Etiology

Members of the genus Listeria are facultatively anaerobic, non–spore-forming, motile, gram-positive bacilli that are catalase positive. The 6 Listeria species are divided into 2 genomically distinct groups on the basis of DNA-DNA hybridization studies. One group contains the species Listeria grayi, considered nonpathogenic. The 2nd group contains 5 species: the nonhemolytic species Listeria innocua and Listeria welshimeri and the hemolytic species L. monocytogenes, Listeria seeligeri, and Listeria ivanovii. L. ivanovii is pathogenic primarily in animals, and the vast majority of both human and animal disease is due to L. monocytogenes.

Subtyping of L. monocytogenes isolates for epidemiologic purposes has been attempted with the use of heat-stable somatic O and heat-labile flagellar H antigens, phage typing, ribotyping, and multilocus enzyme electrophoresis. Electrophoretic typing demonstrates the clonal structure of populations of L. monocytogenes as well as the sharing of populations between human and animal sources.

Selected biochemical tests together with the demonstration of tumbling motility, umbrella-type formation below the surface in semisolid medium, hemolysis, and a typical cyclic adenosine monophosphate (cAMP) test are usually sufficient to establish a presumptive identification of L. monocytogenes.

Epidemiology

L. monocytogenes is widespread in nature, has been isolated throughout the environment, and is associated with epizootic disease and asymptomatic carriage in more than 42 species of wild and domestic animals and 22 avian species. Epizootic disease in large animals such as sheep and cattle is associated with abortion and “circling disease,” a form of basilar meningitis. L. monocytogenes is isolated from sewage, silage, and soil, where it survives for >295 days. Human-to-human transmission does not occur except in maternal-fetal transmission. The annual incidence of listeriosis decreased by 36% between 1996 and 2004 and has remained level since then. However, outbreaks continue to occur. In 2002, an outbreak that resulted in 54 illnesses, 8 deaths, and 3 fetal deaths in 9 states was traced to consumption of contaminated turkey meat. The rate varies among states. Epidemic human listeriosis has been associated with food-borne transmission in several large outbreaks, especially in association with aged soft cheeses; improperly pasteurized milk and milk products; contaminated raw and ready-to-eat beef, pork, and poultry, and packaged meats; and vegetables grown on farms where the ground is contaminated with the feces of colonized animals. The incidence of Listeria infections in the USA in 2008 was 0.29 cases per 100,000 population, being highest in children <4 yr old and next highest in adults >60 yr. The ability of L. monocytogenes to grow at temperatures as low as 4°C increases the risk for transmission from aged soft cheeses and stored contaminated food. Small clusters of nosocomial person-to-person transmission have occurred in hospital nurseries and obstetric suites. Sporadic endemic listeriosis is less well characterized. Likely routes include food-borne infection and zoonotic spread. Zoonotic transmission with cutaneous infections occurs in veterinarians and farmers who handle sick animals.

Reported cases of listeriosis are clustered at the extremes of age. Some studies have shown higher rates in males and a seasonal predominance in the late summer and fall in the Northern hemisphere. Outside the newborn period and during pregnancy, disease is usually reported in patients with underlying immunosuppression, with a 100-300 times increased risk in HIV-infected persons and in the elderly (Table 181-1).

The incubation period, which is defined only for common-source food-borne disease, is 21-30 days but in some cases may be longer. Asymptomatic carriage and fecal excretion are reported in 1-5% of healthy persons and 5% of abattoir workers, but duration of excretion, when studied, is short (<1 mo).

Pathology

One of the major concepts of Listeria pathology and pathogenesis is its ability to survive as an intracellular pathogen. Listeria incites a mononuclear response and elaboration of cytokines, producing multisystem disease, particularly pyogenic meningitis. Granulomatous reactions and microabscess formation develop in many organs, including liver, lungs, adrenals, kidneys, central nervous system (CNS), and, notably, the placenta. Animal models demonstrate translocation, the transfer of intraluminal organisms across intact intestinal mucosa. Histologic examination of tissues including the placenta shows granulomatous inflammation and microabscess formation. Intracellular organisms can often be demonstrated with special stains.

