eradication of Salmonella in domestic animals is possible in the foreseeable future. The increased occurrence of drug-resistant pathogens in foods of animal origin emphasizes the general need for cooking such foods thoroughly prior to consumption. Education of food handlers in the principles of safe food handling is an essential step towards reducing the incidence of foodborne disease resulting from cross-contamination during processing and preparation of foods (see "WHO Five Keys to Safer Food"6). Educating farmers and their families regarding the risks of occupationally acquired infections is also an important step in the control of human infections caused by Salmonella.

1A substance which at low concentrations kills or inhibits the growth of micro-organisms but causes little or no host damage - often in popular terms referred to as an antibiotic (which are in effect only a subgroup of antimicrobials).

2"Antimicrobial classes should be classified as critically important when the drug is in a class that is the only available therapy or one of a limited number of drugs available to treat serious human disease or pathogens that cause foodborne disease." 1st Joint FAO/OIE/WHO Expert Workshop on Non-human Antimicrobial Usage and Antimicrobial Resistance: Scientific assessment, Geneva, 1-5 December 2003.

3Foodborne illness cost calculator


Sources: US Department of Health; The World Health Organization


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