Listeriosis

Agent
Pathogenesis
Epidemiology
Clinical Features
Differential Diagnosis
Laboratory Diagnosis
Treatment
Travel Implications
Disease Prevention and Control
References

Agent

Classification

Listeria and Brochothrix form one of several sublines within the Clostridium bacterial subdivision (see References: Bille 2003). Members of the genus Listeria are classified into six species:

L monocytogenes (the type species)
L ivanovii (two subspecies: ivanovii and londoniensis)
L innocua
L seeligeri
L welshimeri
L grayi

Strains of Listeria species are divided into serotypes on the basis of somatic (O) and flagellar (H) antigens (see References: Bille 2003; AAP 2003; Lorber 2005).
L monocytogenes is the only species pathogenic for humans; it has 13 known strains (1/2a, 1/2b, 1/2c, 3a, 3b, 3c, 4a, 4ab, 4b, 4c, 4d, 4e, and 7).
Most human disease is caused by serotypes 1/2a, 1/2b, and 4b.

Key Microbiologic Characteristics

Listeria organisms have the following characteristics:

Gram-positive rods that occur singly or in short chains (on Gram stain, they may be gram-variable and look like diphtheroids, cocci, or diplococci; laboratory misidentification is common)
Size: 0.5 to 2 microns by 0.4 to 0.5 microns
Genome is 2.9 million base pairs
Non-spore-forming
Facultative anaerobe
Move via 1 to 5 peritrichous flagellae motile at 28°C (less motile at 37°C)
Optimum growth temperature between 30°C and 37°C, but growth occurs at 4°C (refrigeration temperature), an important factor in food contaminated with the bacteria
Produce catalase (except for a few strains) and oxidase test is negative
Produce acid from D-glucose and other sugars

Pathogenesis

Virulence Factors

Factors that influence whether Listeria causes systemic disease include:

Immune status of the host
Virulence of the infecting strain
Size of the inoculum

Virulence genes: Certain virulence genes (prfA, inlA, inlB, inlC) and virulence-associated genes (dal, LisR, and clpP) interspersed within the L monocytogenes genome play important roles in intracellular survival, cell-to-cell spread, and virulence of the organism (see References: Zhang 2004).

PrfA protein is a key regulatory factor for the differential expression of virulence genes within infected host cells (see References: Milohanic 2003).
InlA and B have the ability to invade mammalian cells (see References: Evans 2004).
LisR gene encodes on the two-component signal transduction response regulators and is involved in virulence potential and tolerance to antimicrobials (see References: Cotter 1999).
The clpP gene codes for one of the caseinolytic proteins (clp) involved in degradation of damaged polypeptides and aids in the rapid adaptive response of intracellular pathogens during the process of infection (see References: Gaillot 2000).
Lysteriolysin O, the major virulence factor, in conjunction with phosphatases, enables the bacteria to escape from phagosomes and avoid intracellular death.
ActA, another virulence factor, is required for inducing host actin filament assembly and cell-to-cell transfer.

Iron appears to be an important virulence factor for L monocytogenes. The organism's siderophores allow it to take iron from transferrin, and in vitro experiments demonstrate that iron enhances Listeria growth (see References: Farber 1991).
Clinical associations of Listeria infection with hematochromatosis and outbreaks with transfusion-induced iron overload in dialysis patients highlight the importance of iron as a virulence factor among humans (see References: Nieman 1980; Mossey 1985).
Resistance plasmids that confer resistance to chloramphenicol, macrolides, and tetracyclines have been found in several clinical isolates of L monoctyogenes and may affect treatment of infections in the future (see References: Hadorn 1993); however, a recent study has not demonstrated any change in resistance among strains from Denmark through 2001 (see References: Hansen 2005).

