AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Yersinia pseudotuberculosis is the least common of the 3 main Yersinia species to cause infections in humans. It is primarily a zoonotic infection with variable hosts, including domestic and sylvatic animals and birds. The condition has been associated with food-borne infection, including a few outbreaks. The organism primarily leads to a gastroenteritis (diarrheal component uncharacteristic) characterized by a self-limited mesenteric lymphadenitis that mimics appendicitis. The organism invades mammalian cells and survives intracellularly; the primary virulence factor is a plasmid-encoded protein that causes increased invasiveness. Postinfectious complications include erythema nodosum and reactive arthritis. Thus, a major triad for infection with this organism includes fever, abdominal pain, and rash. Rarely, it has been associated with septic complications (often in patients who are immunocompromised with chronic liver diseases).

The bacillus was first described in 1889 and was later renamed twice before the current name, Y pseudotuberculosis, was established in the 1960s. From the late 1920s to the mid 1960s, the organism was identified as Pasteurella and then Shigella pseudotuberculosis. A Russian researcher named Znamenskiy demonstrated that the organism was, in fact, a causative agent for clinical illness through self-inoculation.

Because Y pseudotuberculosis infection has zoonotic forms, the animal reservoirs for such transmission include many mammalian and avian hosts, such as dogs, cats, horses, cattle, rabbits, deer, rodents, and birds (eg, geese, turkey, ducks, canaries, cockatoos). An example of occupational exposure to Y pseudotuberculosis related to animal reservoirs involves butchers working in abattoirs slaughtering swine.

Pathophysiology

Infections in humans are primarily acquired through the gastrointestinal tract as a result of contaminated food products. Characteristic of yersinial infections, an inoculum of 10⁹ organisms often is needed. Although the bacterial organism generally does not result in diarrheal symptoms, it can cause a range of morbidities including forms of mesenteric lymphadenitis, granulomatous disease, and dissemination with sepsis.

Because the organism does not produce iron-binding compounds, patients with iron-overload states such as hemochromatosis, venous congestion, hemolytic anemia, and cirrhosis are at risk for sepsis. In 1959, an epidemic that occurred on the Pacific coast of Russia was termed the Far East scarlatinoid fever. Interestingly, virulence factors such as the Y pseudotuberculosis–derived mitogen (YPM)—a superantigen—are likely related to the atypical scarlet fever syndromes more recently reported, such as Izumi fever in Japan.

The incubation period varies from 5-10 days. Fecal excretion of the organism can occur several weeks after illness but often does not result in secondary person-to-person cases or clinical relapses. Latent times from 2-20 days have been reported in sporadic outbreaks with peak incidence rates at 4 days after ingestion.

Frequency

United States

No specific pattern indigenous to the United States has been noted. Most Yersinia-related outbreaks in the United States and abroad have been associated with the Yersinia enterocolitica species rather than Y pseudotuberculosis. In 1976, there was a chocolate milk outbreak in Oneida, New York, involving children. This was the first food-borne outbreak reported in the United States with both of the above Yersinia species being studied. Drinking from well water, mountain streams, and soil is associated with infection. Epidemics are uncommon, unlike the increased frequency of outbreaks associated with Y enterocolitica.

International

Distribution is worldwide; most cases occur in the winter season, probably because of the increased seasonal incidence of infection among animals. The increased prevalence in winter may also be due to the enhanced growth characteristics in cold temperatures. Although many cases have been reported in Europe, large-scale outbreaks in the Aomori region of Japan were noted in the early 1990s. Fewer than 30 cases of septicemia have been reported in the literature.

In November 1998, 4 laboratory-confirmed cases of Y pseudotuberculosis were reported to the British Columbia Centre for Disease Control Society (BCCDCS). Through a follow-up case-control study evaluating risk factors in a multivariate analysis, it was ascertained that possibly contaminated homogenized milk was implicated in the outbreak. In 1991, children consuming untreated drinking water in Okayama, Japan, were exposed to Y pseudotuberculosis that led to clinical disease. Isolation of the organism also has been reported in well water (in Czechoslovakia).

In the 1980s, outbreaks in Finland and Japan constituted most of the sporadic cases reported in the literature. In 1995, 8 cases were reported in a Belgian hospital that involved gastrointestinal complaints caused by Y pseudotuberculosis, which were obtained from stool analysis and careful isolation techniques involving cold-enriched media.

Mortality/Morbidity

Most Y pseudotuberculosis infections are self-limited with a low case-fatality rate. However, the infrequent sepsis-associated illnesses in patients with chronic liver disease may be associated with a greater than 75% mortality among these patients.

Race

No specific racial or ethnic predilection has been noted.

Sex

Men are affected 3 times more often than women. The postinfectious complications of erythema nodosum and arthritis are more common in women.

