Listeria Monocytogenes and Listeriosis

OVERVIEW: What every clinician needs to know

Pathogen name and classification

Listeria monocytogenes is a short, nonbranching, nonsporeforming, gram-positive rod. There are several species of Listeria, but only L. monocytogenes is an important cause of human disease. Rarely, L. ivanovii and L. gravi have caused human illness in severely immunosuppresssed persons.

What is the best treatment?

Ampicillin or penicillin is generally considered the drug of choice based on in vitro data, treatment in animal models, and clinical experience. There have been no controlled trials to firmly establish a drug of choice or compare efficacies of alternative agents. Based on in vitro synergy and animal model studies, most authorities recommend adding gentamicin to ampicillin for patients with central nervous system (CNS) infection or endocarditis along with any infection in a neonate or immunosuppressed patient. For adults, the ampicillin dose should be 2g every 4 hours. For synergy, gentamicin should be administered as 3mg/kg per day in three divided doses.
Although continued vigilance is warranted, resistance of L. monocytogenes to the most commonly used agents has been very rare; there is no evidence that resistance is increasing.
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Treating physicians should check with the laboratory about routine sensitivity testing results to be sure the isolate is susceptible.
Those with life-threatening allergies to penicillin should be treated with trimethoprim-sulfamethoxazole (TMP-SMX) with a dose of 20mg/kg intravenously (IV) per day in two divided doses. In occasional cases with rapid clinical response and a mechanism to ensure reliable dosing, early transition to oral therapy with TMP-SMX may be considered at a dose of three single-strength tablets every 6 hours.

Vancomycin is an alternative, but both successes and failures have been reported.

Meropenem is active in vitro and is approved for the treatment of bacterial meningitis. Ertapenem is considerably less active than meropenem and should not be used.

Cephalosporins are ineffective and should be avoided. Because of this, ampicillin or TMP-SMX should be added to the initial therapy for bacterial meningitis in those aged more than 60 years or those with impaired cell-mediated immunity due to disease or immunosuppressive treatment.

Linezolid is active, and efficacy has been demonstrated in case reports.

Tetracyclines, erythromycin, and chloramphenicol lack efficacy and should be avoided.

Quinolones are active in vitro, but clinical experience to this point is minimal.

Daptomycin is variably active in vitro; clinical experience is lacking, but MICs would indicate that daptomycin cannot be recommended to treat listeriosis.
Iron is a virulence factor for Listeria. In patients who are iron deficient, it is prudent to withhold iron replacement until the infection is cured or under excellent control.

How do patients contract this infection, and how do I prevent spread to other patients?

