38 - 156 Listeria monocytogenes Infections

156 Listeria monocytogenes Infections

Karen P. Neil, Jennifer P. Collins,

Patricia M. Griffin

Listeria monocytogenes

Infections Listeria monocytogenes is a ubiquitous environmental saprophyte and an intracellular pathogen in several animals. Humans develop L. monocytogenes infection—listeriosis—primarily through foodborne transmission. The clinical spectrum of listeriosis ranges from febrile gastroenteritis in healthy persons to invasive disease, including bac­ teremia and meningoencephalitis. The major risk groups for invasive disease are pregnant women and their neonates, older adults, and immunocompromised persons. Febrile gastroenteritis is rarely diag­ nosed because Listeria are not detected by routine stool cultures or in rapid diagnostic tests for stool specimens, so the term listeriosis gener­ ally refers to invasive infection. ■ ■MICROBIOLOGY L. monocytogenes lives in soil and decaying vegetable matter. Numer­ ous bird and mammal species are reservoirs. L. monocytogenes is a nonsporulating, facultatively anaerobic, short, gram-positive rod that grows well on blood agar, demonstrating small zones of β-hemolysis. Organisms sometimes appear gram-variable and resemble cocci, dip­ lococci, or diphtheroids; this appearance can obscure the diagnosis. On light microscopy, L. monocytogenes demonstrates characteristic tumbling motility. It grows optimally at 30–37°C but can grow at refrigerator temperatures as low as 4°C. In addition to its ability to grow at cold temperatures, Listeria’s tolerance to low-pH and high-salt environments facilitates its environmental survival. Serotypes are usu­ ally determined on the basis of somatic (O) and flagellar (H) antigens. Nearly all human illness is caused by serotypes 1/2a, 1/2b, and 4b. ■ ■PATHOGENESIS Infection with L. monocytogenes typically occurs through ingestion of contaminated food. The infectious dose has not been well established but is likely to be very low for persons with severely impaired cellular immunity. Increased gastric pH, such as that due to proton pump inhibitors, probably promotes the organism’s survival in the gastroin­ testinal tract. After transcytosis across the intestinal epithelium, the bacteria travel via mesenteric lymph nodes and the bloodstream to the liver and spleen, its target organs; dissemination to other organs can occur. L. monocytogenes can also migrate across the blood-brain bar­ rier and the placenta. Virulence factors include internalins (InlA, InlB), which promote invasion into normally nonphagocytic host cells. A pore-forming cytolysin (listeriolysin O; LLO) and phospholipases facilitate evasion of intracellular killing by mediating escape from the internalization vacuole into the cell cytosol. The surface protein ActA facilitates direct cell-to-cell movement within the cytosol, allowing L. monocytogenes to avoid encountering components of the host immune system, such as antibodies and complement, during dissemination. Iron promotes growth of the organism in vitro, an effect that explains why liste­ riosis has been associated with iron-overload conditions, including hemochromatosis. ■ ■IMMUNE RESPONSE Although L. monocytogenes is ubiquitous in the environment, infection is rare because of both innate and adaptive host immune responses. Studies of mice have contributed to a detailed understanding of the immune response to infection. Activation of innate immunity is important for host survival. Interferon γ and tumor necrosis factor α (TNF-α) are among the key cytokines involved in this response. T cells are the primary drivers of the adaptive immune response, furthering the clearance of infected cells. Cytotoxic (CD8+) T cells are the main contributors to long-term immunity.

These immune mechanisms explain the association between inva­ sive listeriosis and immunocompromising conditions, particularly impaired cellular immunity. In light of numerous reports of invasive listeriosis in patients treated with TNF-α inhibitors, the U.S. Food and Drug Administration added listeriosis to the boxed warning for this drug class. Because L. monocytogenes induces a vigorous cell-mediated immune response, attenuated strains that express foreign antigens are undergoing clinical trials as a cancer immunotherapy.

