8.6.38 Listeriosis 1223

8.6.38 Listeriosis 1223

8.6.38  Listeriosis 1223 8.6.38  Listeriosis Herbert Hof ESSENTIALS Listeriosis is caused by the Gram-​positive bacillus Listeria monocytogenes, whose natural habitat is the soil. Consumption of soft cheeses, other dairy products, meat products, seafood, and vegetables is the principal route of infection. Patients at particular risk include those who are immunocompromised, very young, or very old. Pregnant women are also at risk, although they develop only mild disease, but the bacteria can be transmitted to the child either in utero or during birth, causing serious systemic disease. Clinical features and diagnosis—​the disease varies from a mild, influenza-​like illness to fatal septicaemia and meningoencephal- itis. Purulent, localized infections of any organ are sometimes seen. Serology is not helpful for diagnosis, which is confirmed by culture from blood, cerebrospinal fluid, or organ biopsies using enrichment and selective methods or by nucleic acid amplification techniques. Typing of isolates is essential for epidemiologic purposes. Treatment, prognosis, and prevention—​aside from supportive care, the usual treatment of choice is high-​dose intravenous ampicillin, which must be administered for at least 2 weeks. The prognosis is poor, with mortality of up to 30%. Prevention depends upon those that are vulnerable avoiding high-​risk foods. There is no vaccine. Introduction Exposure of humans to Listeria monocytogenes is quite frequent, but infections are rare. Only a small proportion of exposed individuals are likely to become ill but for them, despite precise diagnosis and adequate therapy, the prognosis remains poor. Historical perspective In the 1920s, L. monocytogenes was shown to be capable of inducing systemic infections in experimental animals. About 40 years later, it became obvious that epidemics might occur in humans but it took a further 30 years before listeriosis was shown to be a food-​borne dis- ease in most instances. Today, listeria is an exciting research tool for studying the biology of intracellular microorganisms that trigger a cell-​mediated immune response. Aetiology, genetics, pathogenesis, and pathology Among the various listeria species, L. monocytogenes is the major pathogen for humans (as well as for animals). L.  monocytogenes has specific attributes for invading and surviving and replicating in host cells. Surface proteins such as internalins are critical for the adhesion to specific receptors on host cells. A pathogenicity is- land on the chromosome encoding for haemolysin (listeriolysin), phospholipases, and an actin polymerizing protein is crucial for intracellular survival, traffic in the cytoplasm, and cell-​to-​cell spread. By this means, listeria can cross anatomical barriers such as the in- testinal mucosa, the blood–​brain barrier, and the placenta. Humoral defence mechanisms are largely ineffective in coping with these bac- teria. Rather, a cell-​mediated immune response is required to over- come a listeria infection. Over the course of infection granulomas develop in infected organs, indicating a vigorous immune response. During the acute stage, when a massive multiplication of bacteria takes place intracellularly as well as extracellularly, a purulent in- flammatory reaction is seen at the site of infection. Epidemiology Listeria species are widespread in nature and their natural habitat is the soil; they have been isolated from dust, foodstuffs, animal feed, water, sewage, and numerous animals. Infections of humans are mainly due to only a few special clones. Various food items of both plant and animal origin, contaminated either during growth or during processing, can give rise to an infection. Consumption of soft cheeses such as Brie, Camembert, and blue-​vein types, other dairy products, meat products (e.g. sausages and delicatessen meat), sea- food (graved salmon), and vegetables (lettuce) is the principal route of infection. However, tomatoes, apples, and carrots are practically free of listeria. The ability of listeria to multiply at temperatures from 0 to 40°C is of particular concern if infected foods are stored in the refrigerator and consumed without further cooking. A study of food-​borne illness in the United States of America be- tween 2000 and 2008 estimated an annual incidence of 1600 cases of listeriosis, with a 16% mortality. In 2009 the estimated incidence of laboratory-​confirmed listeriosis was 0.34 per 100 000 population. An increase in listeriosis has also been reported in several European countries, and decreased salt concentrations in prepared foods have been proposed as a possible cause. Transmission from infected animals to humans is unusual, but occupational infections in vet- erinary surgeons or farm workers are reported. Human-​to-​human