Listeriosis is a foodborne illness in humans that occurs year round. Human epidemics and case clusters occur, and there is evidence that seemingly sporadic cases may, in fact, be part of a larger outbreak occurring over a widespread area. Food vehicles of infection have included delicatessen style ready-to-eat meats, particularly poultry products, soft cheeses, hot dogs, milk, and smoked fish. In recent outbreaks, vehicles have included fresh fruits (cantaloupes) and vegetables (sprouts). In some studies, there is an increased frequency of disease in temperate climates during the summer months; other studies do not support this association.
There are no apparent environmental conditions that predispose to listeriosis. Listeriosis is a zoonotic disease, particularly in herd animals. Humans typically acquire infection through ingestion of contaminated food containing viable bacteria. Unlike most foodborne diseases that result in gastrointestinal (GI) distress, human infection following ingestion of Listeria often manifests as invasive disease with bacteremia or meningitis carrying significant morbidity and mortality. Listeriosis is a relatively rare foodborne illness (~1% of US cases) but is associated with a case-fatality rate of 16-20% (second only to Vibrio vulnificus at 35-39%) and causes 19-28% of all foodborne disease-related deaths.
Listeriosis is quite uncommon in the general population, but it is a major cause of bacteremia and CNS infection in those with impaired cell-mediated immunity, such as those with hematopoietic cell or organ transplantation, those with hematological malignancies, and those receiving corticosteroids or anti-tumor necrosis factor agents. There are approximately 1,600 cases in the United States each year with approximately 260 deaths. It occurs worldwide, but prevalence appears to be increased in those countries and communities in which ingestion of unpasteurized cheeses is commonplace (e.g., France, Spain, and the Mexican-American community).
In the early 1990s, food industry regulations were instituted to minimize the risk of foodborne listeriosis through routine surveillance of food processing sites. Within a few years, the incidence of human listeriosis had fallen to almost one-half previous levels and has remained relatively constant ever since.
Other than transmission from an infected mother to her fetus or newborn at birth, human-to-human transmission does not occur, so no special isolation other than standard precautions is necessary.
There is no vaccine.
Anti-infective prophylaxis is not generally recommended. In the event of a foodborne outbreak of febrile gastroenteritis, it might be prudent to give those individuals with underlying immunosuppression who ingested contaminated food a short course of oral ampicillin or TMP-SMX in an attempt to eradicate GI colonization and prevent invasive disease. TMP-SMX given as Pneumocystis prophylaxis has been shown to decrease the frequency of listeriosis in human immunodeficiency virus (HIV)-infected patients and transplantation recipients. Prophylaxis for Group B streptococcal infections given to pregnant women appears to have decreased the incidence of neonatal listeriosis.
At-risk patients should be advised to thoroughly cook raw food from animal sources; keep uncooked meats separate from vegetables, cooked food, and ready-to-eat foods; avoid consumption of unpasteurized milk; and wash hands, knives, and cutting boards after handling uncooked foods. In addition, they should be advised to avoid soft cheeses and delicatessen counter foods, such as prepared salads, meats, and cheeses; and keep cooked perishable foods only short-term in the refrigerator.

What host factors protect against this infection?

Protection against listerial infection is mediated by both innate and adaptive immunity; the adaptive response is primarily mediated by the cellular arm of the immune system. The role of humoral immunity is unknown, but the frequency of listeriosis is not increased in those with immunoglobulin disorders, nor is there any increased frequency in those with deficiencies in neutrophil numbers or function, splenectomy, or complement deficiency.
Those with impaired cell-mediated immunity, whether due to underlying conditions (e.g., pregnancy) or diseases (e.g., lymphoma, acquired immunodeficiency syndrome [AIDS]) or due to therapy (e.g., corticosteroids, anti-tumor necrosis factor [TNF] alpha agents), are at the greatest risk for infection. Those at the extremes of age are also at risk, with the highest infection rates being seen in those aged less than 1 month and aged more than 60 years. In each of these age groups, L. monocytogenes accounts for approximately 20% of bacterial meningitis cases. Pregnant women account for approximately 30% of all cases and 60% of cases in the 20 to 40 years of age group. Iron overload and diabetes are less important risk factors. Invasive infection may occasionally be seen in apparently healthy individuals.
Invaded tissues show inflammation with both acute and chronic inflammatory cells; microabscesses and ill-formed granulomas may be seen in solid organs. When infection occurs in utero, bacteria proliferate in the placenta; the histopathology of the infected placenta with severe inflammation and microabscess formation, even in the absence of visible bacteria, may suggest the possibility of listeriosis to a pathologist.

What are the clinical manifestations of infection with this organism?

The species name comes from the fact that an extract of the L. monocytogenes cell membrane has potent monocytosis-producing activity in rabbits, but monocytosis is almost never seen in human infection.

Infection in pregnancy: During gestation, mild impairment of cell-mediated immunity occurs, and pregnant women are prone to developing listerial bacteremia with an estimated 17-fold increase in risk. The organisms proliferate in the placenta, and cell-to-cell spread facilitates maternal-fetal transmission. For unknown reasons, CNS infection, the most commonly recognized form of listeriosis in other groups, is extremely rare during pregnancy in the absence of other risk factors.Bacteremia manifests clinically as an acute febrile illness, often accompanied by myalgia, arthralgia, headache, and backache. Illness usually occurs in the third trimester, probably related to the major decline in cell-mediated immunity seen at 26 to 30 weeks of gestation. About one-fourth of perinatal infections result in stillbirth or neonatal deaths; premature labor and spontaneous abortion are common. Untreated bacteremia is generally self-limited, although if there is a complicating amnionitis, fever can persist in the mother until the fetus is aborted. Antimicrobial therapy for infection diagnosed during pregnancy may prevent fetal or perinatal infection and its consequences (fetal viability 29% in second trimester; 95% in third trimester).
Neonatal infection: When in utero infection occurs, it may precipitate spontaneous abortion. The fetus may be stillborn or die within hours of a disseminated form of listerial infection known as granulomatosis infantiseptica, which is characterized by widespread microabscesses and granulomas particularly prevalent in the liver and spleen. In this entity, abundant bacteria are often visible on Gram stain of meconium.