Age

More than three fourths of patients are children aged 5-15 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Symptoms of illness after infection include abdominal pain (often right lower quadrant location) and fever. Diarrhea is not common. The recently described syndrome of Izumi fever also can include more systemic symptoms. Late complications of yersinial infection also can include reactive arthritis and rheumatologic manifestations.

• Other clinical problems associated with the enteric form have included terminal ileitis and intussusception, especially in children. In two thirds of clinical cases, enterocolitis may result and generally lasts 1-3 weeks.
• Izumi fever, a syndrome, has been characterized by scarlatiniform rash, systemic symptoms, and features shared with Kawasaki disease, such as coronary artery aneurysms. Acute renal failure has been reported, although this is distinctly a rare manifestation.
• Other manifestations of infection can include erythema nodosum, arthralgias, reactive arthritis, and ankylosing spondylitis.
• The Far East scarlatinoid fever was first described in the context of Y pseudotuberculosis infection. A scarlatinoid-appearing rash involving the head and neck, upper and lower extremity erythema, mucous membrane enanthem, and strawberry tongue characterize this syndrome.
• In 1998, a single case involving culturing of the organism from a prostatic focus in a 55-year-old man was reported. Although no obvious environmental factors could be determined for the clinical syndrome, the patient was treated successfully with a sulfa-based regimen of oral antibiotics.

Physical

Physical findings may be grouped into 3 main categories, systemic, enteric, and rheumatologic. The predominant and often self-limited presentation is that of a febrile gastroenteritis with right lower quadrant abdominal pain.

• Systemic findings may include fever, skin rash, strawberry tongue, hypotension, and lymphadenopathy.
• Enteric findings include abdominal tenderness with or without rebound indicative of peritoneal involvement. Tenderness may be exquisite over McBurney point.
• Rheumatologic involvement may include joint effusion, tenderness, or decreased range of movement and may be asymmetric in distribution.
• Erythema nodosum lesions (often erythematous indurated tender areas on the anterior surface of the lower extremities) also may be found.
• Ophthalmic findings including uveitis and conjunctivitis also have been reported.

Causes

The syndromes associated with Yersinia species primarily are caused by ingestion or contact with the pathogenic species of the genus Yersinia. The more uncommon species, Y enterocolitica and Y pseudotuberculosis, have been associated with enteric syndromes. The latter organism has several serotypes (I-VI) of which the O-group, types I and II, are mainly responsible for human cases, Type I likely causes 80% of human disease. There is a role of cross-reactivity between bacterial proteins and host antigens in the development of reactive disease; there appears to be a greater role of iron overload in the genesis of the septic variants of the disease.

The following is a list of the major virulence factors associated with Y pseudotuberculosis (specific mechanisms of pathogenicity have not been fully elucidated):

