OVERVIEW: What every clinician needs to know

Pathogen name and classification

Yersinia pseudotuberculosis – A gram-negative coccobacillus in the family Enterobacteriaceae

What is the best treatment?

• Fluoroquinolones are the drugs of choice for Y. pseudotuberculosis infections, based on animal studies and in vitro antimicrobial resistance determinations. Trimethoprim-sulfamethoxazole and aminoglycosides may also have utility in therapy.

• Utility of β-lactam antibiotics is less certain. Most strains will show in vitro susceptibility to β-lactams. However, there are mouse studies in which β-lactams (including third generation cephalosporins) were found not to be efficacious in treatment of infection. In case reports of patients with bacteremia, the fatality rate for patients treated with penicillins and first- and second-generation cephalosporins appears to be slightly higher than for patients treated with fluoroquinolones, aminoglycosides, and trimethoprim-sulfamethoxazole.

How do patients contract this infection, and how do I prevent spread to other patients?

• Epidemiology-

  • Y. pseudotuberculosis is common in the environment, and can be isolated from a wide range of small wild animals, including rodents, moles, raccoons, palm civets, and the like. In mountainous areas of the Shimane Peninsula in Japan, reported isolation rates were 60% from wild mice and 80% from moles; isolation has also been reported from other areas of the Far East, from Europe, and from the United States, where there was a recent epizootic reported among farmed deer in Mississippi.

  • Y. pseudotuberculosis can be isolated from domestic animals (particularly pigs), and from pets, such as cats, who may become infected by consumption of wild rodents. However, rates of infection/colonization are generally much lower than those seen for Y. enterocolitica, with one study of Latvian pigs reporting isolation of Y. pseudotuberculosis from only 3% of pig tonsils and tongue samples at the time of slaughter, versus 35% positive samples for Y. enterocolitica.

  • Multiple outbreaks due to Y. pseudotuberculosis have been reported. In northern and eastern Europe, outbreaks have been associated, in many instances, with raw produce (grated carrots, iceberg lettuce); the exact source of contamination in these instances is not completely clear. There are suggestions that it occurs during processing, which may relate to contamination of product by wild rodents. In studies of sporadic cases/case reports in Europe and Japan, cases appear to be more common among persons living in rural areas, suggesting that risk increases with exposure to wild rodents and/or pets.

  • In common with Y. enterocolitica, Y. pseudotuberculosis is a psychrotroph – it grows well at low temperatures, including refrigerator temperatures. Cases tend to occur in areas with colder temperatures, and during winter months.

  • The incidence of Y. pseudotuberculosis in the United States has been estimated (based primarily on cases identified through positive blood cultures) at 0.04 cases per 1,000,000 persons per year. Y. pseudotuberculosis would appear to be much more common in Japan and northern Europe, although incidence rates are still substantially lower than those for Y. enterocolitica.

• Infection control issues-

  • Y. pseudotuberculosis has not been recognized as a nosocomial pathogen. Standard precautions should be adequate to prevent transmission.

What host factors protect against this infection?

• Outbreak data suggest that young children have an increased susceptibility to illness. For sporadic cases identified on the basis of positive blood cultures, infection tends to be linked with chronic underlying illnesses, including illnesses that result in immunosuppression, diabetes, and iron-overload states.

What are the clinical manifestations of infection with this organism?

• Infection with Y. pseudotuberculosis is generally manifested by fever (93% of patients in a recent outbreak in Finland attributed to grated carrots) and abdominal pain (83%). Vomiting and diarrhea occur in less than a quarter of patients, and tend to be mild. The median incubation period in the Finnish outbreak was 8 days (range 4–25 days); median duration of illness was 18 days (range 1–37 days).

• Abdominal pain tends to be severe, and clinical presentation may be identical to that of acute appendicitis. In the Finnish outbreak noted above, symptoms were so classic that one out of 76 patients for whom data were available still underwent appendectomy, even though a Y. pseudotuberculosis outbreak was known to be occurring. In a study from Ireland, it was estimated (using serology) that as many as 28% of patients diagnosed with acute appendicitis actually had Y. pseudotuberculosis infections. In this same study, Y. enterocolitica infections were thought to account for up to 4% of appendicitis cases – a much lower rate than for Y. pseudotuberculosis. Patients undergoing surgery for presumed appendicitis show evidence of mesenteric adenitis, with a normal or slightly inflamed appendix.

• A subset of patients will present with bacteremia/sepsis. These tend to be patients who are immunocompromised, who have chronic underlying diseases, or who have conditions that predispose to iron overload.