Major Mechanisms of Pathogenesis

Pathogenesis is a multistep process (see References: Lorber 2006; Reido 1994):

Organisms are ingested in contaminated food (experiments in healthy mammals suggest that the infectious dose is at least 10⁹ organisms). They pass through the stomach and into the small intestine. Stomach alkalinization may promote infection (antacids, H2-blockers, or ulcer surgery) (see References: Schlech 1993).
L monocytogenes organisms cross the intestinal barrier via active endocytosis of endothelial cells. The process is facilitated by interaction between the bacterial cell surface protein internalin and an epithelial cell surface receptor, E-cadherin.
LpeA, a PsaA-like membrane protein, also promotes entry into nonmacrophage cells. Once free in the cellular cytoplasm, the bacteria divide and, via induction of host cell actin polymerization, propel themselves to the cell membrane.
Bacteria push against the cell membrane to form filopods (elongated pseudopods) that can be ingested by adjacent cells such as macrophages, enterocytes, and hepatoytes.
The bacterial protein ActA is needed for the induction of host actin filament assembly and cell-to-cell spread.
This mechanism allows the bacteria to spread from cell to cell without being exposed to host antibodies, complement, or neutrophils.
Once the organism spreads, systemic infection is possible. The organism has a tropism for the central nervous system (CNS) and can cause bacteremia, CNS infections (meningitis, rhombencephalitis [brain stem encephalitis], brain abscesses), endocarditis, and localized infection. The incubation period for invasive illness is not well established, but data from several cases related to specific dates of ingestion indicate that the incubation period may range from 11 to 70 days, with a mean of 31 days (see References: Reido 1994).

The mechanisms by which L monocytogenes causes diarrhea are unknown, but diarrhea is likely the result of direct invasion (see References: Ooi 2005).
Resistance to Listeria infection is predominantly through cell-mediated immunity and persons with abnormalities in cell-mediated immunity (including pregnancy) are at increased risk of invasive disease. The role of humoral immunity is not clear; patients with deficiencies in humoral immunity (such as persons with immunoglobulin disorders) are not at increased risk of infection (see References: Lorber 2005).

Epidemiology

Reservoirs

Listeria species are widely distributed in the environment; their primary habitats are the soil and decaying vegetable matter. Silage is a common source of infection among farm animals (see References: OIE 2004).
Animals are an important reservoir and clinical illness in animals occurs (see References: OIE 2004). A wide variety of animal species can be infected by L monocytogenes, although the illness is seen most commonly in ruminants (including sheep, goats, cattle, and [less commonly] pigs). The clinical manifestations in animals include encephalitis, septicemia, and abortion. Rhombencephalitis can lead to ataxia in affected ruminants; this manifestation of infection has been called "circling disease." Although birds are usually subclinical carriers, sporadic cases of listeriosis have been reported in avian species.
Humans also are a reservoir for the organism; L monocytogenes has been isolated from 5% to 10% of stools in healthy adult humans (see References: Schuchat 1993).
Because of their ubiquity, L monocytogenes organisms have many opportunities to enter the food-production and food-processing environments. Recovery rates for the organism of 15% and 70% are common from raw vegetables, unpasteurized milk, fresh soft cheese, and meats (including fresh-frozen and processed chicken and beef in supermarkets and delicatessens) (see References: Farber 1991).

Modes of Transmission

The major mode of transmission is through ingestion of contaminated food, especially ready-to-eat delicatessen meats, hot dogs, and pate (see References: AAP 2003, CDC 1998, Lorber 2005, Yang 2006). Inadequately pasteurized milk (or milk contaminated post-pasteurization), soft cheeses, and other dairy products also are important sources of L monocytogenes (see References: MacDonald 2005; Makino 2005; Dalton 1997; Fleming 1985).
Pregnant women can transmit the infection to their unborn fetuses in utero (through hematogenous spread) or during birth.
Some instances of nosocomial transmission have occurred (particularly in neonatal nurseries) (see References: Nelson 1985; Siegman-Igra 2002). One nursery outbreak involved use of contaminated mineral oil (see References: Schuchat 1991).

Incidence (United States)

Incidence estimates for listeriosis are limited to invasive disease, since Listeria gastroenteritis is usually not diagnosed outside of an outbreak setting and information on sporadic cases of gastroenteritis is lacking.
During the 1980s, the incidence of listeriosis was estimated at approximately 7.4 cases per million population or about 1,850 cases per year with about 425 deaths (see References: Gellin 1991; Ciesielski 1988).
In 1993, the estimated annual incidence (based on active surveillance in selected areas) was 4.4 cases per million population, representing about 1,092 cases with 248 deaths. The decline between the late 1980s and 1993 was correlated with food industry regulations to reduce foodborne listeriosis (see References: Tappero 1995).
The incidence of listeriosis has continued to decline in recent years. Preliminary analysis of data from the Foodborne Diseases Active Surveillance Network (FoodNet) for 2004 and 2005 illustrate this decline (see References: CDC 2005, CDC 2006). The FoodNet system collects data from 10 sites across the country through active, population-based surveillance for laboratory-diagnosed illness. Although the system provides the best available estimate on the incidence of various pathogens transmitted commonly through food, there are a number of limitations to the system and the data do not necessarily reflect the true incidence of infection nationwide (particularly for Listeria gastroenteritis, since stools are not routinely tested for this organism). Given these caveats, the following observations on listeriosis are available from the 2004 and 2005 FoodNet reports.