■ ■EPIDEMIOLOGY L. monocytogenes was first reported as a human pathogen in 1929. Foodborne transmission was not identified until over 50 years later, when a 1983 outbreak investigation implicated coleslaw. It is now known that L. monocytogenes transmission is almost always food­ borne. Listeriosis is a nationally notifiable disease in the United States. According to the Centers for Disease Control and Prevention’s (CDC’s) Foodborne Diseases Active Surveillance Network (FoodNet), the incidence of invasive listeriosis was 2.1–3.3 cases per million persons during 2011–2022 (Fig. 156-1). Although illness is uncommon, liste­ riosis is a substantial contributor to morbidity from foodborne illness because virtually all patients are hospitalized and 18% die. Only about 3% of reported cases of listeriosis are part of a recog­ nized outbreak—i.e., have a source determined; however, outbreak investigations provide data on major foods linked to illness. Strains of L. monocytogenes have survived in production facilities for years. Refrigerated, ready-to-eat foods are of particular concern because the organism’s ability to grow at refrigerator temperatures can result in a small amount of contamination during production growing to much higher levels. PulseNet, the laboratory network for bacterial foodborne disease surveillance, implemented routine subtyping for L. monocyto­ genes in the United States in 1998 and transitioned to whole-genome sequencing in 2013. Improvements in the ability to detect and investi­ gate outbreaks using laboratory-based surveillance has provided more information on known food sources and facilitated recognition of new food sources. CHAPTER 156 Listeria monocytogenes Infections Hot dogs and deli meats were the major sources of U.S. outbreaks until after 2002, when an outbreak linked to turkey deli meat resulted in eight deaths and the recall of >30 million pounds of meat. After that outbreak, the U.S. Department of Agriculture’s Food Safety and Inspection Service (FSIS) issued new regulations requiring vali­ dated L. monocytogenes control programs and intensified testing for L. monocytogenes in ready-to-eat meat and poultry plants. Isolations of L. monocytogenes from ready-to-eat meats continued to decline during 2003–2012 (Fig. 156-1), and outbreaks linked to these products decreased. However, the incidence of listeriosis, which had declined markedly from 1989 through 2001, has not declined significantly since the measures were implemented (Fig. 156-1). Dairy products remain an important source, especially soft cheese made with raw (unpasteur­ ized) milk or produced from pasteurized milk in unsanitary facilities; ice cream and raw milk also have caused outbreaks. Raw produce has been increasingly linked to outbreaks; implicated items include pack­ aged salad, sprouts, enoki mushrooms, cantaloupe and other fruit, caramel apples, and frozen vegetables. Most people with invasive listeriosis are older adults, whose risk increases with each decade over 59 years of age. Most other patients have impaired cellular immunity associated with hematologic malig­ nancy, solid organ or bone marrow transplantation, HIV infection, or receipt of glucocorticoid or other immunosuppressive drugs. The group at highest risk of infection is pregnant women, who almost always have only mild flulike symptoms but who transmit the infec­ tion to the fetus through the placenta. Some neonates may acquire infection in the hospital, as illustrated by an outbreak associated with contaminated mineral oil. Rarely, children and adults with no recog­ nized risk factors develop invasive listeriosis, probably through highly contaminated food. The diagnosis of listeriosis in a hospitalized patient with new symp­ toms should prompt investigation into the food provided during hospi­ talization as a source. In fact, outbreaks have been traced to food served to hospitalized patients, especially those with immunocompromising

Products yielding L. monocytogenes, % ( ) 1989: Case associated with turkey franks; new regulatory policies, industry efforts

