Drug-resistant Salmonella species from animals fed antimicrobics

IIDN1

Infccti )us Diseases Newsletter

Editor Paul D. Hoeprich, MD

Volume 5, Number 4, April 1986

Division of Infectious and Immunologic Diseases University of California, Davis Medical Center

Associate Editors R u t h M. Lawrence, MD

Larry K. Picketing, MD

Charles W. Stratton, MD

Division of Infectious Diseases Texas Tech University Health Sciences Center

Program in Infectious Diseases and Clinical Microbiology The University of Texas Medical School at Houston

Department of Pathology Vanderbilt University Medical Center

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Drug-Resistant Salmonella Species from Animals Fed Antimicrobics 25 Scott D. H o l m b e r g

RNA Viruses and Cancer

28

Dennis J. Slamon and Irvin S. Y. Chen CASE REPORT Elizabeth Kailath

30

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Drug-Resistant Salmonella Species from Animals Fed Antimicrobics Scott D. Holmberg, MD The John Snow Public Health Group, Inc., Boston, Massachusetts

Antimicrobic-resistant strains presently constitute about 25% of Salmonella spp. isolated from humans in the United States. The source of these drug-resistant bacteria is unclear, but it is reasonable to suspect nonhuman animals as they are typically the source of salmonellal infections in humans. Selection of resistant bacteria in nonhuman animals might result from the continuous administration of antimicrobial agents at low doses for promotion of growth and prevention of disease. The practice of adding a penicillin a n d / o r a tetracycline to animal feeds is common, and almost half of all antimicrobics produced yearly in the United States are used for this and other veterinary purposes. Individual steps in the postulated sequence between barnyard and dinner table have been shown. First,it has been demonstrated that animals fed antimicrobics at low doses shed bacteria resistant to the ingested an-

timicrobics. Second, surveys by the United States Department of Agriculture (USDA) of meat and poultry going to market show that a high proportion harbor resistant Salmonella spp. and other Enterobacteriaceae. Third, resistant strains of Salmonella spp. are frequently recovered from humans and have increased in the 30 years during which subtherapeutic antimicrobics have been added to beef, pork, and poultry feed. Finally, several investigators have shown that resistance (R + ) plasmids extracted from Salmonella spp. from humans and from food animals are the same, ie, there is substantial overlap between human and animal pools of drugresistant Salmonella spp. Because of these and other data, many experts agree that antimicrobics important in the treatment of humans should not be used in nonhuman animals. However, this course of action would not be free of adverse economic effects to the pharmaceu-

ISSN 0278-2316

IDINDN 5(4)25-32, 1986

26

Infectious Diseases Newsletter 5(4) April 1986 Table 1. Attributes of 18 Patients with Disease Caused by Multiply Resistant Salmonella newport

Patient no.

Date of onset

Antimicrobic (date started)

Days in hospital

Hamburger from herd"

Comment~,

South Dakota outbreak 1 29/F 2 3/F 3 69/M 4 33/M

12/13/82 12/13/82 12/17/82 2/14/83

Amoxicillin (12/11) Amoxicillin (12/11) Multiple (12/15-1/10) Penicillin (2/11)

17 4 13j' 8

Yes Yes No Yes

Daughter of pt. 1 Secondary case' Dairy-herd owner

Minnesota outbreak 5 20/M 6 33/F 7 43/F 8 43/F 9 20/F 10 34/F 11 8/F 12 33/M 13 20/F 14 37/F

1/18/83 1/26/83 1/28/83 1/29/83 1/31/83 2/1/83 2/1/83 2/2/83 2/6/83 2/8/83

Penicillin (1/10) Amoxicillin (1/25) None None None Penicillin (1/26) Amoxicillin (1/30) Amoxicillin (1/31) Amoxicillin (2/4) Penicillin (2/7)