The overall incidence of laboratory-detected Listeria infections in the United States for 2004 was estimated at 0.27 cases per 100,000 persons (2.7 per million) and the incidence for 2005 was estimated at 0.3 per 100,000 persons (3 per million).
This incidence comes close to approaching the national health objective of 2.5 per 1 million persons for 2010 (see References: HHS: Healthy People 2010).
Compared with data from 1996 to 1998, the 2004 data indicate a 40% decline (confidence interval [CI], 25% to 52%) in Listeria infections (a slight increase occurred in 2005).
Although the incidence of Listeria infections decreased from the period 1996-1998 through 2004, the incidence in 2004 was comparable to that in 2002, after an increase in 2003.

The highest infection rates are observed among infants younger than 1 month of age and adults older than age 60 years (see References: Lorber 2005).
Pregnant women account for about 30% of all cases and 60% of the cases among patients between the ages of 10 and 40 years.
Most cases of listeriosis are sporadic, although foodborne outbreaks are recognized periodically.

Incidence (Global)

Estimates of the annual incidence for nonperinatal and perinatal listeriosis in several developed countries are outlined in the table below (see References: Seigman-Igra 2002). Data for developing countries generally are not available.

Estimated Incidence of Listeriosis for Nonperinatal and Perinatal Disease by Country*
Country	Incidence for non-perinatal infection†	Incidence for perinatal infection‡
Australia	0.3	2
England	0.35	NA
Finland	0.09-0.65	NA
Israel	0.6	1.4
Spain	1.1	0-4.1
Estimated overall incidence	0.1-1.1	0.6-1.4
*See References: Siegman-Igra 2002. The periods of observation differed in each country (both specific years and number of years); the span ranged from 1967 to 1999. †Estimated incidence per 100,000 population. ‡Estimated incidence per 10,000 live births.

During food outbreaks, the incidence of infection in the exposed population may rise to 5 cases per 100,000 (see References: Bille 2003).
An outbreak of listeriosis associated with consumption of soft cheese produced in Switzerland from 1983 to 1987 prompted French authorities to implement prevention measures in 1988. From 1987 to 1997 the incidence of listeriosis declined by an estimated 68% in France. The decrease was most pronounced among pregnant women (84%) and those older than age 65 without predisposing conditions (82%) (see References: Goulet 2001).
A marked increase in the incidence of listeriosis in 1998 in Israel prompted a retrospective national survey that revealed the increase was due to perinatal infections, which accounted for about half of the total cases (see References: Siegman-Igra 2002). An unexpected finding was that about 16% of the infections in adults occurred in hospitals.

Risk Factors for Infection

A case-control study of dietary risk factors for sporadic cases of listeriosis demonstrated that cases were more likely to have consumed soft cheese or food purchased from store delicatessen counters (see References: Schuchat 1992). Eating undercooked chicken also increased the risk of infection for immunosuppressed patients. Several studies have shown that L monocytogenes can be transferred from one contaminated source meat to other meats during mechanical slicing, which could amplify contamination within the deli setting (see References: Vorst 2006).
Persons at elevated risk (see References: AAP 2003; Braden 2003; Farber 1991; Mylonakis 2002; Schuchat 1992; Siegman-Igra 2002) include:

Patients who are more than 50 years old
Immunocompromised patients (including patients taking corticosteroids)
Patients with underlying chronic medical conditions such as diabetes mellitus, alcoholism, cardiovascular diseases, and renal insufficiency
Pregnant women and their unborn fetuses or newborn infants
Infants and young children

Examples of Key Outbreaks

Outbreaks of foodborne listeriosis have been recognized since 1981(see References: Schlech 2000). During the 1980s, most of the outbreaks were characterized by severe invasive disease (including meningitis and bacteremia). Several outbreaks in more recent years have demonstrated that L monocytogenes can cause febrile gastroenteritis, which is clinically similar to illness caused by known enteric pathogens, such as Salmonella and Campylobacter.

