Salmonella is a leading cause of foodborne illness worldwide, with an estimated 1.4 million cases each year in the United States alone (1). Salmonella infections are typically due to consumption of food products of animal origin. Several lines of evidence indicate that antibiotic-resistance among human Salmonella infections results from the use of antimicrobial agents in food animals (2). Below is an overview of antibiotic-resistance and Salmonella and what it means for human health.
Antibiotics and drug-resistance
Many bacterial species have the ability to produce antimicrobial compounds. This ability is needed to give the bacteria an “edge” in microorganism-rich environments. Many of the antibiotics used today originated from bacterial species such as Pennicillium, Cephalosporium, and Streptomyces. Antibiotic-resistance likely also emerged as bacteria began producing compounds in order to survive in their environment, and competing species found ways to counteract these compounds (3).
Antimicrobial agents are currently used for three main reasons: (1) to treat infections in humans, animals, and plants; (2) prophylactically in humans, animals, and plants; and (3) subtherapeutically in food animals as growth promoters and for feed conversion (2). When antibiotic use became the norm in both human and animal medicine, selection pressure increased the bacterial advantage of maintaining and developing new resistance genes that could be shared among bacterial populations (3).
The first suggestion that antibiotic use in livestock led to antibiotic-resistant bacteria was in 1951. Starr and Reynolds reported streptomycin resistance in generic intestinal bacteria from turkeys that had been fed that antibiotic (4).
The use of antibiotics not only selects for antimicrobial-resistant bacteria, but may also increase the likelihood of disease transmission. In 2006, Bauer-Garland et al. researched the transmission of multidrug-resistant (MDR) Salmonella Typhimurium in broiler chicks under selective-pressure. An MDR S. Typhimurium strain had significantly increased transmission when chicks were treated with tetracycline, demonstrating that antimicrobial use influences transmission of antimicrobial-resistant pathogens in poultry (5).
Antibiotics and Salmonella
Although most Salmonella infections are self-limited, causing acute gastrointestinal illness in humans, antimicrobial agents are commonly prescribed to those seeking medical attention. Severe infections that spread to the bloodstream, meningeal linings of the brain, or other deep tissue can also occur. The selection of effective antibiotics is critical for the treatment of invasive infections, but has become more difficult as antibiotic-resistance has increased (2).
In the 1980’s and 90’s, a particular strain of MDR Salmonella, known as Salmonella Typhimurium DT104 (DT104), emerged in the U.S. This strain is typically resistant to at least five drugs: ampicillin, chloramphenicol, streptomycin, sulfisoxazole, and tetracycline (6). Since 1996, the National Antimicrobial Resistance Monitoring System (NARMS) has identified increasing numbers of Salmonella isolates resistant to nine of the 17 antimicrobial agents tested: amoxicillin/clavulanate, ampicillin, cefoxitin, ceftiofur, cephalothin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline. These isolates also have decreased susceptibility or resistance to ceftriaxone, an antimicrobial used to treat serious infections in children (7). Salmonella isolates with this resistance pattern carry a gene that produces AmpC-type enzymes that cause much of the drug-resistance; thus they are referred to as MDR-AmpC.
Salmonella Enteritidis is one of the most common types of Salmonella causing human illness, and is associated with consumption of egg-containing products and chicken (8). Since 1996, an increasing number of S. Enteritidis isolates submitted to NARMS have been resistant to nalidixic acid (a drug closely related to ciprofloxacin, or cipro, the most commonly prescribed antibiotic for Salmonella infections). Of these resistant isolates, 90% also showed decreased susceptibility to cipro (7).
Use of antibiotics in agriculture
Antibiotics are used in food animals for several reasons: treatment of sick animals, prophylaxis to prevent illness during times of increased risk of disease (e.g. transport or weaning), a combination of treatment of sick animals and preventative care for other animals in the herd or flock, and for growth promotion and improved feed utilization. The total amount of antibiotics used in food production animals in the U.S. is not known (3).
Antimicrobial agents have played an important role in animal production since the 1950’s. As livestock and poultry farms have grown and animal density on those farms has increased, the demand for better disease management has increased. The use of antimicrobial agents in animal production has improved animal health and led to higher yields. However, this practice has also contributed to the increased prevalence of antibiotic-resistant bacteria significant to human health (3).
The rising prevalence of MDR Salmonella complicates the treatment of Salmonella infections in both humans and animals. A call for prudent use of antibiotics in both human and animal medicine has been issued for years, with some positive results. In 2005, the U.S. Food and Drug Administration (FDA) placed a ban on the use of enrofloxacin (a drug closely related to cipro) in poultry because of the risk that it promotes drug-resistant bacteria that are harmful to human health (9). Opponents to banning antibiotic use in animal agriculture have pointed out that bans like these have, in some cases, led to increased animal morbidity and mortality, and have sometimes contributed to a greater use of antibiotics to treat ill animals. These other antibiotics may come from drug families of greater relevance to human medicine than the drugs that were banned (3).
New data also suggests that use of cephalosporins in the poultry industry could be impacting clinical use in humans. In July, 2008, the FDA proposed a ban of veterinary use of cephalosporins for unapproved methods (such as injection of eggs in hatcheries) due to the likely emergence of cephalosporin-resistant strains of foodborne bacterial pathogens (10). Since cipro is not approved for treatment of Salmonella infections in children under 18 years of age, cephalosporins are an important treatment option for severe infections (11). The American Veterinary Medical Association (AVMA), which represents both public and private sector veterinarians, argued that the FDA’s proposal was unjustified. FDA withdrew the proposal in November, 2008 in order to reconsider all available data on the subject (10).
