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