Continuing Education Activity

Listeria monocytogenes is a facultative, intracellular, gram-positive rod that is responsible for causing the infection listeriosis. Listeria causes severe infection in the elderly, neonates and the immunocompromised with only a self-limited gastrointestinal infection in the immunocompetent. This activity illustrates the evaluation and management of listeriosis and reviews the role of the interprofessional team in improving care for patients with this condition.

Objectives:

• Summarize the epidemiology of listeria along with the typical food that has the highest rate of transmitting infection.
• Describe the use of bacterial culture in the evaluation of listeria.
• Review the antibiotics used in the treatment of listeria meningitis.
• Explain the importance of improving care coordination among the interprofessional team members for the early recognition of signs of a systemic inflammatory response and thus, improve outcomes for patients affected by listeria.

Introduction

Listeria monocytogenes is a gram-positive, facultative intracellular rod bacteria that is catalase positive and beta-hemolytic when grown on blood agar. There have been several historical foodborne illness breakouts involving L. monocytogenes. In 1981, L. monocytogenes was revealed to be a foodborne illness linked to a variety of foods.  In 1985, a massive outbreak of L. monocytogenes was traced to a brand of soft cheeses involving 142 cases, 28 deaths, and 20 fetal losses.[1] While L. monocytogenes is not the most common foodborne illness, it has the highest mortality rate secondary to its unique virulence factors.[2]

L. monocytogenes’ virulence factors include but are not limited to intracellular mobility via actin polymerization and the ability to replicate at refrigerator temperatures. This makes it difficult for food industries to control. Transmission of the bacteria occurs via the fecal-oral route and most commonly involves foods such as cold deli meats and unpasteurized dairy products. The number of cases involving L. monocytogenes has decreased in recent years thanks to advances in prevention, detection, and treatment.

Infection via L. monocytogenes (listeriosis) includes but is not limited to sepsis, meningitis, encephalitis, spontaneous abortion, or fever and self-limiting gastroenteritis in a healthy adult. Populations at the most risk for L. monocytogenes infection include pregnant females, infants, immunocompromised individuals, and elderly.

Etiology

Listeria commonly causes meningitis in the young (neonates), elderly, and immunocompromised patient population. Healthy individuals infected with L. monocytogenes typically have a self-limiting gastrointestinal infection with fever and diarrhea. The Listeria family consists of 10 different species with L. monocytogenes found most consistently in humans. L. monocytogenes has 13 different serotypes based on a variety of flagellar and surface antigens.  However, there are only three serotypes (1/2a, 1/2b, 4a) that inflict disease in humans.[3] In general, the infectious dose of L. monocytogenes is large, meaning one must ingest a large number to cause clinical infection, but as growth and division can continue at refrigerator temperatures, these levels can be reached despite typical food storage precautions. Host immune response also affects the infectious dose. Utilization of proton pump inhibitors or other stomach acid suppression modalities makes it easier for L. monocytogenes to pass through the stomach and invade enterocytes.

Epidemiology

According to the Center for Disease Control (CDC), approximately 1,600 people get listeriosis each year with approximately 260 people dying from the disease. The disease is most prevalent in pregnant women, infants, immunocompromised, and elderly (65 and older). Pregnant women are also at risk as they can acquire L. monocytogenes and pass it to their unborn fetus.

L. monocytogenes is ubiquitous as it can be found in soil, water, and decaying vegetation. The bacterium can also be found in the human digestive tract. Foods that have the highest rates of L. monocytogenes related infections include:

• Raw sprouts
• Unpasteurized milk
• Soft cheeses
• Cold deli meats
• Cold hot dogs
• Smoked seafood

Pathophysiology

Primary Virulence Factors

• Internalins (InlA and InlB): Bacterial surface proteins for host cell attachment
• Listeriolysin O (LLO): Helps the bacteria escape from host cell vacuole
• Actin polymerization (ActA): Helps the bacteria move within and between cells
• Phosphatidylinositol-specific phospholipase C (PI-PLC): Helps the bacteria escape host cell vacuole and cause membrane disruption

L. monocytogenes can grow at refrigerator temperatures.  Low temperatures induce enzymes such as RNA helicase which improves L. monocytogenes’ activity and replication at low temperatures. The ability to produce biofilms enhances L. monocytogenes ability to survive harsh environments. L. monocytogenes also utilizes flagella at lower temperatures. This mechanism enables the ability to propel itself and latch onto enterocytes early in infection, but eventually losing the flagella the longer the bacteria is exposed to higher temperatures.