transmission occurs only during pregnancy, when the bacteria col- onizing the mother infect the fetus in utero or the neonate in the birth canal. In most cases disease occurs sporadically, but small epi- demics are occasionally observed due to commercially distributed, highly contaminated food items. Predisposing conditions include advanced age, pregnancy, glucocorticoid therapy, haematological or solid organ tumours, organ transplantation (especially renal), HIV infection, diabetes mellitus, endstage renal disease, chronic liver disease, collagen vascular diseases, and iron overload. Hospital-​ acquired listeriosis has been reported and has been associated with consumption of contaminated food. Nosocomial transmission be- tween neonates has been associated with poor hand hygiene, close contact between infected patients and their mothers, skin care prod- ucts, and instruments such as rectal thermometers or stethoscopes. Prevention A vaccine against L.  monocytogenes has not yet been developed. Most infections are food-​borne; food items are contaminated either intrinsically or during processing or during storage in the refriger- ator. The abovementioned foods often contaminated with Listeria

section 8  Infectious diseases 1224 should be avoided by people at special risk, and they should also not eat some preprepared food items unless they are thoroughly re- heated to piping hot temperatures. Food items that commonly carry listeria, such as salads and mushrooms, should be kept separately in the refrigerator from those likely to be free of these bacteria, such as cold meats and other ready-​to-​eat food, otherwise there will be cross-​contamination. Improvement in the microbiological safety of food production processes and the continued education of the public will further re- duce the risk of infection. Inactivation of L. monocytogenes by radiation is readily achieved without changing the appearance or taste of foods. A combination of ultrasound treatment and rinsing of food stuff with 2% organic acids for 5 min is also able to reduce the contamination with these pathogens. Clinical features Listeriosis is generally an opportunistic infection of elderly people, with men more frequently affected than women. Furthermore, im- munocompromised patients such as those with haematological or solid organ tumours, organ transplant recipients, patients with se- vere underlying illness such as diabetes mellitus, endstage kidney disease, liver cirrhosis or iron overload, and pregnant women and newborn babies are at increased risk. Occasionally people without these risk factors can be infected as well. In a few cases, a mild gastroenteritis precedes the systemic infection. The clinical presen- tation varies from a mild influenza-​like illness to fatal septicaemia and meningoencephalitis. Purulent localized infections of any organ occasionally occur. Recognized syndromes include maternofetal and neonatal listeri- osis, septicaemia, meningoencephalitis, cerebritis, and localized in- fections of various solid organs. Outbreaks of gastroenteritis with fever, diarrhoea, nausea, vomiting, and arthromyalgia have been described even in immunocompetent adults who have ingested con- taminated food. The diagnosis is usually missed because diarrhoeal stools are not cultured selectively for listeria. Septicaemia occurs mainly in adult patients with malignancies, in transplant recipients, and in immunosuppressed and elderly people. Most present with fever, hypotension, and shock. Many patients also develop meningitis. Meningitis may start abruptly but, in adults, can also develop insidiously, with progressive neurological signs espe- cially meningism. Fever may not be marked, particularly in elderly or immunosuppressed people. A purulent reaction is seen in the cerebrospinal fluid with most of the Gram-​positive bacteria lying extracellularly. Cerebritis in combination with meningitis, or separately, is in- creasingly recognized, particularly in immunosuppressed patient. Headache, fever, and varying degrees of paralysis and cerebral dis- orders such as dizziness or loss of consciousness may be observed. Rhombencephalitis begins with a headache, fever, nausea, and vomiting followed after several days with asymmetrical progressive cranial nerve palsies and decreased consciousness. Infection of the cerebellum might be followed by ataxia and problems of coordin- ation. MRI or CT may show areas of uptake without ring enhance- ment. Sometimes a brain abscess is diagnosed. In such cases the cerebrospinal fluid may show few, if any, inflammatory cells, and protein and sugar concentrations are normal. Intracerebral foci may be sealed off, so that bacteria or even bacterial DNA are not detected in cerebrospinal fluid or blood, leading to a missed diagnosis. Localized infections are rare, occurring mainly in