• Yersinia species have encoded several plasmid virulence factors. More specifically, Y pseudotuberculosis has a 70-kd plasmid that encodes for a contact-dependent type III secretion system that delivers virulence factors known as Yersinia outer proteins (Yops). This mode of delivery is crucial for the pathogenicity of Y pseudotuberculosis. The major Yops include the following:
• • YopE enters host mammalian cells through a type III secretion system. It is a RhoGTPase-activating protein (RhoGAP) that targets the RhoGTPase activity of GTP-binding proteins. In various host cells, this RhoGAP catalytic activity of YopE has been shown to play a role in the disruption of actin filaments arrangement, promotion of cell rounding, prevention of host cell membrane pores that would result because of entry of type III translocation machinery, and inhibition of phagocytosis. Additionally, YopE (along with YopH and YopJ) plays a role in dampening proinflammatory signals of the host cell by decreasing the production of interleukin-8. Mice orally infected with a YopE- mutant form of Y pseudotuberculosis lacked the ability to colonize the spleen when compared with wild-type Y pseudotuberculosis.
  • YopJ is disruptive to host cell functioning through the action of binding to the superfamily of protein kinases, leading to blocking key phosphorylation steps. Ultimately, this process results in a decrease in cellular interleukin-8 and tumor necrosis factor production. YopJ works by inhibiting nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) signaling pathways and promoting apoptosis in macrophages. YopJ works alongside YopE and YopH in the critical process of depressing proinflammatory signals by the host cell. YopJ is translocated into the host cell through a type III secretion system.
  • YopT is a virulent factor that is not found in all the pathogenic species of Y pseudotuberculosis. YopT is also translocated to the host cell through a type III secretion system. Like YopE, YopT plays a role in disrupting actin filament arrangement (thus also contributing to cell rounding) and preventing phagocytic activity by the host cell. The catalytic activity of YopT has been shown to be that of a cysteine protease.
  • YopH is a virulence factor that shares many of the roles already described for YopE. YopH takes part in disrupting actin filament arrangement, decreasing the production of interleukin-8, contributing to cell rounding, and preventing phagocytic activity by the host cell. The tyrosine phosphatase activity of YopH is thought to contribute to the antiphagocytic and actin filament disruption roles. Like many other virulent Yops, YopH is translocated to the host cell by the type III secretion system.
• YopB is a protein that makes up part of the type III secretion system that is required to translocate many virulence factors of Y pseudotuberculosis. YopB is thought to trigger a proinflammatory signal from the host cell when the type III secretion system docks onto the plasma membrane of the host cell.
• YopD is also a protein that makes up part of the type III secretion system. It has been shown to be an important component because YopD- mutants cannot accomplish translocation. Additionally, YopD is integral in the formation of pores on the host plasma membrane during the infection process.
• Another virulence factor is the superantigen Y pseudotuberculosis–derived mitogen (YPM), an exotoxin. Generally, superantigens are bacterial or viral classes of proteins that are mediators of immune system activation. YPM selectively stimulates T lymphocytes that have V beta–containing gene segments and induce excessive amounts of inflammatory cytokines that appear to correlate to an increase in systemic symptoms. This is analogous to the role of superantigens in a similar disease, such as Kawasaki disease and even staphylococcal and streptococcal toxic shock syndromes.
• Another group of mediators of Y pseudotuberculosis pathogenesis is collectively known as adhesion molecules.
• • These proteins bind onto the host cell and aid in facilitating the internalization of Y pseudotuberculosis into the host. Two major proteins in this group are invasin and yadA. Y pseudotuberculosis strains that have the Inv gene (which encodes invasin) have enhanced invasion properties for epithelial host cells. Invasin of Y pseudotuberculosis binds to integrins on the M cells of Peyer patches. These integrins also bind to collagen and fibronectin.
  • Additionally, invasin is involved in promoting the internalization of bacteria across these eukaryotic M cells. The yadA outer membrane protein binds to laminin, collagen, and fibronectin that are themselves bound to their respective beta-1 integrin receptors on the cell surface. These binding interactions contribute to the processes of bacterial adhesion onto the host cell surface and bacterial internalization into the host cell.
• Another molecular mechanism of pathogenesis is the high pathogenicity island (HPI) of Y pseudotuberculosis. It contains the gene that codes for yersiniabactin, the important siderophore used for iron uptake. HPI has been shown to be common among the highly pathogenic species of Yersinia. Furthermore, the level of virulence increased when genes of HPI were transferred to a biotype 2 strain of Y enterocolitica that is ordinarily observed to display low pathogenicity. The significant role that pathogenic islands play in the virulence of a wide variety of infectious bacteria continues to be recognized.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

The main differential diagnosis is for the predominant presentation of the disease—the gastroenteritis and mesenteric lymphadenitis syndromes. However, given the other unusual forms, including the Izumi fever syndrome suggestive of atypical scarlet fever or rheumatologic complications, such as erythema nodosum and/or reactive arthritides, the corresponding differential diagnoses for such presentation likely would be quite variable.

In such cases, refer to the differential diagnosis including, but not necessarily limited to, the following:

Erythema nodosum
Juvenile rheumatoid arthritis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The laboratory diagnosis of Y pseudotuberculosis infection is a matter of confirming the presence of the organism to support the clinical diagnosis of the associated syndromes.
• • Because this is a bacterial infection and it ought not to be present in sterile fluids, the acquisition by culture from sources such as blood, cerebrospinal fluid (CSF), peritoneal fluid, synovial fluid, or other organ-based biopsy (eg, intestinal tissue, skin) is confirmatory.
  • Besides diagnostic measures that include serological tests (discussed below), researchers have also developed various polymerase chain reaction (PCR) methods that are sensitive, efficient, and accurate tools for identifying and serotyping Y pseudotuberculosis.
  • Histologic examination of specific tissue, such as mesenteric lymph nodes, may yield both pathologic and microbiologic presence of organism.
• Microbiology: Y pseudotuberculosis belongs to the genus Yersinia, which has 2 other pathogens that infect humans—Y enterocolitica and Yersinia pestis. Y pseudotuberculosis and Y pestis have a remarkable 97-100% homology. Y pseudotuberculosis is a gram-negative, non–lactose-fermenting coccobacillus that chemically is differentiated from other species, such as Y enterocolitica, by its fermentation of sorbitol, ornithine decarboxylase activity, and other tests. The optimum growth of yersinia occurs on MacConkey medium at 20-35°C. The organism is urease positive.
• • Bacteriology: Y pseudotuberculosis is both aerobic and facultatively anaerobic; it is a gram-negative coccobacillus that grows slowly on blood and chocolate agar plates, forming small colonies with a gray and translucent characteristic at 24-72 hours. It has a good growth pattern on MacConkey or eosin-methylene blue (EMB) agar plates but is enhanced noticeably at lower temperatures (eg, 4°C cold enrichment in buffered saline) and is in fact motile at temperatures lower than 28°C. Biochemically, it is oxidase-negative, urea-splitting, and catalase-producing, and it does not ferment lactose.
  • Stool: Isolation of organism from stool is difficult given the slow growth pattern and overgrowth of normal fecal flora. However, stool culture yield may be increased by means of cold enrichment, special culture media (eg, CIN [Cefsulodin-Irgasan-Novobiocin] agar), or alkali treatment. These methods generally are not cost effective.
  • Blood, peritoneal fluid, pharyngeal exudate, and synovial fluid may yield the organism.
• Serology
• • Enzyme-linked immunosorbent assay (ELISA) and agglutination tests may be ordered; the antibodies (against the O antigen) may appear soon after the onset of illness and are expected to wane over 2-6 months. Paired serum specimens taken 2 weeks apart that indicate a 4-fold rise in agglutinating antibodies can support the diagnosis. Hemagglutination reaction tests that detect the pili (fimbriae) of either Y pseudotuberculosis or Y pestis have also been developed. Hemagglutination titers of 1:160 or higher are considered generally significant and indicative of true infection.
  • However, cross-reaction between antibodies against other organisms may obscure the diagnostic picture. These other organisms include other Yersinia, Vibrio, Salmonella, Brucella, and Rickettsia species.
  • Researchers have developed monoclonal antibodies that can identify serogroup-specific protein epitopes of Y pseudotuberculosis strains (grown at specific temperatures) from each of the 6 serogroups of the species. These monoclonal antibodies have been shown to not positively react with other Yersinia, Salmonella, Shigella, Escherichia, and Proteus species. This research has great potential to be developed into a potent serotyping tool for Y pseudotuberculosis.