1998: PulseNet began subtyping

2000: Listeriosis made nationally notifiable

1988 1990 1992 1994 1996 1998 2000 2002 2004 Year 2006 2008 2010 2012 2014 2016 2018 2020 2022 FIGURE 156-1  Incidence of listeriosis and percentage of ready-to-eat meat and poultry products from Food Safety and Inspection Service (FSIS) testing with cultures that yielded L. monocytogenes, United States, 1989–2022. Incidence data are from the Centers for Disease Control and Prevention’s active sentinel site surveillance and include data from an early surveillance system (1986–1995) and from the Foodborne Diseases Active Surveillance Network (FoodNet) database (1996–2022). The incidence was 7.3 cases per million in 1986. Product data for 1990–2022 are from the U.S. Department of Agriculture Food Safety and Inspection Service Microbiological Testing Program for Ready-to-Eat Meat and Poultry Products and related publications (P Levine et al: J Food Prot 64:1188, 2001; SW Mamber et al: J Food Prot 83:1598, 2020; and the 2010 FSIS Comparative Risk Assessment for L. monocytogenes in RTE Meat and Poultry Deli Meats). conditions; implicated foods include sandwiches, butter, precut celery, Camembert cheese, sausage, tuna salad, and ice cream. Although very rare, transmission of L. monocytogenes has also occurred through transfusion of platelet products, and febrile illness with bacteremia has occurred in persons who received an attenuated strain as a vaccine vector. PART 5 Infectious Diseases Listeriosis is an important problem worldwide. A large 2017–2018 outbreak of listeriosis in South Africa, linked to a ready-to-eat pro­ cessed meat product, disproportionately affected people living with HIV and pregnant women. No outbreak-associated cases were detected in the 15 countries that imported the product; this discrepancy sug­ gests that listeriosis is underrecognized in low- to middle-income countries, particularly those with a high prevalence of HIV infection. ■ ■CLINICAL MANIFESTATIONS L. monocytogenes infection can manifest in several ways. The incu­ bation period differs according to host factors and dose consumed: on average, this interval is <24 h for gastroenteritis and ~11 days for invasive disease, although it can be much longer. Data from outbreak investigations suggest that the incubation period is longer in pregnant women than in nonpregnant adults. Febrile Gastroenteritis  Listeria organisms typically pass through healthy people without causing symptoms, but acute febrile gastroen­ teritis can occur. Outbreak investigations of L. monocytogenes febrile gastroenteritis have identified high organism density in implicated foods, suggesting that a large inoculum must be ingested to cause ill­ ness. Major manifestations are fever, diarrhea, headache, and constitu­ tional symptoms. Illness is usually self-limited, with symptoms lasting an average of 1–3 days. Bacteremia  Bacteremia without a focus is the most common mani­ festation of invasive listeriosis. Major features are fever, chills, myalgias, and arthralgias, sometimes preceded by nausea or diarrhea—markers of the initial gut infection. Bacteremia can cause neurolisteriosis or localized infection at other sites, in which case the diagnosis may be suggested by neurologic or other focal findings. In a large French cohort study, the 3-month mortality rate for L. monocytogenes bacte­ remia was 46%; factors associated with death included multiorgan fail­ ure, neoplasia, worsening of preexisting comorbidities, monocytopenia (<200 cells/μL), older age, and female sex. Neurolisteriosis  L. monocytogenes has an affinity for the cen­ tral nervous system. Neurolisteriosis is the second most common

Incidence per million persons ( )

2003: New regulations for ready-to-eat meat and poultry plants

manifestation of invasive listeriosis. Signs of meningitis along with altered mental status, seizures, or focal neurologic findings sug­ gest meningoencephalitis. A French cohort study found that 84% of patients with neurolisteriosis presented with meningoencephalitis. The onset of neurologic disease can be sudden or subacute and occur over several days. Patients typically present with signs and symp­ toms similar to those in other bacterial meningitides. Compared with other bacterial meningitides, cerebrospinal fluid (CSF) pleocytosis and CSF neutrophil predominance are typically less pronounced; most patients (~60–75%) have CSF white blood cell counts of <1000/μL, but some have high levels. Approximately 30–40% of patients have low CSF glucose levels. Gram’s staining of CSF sediment can show the expected gram-positive rods but commonly shows no organisms and sometimes shows gram-positive cocci, diplococci, or diphtheroids. In a U.S. study, L. monocytogenes caused <5% of cases of community-acquired bacte­ rial meningitis in adults. Uncommon neurolisteriosis manifestations include cerebritis, focal abscess, and rhombencephalitis (encephalitis of the cerebellum and brainstem). Patients with macroscopic abscesses often have positive blood cultures, but CSF findings may be normal in the absence of concurrent meningitis. Abscesses may be misdiagnosed as a primary or metastatic malignancy; they rarely occur in the cerebellum or spinal cord. Rhombencephalitis disproportionately affects otherwise healthy older adults. The classic presentation is biphasic, beginning with fever and headache and continuing after several days with signs of brainstem or cerebellar involvement, such as asymmetric cranial nerve palsies, ataxia, tremor, hemiparesis, or hemisensory deficits. Nearly half of patients with rhombencephalitis experience respiratory failure. The diagnosis may be delayed by the subacute course and by CSF findings, which are often only minimally abnormal. Magnetic resonance imag­ ing (MRI) is superior to computed tomography (CT) for the diagnosis of neurolisteriosis, including rhombencephalitis. Overall, the 3-month mortality rate for neurolisteriosis was 30% in a French cohort study; death was associated with the same risk factors as those documented for bacteremia. Neurolisteriosis-associated mortal­ ity was also higher among patients with a positive blood culture and among those treated with dexamethasone. Nearly half of survivors had long-term neurologic impairment. Focal Infections  Hematogenous dissemination of L. monocyto­ genes infrequently causes endocarditis, pneumonia, localized abscesses in the liver or other internal organs, peritonitis, septic arthritis, osteo­ myelitis, urinary tract infection, or skin lesions. Direct inoculation has

