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Mount Sinai Hospital is a University of Toronto patient care, teaching, and research centre.
Mount Sinai Hospital is a University of Toronto patient care, teaching, and research centre.
Clinical Showcase

60-year-old Woman with Fever, Chills and Hematochezia

Clinical Case:

A 60-year-old Italian-speaking woman with chronic lymphoblastic leukemia presents with a 3-day history of fever, chills and hematochezia. Initially she was seen in the oncology clinic, started on ciprofloxacin and metronidazole and sent immediately to the emergency. She was diagnosed with CLL 9 years ago and had received radiotherapy and various chemotherapy agents. Most recently she received fludarabine and cyclophosphamide one month ago.

On examination she had a temperature of 39.4°C with a blood pressure of 100/70 and heart rate of 120 bpm. The neurologic examination was normal and she did not have signs of meningismus. There was marked abdominal lymphadenopathy and prolapsed hemorrhoids that were most likely the cause of the blood in her stool.

Her routine blood work was normal. There was no growth from her urine culture. However, gram-positive bacilli were seen in one out of two blood culture bottles after one day of incubation. The bacteria were described as small coccobacilli in short chains. (Figure 1)

The patient was immediately switched to ampicillin 2g IV q4h and gentamicin 80mg IV q8h. She quickly improved and was stepped down to just ampicillin for a total of two weeks. Upon further questioning, it was revealed that in the week prior to her illness she ingested unpasteurized goat cheese imported from Italy.

Figures:

Figure 1: Gram Stain of Isolate reveals gram-positive bacilli.

Questions:

  • What is the bacterium found in her blood? What diseases can this bacterium cause?
  • Where is this bacterium normally found? How does it cause disease in humans? Which populations are at most risk? What advice would you give this patient upon discharge?
  • Describe the mechanism of pathogenesis at the cellular and molecular level.
  • How would you confirm the identity of this organism?
  • What antibiotics can be used against this bacterium? Which common antibiotics have no activity against it?

Discussion:

Listeria monocytogenes is a facultative anaerobic gram-positive rod that can cause serious infections in humans and animals. While it is well known as an animal pathogen, L. monocytogenes is a relatively rare cause of human illness. L. monocytogenes is ubiquitous in nature as a soil organism and has many opportunities to enter the human foodchain. The pathogenesis of listeriosis depends on the ability of the organism to survive and replicate inside host cells including macrophages. L. monocytogenes was discovered by Murray, Webb and Swann in 1926 during an outbreak among lab rabbits and guinea pigs in Cambridge, England. This new species was originally named Bacterium monocytogenes because of a profound mononuclear leucocytosis observed in infected animals. It should be noted that while mononuclear leucocytosis is a characteristic of some animal infections, it is not a normal feature of human listeriosis. Other names were also used including Erysipelothrix and Listerella before Listeria was finally adopted in 1927 to honor Dr. Joseph Lister, the English surgeon who discovered antisepsis.

L. monocytogenes primarily causes meningitis, encephalitis and septicemia especially in the elderly or persons with lower cell-mediated immunity. It can start with non-sepcific symptoms of fever, malaise and myalgia or gastrointestinal symptoms before progressing to a more serious illness such as meningitis in predisposed individuals. Focal infections are rare but can occur in the immunocompromised through seeding during the bacteremic phase of the infection. These include endocarditis, endophthalmitis, septic arthritis, osteomyelitis, liver abscesses, cholecystitis, peritonitis and pleuropulmonary infection. Cutaneous infections are also possible in healthy people who have had skin contact with L. monocytogenes.

In pregnant women, L. monocytogenes causes a flu-like illness that can lead to infection of the fetus. Perinatal infections can lead to abortion, stillbirth or delivery of a seriously ill baby with early onset listeriosis characterized by pneumonia, septicemia and disseminated abscesses. Neonatal listeriosis usually occurs term babies who are infected days to weeks post-delivery and presents with meningitis rather than septicemia.

While most cases are sporadic, outbreaks have been documented. Foods that have been implicated include coleslaw, soft cheeses, pate, poultry, turkey frankfurters, mushrooms, milk and pork tongue in jelly. A transient carrier state can occur in 2 to 20% of animals and humans. Factors that are important in establishing infection include the host immune status, gastric acidity and inoculum size.

L. monocytogenes is a facultative intracellular pathogen that can survive inside host macrophages. It is believed that the bacteria penetrate the intestinal epithelium through specialized epithelial cells overlying the Peyer’s patches called M cells. After invading and replicating in the epithelial and phagocytic cells, it spreads to the liver and spleen through the bloodstream. Most are killed in the liver within the first 6 hours. However, if any bacteria survive, the liver becomes the primary site of replication for the bacteria. Subsequently they disseminate hematogenously preferentially to the brain and placenta to cause a more serious disease. Its ability to survive inside phagocytic cells is thought to allow entry past the blood-brain barrier and the transplacental barrier.

L. monocytogenes is also able to spread from cell to cell without entering the extracellular environment. To invade host cells, L. monocytogenes binds to a host receptor called E-cadherin via a bacterial ligand called internalin. After entry into the host cell, it resides in a vesicle. Then it must produce a hemolysin called listeriolysin to lyse the phagosome and escape into the cytoplasm where it can replicate. Through the expression of a protein called ActA, it can then harness the host cell’s actin machinery to move inside the cytoplasm. Upon reaching the cell membrane, it can cause the pseudopod-like protrusions that reach out to neighboring cells. Through an unknown mechanism, the bacterium induces the neighboring cell to engulf the pseudopod containing the bacterium. It ends up in a second phagosome and the life cycle is repeated. Thus it can spread from one cell to the next while avoiding the host humoral immune response.

Listeriae are gram-positive non-sporulating bacilli or coccobacilli occurring singly or in short chains. Occasionally palisades and Y-form patterns can lead to confusion with Corynebacterium. The occasional rod over 10 µm resembles Erysipelothrix and coccoid forms can be mistaken for Streptococci. Confirmation of the identity requires isolation and culture. Colonies are small, smooth and grayish in color. L. monocytogenes exhibits tumbling motility at ambient temperatures (20 to 25°C) due to the presence of up to four peritrichous flagella. It is also catalase positive, oxidase negative, hydrolyzes esculin, and has positive Voges-Proskauer and methyl red reactions. L. monocytogenes produces a hemolysin resulting in β-hemolysis on sheep blood agar plates. A synergistic hemolysis also occurs with β-lysin-producing Staphylococcus aureus in the CAMP test. A DNA probe assay is available for confirmation of colonies on primary plates. Though not commercially available, PCR-based tests have been shown to be highly sensitive and specific for detecting L. monocytogenes in CSF and tissue.

The pattern of antibiotic susceptibility has remained unchanged for many years. Penicillin or ampicillin with or without an aminoglycoside is generally recommended for treatment of listeriosis. Penicillin alone is bacteriostatic against Listeria but an aminoglycoside can enhance the activity of penicillin against L. monocytogenes. Trimethoprim-sulphamethoxazole alone has also been used with success in listeriosis. Resistance to chloramphenicol, macrolides and tetracyclines has been reported in some clinical isolates. However, L. monocytogenes is intrinsically resistant to cephalosporins and these agents should never be used if Listeria is suspected.

References:

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