Imaging Studies

• With the primary enteric presentation of a mesenteric lymphadenitis, CT scans or, possibly, ultrasound visualization of the abdomen and pelvis may reveal enlarged mesenteric lymph nodes and/or peritoneal findings, including appendiceal inflammation, peri-appendiceal fluid, and/or terminal ileitis.
• If pneumonic or septic presentations occur, a chest x-ray may reveal infiltrates indicative of an acute pneumonia.

Other Tests

• In the unusual presentation of a Kawasaki disease–like variant, Izumi fever, ECG abnormalities may be indicative of ischemia if coronary artery circulation is compromised by the presence of aneurysms. These abnormalities especially may be present in children with this syndrome.

Procedures

• Exploratory laparotomy often is needed if prominent mesenteric lymphadenitis is present in a critically ill patient. This procedure would serve both diagnostic and therapeutic purposes and enable actual intestinal and/or appendiceal tissue to be obtained and analyzed for histopathologic and microbiologic examinations.

Histologic Findings

Although the affected appendix may even be normal in appearance, involved lymph nodes (mesenteric) typically show epithelioid granulomatous changes, lymphoid hyperplasia, coagulative necrosis, and histiocytic cell hyperplasia. Enteric lesions may be associated with crypt hyperplasia, microabscesses, and villus shortening.

Staging

No staging, per se, is warranted in this condition. The most common forms of Y pseudotuberculosis infection are self-limited gastroenteritis or mesenteric lymphadenitis syndromes. If the underlying host has diabetes, chronic liver disease such as chronic hepatitis, hemochromatosis, or is immunosuppressed, the more serious forms of sepsis accompanied by systemic disease may be present. This circumstance is not common.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Often Y pseudotuberculosis is self-limited. However, more toxic presentations including septic syndromes, severe dehydration, or other obscured diagnostic issues may warrant hospitalization. General supportive care of such patients is needed.

Surgical Care

If complications such as severe abdominal pain, including acute abdominal presentations, peritoneal findings, or, uncommonly, intussusception occur, then exploratory laparotomy may be warranted. This intervention is not common.

Consultations

Infectious diseases consultation may be helpful. Gastroenterologists or surgeons may be needed if invasive diagnostic or therapeutic interventions are warranted. For unusual presentations, such as rheumatologic, dermatologic, or ocular complications, the respective consultations may be helpful primarily to assist in considering Y pseudotuberculosis in the differential diagnosis.

Diet

No special diet is recommended; however, given the enteric nature of the symptoms and associated abdominal pain, diarrhea, fever and anorexia accompanying such illness, it may be prudent to either keep nothing by mouth (NPO) status through the diagnostic phase of the disease and push fluids to prevent dehydration as needed, often by intravenous route. It is expected that with the resolution of enteric syndromes, the natural appetite will improve, and, accordingly, it is appropriate to ensure adequate caloric intake.

Activity

Bedrest through the acute illness is recommended. Activity as tolerated can be resumed once the enteric and systemic symptoms resolve.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

It often is not necessary to treat Y pseudotuberculosis infection with antimicrobials. However, if critical illness along with younger age or immunosuppressed status is present, it may be prudent to treat with beta-lactam antibiotic therapy. Antibiotic therapy (initially IV) is warranted if the septic form of the disease occurs. Guidance by in vitro testing may be helpful; initial empiric therapy should include an aminopenicillin (eg, ampicillin plus/minus a beta-lactamase inhibitor) and ideally, an aminoglycoside.

