Listeria monocytogenes

Background

Microbiology

• Facultatively anaerobic, intracellular, non-sporulating, catalase positive, oxidase negative, short, non-branching, Gram-positive bacillus that grows readily on blood agar, producing incomplete β-hemolysis
  • Can be Gram-variable and pleomorphic
  • Can be initially misidentified as a diphtheroid
• 1 to 6 polar flagellae with tumbling motility at 25ºC
  • Demonstrates "umbrella" motility in the tube
• Can grow at refrigerator temperatures, as low as 4ºC
• Doesn't grow on usual stool culture plates
• 13 serovars based on cellular O and flagellar H antigens
  • Most disease from 4b, 1/2a, and 1/2b

Epidemiology

• In newborns, transmitted vertically from the mother
• In others, it is acquired from ingestion of contaminated food followed by mucosal invasion and bacteremia
• The bacterium can grow at fridge temperatures
• Both sporadic cases as well as foodborne outbreaks
  • Largest outbreak in Canada was associated with deli meats in 2008
  • Other outbreaks include ice cream (2015), frozen foods (2016), deli meat at a Druxy's in Princess Margaret Hospital (2018), prepackaged salads and kale (2018)
  • Refer to the Canada Food Inspection Agency for current recalls

Pathophysiology

• In gut, it is phagocytosed into endothelial cells, then disseminates hematogenously
  • Endocytosis is aided by LPXTG on the mucosal cell surface and helps it to adhere, as well as E-cadherin, which activates phagocytosis
    • Some hypothesize that uptake of Listeria is increased by concurrent GI infections
  • Listeriolysin O, the major virulence factor, is a pore-forming toxin that prevents T-cell response
  • Listeriolysin O and phspholipases help is escape the phagosome
  • Once in the cytoplasm, they activate actin to carry them to the cell membrane, where they push out and form filopods which can be phagocytosed by nearby cells
  • Moves from cell to cell without time spent outside
• In the CNS, it can invade the blood-brain barrier endothelial cells directly, or it can be transported across by cirtculating white blood cells ("Trojan horse" mechanism), or it can be inoculated into oral tissues followed by macrophage phagocytosis and invasion of cranial nerves
  • The latter may be most important for rhomboencephalitis
• Immune response primarily cell-mediated rather than antibody-mediated, since the bacterium doesn't spend any time outside of cells

Risk Factors

• Mostly around impaired cellular immunity
• Lymphoma, pregnancy (especially third trimester), advanced HIV, and corticosteroid immunosuppression, especially in transplant recipients
• In HIV and transplantation, may be prevented by Pneumocystis prophylaxis
• Use of anti-TNF-α medications
• Antacids that lower stomach acidity

Clinical Manifestations

• Incubation period for invasive disease is 30 days (range 11 to 90 days)

Bacteremia

• Most common presentation outside of neonatal period is as a non-specific febrile illness
• Can cause non-specific febrile illness, often with a prodrome of diarrhea and nausea, myalgias

Febrile Gastroenteritis

• Diarrhea, nausea, and vomiting, often with fever
• Associated with foodborne outbreaks, including chocolate milk, cold corn and tuna salad, cold smoked trout, deli meat
• Non-invasive in healthy patients
• Needs high innoculum

CNS Infections

• Causes a spectrum of CNS disease from meningitis to encephalitis to rhombencephalitis to abscesses

Meningitis

• A bacterial meningitis with high mortality, usually in very young, old >50 years, pregnant, or immunocompromised
  • Malignancy is the most common risk factor, followed by transplantation, alcohol use disorder, immunosuppression, diabetes, and HIV
• Symptoms include subacute presention of fevers, nausea, and headache, with meningismus, and altered and fluctuating mental status
• Focal neurologic deficits
• Can sometimes have movement disorders, including ataxia, termors, and myoclonus, as well as seizures
• Two thirds have neutrophil-predominant CSF
• Mortality 15-30%
• Even if cured, can be left with permanent focal neurologic deficits

Encephalitis/Cerebritis

• Localized parenchymal infection that can lead to abscess formation
• Altered consciousness and cognitive dysfunction
• CSF cultures only positive about half the time
• Can mimic herpes encephalitis