been reported as a rare cause of ocular infection, skin infection, and lymphadenitis. Infection in Pregnant Women and Neonates  The risk of Listeria infection during pregnancy is increased due to impaired maternal cell-mediated immunity. Pregnancy-associated listeriosis is most common in the third trimester, although this may in part reflect underdiagnosis of earlier infections. Typically, pregnant women are either asymptomatic or have a mild, flulike illness with fever, headache, myalgias, or arthralgias. Neurolisteriosis and death are rare in pregnant women without other risk factors. Although nearly all infected women fully recover, only a minority (~5%) have a normal delivery and post­ partum course, and three-quarters of the live-born infants are ill. In a French cohort study with 107 pregnancies in which L. monocytogenes was isolated from the mother, fetus, or neonate, 24% ended with fetal loss, 45% with premature birth, 6% with late-onset listeriosis in the neonate, and 21% with term delivery with fever or signs of fetal distress (i.e., meconium release into amniotic fluid, abnormal fetal heart rate). Fetal loss is uncommon after 29 weeks of gestation. Granulomatosis infantiseptica is a severe in utero infection caused by L. monocytogenes and characterized by disseminated microabscesses and granulomas in the skin, liver, and spleen; most infants with this condition are stillborn or die soon after birth. Neonatal listeriosis usually manifests in one of two ways: early-onset sepsis is hypothesized to result from in utero infection because it is typically diagnosed within 48 h after birth and is often associated with prematurity, whereas late-onset meningitis is thought to result from infection acquired at or soon after birth because it is typically diagnosed at ~2 weeks of age in full-term infants. A recent update from the above study that included additional years of data found that 70% of the 189 live-born infants developed early-onset listeriosis and 6% developed late-onset listeriosis; the other infants appeared uninfected (i.e., had negative cultures) and were well (14%) or had nonspecific signs (10%) that the authors attributed likely to prematurity. Overall, 3% of the 189 live-born infants died. ■ ■DIAGNOSIS Because symptoms of listeriosis overlap with those of other infections, a high index of suspicion can facilitate timely diagnosis. Pregnant women with suspected listeriosis should have blood drawn for cultures, although blood cultures are positive only about half the time. Isolation of L. monocytogenes from a normally sterile site, such as blood, CSF, amniotic fluid, placental tissue, or fetal tissue, is diagnostic. Listeria must be distinguished from other gram-positive rods, especially diph­ theroids. L. monocytogenes can be isolated from sterile specimens on routine medium; selective enrichment medium (such as PALCAM Listeria Selective Agar or Oxford Agar) enhances the capacity for isola­ tion of the organism from nonsterile specimens, such as stool. Stool culture is not indicated in the evaluation of invasive listeriosis; culture on selective medium can be helpful for outbreak investigations of febrile gastroenteritis. Commercially available multiplex polymerase chain reaction panels for CSF specimens include L. monocytogenes as a target and may be a useful adjunct to culture. Matrix-assisted laser desorption/ ionization time-of-flight (MALDI-TOF) mass spectrometry can rapidly identify an isolate as L. monocytogenes. Whole-genome sequencing has been a valuable tool for solving outbreaks, including a nosocomial out­ break associated with ice cream served in hospital milkshakes. TREATMENT Infections Caused by Listeria monocytogenes L. monocytogenes treatment has not been evaluated in clinical tri­ als. Recommendations are based on in vitro animal studies and observational clinical data. High-dose ampicillin (adult dose, 2 g IV every 4 h) or penicillin G (adult dose, 4 million units IV every 4 h) constitutes first-line therapy. Because penicillins are only weakly bactericidal against L. monocytogenes, many experts recom­ mend adding gentamicin for synergy (1.0–1.7 mg/kg every 8 h if renal function is normal), particularly if the infection is severe. Small studies have had varying results with regard to the benefits