Ampicillin may play a role in shortening the duration of culture positivity in patients infected with the Kawasaki-like variant of Y pseudotuberculosis infection; however, it does not likely alter the clinical situation. Combination therapy is not absolutely needed in most cases. The aminoglycoside streptomycin has been used to treat Yersinia infections, although gentamicin and tobramycin are considered appropriate. Third-generation cephalosporins have also been used. Another antibiotic that may have an important role is chloramphenicol (for patients with allergies to penicillin or aminoglycoside).

Drug Category: Antimicrobials

Therapy must be comprehensive and cover all likely pathogens in the context of the clinical setting.

Drug Name	Streptomycin sulfate
Description	Especially recommended in combination therapy with broad-spectrum antibiotics (eg, ampicillin, piperacillin) for septic presentations and/or immunosuppressed hosts. Recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.
Adult Dose	1 g IM qd; daily dosing likely more appropriate than intermittent dosing 2 times/wk dosing: 15 mg/kg/d IM; not to exceed 1 g/d 3 times/wk dosing: 25-30 mg/kg/d IM; not to exceed 1.5 g/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Nephrotoxicity may be increased with aminoglycosides, cephalosporins, penicillins, amphotericin B, and loop diuretics
Pregnancy	D - Unsafe in pregnancy
Precautions	Narrow therapeutic index; not intended for long-term therapy; caution in renal failure not on dialysis, myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission

Drug Name	Tobramycin (Nebcin)
Description	Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.
Adult Dose	Life-threatening infections: 5 mg/kg/d IV q24h, reduce to 3 mg/kg/d as soon as clinically indicated; not to exceed 5 mg/kg/d; adjust dose based on CrCl and changes in volume of distribution
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Increases effects of neuromuscular blockers and potentiates effect of extended spectrum penicillins; concurrent administration with amphotericin B, cephalosporins, and loop diuretics increases risk of nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal impairment, preexisting auditory or vestibular impairment, and in patients with neuromuscular disorders; aminoglycosides are associated with nephrotoxicity and ototoxicity

Drug Name	Gentamicin (Garamycin)
Description	Aminoglycoside antibiotic for gram-negative coverage. Used in combination with both an agent against gram-positive organisms and one that covers anaerobes.
Adult Dose	Serious infections and normal renal function: 3 mg/kg/d IV q8h Loading dose: 1-2.5 mg/kg IV q8h Maintenance dose: 1-1.5 mg/kg IV q8h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; non–dialysis-dependent renal insufficiency
Interactions	Coadministration with other aminoglycosides, cephalosporins, penicillins, and amphotericin B may increase nephrotoxicity; enhances effects of neuromuscular blocking agents thus prolonged respiratory depression may occur; coadministration with loop diuretics may increase auditory toxicity; possible irreversible hearing loss of varying degrees may occur (monitor regularly)
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Narrow therapeutic index (not intended for long-term therapy); caution in renal failure (not on dialysis), myasthenia gravis, hypocalcemia, and conditions that depress neuromuscular transmission; adjust dose in renal impairment

Drug Name	Chloramphenicol (Chloromycetin)
Description	Binds to 50 S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.
Adult Dose	500 mg PO/IV q6h for 10 d; not to exceed 4 g/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Concurrently with barbiturates, chloramphenicol serum levels may decrease while barbiturate levels may increase causing toxicity; manifestations of hypoglycemia may occur with sulfonylureas; rifampin may reduce serum levels, presumably through hepatic enzyme induction; may increase effects of anticoagulants; may increase serum hydantoin levels, possibly resulting in toxicity; chloramphenicol levels may be increased or decreased
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Use only for indicated infections, or as prophylaxis for bacterial infections; serious and fatal blood dyscrasias (aplastic anemia, hypoplastic anemia, thrombocytopenia, granulocytopenia) can occur; evaluate baseline and perform periodic blood studies approximately every 2 d while in therapy; discontinue upon appearance of reticulocytopenia, leukopenia, thrombocytopenia, anemia, or findings attributable to chloramphenicol; adjust dose in liver or kidney dysfunction; caution in pregnancy at term or during labor because of potential toxic effects on fetus (gray syndrome)

Drug Name	Piperacillin (Pipracil)
Description	Inhibits biosynthesis of cell wall mucopeptides and stage of active multiplication. Has antipseudomonal activity.
Adult Dose	Serious infection: 4 g IV q8h; not to exceed 24 g/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	At high concentrations, piperacillin may physically inactivate aminoglycosides; probenecid may increase levels; coadministration with aminoglycosides has synergistic effects
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Caution in renal impairment or history of seizures