A 1997 outbreak of febrile gastroenteritis caused by Listeria occurred among attendees of a Holstein cow show in Illinois and was traced to contaminated chocolate milk. About 75% of the 60 people who consumed the milk had diarrhea and fever. The most common symptoms among those affected were diarrhea, fever, chills, and headache. About 50% had nausea and 26% experienced vomiting. Antibodies to listeriolysin O proved to be a useful tool for retrospectively identifying ill persons (see References: Dalton 1997).
L monocytogenes (serotype 4b) was implicated in a 1998 outbreak of invasive illness that was linked to consumption of contaminated hot dogs and was responsible for 101 human cases, including 21 deaths. The strains represented a novel strain of serotype 4b, designated epidemic clone II (see References: CDC 1998; CDC 1999). Southern blots, genomic analysis, and polymerase chain reaction analysis revealed that this strain had DNA fragments adjacent to internalin (inlA), a well-characterized virulence determinant gene (see References: Evans 2004).
Investigation of a 2002 multistate outbreak in the northeastern United States identified 46 culture-confirmed cases of invasive disease with seven deaths and three stillbirths in eight states. Most cases were in Pennsylvania, New York, New Jersey, and Delaware.

The outbreak was linked to eating deli turkey. Pulsed-field gel electrophoresis (PFGE) patterns revealed that outbreak isolates had a relatively uncommon pattern (see References: CDC 2002).
The outbreak strain was isolated from two of 18 previously unopened turkey packages produced by one of the processing plants (see References: Gottlieb 2006).
On the basis of these findings, the company that produced the product issued a recall of 27.4 million pounds of fresh and frozen ready-to-eat turkey and chicken products.
Over the following year, the US Department of Agriculture's Food Safety and Inspection Service (FSIS) completed a risk assessment for L monocytogenes in deli meats (see References: FSIS 2003; USDA 2003) and finalized and issued a new regulation aimed at further reducing contamination of ready-to-eat deli meats and poultry products (see References: FSIS 2004).

In Italy in 1997 an outbreak of febrile gastroenteritis occurred that involved 1,566 illnesses among schoolchildren who ate a catered tuna and corn salad. A total of 292 patients were hospitalized; 87% of stool cultures were positive for L monocytogenes and one blood culture grew the organism. Strains isolated from patients and from food and environmental samples were identical (see References: Aureli 2000; Ooi 2006).

Clinical Features

L monocytogenes can cause a number of clinical illnesses, which are outlined below.

Febrile gastroenteritis: The illness is characterized by fever and nonbloody watery diarrhea of 2 to 3 days duration (blood may rarely be present in the stool). Illness usually occurs in previously healthy individuals (see References: Reido 1994; Ooi 2005). Some investigators have suggested that the Listeria is a coinfecting organism rather than the cause of illness (see References: Schlech 2000).
Bacteremia: This is the most common manifestation of invasive disease in nonpregnant adults and may occur with or without meningitis. Clinically, bacteremia appears as an acute febrile illness, often with myalgias, arthralgias, headache, and backache. Patients also may have prodromal illness with diarrhea and nausea. Transient bacteremia may go undetected in otherwise healthy patients.
Infection in pregnancy: Illness may occur at any point during pregnancy, but usually occurs in the third trimester (see References: Weinberger 1984; Mylonakis 2002). Pregnant women generally experience an influenzalike illness with or without gastrointestinal symptoms.

Pregnant women have an estimated 17-fold increase in risk of listerial bacteremia, but CNS infections, common in other groups, are rare without presence of other risk factors (see References: Gellin 1991).
Intrauterine infection occurs via maternal bacteremia and can lead to amnionitis, preterm labor, spontaneous abortion, stillbirth, or infection of the neonate (see References: Schuchat 1991). About 22% of perinatal infections result in stillbirth or neonatal death from disseminated infection. Two thirds of surviving infants manifest neonatal listeriosis, but diagnosis of listeriosis early in pregnancy and treatment can result in a healthy infant (see References: Lorber 2005; Weinberger 1984; Mylonakis 2002).