Pathogenesis

Listeria organisms usually enter the host through the gastrointestinal tract. Gastric acidity provides some protection, and drugs that raise gastric pH may promote infection. Studies of intracellular and intercellular spread of L. monocytogenes have revealed a complex pathogenesis. Four pathogenic steps are described: internalization by phagocytosis, escape from the phagocytic vacuole, nucleation of actin filaments, and cell-to-cell spread. Listeriolysin, a hemolysin and the best-characterized virulence factor, probably mediates lysis of vacuoles and is responsible for the zone of hemolysis when grown on blood-containing solid media. In cell-to-cell spread, locomotion proceeds via cytochalasin-sensitive polymerization of actin filaments, which extrude the bacteria in pseudopods, which in turn are phagocytosed by adjacent cells, necessitating escape from a double-membrane vacuole. This mechanism protects intracellular bacteria from the humoral arm of immunity and is responsible for the well-known requirement of T cell–mediated activation of monocytes by lymphokines for clearance of infection and establishment of immunity. The significant risk for listeriosis in patients with depressed T-cell immunity speaks for the role of this arm of the immune system. The role of opsonizing antibody in protecting against infection is unclear.

Clinical Manifestations

The clinical presentation of listeriosis is highly dependent on the age of the patient and the circumstances of the infection.

Diagnosis

Listeriosis should be included in the differential diagnosis of infections in pregnancy, of neonatal sepsis and meningitis, and of sepsis or meningitis in older children who have underlying malignancies, are receiving immunosuppressive therapy, or have undergone transplantation. The diagnosis is established by culture of L. monocytogenes from blood or cerebrospinal fluid (CSF). Cultures from the maternal cervix, vagina, or lochia and the placenta if possible should be obtained when intrauterine infections lead to premature delivery or early-onset neonatal sepsis. Cultures from closed-space infections may also be useful. It is helpful to alert the laboratory to suspected cases so that Listeria isolates are not discarded as contaminating diphtheroids.

Histologic examination of the placenta is also useful. Polymerase chain reaction assays detect L. monocytogenes, but commercial assays are not available. Serodiagnostic tests have not proved useful.

Treatment

The emergence of multiple-antibiotic resistance mandates routine susceptibility testing of all isolates. The recommended therapy is ampicillin (100-200 mg/kg/day divided every 6 hr intravenously [IV]; 200-400 mg/kg/day divided every 6 hr IV if meningitis is present) alone or in combination with an aminoglycoside (5.0-7.5 mg/kg/day divided every 8 hr IV). The aminoglycoside enhances the bactericidal activity and is generally recommended in cases of endocarditis and meningitis. The adult dose is ampicillin 4-6 g/day divided every 6 hr plus an aminoglycoside. The ampicillin dose is doubled if meningitis is present. Special attention to dosing is required for neonates, who require longer dosing intervals because of the longer half-lives of the antibiotics in their bodies. L. monocytogenes is not susceptible to the cephalosporins, including third-generation cephalosporins. If these agents are used for empirical therapy for neonatal sepsis or meningitis in a newborn, ampicillin must be added for the possibility of L. monocytogenes infection. Vancomycin, vancomycin and an aminoglycoside, trimethoprim-sulfamethoxazole, and erythromycin are alternatives. The duration of therapy is usually 2-3 wk, with 3 wk recommended for immunocompromised persons and patients with meningitis. A longer course is needed for endocarditis, brain abscess, and osteomyelitis.

Prognosis

Early gestational listeriosis may be associated with abortion or stillbirth, although maternal infection with sparing of the fetus has been reported. There is no convincing evidence that L. monocytogenes is associated with repeated spontaneous abortions in humans. The mortality rate is >50% for premature infants infected in utero, 30% for early-onset neonatal sepsis, 15% for late-onset neonatal meningitis, and <10% in older children with prompt institution of appropriate antimicrobial therapy. Mental retardation, hydrocephalus, and other CNS sequelae are reported in survivors of Listeria meningitis.

Prevention

Listeriosis can be prevented by pasteurization and thorough cooking of foods. Irradiation of meat products may also be beneficial. Consumption of unpasteurized or improperly processed dairy products, especially aged soft cheeses, uncooked and precooked meat products that have been stored at 4°C for extended periods, and unwashed vegetables should be avoided (Table 181-3). This avoidance is particularly important during pregnancy and for immunocompromised persons. Infected domestic animals should be avoided when possible. Careful handwashing is essential to prevent nosocomial spread within obstetric and neonatal units. Immunocompromised patients given prophylaxis with trimethoprim-sulfamethoxazole are protected from Listeria infections. Cases and especially outbreaks should be reported immediately to public health authorities so that timely investigation can be initiated in order to interrupt transmission from the contaminated source.