Drug Name	Cefotaxime (Claforan)
Description	Third-generation cephalosporin with gram-negative spectrum. Lower efficacy against gram-positive organisms. For septicemia caused by susceptible organisms. Arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth.
Adult Dose	Moderate-to-severe infections: 2 g IV q6h Life-threatening infections: 1-2 g IV/IM q4h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Probenecid may increase levels; coadministration with furosemide and aminoglycosides may increase nephrotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Adjust dose in severe renal impairment; associated with severe colitis

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Supportive care for patients with sepsis
• • General hospital acute level care (intensive medical/surgical care may be needed, although uncommon unless the patient is severely ill)
  • Intravenous fluids, frequent monitoring, serial examinations, radiographic studies, intravenous antibiotics, and care subject to any complicating host- or disease-related factors

In/Out Patient Meds

• In outpatient settings or mild inpatient situations, vigilant observation without the use of antibiotics is reasonable. (See Complications, Prognosis.) Y pseudotuberculosis infection is often benign and self-limited.

Deterrence/Prevention

• Food-borne epidemics can occur. Contact precautions, especially in the inpatient setting, apply to appropriate barriers (eg, gown, gloves) to exposure to enteric secretions, such as with diarrhea. Avoid ingestion of uncooked meat, contaminated water, or unpasteurized milk. Careful handwashing should follow consumption or handling of chitterlings (pork intestines).

Complications

• Postinfectious sequelae may include arthritis and erythema nodosum. Additionally, severe infection may be complicated by formation of coronary aneurysms, septic features associated with iron-overload states, and renal involvement with tubulointerstitial nephritis. Intussusception also has been reported in children.

Prognosis

• Generally infection with Y pseudotuberculosis resulting in uncomplicated mesenteric lymphadenitis can be self-limited, often not requiring antibiotics. Septic forms or those associated with systemic manifestations are serious conditions with a high mortality rate (often 75% mortality despite antibiotic therapy).