More commonly, neonatal infection manifests similar to that noted with group B streptococcal disease in which one of two forms can occur: early-onset sepsis syndrome, usually associated with prematurity and probably acquired in utero; and late-onset meningitis, occurring at approximately 2 weeks of age in term infants, who most likely acquired organisms from the maternal vagina at parturition. Purulent conjunctivitis and a disseminated papular rash have been described rarely in neonates with early onset disease, but clinical infection is otherwise similar to that due to other bacterial pathogens.
Bacteremia: Bacteremia without an evident focus is the most common manifestation of listeriosis after the neonatal period. Clinical manifestations typically include fever and myalgias; a prodromal illness with nausea and diarrhea can occur.
CNS: Organisms that cause bacterial meningitis most frequently (Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae) rarely cause parenchymal brain infections, such as cerebritis and brain abscess. By contrast, L. monocytogenes has tropism for the brain itself (particularly the brainstem), as well as for the meninges. Many patients with meningitis experience altered consciousness, seizures, or movement disorders and truly have meningoencephalitis.

Meningitis: L. monocytogenes accounts for 20% of bacterial meningitis cases in neonates and 20% in those aged more than 60 years. Worldwide, L. monocytogenes is one of the three major causes of neonatal meningitis, is second only to pneumococcus as a cause of bacterial meningitis in adults aged more than 50 years, and is the most common cause of bacterial meningitis in patients with lymphoma, patients with organ transplants, or those receiving corticosteroid immunosuppressive therapy for any reason.

Clinically, meningitis due to L. monocytogenes is usually similar to that due to more common causes, but the presentation may be subacute. The first prospective study of meningitis due to L. monocytogenes was reported in 2006.

Notable clinical features of listerial meningitis included headache in 88%, nausea in 83%, and fever in 90%; but only 75% of patients had a stiff neck at the time of presentation. A focal neurologic deficit was present in 37%. Only 43% had the classic meningitis triad of fever, neck stiffness, and change in mental status. At the time of presentation, 19 out of 30 patients had symptoms persisting for more than 24 hours, and eight had symptoms for 4 days or more.

Remarkable cerebrospinal fluid (CSF) findings included a median white blood cell count of 620 (range 24-16,003) and protein of 2.52g/L. Spinal fluid Gram stain revealed a gram-positive rod in only 28% of patients while blood cultures were positive for L. monocytogenes in 46% of patients. Sequelae in survivors included hemiparesis in two patients and cranial nerve palsies in two others; mortality was 15%.

Brainstem encephalitis (rhombencephalitis): An unusual form of listerial encephalitis involves the brainstem. In contrast to other listerial CNS infections, this illness usually occurs in healthy older children and adults.

The usual clinical picture is one of a biphasic illness with a prodrome of fever, headache, nausea, and vomiting lasting approximately 4 days, followed by the abrupt onset of asymmetric cranial nerve deficits, cerebellar signs, and hemiparesis or hemisensory deficits, or both. Respiratory failure develops in approximately 40% of cases.

Nuchal rigidity is present in approximately 50%, CSF is only mildly abnormal, and CSF culture is positive in approximately one-third; almost two-thirds are bacteremic. Magnetic resonance imaging is superior to computed tomography (CT) scan for demonstrating rhombencephalitis.

Mortality is high, and serious sequelae are common in survivors.