• In Japan, Y. pseudotuberculosis has been implicated as a causative agent in some cases of Izumi fever, and some patients have been found to meet strict criteria for Kawasaki syndrome.

What common complications are associated with infection with this pathogen?

• Erythema nodosum, reactive arthritis, and other autoimmune conditions have been linked with Y. pseudotuberculosis infection. As noted with Y. enterocolitica, the rate of autoimmune complications appears to be much higher in Scandinavia. In the Finnish outbreak noted above, erythema nodosum occurred a median of 19 days (range 6–29 days) after exposure to the microorganism.

How should I identify the organism?

• Y. pseudotuberculosis grows on blood and nutrient agar, and is readily isolated from blood cultures. For patients with suspected mesenteric adenitis, which may include mild diarrhea, isolation from stool should be attempted. Similar to Y. enterocolitica, isolation from stool is facilitated by use of cefsulodin-irgasan-novobiocin (CIN) agar. Given the ability of the microorganism to grow in the cold, use of a cold enrichment step is also helpful. Where stool cultures are ordered, the laboratory should be notified that a Yersinia species is suspected, so that appropriate procedures can be used.

• Serologic studies, with acute and chronic serum samples, have also been used to identify infection. While of clear value, interpretation of data is complicated by the cross-reactivity of Yersinia antigens with other antigens from microorganisms.

How does this organism cause disease?

• Y. pseudotuberculosis is an invasive, intracellular pathogen, capable of growth within macrophages. Virulence is mediated by a 70kb virulence plasmid, pYV, as well as by chromosomal genes, including the invasin gene. Much of the early work with invasin was done using Y. pseudotuberculosis as a model. From an evolutionary standpoint, Yersinia pestis, the causative agent of plague, appears to have evolved in the very recent past from Y. pseudotuberculosis, in association with the "stripping down" of a series of key genetic regions.

• As we are coming to recognize with other bacterial pathogens, changes in environmental and/or host conditions can result in changes in gene expression profiles, with corresponding shifts in virulence. In particular, growth of the microorganism in human plasma appears to trigger a series of major transcriptional regulatory events, impacting virulence.

• Autoimmune/postinfectious complications appear to be mediated by cross-reactivity between Yersinia and host antigens. Identification of the specific antigens involved in this cross-reactivity remains an area of active investigation.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Data on therapy for Y. pseudotuberculosis are extremely limited; recommendations are based on data from animal models and reported case series.

Other background material:

Jalava, K, Hakkinen, M, Valkonen, M. "An outbreak of gastrointestinal illness and erythema nodosum from grated carrots contaminated with Yersinia pseudotuberculosis". J Infect Dis. vol. 194. 2006. pp. 1209-16.

(Description of a recent large outbreak associated with grated carrots; provides data on clinical presentation and epidemiology.)

Vincent, P, Leclercq, A, Martin, L, Duez, JM, Simonet, M, Carniel, E. "Sudden onset of pseudotuberculosis in humans, France, 2004-05". Emerg Infect Dis. vol. 14. 2008. pp. 1119-22.

(Description of investigation of sporadic cases occurring across a 2-year period in France, providing epidemiologic data, and raising questions about the possible role of wild rodents in spreading the disease.)

Kaasch, AJ, Dinter, J, Goeser, T, Plum, G, Seifert, H. "Yersinia pseudotuberculosis bloodstream infection and septic arthritis: case report and review of the literature". Infection. vol. 40. 2012. pp. 185-90.

(A review of the literature on bloodstream infections.)

Isberg, RR, Voorhis, DL, Falkow, S. "Identification of invasin: a protein that allows enteric bacteria to penetrate cultured mammalian cells". Cell. vol. 50. 1987. pp. 769-78.

(A classic paper describing the identification of invasin, based on studies done with Y. pseudotuberculosis.)

Pouillot, F, Fayolle, C, Carniel, E. "Characterization of chromosomal regions conserved in Yersinia pseudotuberculosis and lost by Yersinia pestis". Infect Immun. vol. 76. 2008. pp. 4592-9.

(The paper provides a description of some of the genetic changes that occurred in Y. pseudotuberculosis leading to the emergence of Y. pestis, the causative agent of plague.)

Rosso, ML, Chauvaux, S, Dessein, R. "Growth of Yersinia pseudotuberculosis in human plasma: impacts on virulence and metabolic gene expression". BMC Microbiol. vol. 8. 2008. pp. 211.

(A look at changes in transcriptional regulation of the pathogen [and associated increases in virulence] when it is present in plasma.)