Patient Education

• Helping the patient/family to be familiar with forms of exposure, routes of infection, variable manifestations of the disease, difficulties in the diagnostic issues, and the potential for complications (although uncommon) that may be associated, such as sepsis, reactive arthritis, erythema nodosum, and rare events such as cardiac or renal sequelae.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Keep the unusual nature of the infection in addition to the potential to delay or miss the diagnosis because of its variable presentation in mind in the evaluation process and documentation. Also, because a wide variety of differential diagnostic considerations can be available based on which features predominate in a given patient (intestinal vs extra-intestinal), documentation and communication with patient, family, and colleagues should be realistic and comprehensive.
• Patients with sepsis and those with complicated mesenteric adenitis syndromes should be treated promptly, and consultation with infectious diseases and gastroenterology (adult or pediatric as indicated) is recommended.
• Because of the uncertainties involved in predicting the extent of disease and/or potential for the postinfectious sequelae, practitioners may choose to empirically treat patients with uncomplicated presentations with antimicrobial regimens. However, no significant data support the use of antibiotic therapy to directly reduce the probability for postinfectious sequelae.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Abe J, Onimaru M, Matsumoto S, et al. Clinical role for a superantigen in Yersinia pseudotuberculosis infection. J Clin Invest. Apr 15 1997;99(8):1823-30. [Medline].
• Abe J, Takeda T. Characterization of a superantigen produced by Yersinia pseudotuberculosis. Prep Biochem Biotechnol. May-Aug 1997;27(2-3):173-208. [Medline].
• Amromin I, Chapnick EK, Morozov VG. Nonplague yersiniosis: report of four cases and review of the literature. Infect Dis Clin Pract. 2000;9:236-40.
• Bearden SW, Fetherston JD, Perry RD. Genetic organization of the yersiniabactin biosynthetic region and construction of avirulent mutants in Yersinia pestis. Infect Immun. 1997;65(5):1659-1668. [Full Text].
• Black DS, Bliska JB. The RhoGAP activity of the Yersinia pseudotuberculosis cytotoxin YopE is required for antiphagocytic function and virulence. Mol Microbiol. 2000;37(3):515-527. [Full Text].
• Black DS, Bliska JB. Identification of p130Cas as a substrate of Yersinia YopH (Yop51), a bacterial protein tyrosine phosphatase that translocates into mammalian cells and targets focal adhesions. Embo J. 1997;16(10):2730-2744. [Full Text].
• Bliska JB. Yop effectors of Yersinia spp. and actin rearrangements. Trends Micriobiol. 2000;8(5):205-208.
• Brubaker RR. The V antigen of yersiniae: an overview. Contrib Microbiol Immunol. 1991;12:127-33. [Medline].
• Butler T. Yersinia species, including plague. In: Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. 4th ed. NY:. Churchill Livingstone;1999:2406-2414.
• Center for Food Safety & Applied Nutrition. Yersinia enterocolitica. In: Foodborne Pathogenic Microorganisms and Natural Toxins Handbook [Center for Food Safety & Applied Nutrician Web site]. 1991;Available at: http://vm.cfsan.fda.gov/~mow/chap5.html. [Full Text].
• Cornelis GR. Molecular and cell biology aspects of plague. Proc Natl Acad Sci U S A. Aug 1 2000;97(16):8778-83. [Medline].
• Cornelis GR, Boland A, Stainier I, et al. The virulence plasmid of Yersinia, an antihost genome. Microbiol Mol Biol Rev. 1998;62(4):1315-1352. [Full Text].
• Fallman M, Persson C, Wolf-Watz H. Yersinia proteins that target host cell signaling pathways. J Clin Invest. Mar 15 1997;99(6):1153-7. [Medline].
• Feodorova VA, Samelija JG, Devdariani ZL. Heat-stable serogroup-specific proteins of Yersinia pseudotuberculosis. Journal of Medical Microbiology. 2003;52:389-395. [Full Text].
• Gaston JS, Cox C, Granfors K. Clinical and experimental evidence for persistent Yersinia infection in reactive arthritis. Arthritis Rheum. Oct 1999;42(10):2239-42. [Medline].
• Gomez HF, Cleary TG. Yersinia pseudotuberculosis. Oski's Pediatrics: Principles and Practice. 1999; Chapter 188..
• Heesemann J, Gaede K. Mechanisms involved in the pathogenesis of Yersinia infections. Rheumatol Int. 1989;9(3-5):213-7. [Medline].
• Heise T, Dersch P. Identification of a domain in Yersinia virulence factor YadA that is crucial for extracellular matrix-specific cell adhesion and uptake. Proc Natl Acad Sci U S A. 2006;103(9):3375-3380. [Full Text].
• Hinnebusch BJ. Bubonic plague: a molecular genetic case history of the emergence of an infectious disease. J Mol Med. Sep 1997;75(9):645-52. [Medline].
• Hubbert WT, Petenyi CW, Glasgow LA, et al. Yersinia pseudotuberculosis infection in the United States. Speticema, appendicitis, and mesenteric lymphadenitis. Am J Trop Med Hyg. Sep 1971;20(5):679-84. [Medline].
• Iriarte M, Cornelis GR. YopT, a new Yersinia Yop effector protein, affects the cytoskeleton of host cells. Mol Microbiol. 1998;29(3):915-929. [Full Text].
• Juris SJ, Shao F, Dixon JE. Yersinia effectors target mammalian signalling pathways. Cell Microbiol. 2002;4(4):201-211. [Full Text].
• Kageyama T, Ogasawara A, Fukuhara R, Narita Y, Miwa N, Kamanaka Y, et al. Yersinia pseudotuberculosis infection in breeding monkeys: detection and analysis of strain diversity by PCR. J Med Primatol. 2002;31:129-135. [Full Text].