L. monocytogenes has cell-surface galactose residues, lipoteichoic acids, and surface proteins called "internalins" (internalin A and B) that binds primarily to gastrointestinal epithelial cells via host protein cadherin, allowing entry into the cell. After invasion into host cells, the bacteria has a propensity to initiate a cell-mediated immune response in the host. Phagocytized L. monocytogenes can lyse the internalized vacuole via a pore-forming cytotoxic protein called "listeriolysin O," (LLO) among other phospholipase proteins which are not pore-forming.  LLO is also responsible for the beta-hemolysis seen when grown on blood agar. Once free of the vacuole, the bacteria can disrupt the normal cellular processes by moving through the cell via actin polymerization.  The bacterium surface protein, ActA, is stimulated by host intracellular proteins that innately regulate actin filaments. These actin monomers are connected asymmetrically (only at one end) utilizing host intracellular cytoskeleton filaments. This tail, often referred to as a rocket tail, gives the bacteria the ability to move swiftly through the intracellular cytosol, between cells, or disseminate hematogenously.

Cadherin is an epithelial attachment protein that is found in abundance in the blood-brain barrier as well as the placental-fetus barrier which may explain why the bacteria can infect neonates and cause meningitis. L. monocytogenes forms "rocket tails" via actin polymerization that allows the bacteria to move rapidly between cells, avoid antibody detection, and spread hematogenously.

Once the infection has occurred, L. monocytogenes can cause amnionitis, sepsis, spontaneous abortion in pregnant women, granulomatosis infantiseptica, and meningitis. Healthy individuals infected with L. monocytogenes typically have self-limiting gastroenteritis with diarrhea and vomiting.

History and Physical

Always consider treating for L. monocytogenes in the following patient populations:

• Neonates (Usually younger than 29 days old)
• Elderly
• Immunocompromised
• Pregnant women

Listeria meningitis presents with fever, neck stiffness, headache, altered mental status, neurological deficits, and other classic signs of meningitis. The patient may demonstrate a positive Brudzinski's or Kernig's sign on physical exam. The patient may have an altered mental status and may not be alert and oriented to their name, location, and date. Inquire about the use of stomach acid suppressors as they increase the risk of L. monocytogenes infection.

Pregnant women or otherwise healthy adults may present with general "flu-like" illness including fever, diarrhea, headache, chills, nausea, vomiting, myalgias. Although, some patients may be completely asymptomatic.

For additional history, ask about any food the patient has recently ingested, particularly milk, soft cheeses, and cold deli meats or hot dogs.

Evaluation

The diagnosis of L. monocytogenes requires a culture of the bacteria from the blood, cerebral spinal fluid, or placental fluid. Once in the lab, Listeria species grows on a special type of agar called Meuller-Hinton agar. Culture will reveal gram-positive rods with colonies that are beta-hemolytic.

According to the CDC, stool cultures are neither sensitive nor specific for diagnosing L. monocytogenes.

Treatment / Management

Preventing transmission of L. monocytogenes involves avoiding foods commonly contaminated with L. monocytogenes and proper hand-washing technique.

Initial presentation of the patient requires analysis of their hemodynamic status and resuscitating as needed.

If meningitis is suspected, consider doing the following:

• Blood cultures
• Lumbar puncture
• Antibiotics
• CT scan of the head, non-contrast

The antibiotic treatment of choice is intravenous (IV) ampicillin or penicillin G. An alternative treatment is trimethoprim-sulfamethoxazole if the patient has a penicillin allergy.[4] L. monocytogenes is inherently resistant to all cephalosporin antibiotics.

Since other causes of meningitis include gram-positive organisms such as Streptococcus pneumoniae and gram-negative organisms such as Neisseria meningitidis, Ceftriaxone is added as a treatment regimen. Gentamicin is utilized to mostly cover for gram-negative etiologies of meningitis such as Escherichia coli in the infant population. Finally, Vancomycin is added for Methicillin-resistant Staphylococcus aureus coverage.