immuno- suppressed people. They include soft-​tissue abscesses, osteo- myelitis, septic arthritis, cholecystitis, peritonitis, endocarditis, endophthalmitis, and pneumonia. They usually result from seeding during an initial bacteraemic phase, but focal skin and eye infection can also result from direct occupational exposure. In materno-​fetal listeriosis, the mother may develop fever, head- ache, myalgia, and low back pain due to the bacteraemic phase of the disease. Transplacental infection causes placentitis, amnionitis, and, depending on the time until delivery, spontaneous septic abortion or premature labour with delivery of a severely infected baby. Neonatal listeriosis of early onset results from intrauterine infec- tion and has a high mortality. The amniotic fluid is greenish and the baby septic and jaundiced, with signs of purulent conjunctivitis, bronchopneumonia, meningitis, and/​or encephalitis. Granulomas affect many organs, hence the term ‘granulomatosis infantisepticum’. Late-​onset disease, developing several days to weeks after birth in a baby who was initially healthy, presents with meningitis. The in- fection may have been acquired from the mother’s genital tract or through cross-​infection as a nosocomial infection. Differential diagnosis Since various organs may be affected, listeriosis may mimic several quite different local or systemic infectious diseases. The septic mani- festations are non​specific and, particularly in immunocompromised patients and elderly people, one should think of listeriosis. Listeria meningitis develops insidiously in most instances, in contrast to other bacterial disorders. In particular, listeria encephalitis is difficult to recognize initially because it can resemble, for instance, a cerebro- vascular accident. This infection should be considered in any patient with an acute brain stem or cerebellar disorder associated with fever, particularly if there are no risk factors for cerebrovascular disease. Bacteraemia accompanied by fever and, eventually, shock can mimic Gram-​negative sepsis. Encephalitis, which may develop slowly, can be confused in elderly people with cerebrovascular dis- ease or even with brain metastases. Criteria for diagnosis Listeria are non​sporing, facultatively anaerobic, Gram-​positive rods. Enrichment and selective methods are now well established for the isolation of these non​fastidious bacteria from the environment, food, or human specimen. Blood, cerebrospinal fluid, meconium, amniotic fluid, placental tissue, lochia, and swabs from purulent dis- charge from various organs can yield the pathogens. Gram-​positive rods may be seen in a stained smear. Sometimes they are very short and thus can be mistaken for streptococci. A predominance of monocytes among the inflammatory cells, which might lead to early suspicion of listeria, is not regularly seen. Differentiation of the various species is generally possible by means of commercially avail- able biochemical tests or massspectrometry. Serovars 1/​2a, 1/​2b, and 4b are the most prominent among human isolates. Several genetic

8.6.38  Listeriosis 1225 typing methods are used to trace food sources, distinguish relapses from reinfections, and investigate outbreaks. Overall more than 17 different Listeria spp. have been described, most of which originate from the environment. L. monocytogenes is the major pathogen, although occasional human infections with L. ivanovii and L. seeligeri have been re- ported. L. welshimeri, L. innocua, L. marthii, and L. grayi are not known to cause disease. The crucial difference is that pathogenic isolates display various virulence factors not present in non​patho- genic ones. In various isolates of L. monocytogenes, these proper- ties can be differentially expressed, so that the pathogenicity will vary from strain to strain. Nucleic acid amplification techniques have also been used to de- tect the bacteria or, for example, in patients pretreated with anti- biotics. However, serology is non​specific and does not aid diagnosis. Treatment Practically all strains of L. monocytogenes are susceptible to a large range of common antibiotics including ampicillin, gentamicin (which acts synergistically in vitro with ampicillin), co-​trimoxazole, erythro- mycin, tetracycline, chloramphenicol, vancomycin, and rifampicin. On the other hand, L. monocytogenes is inherently resistant in vitro to the cephalosporins and fosfomycin. It is also resistant to nalidixic acid but susceptible to the newer quinolones such as moxifloxacin. It should be borne in mind, however, that many of the bacteria reside intracellularly where they are protected from some of the ac- tive antimicrobial agents. Paradoxically, fosfomycin is active against intracellular Listeriae because in this particular environment, with low availability of essential nutrients