• Kim W, Song MO, Song W, Kim KJ, Chung SI, Choi CS, et al. Comparison of 16S rDNA analysis and rep-PCR genomic fingerprinting for molecular identification of Yersinia pseudotuberculosis. Antonie Van Leeuwenhoek. 2003;83(2):125-133.
• Koo JW, Cho CR, Cha SJ, Chung CY. Intussusception associated with Yersinia pseudotuberculosis infection. Acta Paediatr. Oct 1996;85(10):1253-5. [Medline].
• Lesic B, Carniel E. Horizontal transfer of the high-pathogenicity island of Yersinia pseudotuberculosis. J Bacteriol. May 2005;187(10):3352-8. [Full Text].
• Marra A, Isberg RR. Invasin-Dependent and Invasin-Independent Pathways for Translocation of Yersinia pseudotuberculosis across the Peyer’s Patch Intestinal Epithelium. Infection and Immunity. 1997;65, No. 8:3412-3421. [Full Text].
• Mecsas J, Strauss EJ. Molecular mechanisms of bacterial virulence: type III secretion and pathogenicity islands. Emerg Infect Dis. 1996;2(4):270-288. [Full Text].
• Merilahti-Palo R, Lahesmaa R, Granfors K, et al. Risk of Yersinia infection among butchers. Scand J Infect Dis. 1991;23(1):55-61. [Medline].
• Nagel G, Lahrz A, Dersch P. Environmental control of invasin expression in Yersinia pseudotuberculosis is mediated by regulation of RovA, a transcriptional activator of the SlyA/Hor family. Mol Microbiol. 2001;41(6):1249-1269. [Full Text].
• Naiel B, Raul R. Chronic prostatitis due to Yersinia pseudotuberculosis. J Clin Microbiol. Mar 1998;36(3):856. [Medline].
• Naktin J, Beavis KG. Yersinia enterocolitica and Yersinia pseudotuberculosis. Clin Lab Med. Sep 1999;19(3):523-36, vi. [Medline].
• Neyt C, Cornelis GR. Insertion of a Yop translocation pore into the macrophage plasma membrane by Yersinia enterocolitica: requirement for translocators YopB and YopD, but not LcrG. Mol Microbiol. 1999;33(5):971-981. [Full Text].
• Nowgesic E, Fyfe M, Hockin J, et al. Outbreak of Yersinia pseudotuberculosis in British Columbia--November 1998. Can Commun Dis Rep. Jun 1 1999;25(11):97-100. [Medline].
• Orth K, Palmer LE, Bao ZQ, et al. Inhibition of the mitogen-activated protein kinase kinase superfamily by a Yersinia effector. Science. Sep 17 1999;285(5435):1920-3. [Medline].
• Paff JR, Triplett DA, Saari TN, et al. Clinical and laboratory aspects of Yersinia pseudotuberculosis infections, with a report of two cases. Am J Clin Pathol. Jul 1976;66(1):101-10. [Medline].
• Pelludat C, Hogardt M, Heesemann J. Transfer of the core region genes of the Yersinia enterocolitica WA-C serotype O:8 high-pathogenicity island to Y. enterocolitica MRS40, a strain with low levels of pathogenicity, confers a yersiniabactin biosynthesis phenotype and enha. Infect Immun. 2002;70(4):1832-1841. [Full Text].
• Perry RD, Balbo PB, Jones HA, Fetherston JD, DeMoll E. Yersiniabactin from Yersinia pestis: biochemical characterization of the siderophore and its role in iron transport and regulation. Microbiology. 1999;145:1181-1190. [Full Text].
• Persson C, Nordfelth R, Fallman M, et al. Localization of the Yersinia PTPase to focal complexes is an important virulence mechanism. Mol Microbiol. 1999;33(4):828-838. [Full Text].
• Persson C, Nordfelth R, Wolf-Watz H, et al. Cell-surface-bound Yersinia translocate the protein tyrosine phosphatase YopH by a polarized mechanism into the target cell. Mol Microbiol. 1995;18(1):135-150.
• Revell PA, Miller VL. A chromosomally encoded regulator is required for expression of the Yersinia enterocolitica inv gene and for virulence. Mol Microbiol. 2000;35(3):677-685. [Full Text].
• Rosqvist R, Bolin I, Wolf-Watz H. Inhibition of phagocytosis in Yersinia pseudotuberculosis: a virulence plasmid-encoded ability involving the Yop2b protein. Infect Immun. 1988;56(8):2139-2143. [Full Text].
• Sanekata T, Yoshikawa N, Otsuki K, Tsubokura M. Yersinia pseudotuberculosis isolation from cockatoo. J Vet Med Sci. Feb 1991;53(1):121-2. [Medline].
• Sato K, Komazawa M. Yersinia pseudotuberculosis infection in children due to untreated drinking water. Contrib Microbiol Immunol. 1991;12:5-10. [Medline].
• Shao F, Merritt PM, Dixon JE. A Yersinia effector and a Pseudomonas avirulence protein define a family of cysteine proteases functioning in bacterial pathogenesis. Cell. 2002;109(5):575-588.
• Uchiyama T, Kato H. The pathogenesis of Kawasaki disease and superantigens. Jpn J Infect Dis. Aug 1999;52(4):141-5. [Medline].
• Usui D, Ishii Y, Akaike H, et al. [Yersinia pseudotuberculosis type 4a infection meeting the diagnostic criteria for Kawasaki disease complicated by disseminated intravascular coagulation]. Kansenshogaku Zasshi. Nov 2005;79(11):895-9.
• Van Noyen R, Selderslaghs R, Bogaerts A, et al. Yersinia pseudotuberculosis in stool from patients in a regional Belgian hospital. Contrib Microbiol Immunol. 1995;13:19-24. [Medline].
• Viboud GI, So SS, Ryndak MB, Bliska JB. Proinflammatory signalling stimulated by the type III translocation factor YopB is counteracted by multiple effectors in epithelial cells infected with Yersinia pseudotuberculosis. Mol Microbiol. 2003;47(5):1305-1315. [Full Text].
• Viboud GI, Bliska JB. A bacterial type III secretion system inhibits actin polymerization to prevent pore formation in host cell membranes. Embo J. 2001;20(19):5373-5382. [Full Text].
• Viboud GI, Bliska JB. Yersinia outer proteins: role in modulation of host cell signaling responses and pathogenesis. Annu Rev Microbiol. 2005;59:69-89. [Full Text].
• de Almeida AM, Guiyoule A, Guilvout I, Iteman I, Baranton G,, et al. Chromosomal irp2 gene in Yersinia: distribution, expression, deletion and impact on virulence. Microb Pathog. 1993;14(1):9-21. [Full Text].

Article Last Updated: May 5, 2006