For broad coverage of bacterial meningitis in populations susceptible to L. monocytogenes, consider the following regimens:

• Less than one month old: Ampicillin plus gentamicin
• Adults with depressed cellular immunity or older than 50 years old: Vancomycin plus ceftriaxone plus ampicillin

For prevention of L. monocytogenes in the general population, the FDA has also approved a variety of different food additives including bacteriophage (Listeria Phage P100) sprays. The spray contains a bacteriophage virus that can eliminate L. monocytogenes. The spray would be primarily utilized on deli meats and cheeses.[5]

Differential Diagnosis

Consider other infectious organisms that also cause meningitis including but not limited to herpes simplex virus, Neisseria meningitidis, and Streptococcus pneumoniae. A lumbar puncture can help distinguish between bacterial causes and viral causes. Bacterial causes of meningitis typically have a high polymorphonuclear leukocyte count.

Other causes of a headache and/or fever include but are not limited to:

• Influenza Virus Infection
• Strep Pharyngitis
• Migraine headache
• Tension headache
• Cluster headache
• Subarachnoid Hemorrhage
• Acute otitis media
• Subdural hematoma
• Epidural hematoma
• Mononucleosis
• Intracranial mass/tumor

Prognosis

Studies have shown that L. monocytogenes is the third leading cause of death from food-borne illnesses in the United States, with approximately 260 deaths annually.[6] Mortality rates with confirmed L. monocytogenes infection are around 15% but can be higher depending on patient status and comorbidities.[6] Nearly 25% of pregnancy-related cases have poor outcomes including fetal demise.[8] Early recognition and treatment with ampicillin, penicillin G, or trimethoprim-sulfamethoxazole are very effective in treating L. monocytogenes.

Consultations

Infectious disease specialists should be consulted when managing patients with suspected meningitis or bacteremia secondary to L. monocytogenes infection.

Deterrence and Patient Education

If patient risk factors are present (pregnant, elderly, immunocompromised) patients should be cognizant of what foods they are ingesting. Be wary of the following foods: 

• Raw sprouts
• Unpasteurized milk
• Soft cheeses
• Cold deli meats
• Cold hot dogs
• Smoked seafood

Pearls and Other Issues

• Always consider L. monocytogenes as an infectious agent in a patient that is a neonate, elderly, or immunocompromised.
• Transmission involves the fecal-oral route. L. monocytogenes is a foodborne illness that can replicate at refrigerator temperatures.
• Ampicillin or trimethoprim-sulfamethoxazole is the treatment of choice along with other broad-spectrum antibiotics until an infectious agent can be confirmed.
• Early recognition is the key to an increased chance of survival.  
• L. monocytogenes is uniformly resistant to cephalosporin antibiotics.

Enhancing Healthcare Team Outcomes

L. monocytogenes is a foodborne illness that has the propensity to cause meningitis or fetal demise in unborn infants, and as such, requires management by an interprofessional healthcare team. Primary care clinics and emergency departments are the first line of defense in diagnosing patients with meningitis and initiating appropriate therapy. Intake nurses and triage staff have an important role in recognizing unstable vital signs that might trigger systemic inflammatory response (SIRS) criteria and should alert the physician of these findings. Having a high suspicion for meningitis, performing diagnostic testing, and starting with broad-spectrum antibiotics in the emergency department to cover the most likely organisms based on patient risk factors. Early detection and diagnosis of meningitis are critical for good outcomes. If the patient is diagnosed with meningitis, this will require admission to the hospitalist team with a consultation with an infectious disease physician to help narrow the spectrum of antibiotic coverage by analyzing cerebrospinal fluid and blood cultures. Infectious disease physicians and hospitalists should work closely with pharmacists to choose the correct antibiotics for the patient, based on the most up-to-date antibiogram data. After recovery and discharge, the patient should establish care or follow-up with their primary care physician. Nursing staff need to be fully apprised of the condition, and monitor on all follow-up visits to ensure that there is no regression in the patient's condition, and will report any concerns to the treating physician promptly. Finally, there should be hospital committees in place as well as protocols for the treatment of L. monocytogenes associated infections.[6] (Level IV)

Outcomes

Currently, available data shows that the overall mortality of L. monocytogenes, when it progresses to meningitis or sepsis, is relatively high compared to other food-borne illnesses. The mortality percentage increases in patients that have more comorbidities.[7] A patient without coexisting disease has an approximately 10.7% mortality rate versus a patient with several comorbidities including diabetes and heart disease who has a mortality rate is near 24%.[6] Immunocompetence also plays a large role in overall mortality for patients.