Brain abscess: Macroscopic brain abscesses account for approximately 10% of CNS listerial infections.

Bacteremia is almost always present, and concomitant meningitis with isolation of L. monocytogenes from the CSF is found in 25%; both of these features are rare in other forms of bacterial brain abscess.

Approximately 50% of cases occur in known risk groups for listerial infection.

Subcortical abscesses located in the thalamus, pons, and medulla are common; these sites are exceedingly rare when abscesses are due to other bacteria.

Mortality is high, and survivors usually have serious sequelae.
Endocarditis: Listerial endocarditis is rare. It affects the population at risk for viridans streptococcal endocarditis, produces both native valve and prosthetic valve disease, and has a high rate of septic complications and a mortality of almost 50%.
Febrile gastroenteritis: Many patients with listeria meningitis or bacteremia give a history of antecedent GI illness, often accompanied by fever. Although isolated cases of GI illness due to L. monocytogenes appear to be quite rare, at least seven outbreaks of foodborne gastroenteritis due to L. monocytogenes have been documented. Illness typically occurs 24 hours (range 6 hours to 10 days) after ingestion of a large inoculum of bacteria and usually lasts 1 to 3 days (range 1-7 days); attack rates have been quite high (52-100%). Common symptoms include fever, watery diarrhea, nausea, headache, and pains in joints and muscles. Vehicles of infection have included chocolate milk, cold corn and tuna salad, cold smoked trout, and delicatessen meat. L. monocytogenes should be considered a possible etiology in outbreaks of febrile gastroenteritis when routine cultures fail to yield a pathogen.
Localized infection: Rare reports of focal infections from which L. monocytogenes have been isolated include direct inoculation resulting in conjunctivitis,skin infection, and lymphadenitis. Bacteremia can lead to hepatic infection, cholecystitis, peritonitis, splenic abscess, pleuropulmonary infection, pyogenic arthritis, osteomyelitis,pericarditis, myocarditis, arteritis, and endophthalmitis.There is nothing clinically unique about these localized infections; many, but not all, have occurred in those known to be at risk for listeriosis.

What common complications are associated with infection with this pathogen?

Listeria meningitis may lead to obstructive hydrocephalus. Patients surviving encephalitis or brain abscess often have focal neurological deficits or a seizure disorder. Bacteremia during pregnancy may lead to premature labor, spontaneous abortion, stillbirth, or neonatal sepsis. Other reported complications of invasive disease include disseminated intravascular coagulation,adult respiratory distress syndrome, and rhabdomyolysis with acute renal failure.

How should I identify the organism?

Listeria is most often isolated from blood culture and CSF culture. Febrile patients with impaired cell-mediated immunity should have blood cultures obtained. Those with a clinical picture of meningoencephalitis should have blood and CSF cultures taken. Listeria may be grown from aspirates of localized abscesses (liver, brain, etc.) when present.
Listeria are readily stained by standard Gram stain and appear as short, nonbranching, gram-positive rods resembling diphtheroids. Occasionally, the organisms may be gram-variable, particularly on direct stain from CSF. Also, on occasion, the stained organisms may resemble cocci or diplococci.
Listeria are easily cultured by routine microbiological techniques. Molecular techniques, such as pulsed-field gel electrophoresis, can be used to separate isolates into distinct groups and are useful in identifying and tracking epidemics.

Blood agar is the preferred media for culture of normally sterile specimens, such as blood, CSF, pleural fluid, and joint fluid. In patients with suspected febrile gastroenteritis, the stool should be cultured, but media used to identify typical GI pathogens will inhibit the growth of Listeria. If culturing stool, the lab should be informed. Selective media are available to isolate Listeria from specimens, such as stool or food, that contain many organisms.

On blood agar, colonies appear small and white-gray. When grown on blood-free agar and viewed with light transmitted at a 45° angle (Henry’s illumination), colonies of L. monocytogenes appear blue-gray, whereas other bacteria appear yellow-orange. Under the microscope, a characteristic tumbling motility can be demonstrated at room temperature.