Antibiotic-Resistant Salmonella in the Food Supply
Antibiotic-resistant Salmonella have been isolated from various food products. In 1998, 20% of ground meat samples were positive for Salmonella, and 84% of these were resistant to at least one antibiotic in the Washington, D.C. area (12). From 1999 to 2003, 18% of Salmonella isolates from various food products tested by the FDA were resistant to two or more antimicrobials (13).
A case-control study of Salmonella Newport infections in the U.S. found that MDR-AmpC infections are acquired through the U.S. food supply from bovine and possible poultry sources (14). Between 2004 and 2005, processed poultry from the mid-Atlantic area of the U.S. was positive for Salmonella in high numbers. Eighty percent of positive samples were resistant to at least one antimicrobial and 53% were resistant to three or more antimicrobials (15). In 2005, Salmonella was detected on 72% of broiler chicken carcasses prior to evisceration and on 20% of carcasses postchill in a sample of 20 U.S. processing plants. Only 15% of the S. Typhimurium var. 5- isolates were pan-susceptible, and more than half of these isolates were resistant to three or more antibiotics (16). In 2006, 22% of raw and ready-to-eat turkey meat purchased in a Midwestern U.S. city was positive for Salmonella. Of these isolates, 62% were multidrug-resistant (17). These results clearly show that MDR Salmonella are present in the food supply, and continued monitoring and research is necessary to track these alarming trends.
Human Infections
Several studies have been published focusing on the severe health consequences from multidrug-resistant Salmonella infections. In 2002, Helms et al. reported on a study in Denmark looking at antibiotic-resistant S. Typhimurium. Patients with MDR infections were 4.8 times more likely to die than the general population, and patients with quinolone-resistant infections were 10.3 times more likely to die (18). In 2004, Helms also reported that patients with quinolone-resistant S. Typhimurium infections had a two-fold increased risk of invasive illness or death within 90 days of infection compared to patients with pan-susceptible infections (19).
Also in 2004, Martin et al. reported on Canadians with MDR S. Typhimurium infection. Hospitalization was more likely in those with MDR infections, and the majority of these hospitalizations were directly attributed to the resistance patterns of the infections (20).
In 2005, Varma et al. published data on bloodstream infections and hospitalizations.
Patients infected with a Salmonella isolate resistant to one or more clinically important antibiotic were three times more likely to be hospitalized with a bloodstream infection than patients with pan-susceptible infections (21).
Outbreaks
Several outbreaks of multidrug-resistant Salmonella infections have been documented in the United States, including an outbreak associated with unpasteurized Mexican-style aged cheese (22), ground beef outbreaks (23, 24, 25, 26), and an outbreak associated with pasteurized milk (27).
In one investigation, hamburger was traced back through meat processing to well beef cattle that had been fed antibiotics (23). In another investigation, chloramphenicol-resistant S. Newport was traced through processing of contaminated ground beef to a dairy farm area. Chloramphenicol-resistant Salmonella was found in manure lagoons, abattoirs, ill dairy cattle, and ground beef. Isolation of chloramphenicol-resistant Salmonella was correlated with chloramphenicol use on the farms (24).
Outbreaks like these can result in multiple hospitalizations and death among individuals with the most severe infections. The multidrug-resistant nature of these organisms makes treatment failure more likely. Antimicrobial agents, particularly fluoroquinolones like cipro, are lifesaving for approximately 2,000 people each year in the U.S. If even 10% of Salmonella isolates in the United States were to become resistant to cipro, and 5% of persons with invasive cipro-resistant infections were to die, the result would be an increase of 10 deaths per year. If 50% of strains became resistant, an additional 100 deaths per year would be expected (2).
Conclusions
There are several reasons to conclude that antibiotic-resistance among human Salmonella isolates are the result of the use of antimicrobial agents in food animal production: (1) tracebacks from foodborne disease outbreaks have shown food animals as the ultimate source of infection (outbreak refs), (2) antimicrobial resistance patterns and genetic fingerprints have shown strong correlation between animal and human Salmonella (2, 6), and (3) antibiotic-resistance in human Salmonella isolates have shown more correlation with antibiotic use in animals than with antibiotic use in humans (2).
Dissemination of MDR Salmonella appears to contribute to changes in resistance patterns. In the U.S., there aren’t restrictions on movement of animal herds positive for S. Typhimurium, though the purchase of infected animals is known to be a risk factor for dissemination. Routine surveillance and intervention (including traceback and quarantine) has reduced the incidence of salmonellosis in food animals in Europe, specifically Norway and Sweden. Biosecurity measures, including protection of feed from rodents and birds, limiting human traffic, disinfection, and separation of newly purchased animals from the larger herd or flock, in addition to testing and quarantine would reduce the risk of introducing MDR Salmonella into a herd or flock. Addressing this issue would subsequently help prevent the unimpeded spread of MDR Salmonella through food animals with consequent human foodborne infection (28).
Some of the same farm management strategies that could help to prevent foodborne disease could also help prevent MDR Salmonella from circulating in the food supply. It ultimately comes down to cost vs. benefit at every step in the chain of responsibility among food producers. Farmers and their veterinarians should be responsible for judicious use of antibiotics in the animal industry just as physicians should be judicious in their use of antibiotics in human medicine. Farmers also need to implement biosecurity measures as outlined above to address problem of dissemination of MDR Salmonella in addition to other infectious agents. In an ideal world, slaughter and food manufacturing facilities would also follow suit, using the best possible practices to minimize foodborne disease transmission to consumers, and federal regulatory agencies would monitor each step in the overall process to ensure the best food safety practices possible. If the problem of antibiotic-resistance is not controlled, larger outbreaks with more severe consequences can be expected. Considering MDR Salmonella to be an official “adulterant” in foods would be a prudent step in helping to curb this emerging foodborne disease threat.
References
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