of gentamicin. A large study provided evidence favoring amoxi­ cillin-gentamicin as first-line therapy. Patients who are allergic to penicillin should undergo desensitization or be treated with trime­ thoprim-sulfamethoxazole (TMP-SMX; 5 mg/kg per dose of the tri­ methoprim component, given IV every 6–12 h). TMP-SMX should be avoided during the first trimester because it has been associated with neural tube and cardiovascular defects and in the perinatal period because it may increase the risk of kernicterus. Resistance to TMP-SMX has been reported; thus, antibiotic susceptibility testing should be performed if this drug is considered. Treatment failures have been reported with meropenem despite in vitro susceptibility of the organism. L. monocytogenes is susceptible in vitro to several other drugs, including vancomycin, linezolid, tetracycline, macro­ lides, and fourth-generation fluoroquinolones (e.g., moxifloxacin), but relevant clinical reports are limited. Cephalosporins are not effective. A study with 252 patients with neurolisteriosis found significantly reduced survival rates among the 32 patients treated with adjunctive dexamethasone; the authors suggest avoiding this drug in neurolisteriosis. Prepartum antibiotic treatment of preg­ nant women with listeriosis, initiated at least 1 day before delivery, enhances the chance of delivering a healthy infant.

The optimal duration of antibiotic therapy has not been estab­ lished. Treatment duration usually depends on the clinical syn­ drome, disease severity, patient attributes, and response to treatment. The typical minimal treatment duration is 2 weeks for bacteremia, 2 weeks for early-onset neonatal disease, 3 weeks for meningitis, 4–6 weeks for endocarditis, and 6–8 weeks for brain abscess or encephalitis. Longer courses may be needed when patients are immunocompromised or are not improving as expected. Patients with neurolisteriosis do not routinely require a follow-up lumbar puncture if they are improving clinically during antibiotic therapy. CHAPTER 156 ■ ■PREVENTION Implementation of general precautions to prevent foodborne illness can help prevent listeriosis. These measures include fully cooking meats; washing fresh produce; cleaning hands, utensils, and kitchen surfaces after handling uncooked foods; and avoiding unpasteurized dairy products. Persons at increased risk for listeriosis should take addi­ tional precautions, including avoiding unpasteurized milk, soft cheeses (particularly those made with unpasteurized milk), refrigerated pâté or meat spreads, and premade deli salads (e.g., coleslaw; potato, tuna, or chicken salad). Hot dogs, fermented or dry sausages, and refriger­ ated, ready-to-eat delicatessen foods (e.g., smoked fish, deli meat, cheese sliced at a deli) should be avoided or heated until the internal temperature is 165°F or until they are steaming hot. Additional CDC recommendations can be found at www.cdc.gov/listeria/prevention

.html. Testing and treatment are not indicated for an asymptomatic person who has eaten a product recalled because of L. monocytogenes contamination, even if the person has risk factors for invasive listerio­ sis. Hospital dietary services should implement safe food-preparation procedures for immunocompromised patients and should not serve these patients higher-risk foods. Care of patients with listeriosis includes only standard precautions because person-to-person trans­ mission is rare. TMP-SMX given as prophylaxis for Pneumocystis jir­ ovecii infection (e.g., to people infected with HIV or organ transplant recipients) helps prevent listeriosis. Listeria monocytogenes Infections ■ ■FURTHER READING Charlier C et al: Clinical features and prognostic factors of listeriosis: The MONALISA National Prospective Cohort Study. Lancet Infect Dis 17:510, 2017. Charlier C et al: Neonatal listeriosis presentation and outcome:

A prospective study of 189 cases. Clin Infect Dis 74:8, 2022. Conrad AR et al: Listeria monocytogenes illness and deaths associated with ongoing contamination of a multiregional brand of ice cream products, United States, 2010–2015. Clin Infect Dis 76:89, 2023. Farley MM: Listeria monocytogenes, in Principles and Practice of Pediatric Infectious Diseases, 6th ed, Long SS et al (eds). Philadelphia, Elsevier, 2023, pp 797–802.