5 8 0 0 6 0 4 5 13 0

Yes Yes Yes No Yes No No Yes Yes Yes

Other cases 15 16 17 18

2/5/83 2/10/83 4/14/83 5/4/83

None Penicillin (2/8) None None

0 6 0 0

No Yes Yes Yes

Age/sex

18/F 30/M 6/M 17/M

"Cold" (1/24) Husband of pt. 6

North Dakota Iowa Son of pt. 4 Son of pt. 7

"Hamburger at home supplied directly from the suspected herd or purchased from markets thought to be supplied with meat from the herd. t'Days between onset of diarrhea and death in hospital. 'Patient underwent endoscopy directly after patient 1. Reprinted with modifications by permission of the New England Journal of Medicine (1984; 311:617-622). tical industry, the feed additive industry, and many farmers. These groups have repeatedly asked for more definitive data to establish a threat to human health before there is regulation by the Food and Drug Administration (FDA) of certain antimicrobics now added to animal feeds. One major obstacle to determining whether drug-resistant bacteria from animals pose a real threat to human health has been the inability to trace all the steps of the sequence from farm to consumer. The complexities of food marketing and distribution make it virtually impossible to trace an individual chicken or hamburger on the dinner table back to its animal sources. Conversely, it would be as difficult, and unethical, to follow enteric pathogens leaving the barnyard or feedlot through the complex slaugh-

ter and distribution system to individual humans who then develop serious illness. Because of these problems it has not been possible to trace drug-resistant Salmonella spp. or other pathogens (Camplyobacter spp., Escherichia coli ) retrospectively or prospectively from specific animals fed antimicrobics to specific persons who have developed serious illness. In early February 1983, laboratory-based surveillance of Salmonella spp. by the Minnesota Department of Health showed that there was a marked increase of Salmonella newport isolates of an unusual serotype in that state. Preliminary interviews showed that many of the patients had been taking antimicrobics for nondiarrheal illnesses just before the onset of salmonellosis. An investigation was begun to examine the pos-

sibility that the outbreak was caused by a contaminated antimicrobic. This hypothesis was rejected after it was found that the patients had taken different antimicrobial agents made by different manufacturers and obtained from different pharmacies. In all, 10 patients with multiply resistant S. newport in Minnesota with dates of onset in the 21 days between January 18 and February 8 were identified (patients 5-14, Table 1). Of the 10 ill persons, 7 had taken amoxicillin or penicillin in the week before onset of salmonellosis for nondiarrheal medical problems such as pharyngitis, bronchitis, thyroiditis, and otitis media. Also, of the 10 ill persons, 6 had been ill enough to require hospitalization for an average of 8 days each. The S. newport isolates from these Minnesota cases were resistant

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27 Infectious Diseases Newsletter 5(4) April1986 to ampicillin, carbenicillin, and tetracycline and carried a distinctive single 38-kilobase (24-megadalton) R-plasmid. Our hypothesis was that many patients were mildly ill or asymptomatically infected; if antimicrobics were taken to which the S. newport was resistant, disease might result as antimicrobic-susceptible competitors were inhibited. However, epidemiologic investigation and home visits in Minnesota to determine the source of the epidemic S. newport revealed that the patients had eaten no unusual foods. The only exposure common to the ill persons was the consumption of hamburger in the week before illness, but this exposure--ie, ground beef consumption--was not significantly different from that seen in control groups. We contacted all state and territorial epidemiologists to find out whether other S. newport with the new distinctive antimicrobic resistance were isolated elsewhere. In South Dakota there were four infections in humans with S. newport of the same plasmid profile and antimicrobic resistance pattern as seen in the S. newport recovered from the Mihnesota cases; the four patients in South Dakota (patients 1-4, Table 1) also had taken penicillins just before the onset of their salmonellosis. One of the South Dakota patients (patient 3, Table 1), was admitted to hospital after suffering internal injuries and developed diarrhea 8 days after sigmoidoscopy. He was the next patient examined by the same staff using the same equipment that had been employed for sigmoidoscopy of patient 1 on the previous afternoon. During his hospital stay, patient 3 received many different antimicrobics and died of S. newport sepsis 20 days after endoscopy. We considered patient 3 a secondary patient. The other three primary patients (patients 1, 2, and 4, Table 1) were related by marriage but had not