Neonatal infection: Two forms of illness can occur: early onset and late onset (see References: Schuchat 1991).

Early onset disease results from uterine infection and is recognized soon after birth. Infants generally present with sepsis (similar to group B streptococcal disease); signs of meningitis are uncommon. The early onset form often is associated with prematurity. Common findings include respiratory distress, fever, and neurologic abnormalities (see References: Mylonakis 2002). Death can occur from overwhelming disseminated infection (granulomatosis infantiseptica).
Late onset disease occurs about 2 weeks after birth and results from infection at birth, during cesarean section, or possibly via nosocomial transmission. Late onset disease is more likely to present as meningitis. Clinical infection is similar to that of other bacterial pathogens (see References: Lorber 2005; Braden 2003; Wenger 1990).
The case-fatality rate for neonatal disease is high (20% to 30%).

CNS infection (meningitis, rhombencephalitis, brain abscess):

L monocytogenes has a predilection for the brain, especially the brain stem and the meninges.
Patients who have meningitis can have altered consciousness, seizures, movement disorders, or all of these.
L monocytogenes represents the fifth most common cause of meningitis but has the highest mortality (22%) (see References: Wenger 1990; Braden 2003).
Rhombencephalitis (encephalitis of the brain stem) is an unusual form of listerial infection and usually occurs in healthy adults. Patients with rhombencephalitis often have a biphasic disorder with a prodrome of fever, headache, nausea, and vomiting that lasts about 4 days, followed by abrupt onset of asymmetric cranial nerve deficits; cerebellar signs; and hemiparesis, hemisensory deficits, or both (see References: Armstrong 1993).
Brain abscesses make up about 10% of CNS listerial infections. Bacteremia is nearly always present, and concomitant meningitis, with L monocytogenes isolated from cerebrospinal fluid, occurs in 25% to 40% (see References: Eckburg 2001).

Endocarditis: This occurs in about 7.5% of adult listerial infections. Patients at risk are those with underlying valvular heart disease and prosthetic valves. The infection has a high rate of septic complications and a mortality rate of 48% (see References: Lorber 2005; Carvajal 1988).
Localized infections: These are rare. Direct inoculation can result in conjunctivitis, skin infection, and lymphadenitis (see References: Lorber 2005).

Clinical Features of L monocytogenes Febrile Gastroenteritis
Incubation period	9-48 hr after ingestion of contaminated item
Presenting features	—Watery diarrhea (blood rarely present in the stool) —Fever —Chills —Nausea —Vomiting Symptoms noted during a large outbreak of febrile gastroenteritis include the following (see References: Aureli 2000): —Fever >38°C (adults: 57%, children 76%) —Headache (adults: 88%, children 86%) —Abdominal pain (adults: 72%, children: 72%) —Nausea (adults: 60%, children: 54%) —Vomiting (adults: 19%, children: 40%) —Diarrhea (adults: 52%, children: 40%) —Joint pain (adults: 45%, children:24%)
Laboratory features	—Generally unremarkable —L monocytogenes may be isolated from stool or occasionally blood, if bacteremia occurs
Duration of illness	Several days
Complications	Systemic infections: —Central nervous system infection (meningitis, rhombencephalitis [brain stem encephalitis], brain abscess) —Bacteremia —Localized infection —Endocarditis —For pregnant women, infection of the fetus or newborn
Case-fatality rate	—Febrile gastroenteritis is not fatal, unless the infection progresses to invasive disease —Pregnant women and their fetuses, newborn infants, immunocompromised patients, and the elderly are at increased risk of invasive disease (see table below)
Adapted from Lorber 2005; CDC 2002; CDC 2004 (see References).