such as glucose, the bacteria have to activate influx pumps which also transport fosfomycin into the bacterial cell, where it can perform its antibacterial activity. The clinical benefit of this phenomenon is not yet clear. There are no controlled trials of antibiotic treatment for listeri- osis. According to clinical experience, high-​dose intravenous ampi- cillin (i.e. 4 × 2–​3 g/​day) in combination with gentamicin (360 mg, or in a dose adjusted with the help of serum concentration meas- urements, once daily in a 60-​min infusion) remains the treatment of choice for adults. This combination should be given for 2 weeks at least. If necessary, ampicillin alone can be continued for another week or even longer (e.g. in case of endocarditis, until clinical reso- lution). For children, a daily dose of 200–​300 mg/​kg ampicillin, perhaps combined with 3–​5 mg/​kg gentamicin, is recommended. Gentamicin is best avoided in pregnancy, when ampicillin may be used alone, or erythromycin (2 g/​day intravenously for 2–​3 weeks) if the patient is allergic to penicillin. Recently, it has been ques- tioned whether the combination is better than ampicillin alone. Intravenous co-​trimoxazole (daily dose 20 mg/​kg trimethoprim

• 100 mg/​kg sulfamethoxazole in four divided doses) is the best second-​line treatment for meningoencephalitis. This drug can also be considered for oral sequence therapy after an intravenous ampi- cillin regimen. Since rifampicin is able to attack intracellular bac- teria, a combination with this drug (600 mg intravenously daily for 14 days for adults but not for pregnant women or neonates) is the- oretically helpful for cure. There is convincing evidence from cell culture and animal experiments as well as a few case reports that fluorquinolones could promote successful cure. Linezolid is also ac- tive against listeria, but clinical experience is limited to case reports. It is very important to be aware that treatment with cephalo- sporins is likely to fail. Since acute pyogenic meningitis is usually treated initially with ceftriaxone or cefotaxime until the pathogen is known, ampicillin should also be given with this initial treatment whenever listeriosis is a clinical possibility, unless a Gram-​stained cerebrospinal fluid sample shows good evidence of another bacterial cause. Carbapenems, such as meropenem and imipenem, have ex- cellent in vitro activity against Listeria spp. Although it has not been approved for the treatment of listeriosis, meropenem is approved for the treatment of bacterial meningitis and has been successfully used to treat listeriosis. Prognosis Despite antibiotic therapy, the mortality of systemic listeriosis re- mains high at up to 30%. Since listeriosis occurs primarily in im- munocompromised patients who lack normal defence mechanisms, relapses may occur if the antibiotic regimen is too short, allowing intracellular bacteria to survive. Such endogenous relapses are not attributable to resistant bacteria and so the same regimen can be ap- plied for a second round. Sequelae may be serious. Food industry Today, the Hazard Analysis and Critical Control Points (HACCP) management system is now standard in the food industry in Western countries. Once it becomes clear that a working plant is permanently colonized with pathogenic listeria, laborious and expensive inter- vention and management procedures are necessary. When listeria are detected during screening of food items, the production com- pany must withdraw the affected batches from the market. Areas of uncertainty or controversy So far, the infective dose required for induction of overt disease has not been defined. It may depend on cofactors such as concomitant enteric pathogens and, in particular, on the immune status of the host. Since so many foodstuffs are contaminated, it is practically im- possible to guarantee in everyday life that all dishes are free from lis- teria. Some authorities therefore tolerate certain numbers of bacteria. However, zero tolerance is appropriate for food prepared for babies or sick people. An exact definition of the incubation period is not yet possible. After ingestion of a high inoculum, symptoms appear within a few hours, but it is likely that in some cases days may elapse before invasion occurs. Few individuals harbor Listeria spp. in their gut. It is still a matter of debate whether these bacteria only transiently col- onize the intestinal tract after oral intake of contaminated food items or whether they belong to to autochthoneous microbiome of the host. Likely developments in the near future At least two different genetic lineages of L. monocytogenes isolates have been described in food items or in listeriosis cases. It is a matter of discussion whether this distinction might allow the health risk of contaminated food items to be evaluated.