eaten together or socialized with one ,another in the previous year, although they came from two farms near each other in South Dakota. The only common exposure for these patients was a relative's feedlot beef farm adjacent to the dairy farm of patient 4. All three patients frequently ate at the beef farm and had received beef from the beef farm in the previous year. We discovered that the epidemic S. newport strain, with the distinctive plasmid, had been isolated from the tissues of a calf that had died during an outbreak of diarrheal disease in patient 4's dairy cows in November 1982; we were still able to recover this S. newport by culture of these cattle in March 1983. However, milk from the dairy herd was pasteurized and was only locally distributed. Thus, this dairy herd did not seem a likely source for the epidemic in Minneapolis-St. Paul, some 200 miles away. A beef herd at the beef farm was slaughtered just before the outbreak occurred in the Twin Cities area; these animals were fed subtherapeutic doses of chlortetracycline intermittently. However, no cattle remained at the beef farm for culture, and samples of meat obtained from freezers of the South Dakota farms were not of the beef thought to have caused illness in humans. To investigate the possibility that the epidemic S. newport might not have been spread by beef cattle from the epidemiologically suspect beef farm, we examined all 91 strains of S. newport that were isolated from animals in the United States and forwarded to USDA Veterinary Laboratory Services in Ames, Iowa, before infections in animals and humans were first reported in South Dakota. We did not find the single-plasmid-bearing epidemic strain in any other animals except from the dairy herd. Examination of all isolates of S. newport from humans in Minnesota, Wisconsin, South Dakota, North © 1986 Elsevier Science Publishing Co., Inc. 0278-2316/86/$0.00 + 2.20

Dakota, Iowa, and Nebraska from early 1982 until mid-1983 yielded not one single-plasmid-bearing strain; moreover, patients 1-4 had not traveled outside of South Dakota during the epidemic period. Thus, no animal or human source for this multistate outbreak was found from laboratory (plasmid) analysis of isolates of S. newport from humans and animals. However, we did find additional persons infected with the epidemic strain (patients 15-18, Table 1). To discover how these apparently unrelated cases occurred in a wide geographic area over a prolonged period, we also examined the distribution of the beef from the herd slaughtered just before the S. newport outbreak occurred in Minnesota. From computer records at sites of slaughter and processing we were able to determine that the 105 cattle comprising this herd were slaughtered in January 1983, and that 59 carcasses were processed into boxed beef--ground by supermarkets into hamburger--in Nebraska (Figure 1). On the day after processing, three partial shipments of boxed beef, about 40,000 pounds that included meat from the suspect and other herds, were sent to a meat brokerage firm near Minneapolis-St. Paul. The boxes were numbered and could be traced through the computerized records of the meat broker to six of seven supermarkets named as the source of ground hamburger for the eight patients living in the Twin Cities area (Figure 1). Also, 3 days after the herd was butchered, 30,000 pounds of "50 : 50 trim," used for hamburger, were shipped to a meat brokerage firm that supplied meat used by two other patients identified in southern Minnesota (patient 5) and Iowa (patient 16). In sum, our investigation showed that an identical strain of S. newport was recovered from 18 persons in four Midwestern states, a strain of S. newport genetically distinct from

28 Infectious Diseases Newsletter 5(4) April 1986 ®

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Figure l. Geographic distribution of 18 patients with disease caused by multiply resistant Salmonella newport from December 1982 through June 19831(circled numbers). The origin and shipment (broken lines) of the infected beef are indicated. Reprinted with modifications by permission of the New England Journal of Medicine (1984: 311:617 622). all but one of over 160 strains of S. newport isolated from humans and animals during the 18 months preceding the cluster of human cases. The one animal isolate identical to the outbreak was recovered f r o m a dairy herd adjacent to a beef herd fed subtherapeutic doses of antimicrobics to p r o m o t e growth. Patients with the distinctive S. newport infection either received their meat directly from this f a r m (and herd) or purchased it from supermarkets apparently supplied with meat from the herd. It is unlikely that these events were unrelated. Aside from the illustration of a n i m a l - t o - h u m a n spread of resistant bacteria, what is the importance of these 18 cases of drug-resistant, nontyphoidal salmonellosis? First, surveys have shown that the number of cases of salmonellosis reported to the Centers for Disease Control ( C D C ) is a small fraction of the n u m b e r of victims actually involved, usually less than 1%. In the outbreak