Clinical Features of L monocytogenes Invasive Disease
Incubation period	2-6 wk
Presenting features	—Fever, myalgias, nausea, diarrhea —Pregnant women may present with a mild influenza-like illness —Patients may present with CNS signs and symptoms (cranial nerve palsies, nuchal rigidity, altered mental status, ataxia, focal neurologic findings, seizures)
Laboratory features	—Leukocytosis with predominance of PMNs —L monocytogenes isolated from blood, CSF, or other site —For patients with meningitis, CSF may demonstrate: ~Pleocytosis with predominance of PMNs ~Elevated CSF protein level ~ CSF glucose level usually within normal limits (but may be low) ~ Gram stain may show gram-positive rods (which may also look like diphtheroids, cocci, or diplococci)
Duration of illness	Variable
Complications	—CNS infection (meningitis, rhombencephalitis, brain abscess) —Localized infections —Endocarditis —Disseminated intravascular coagulation (DIC) —Adult respiratory distress syndrome (ARDS) —Rhabdomyolysis with acute renal failure —Adult and infant survivors with CNS involvement often have neurologic sequelae —Infection in pregnant women can lead to premature delivery, spontaneous abortion, stillbirth, and neonatal infection
Case-fatality rate (CFR)	—High fatality rate in neonates (20%-30%) —In outbreak investigations involving invasive disease, the CFR in adults is approximately 20%
Abbreviation: CNS, central nervous system; CSF, cerebrospinal fluid; PMNs, polymorphonuclear cells Adapted from Bula 1995; CDC 2002; Lorber 2005 (see References).

Differential Diagnosis

Conditions/Causative Agents to Consider in Differential Diagnosis of Suspected Listeriosis

Main presenting syndrome: Gastroenteritis
Bacillus cereus
Campylobacter species
Clostridium perfringens
Cryptosporidium parvum
Cyclospora cayetanensis
Enterotoxigenic Escherichia coli (ETEC)
Giardia lamblia
Isospora belli
Plesiomonas shigelloides
Shigella species
Vibrio cholerae
Vibrio parahemolyticus
Yersinia enterocolitica

Main presenting syndrome: Meningitis
Meningococcal meningitis (Neisseria meningitidis)
Meningitis caused by other bacterial agent (eg, Streptococcus pneumoniae, gram-negative bacilli)
In infants, Streptococcus agalactiae (Group B streptococcus)
West Nile virus
Other viral meningitis or encephalitis

Main presenting syndrome: Fever, sepsis, or other systemic illness
Typhoid fever (Salmonella Typhi)
Staphylococcal or Streptococcal toxic shock syndrome (TSS)
Other bacterial infection

Adapted from CDC 2004, Lorber 2005 (see References).

Laboratory Diagnosis

Listeria infection is diagnosed by isolating the causative organism from culture of blood, cerebrospinal fluid (CSF), or focal lesions. Listeria also can be isolated from food samples (see References: AAP 2003).

Listeria species usually are identified by culture methods and biochemical testing (see References: Bille 2003).

Stool samples usually are not useful for diagnosis of sporadic cases because of asymptomatic fecal carriage.
Molecular techniques are available to compare electrophoretic patterns of strains, and additional types of molecular and microassays are being developed. These may prove more important in the future as they become standardized (see References: Borucki 2004).

Specimen Collection and Transport for Foodborne Outbreaks

The following information is drawn from Bille 2003 and CDC 2003 (see References).

Collection

Clinical specimens (blood, CSF, amniotic fluid) should be collected as soon as possible after onset of illness.
Listeria may be isolated from food samples; food samples (preferably at least 100 g) must be collected aseptically in sterile containers.
Stool samples may be collected for epidemiologic studies of outbreaks but are not useful for diagnosing systemic illness.

Transport

Clinical samples can be stored at 4^oC for 24 to 48 hours.
Food samples should be stored refrigerated; suspected frozen food products such as ice cream should remain frozen.

Standard Diagnostic Tests

The following information is drawn from Bille 2003 (see References).

Clinical specimens from normally sterile sites (blood, CSF, amniotic fluid) can be directly plated onto tryptic soy agar containing 5% sheep, horse, or rabbit blood.
When plated on LPM agar, Listeria colonies appear blue under oblique lighting while other bacteria appear yellowish or orange.
Chromogenic media can be used and many types are available; these can identify, but not differentiate between L monocytogenes and L ivanovii.
Samples for blood culture can be inoculated into conventional blood culture broth.
Clinical specimens obtained from nonsterile sites as well as food and environmental specimens should be enriched for Listeria species before being plated (see References: Bille 2003).

Table 4: Useful Biochemical tests

Differential metabolism of sugars and other biochemical properties can be used to distinguish L monocytogenes (the only species pathogenic for humans) from L innocua, the most common nonpathogenic species isolated.