Listeria are catalase-positive and oxidase-negative and produce incomplete beta-hemolysis on blood agar. Unlike most bacteria, Listeria grow well at refrigerator temperature (4-10°C) and, by so-called cold enrichment, can be separated from other contaminating bacteria by long incubation in this temperature range.

Listeria grow within 24 hours routinely.

CSF cultures in those with meningitis are almost always positive, unless the patient received antimicrobials prior to obtaining the specimen. Blood cultures are often positive in patients with meningitis or brain abscess (>75%).
Polymerase chain reaction (PCR) for listerial infection is not commercially available and, to date, has not been helpful in the early diagnosis of meningitis due to this organism.
In one outbreak of febrile gastroenteritis, measurement of antibodies to listeriolysin O, a major virulence factor, was useful in implicating Listeria as the cause and identifying those who had been infected weeks after all clinical evidence of infection had resolved.

How does this organism cause disease?

Listeria enters the human host through contaminated food. In the intestine, it crosses the mucosal barrier by active endocytosis of organisms by endothelial cells. Once in the bloodstream, hematogenous dissemination can bring the organism to any site; Listeria has a particular predilection for the CNS. There is evidence that in ruminants Listeria may invade the oral or perioral mucosa or skin and travel directly up cranial nerves to invade the CNS; this may be how rhombencephalitis is acquired in humans.
Listeria are intracellular organisms. Several virulence factors enable L. monocytogenes to function as an intracellular organism. A specific surface protein, LPXTG, helps L. monocytogenes adhere to mucosal surfaces. The bacterium possesses the cell surface protein, internalin, that interacts with E-cadherin, a receptor on macrophages and intestinal lining cells, to induce its own ingestion. The major virulence factor, listeriolysin O, along with phospholipases, enables Listeria to escape from the phagosome and avoid intracellular killing.
Once free in the cytoplasm, the bacterium can divide and, by inducing host cell actin polymerization, propel itself to the cell membrane. Subsequently, by means of pseudopod-like projections, it can invade adjacent macrophages. The bacterial surface protein Act A is necessary for the induction of actin filament assembly and cell-to-cell spread and, therefore, is a major virulence factor. The adjacent cell can “take a bite” of the pseudopod containing the Listeria and internalize the organism in a new vacuole. Again, listeriolysin O aided by phospholipases, destroys the phagosome, leaving Listeria free in the cytoplasm of a new cell. Thus, through this novel life cycle, L. monocytogenes moves from cell to cell, evading exposure to antibodies, complement, or neutrophils.
Ability to scavenge iron, essential for the life of most microorganisms, appears to be an important virulence factor of L. monocytogenes. Siderophores of the organism enable it to take iron from transferrin.In vitro, iron enhances organism growth, and, in animal models of listerial infection, iron overload is associated with enhanced susceptibility to infection and iron supplementation with enhanced lethality, whereas iron depletion results in prolonged survival. The clinical associations of sporadic listerial infection with hemochromatosis and of outbreaks with transfusion-induced iron overload in patients receiving dialysis attest to the importance of iron acquisition as a virulence factor in humans.
These virulence factors enable Listeria to be a successful intracellular parasite. Since cell-mediated immunity is the major mechanism by which we deal with intracellular organisms, it is no surprise that those with impaired cellular immune systems, whether from illness or therapy, are those most often affected.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

Fortunately, listeriosis remains an uncommon human infection. Largely due to its infrequency, there are no studies available to provide significant data on specific management and treatment. Below are some references that may be useful to the practitioner.

Aureli, P, Fiorucci, GC, Caroli, D. “An outbreak of febrile gastroenteritis associated with corn contaminated by “. N Engl J Med. vol. 342. 2000. pp. 1235-41. (This is a report of the largest foodborne outbreak due to Listeria.)

Brouwer, MC, van de Beek, D, Heckenberg, SG. “Community-acquired meningitis in adults”. Clin Infect Dis. vol. 43. 2006. pp. 1233-8. (This is the only prospective study of meningitis due to Listeria.)

Clauss, HE, Lorber, B. “CNS infection with “. Curr Infect Dis Rep. vol. 10. 2008. pp. 300-6. (This is a succinct review of CNS listeriosis.)