Rhombencephalitis

• Brainstem encephalitis
• Can occur in health adults
• Diphasic illness, with prodrome of fever, headache, nausea, and vomiting lasting 4 days, followed by asymmetric cranial nerve deficits, cerebellar dysfunction, and focal neurological deficits
• Half of patients have respiratory failure
• CSF often only mildly abnormal

Brain Abscess

• Often bacteremic and concurrent meningitis
• Can have abscesses in unusual locations, including subcortical abscesses of the thalamus, pons, and medulla

Spinal Cord Infection

• Rare cases

Endocarditis

• Can affect both native and prosthetic valves
• Mortality 50%

Neonatal Listeriosis

• Infection in first and second trimester frequently result in intrauterine fetal death
• Later in pregnancy, stillbirth or spontaneous abortion is common
• Presents in prematurity or neonatal period as early-onset sepsis, likely acquired in utero during third trimester
  • Disseminated listeriosis called granulomatosis infantiseptica
  • Widespread abscesses and granulomas, especially in lungs, liver, and spleen
  • Can have a miliary pattern on chest x-ray
  • Listeria can be isolated from conjunctiva, ear, nose, throat, meconium, amniotic fluid, placenta, blood, and sometimes CSF
• Can also present in term births as late-onset meningitis (~2 weeks post-partum)
  • Probably acquired during delivery, since it is far less common with cesarean section
• Mortality in neonatal infections is high at around 45%

Other Sites of Infection

• Conjunctivitis, skin infection, and lymphadenitis
• Hepatitis, liver abscesses, cholecystitis, perintonitis, splenic abscesses, pleural and pulmonary infections, septic arthritis, osteomyelitis, necrotizing fasciitis, pericarditis, myocarditits, arteritis, and endophthalmitis

Diagnosis

• Can be directly seen in blood or CSF, and cultured
  • Grows on blood agar with incomplete beta-hemolysis
  • Can also do cold-enrichment, incubating the plates at 4 to 10 ºC
  • Growth may be inhibited by usual stool culture plates
• Serology to listeriolysin O can be helpful in non-invasive disease
• PCR is possible for CSF and tissue, detecting the hly gene that encodes listeriolysin O
• MRI can diagnose abscess (vs meningitis)

Management

• Good supportive care
• It has intrinsic resistance to cephalosporins
• Ampicillin 2 g IV q4h is standard
  • Delayed bactericidal activity
• TMP-SMX 5/25 mg/kg IV q8h is second-line
• If severe, can combine ampicillin and TMP-SMX
  • Lower failure rate with fewer neurological sequelae than amp/gent
• Vancomycin and meropenem can be considered third-line
• Daptomycin and linezolid have in vitro activity
• Duration
  • Bacteremia: 2 weeks
  • CNS involvement: 3 weeks
  • Rhomboencephalitis or abscess: at least 6 weeks with serial imaging
  • Endocarditis: 4 to 6 weeks

Prevention

• Follow good food preparation practices

General Recommendations

Washing and Handling Food

• Rinse raw produce under tap-water, including produce you later peel
• Scrub firm produce with a clean brush
• Dry it with a clean cloth

Clean and Safe Kitchen

• Wash everything
• Make sure your freezer freezes
• Clean fridge spills quickly

Cook Meat Well

• Cook it to safe internal temperature
• Use pre-packaged stuff as quickly as possible
• Use leftovers within 3 to 4 days

Safer Foods

• No unpasteurized milk or milk products

Higher-risk Persons

Meats

• No hot dogs, deli meats, fermented or dry sausages, unless they are cooked to 165ºF before serving
• Avoid getting hot dog juice or other meat juice on things
• Don't eat pate or meat spreads that aren't canned, and refridgerate after opening

Cheeses

• Only eat soft cheeses if they are made with pasteurized milk

Seafood

• No refrigerated smoked seafood unless it is cooked or canned
• Canned seafood is safe

Melons

• Wash hands after handling the melon
• Scrub the melon clean and drug it well, sanitizing the brush between uses
• Don't keep cut pieces for longer than 7 days
• Don't leave out for longer than 4 hours