Biochemical Differentiation of Listeria species
	L monocytogenes	L innocua	L grayi	L ivanovii	L ivanovii subsp londoniensis	L seeligeri	L welshimeri
Beta-hemolysis	+	–	–	++	++	+	–
CAMP test reaction
S aureus	+	–	–	–	–	+	–
Rhodoccus equi	V	–	–	+	+	–	–
Produce acid from:
Mannitol	–	–	+	–	–	–	–
Alpha-Methyl-D-mannoside	+	+	+	–	–	–	+
L-rhamnose	+	V	V	–	–	–	V
Soluble starch	–	–	+	–	–	ND	ND
D-xylose	–	–	–	+	+	+	+
Ribose	–	–	V	+	–	–	–
N-acetyl-beta-D- mannosamine	ND	ND	ND	V	+	ND	ND
Hippurate hydrolysis	+	+	–	+	+	ND	ND
Reduction of nitrate	–	–	V	–	–	ND	ND
Associated serovars	1/2a; 1/2b; 1/2c; 3a; 3b; 3c; 4a; 4ab; 4b; 4c; 4d; 4e; 7	4ab;US; 6a; 6b	S	5	5	1/2a; 1/2b; 1/2c; US; 4b; 4d; 6b	1/2b; 4c; 6a; 6b; US
Abbreviation: CAMP, Christie, Atkins, Munch-Peterson (see References: Seeliger 1986); +, ≥90% strains are positive; –, ≥90% strains are negative; ND, not determined; V, variable; US, undesignated serotype; S, specific; ++, usually a wide zone or multiple zones. Adapted from Bille 2003 (see References).

Antimicrobial Susceptibility

L monocytogenes has had a relatively stable susceptibility and antimicrobial resistance pattern for many years (see References: Bille 2003; Hansen 2005).
L monocytogenes is susceptible to penicillin, ampicillin, gentamicin, erythromycin, tetracycline, rifampin, and chloramphenicol but only moderately susceptible to quinolones (References: Bille 2003).
Most Listeria species show a high natural resistance to cephalosporins, particularly those with broad spectrum (see References: Hof 1997).
Resistance to certain antibiotics (including streptomycin, kanamycin, gentamicin, erythromycin, trimethoprim, and rifampin) has been noted occasionally in isolates from food (see References: Hof 1997).
Trimethoprim-sulfamethoxazole and aminoglycosides are among the few agents that are bactericidal to L monocytogenes.
Plasmids that confer resistance to chloramphenicol, macrolides, and tetracyclines have been found in several clinical isolates of L monocytogenes and have raised concerns about treatment (see References: Hadorn 1993; Charpentier 1999).

Additional or Specialized Diagnostic Tests

The following information is drawn from Bille 2003 and Gasanov 2005 (see References).

Several tests are available or in development and the growth of molecular techniques may supplant traditional tests once the new techniques are standardized and validated.
Commercially available tests for the rapid detection of Listeria in selective enrichment broths from food rely on immunoassays that employ monoclonal antibodies but are not designed for analysis of clinical samples.
Miniaturized biochemical testing: Commercially available tests for the genus include 10 biochemical tests in a microprobe format. A patented test for arylamidase allows clinicians to distinguish between L monocytogenes (positive) and L innocua (negative).
DNA probe assay for colony confirmation: This technique is a 30-min chemiluminescence test for rapid confirmation of L monocytogenes from colonies on primary isolation plates.
DNA microrestriction pattern analysis: Characterizes chromosomal DNA by restriction endonuclease analysis or ribosomal DNA gene restriction patterns (ribotyping) useful for preliminary recognition, but patterns do not adequately discriminate for epidemiologic investigations of outbreaks (see References: Gasanov 2005).
DNA macrorestriction PFGE pattern analysis: This technique involves pulsed field gel electrophoresis of restriction endonuclease digestion of bacterial DNA. PulseNet laboratories (a network of public health laboratories across the country) use highly standardized protocols to subtype bacteria by PFGE. A 1-day standardized protocol for subtyping L monocytogenes was added to PulseNet in 1998. Subtyping of isolates can be useful in identifying undetected outbreaks (see References: Sauders 2003).
RAPD (random amplification of polymorphic DNA): This technique can be used to type L monocytogenes isolates for epidemiologic purposes; however, it has not yet been standardized.