Drevets, DA, Bronze, MS. “: epidemiology, human disease, and mechanisms of brain invasion”. FEMS Immunol Med Microbiol. vol. 53. 2008. pp. 151-65.

Elinav, H, Hershko-Klement, A, Valinsky, L. “Pregnancy-associated listeriosis: clinical characteristics and geospatial analysis of a 10-year period in Israel”. Clin Infect Dis. vol. 59. 2014. pp. 953-61. (This paper demonstrates that treatment of a pregnant woman with listeriosis can result in a healthy birth and that the likelihood of a good outcome increases later in pregnancy).

Godshall, CE, Suh, G, Lorber, B. ” Cutaneous listeriosis”. J Clin Microbiol. vol. 51. 2013. pp. 3591-3596. (This is the most complete review of skin infection due to Listeria).(This is a description of the pathogenesis of listeriosis with particular attention to CNS invasion.)

Goulet, V. “What can we do to prevent listeriosis in 2006?”. Clin Infect Dis. vol. 44. 2007. pp. 529-30. (The title says it all.)

Grant, MH, Ravreby, H, Lorber, B. “Cure of meningitis after early transition to oral therapy”. Antimcrobial Agents Chemother. vol. 54. 2010. pp. 2276-7. (This source provides evidence that in certain cases CNS listeriosis can be treated with oral therapy.)

Jacob, J, Lorber, B. ” Listeriosis after transient infectious or mechanical disturbance of the gastrointestinal tract”. Infect Dis Clin Pract. vol. 23. 2015. pp. 13-15. (Interesting reports of invasive listeriosis following procedures on the GI tract (colonoscopy) or infections of the GI tract (shigellosis; C. difficile).

MacDonald, PDM, Whitwam, RE, Boggs, JD. “Outbreak of listeriosis among Mexican immigrants as a result of consumption of illicitly produced Mexican-style cheese”. Clin Infect Dis. vol. 40. 2005. pp. 677-82. (This is a description of listeriosis outbreak in a US community related to specific dietary habits.)

McCollum, JT, Cronquist, AB, Silk, BJ. “Multistate outbreak of listeriosis associated with cantaloupe.”. N Engl J Med. vol. 369. 2013. pp. 944-53. (Report of an unusual outbreak due to fresh fruit demonstrating the potential for previously undescribed food vehicles to cause human listeriosis and reminding us of the importance of carefully washing vegetables and fruits before eating.)

Mylonakis, E, Hohmann, EL, Calderwood, SB. “Central nervous system infection with 33 years’ experience at a general hospital and review of 776 episodes from the literature”. Medicine. vol. 77. 1998. pp. 313(This is a comprehensive, detailed review of CNS listeriosis.)

Mylonakis, E, Paliou, M, Hohmann, EL. “Listeriosis during pregnancy: a case series and review of 222 cases”. Medicine. vol. 81. 2002. pp. 260-9. (This is an excellent clinical review of listeriosis during pregnancy.)

Ooi, ST, Lorber, B. “Gastroenteritis due to “. Clin Infect Dis. vol. 40. 2005. pp. 1327-32. (This is a review of the recently described entity of febrile gastroenteritis due to Listeria.)

Schett, G, Herak, P, Graninger, W. “-associated arthritis in a patient undergoing etanercept therapy: case report and review of the literature”. J Clin Microbiol. vol. 43. 2005. pp. 2537-41. (This is a review of new association of listeriosis complicating anti-TNF therapies.)

Swaminathan, B, Gerner-Smidt, P. “The epidemiology of human listeriosis”. Microbes Infect. vol. 9. 2007. pp. 1236-43. (This is a comprehensive review of epidemiology.)

Voetsch, AC, Angulo, FJ, Jones, TF. “Reduction in the incidence of invasive listeriosis in foodborne diseases active surveillance network sites, 1996-2003”. Clin Infect Dis. vol. 44. 2007. pp. 513-20. (This is documentation of reduction in incidence of listeriosis following new regulations governing food safety.)

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