we studied, 40,000 pounds of potentially contaminated meat were distributed, and many people may have been mildly or moderately ill without coming to the attention of health professionals or having a stool culture performed. Second, a review of the experience of C D C teams that investigated 52 outbreaks of salmonellosis between 1971 and 1983 disclosed a case fatality rate for patients infected with antimicrobic-resistant Salmonella spp. of 4.2% (13/312 p a t i e n t s ) - - m u c h higher than the 0.2% for patients with antimicrobic-susceptible Salmonella spp. (4/1912 patients). In outbreaks with identified sources, food animal products were the source of 11 (69%) of 16 outbreaks caused by drug-resistant Salmonella spp. It appears that antimicrobicresistant Salmonella spp. frequently come from animals used for food, and may cause serious disease. The investigation described here demonstrates how difficult it is to untangle the complex chain of transmission by which resistant bacteria from animals infect humans. It is clear that antimicrobicresistant Salmonella spp. of animal origin can cause serious disease in humans, and that the emergence and persistence of such organisms is a complication of usage of antimicrobics in humans and animals. Thus, we advocate more prudent use of antimicrobics in both populations.

Bibliography Garside JS, Gordon RF, Tucker JF: The emergence of resistant strains of

Salmonella typhimurium in the tissues and alimentary tracts of chickens following the feeding of an antibiotic. Res Vet Sci 1:184-199, 1960. Holmberg SD, Osterholm MT, Senger KA, et al: Drug-resistant Salmonella from animals fed antimicrobials. N Engl J Med 311:617-622, 1984. Holmberg SD, Wells JG, Cohen ML: Animal-to-man transmission of antimicrobial-resistant Salmonella: investigations of U.S. outbreaks, 1971-1983. Science 225:833-835, 1984. Levy SB, FitzGerald GB, Macone AB: Spread of antibiotic-resistant plasmids from chicken to chicken and from chicken to man. Nature 260:40-42, 1976. Linton AH, Howe K, Bennett PM, et al: The colonization of the human gut by antibiotic resistant Escherichia coli from chickens. J Appl Bacteriol 43:465-469, 1977. National Research Council to Study the Human Health Effects of Subtherapeutic Antibiotic Use in Animal Feeds: The effects on human health of subtherapeutic use of antimicrobials in animal feeds. Washington, DC: National Academy of Sciences, 1980. O'Brien TF, Hopkins JD, Gilleece ES, et al: Molecular epidemiology of antibiotic resistance in salmonella from animals and human beings in the United States. N Engl J Med 307:1-6, 1982. Ryder RW, Blake PA, Mulin AC, et al: Increase in antibiotic resistance among isolates of Salmonella in the United States, 1967-75. J Infect Dis 142:485-491, 1980. Schroeder SA, Terry PM, Bennett JV: Antibiotic resistance and transfer factor in Salmonella, United States 1967. J Am Med Assoc 205:903-906, 1968. Stallones RA: Epidemiology and public policy: pro- and anti-biotic (editorial). Am J Epidemiol 115:485-491, 1982.

R N A Viruses and Cancer Dennis J. Slamon and Irvin S.Y. Chen Division of Hematology-Oncology, Jonsson Comprehensive Cancer Center, UC LA School of Medicine, Los Angeles, California The viral etiology of malignant disease was first postulated at the beginning of this century. Direct evi~' 1986 Elsevier Science Publishing Co., Inc. 0278-2316/86/$0.00 + 2.20

dence that an infectious agent could be involved in induction of malignancy came from the pioneering