Serologic Testing

Because diagnosis relies on isolation of the organism, serologic testing has not been used to diagnose listeriosis.
Antibodies to listerolysin O may be helpful in identifying cases with gastroenteritis or mild illness during outbreak investigations (see References: Dalton 1997).

Treatment

No controlled trials to establish a drug of choice or duration of therapy have been completed for Listeria infections (see References: Lorber 2005).
Ampicillin is the preferred drug for treatment; beta-lactams are only bacteriostatic for Listeria.
The American Academy of Pediatrics (AAP) recommends initial therapy with intravenous ampicillin and an aminoglycoside, usually gentamicin. For the penicillin-allergic patient, trimethoprim-sulfamethoxazole should be used (see References: AAP 2003).
Initial therapy for bacterial meningitis in adults older than age 50 should include either ampicillin or trimethoprim-sulfamethoxazole.
Most authorities suggest adding gentamicin to ampicillin for treatment of patients who have severely impaired T-cell function and for all patients with meningitis or endocarditis.
Chloramphenicol should not be used to treat Listeria infections because of its failure and relapse rates.
Currently available cephalosporins have limited activity against Listeria and are not recommended.
Doses suitable for meningitis are suggested for all patients, including those who lack CNS or CSF abnormalities.
Treatment duration is 2 to 6 weeks, depending on the type of illness.

Vaccines

No vaccines are available for Listeria infections.
Prevention is accomplished by maintaining good food-handling precautions.

Travel Implications

Travelers should avoid raw (unpasteurized) milk or products made with raw milk; soft cheeses; and unwashed fruits, vegetables, and nuts (see References: AAP 2003).
Antimicrobial resistance has been detected among some Listeria species abroad.

Disease Prevention and Control

Infection Control Recommendations

Patients with Listeria should be managed using Standard Precautions; additional precautions are not recommended (see References: CDC/HICPAC 1996).

Public Health Prevention Measures

CDC and the Food and Drug Administration (FDA) have made the following recommendations to consumers to prevent foodborne listeriosis (see References: FDA 2003):

For all persons:

Thoroughly cook raw food from animal sources (beef, pork, and poultry).
Thoroughly wash raw vegetables before eating.
Keep uncooked meats separate from vegetables, from cooked foods, and ready-to-eat foods.
Avoid consumption of unpasteurized milk or foods made from raw milk.
Wash hands, knives, and cutting boards after handling uncooked foods.

In addition, persons of high risk (immunocompromised patients, pregnant women, and the elderly) should avoid:

Cross-contamination of food items and food preparation surfaces.
Eating soft cheeses (eg, Mexican-style, feta, brie, Camembert, and blue-veined cheese); hard cheeses, cream cheese, cottage cheese, and yogurt are usually considered safe.
Eating leftover foods or ready-to-eat foods (eg, hot dogs) unless they are heated until steaming hot.
Eating refrigerated smoked seafood, unless it has been cooked in a dish such as a casserole.
Drinking raw (unpasteurized) milk or eating foods that contain unpasteurized milk.
Eating refrigerated pates or meat spreads. Canned or shelf-stable pates and meat spreads may be eaten (see References: AAP 2003).

Because L monocytogenes can grow at refrigerator temperatures, all consumers are advised to reduce their risk of illness by:

Storing perishable items that are precooked or ready-to-eat at 40°F or lower and consuming as soon as possible.
Cleaning their refrigerators regularly.
Using a refrigerator thermometer to make sure that the refrigerator stays at 40°F or below.

In 2001, FDA developed an initial Listeria prevention action plan. In November 2005, the FDA outlined its current action plan for combating listeriosis according to the following objectives (see References: FDA 2005):

Develop and revise guidance for processors that manufacture or prepare ready-to-eat foods and develop or revise guidance for retail and food service and institutional establishments.
Develop and deliver training and technical assistance for industry and food safety regulatory employees.
Enhance consumer and health care provider information and education efforts.
Review, redirect, and revise enforcement and regulatory strategies including microbial product sampling and analytical methods.
Enhance Disease Surveillance and Outbreak Response (in conjunction with CDC).
Coordinate research activities to refine the Risk Assessment, enhance preventative controls, and support regulatory, enforcement, and educational activities.

Physicians should maintain a high index of suspicion for listeriosis in suspected cases as well as taking the following actions:

Ordering the appropriate laboratory tests
Reporting positive culture results to local public health officials

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