Listeria Infection during Biologic Therapy: An Update

Giovanni Casella, Elisabetta Antonelli, Vincenzo Villanacci, Francesco Bachetti, Gabriele Torti, Maria Pina Dore, Gabrio Bassotti

Giovanni Casella, Medical Department, Desio Hospital, Desio (Monza-Brianza), University of Sassari, Italy
Elisabetta Antonelli, Gastroenterology Section, Perugia General Hospital, Perugia, University of Sassari, Italy
Vincenzo Villanacci, Pathology Section, Spedali Civili, Brescia, University of Sassari, Italy
Francesco Bachetti, Gabriele Torti, Gabrio Bassotti, Gastroenterology & Hepatology Section, Department of Medicine, University of Perugia Medical School, Perugia, Italy
Maria Pina Dore, Department of Clinical and Experimental Medicine, University of Sassari, Italy

Conflict-of-interest statement: The author(s) declare(s) that there is no conflict of interest regarding the publication of this paper.

Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

Correspondence to: Giovanni Casella, Medical Department, Desio Hospital, ASST Monza, Via Mazzini, 5, 20833 Desio (Monza Brianza), Italy.
Email: caselgio@tiscali.it
Telephone: +39-0362-383205

Received: November 8, 2016
Revised: December 8, 2016
Accepted: December 12, 2016
Published online: February 21, 2017


The therapeutic use of biological agents such as anti tumor necrosis factor-alpha drugs carries on an increased risk of reactivation of bacterial infections. Among these, listeriosis is a particularly dreadful infection in that may be associated with septic complications such as meningitis and encephalitis and a relatively high mortality rate. This article will discuss listeria infections in patients treated with biological agents.

Key words: Anti-TNF alfa agents; Biological therapy; Inflammatory bowel disorders; Listeriosis; Sepsis

© 2017 The Author(s). Published by ACT Publishing Group Ltd. All rights reserved.

Casella G, Antonelli E, Villanacci V, Bachetti F, Torti G, Dore MP, Bassotti G. Listeria Infection during Biologic Therapy: An Update. Journal of Gastroenterology and Hepatology Research 2017; 6(1): 2261-2264 Available from: URL: http://www.ghrnet.org/index.php/joghr/article/view/1921


The therapy with anti tumor necrosis factor (TNF)-alpha agents such as infliximab, adalimubab, golimumab, etanercept is to date an established approach for several rheumatologic and gastrointestinal diseases; however, such therapy is associated to an increased risk of reactivating granulomatous diseases and other intracellular bacterial infections where the host defenses are macrophage dependent[1]. Thus, Listeriosis may develop more frequently in patients receiving anti TNF-alpha therapies[1].


Listeria monocytogenes is a gram positive, anaerobic, short rod-like bacterium with a median incubation period of 35 days (range 1 to 91 days). The contact with this bacterium happens through ingestion of foods such as soft or unpasteurized cheese, unwashed vegetables, and uncooked meat[2]. Also water tanks contaminated by swallows may be a source of infection[3] and we must always consider the failure of basic sanitation measures in Industry, particularly the special condition of food served in hospitals where a strict control is needed in food preparation to avoid the bacterium’s transmission to vulnerable individuals[3]. Listeriosis is considered a relatively rare infection in adults[4], and it is regarded as an opportunistic infection affecting principally subjects with malignancy and/or on immunosoppressive therapy[4], as well as pregnant women, newborns and elderly subjects[4]. A human disease caused by Listeria monocytogenes was described for the first time in 1929 by Nyfeldt[5]; however, the mechanisms of Listeria infection have not been clearly elucidated yet[1]. TNF-alpha has an important role as a defense against intracellular organism such as Listeria, by increasing the number of macrophages and the amount of nitric oxide in the involved area, both of paramount importance for microbial killing[6]. The immunity to Listeria is mediated through T-cell lymphokine activation of macrophages; the latter are responsible for and determinant to clear Listeria from the blood[7]. Soulat et al[8] reported that the host DEAD-box RNA helicase DDX3X may be considered a “key component” involved in the transcriptional induction of a type 1 IFN response to Listeriosis infection. Soulat et al[8] reported the mice deficient for DDX3X show a complex immune imbalance with increased predisposition to Listeriosis infection for a reduced production of cytokines and INF-gamma and impaired maturation of lymphoid lineage determining a reduction in Natural Killer (NK) cell population[8].

The therapeutical use of anti TNF-alpha agents impairs the effect of endogenous TNF-alpha and it may promote the development of Listeriosis[9], since Listeria monocytogenes DNA has been found in the intestine of inflammatory bowel disease (IBD) patients and in control subjects[10]. Thus, mucosal damage in IBD patients with intestinal presence of Listeria may represent a predisposing condition to develop systemic Listeriosis during anti-TNF therapy, due to bacterial invasion from the gut to the bloodstream[10], since it has been suggested that the intestine may represent the entrance of the bacterium in the systemic circulation[11]. Therefore, intestinal mucosal damage in IBD patients chronically harboring Listeria may make them more susceptible to develop Listeriosis during anti-TNF therapy, particularly in case of ingestion of processed meat that increase this risk[10].


The clinical spectrum of Listeria infection includes febrile gastroenteritis, bacteremia, meningitis and meningoncephalitis, focal infections as septic arthritis, and endocarditis; cutaneous infections, polyserositis and cholecystitis have also been described[12,13]. Bierhoff et al[14] described 2 cases of Listeria Peritonitis in patients on peritoneal dialysis[14]. The mortality rate, if the condition is undiagnosed, is high (13-34%)[15]; in non-immunosuppressed patients, 80% has a central nervous system (CNS) infection and 52% of immunosuppressed patients show septicemia[12]. Rhomboencephalitis may show with the clinical signs of cerebellar ataxia and it is more frequent with hypervirulent clones of Listeria[3]. Brain Abscess may be present in 10% of all cases of Neurolisteriosis and in 85% of these cases, blood cultures are positive suggesting a bloodstream diffusion[16]. Al-Harbi et al[16] described the development of brain abscess after Rituximab infusion in a patient with Pemphigus Vulgaris.


The first description of Listeria monocytogenes infection during infliximab treatment had been reported in 2000 by Morelli and Wilson[9]. A review of the United States Food and Drug Administration’s (FDA) Adverse Events reporting program described 3 patients on infliximab therapy for Crohn’s disease (CD) that developed septicemia and/or meningitis; one of these died[1]. Aparicio et al[17] stressed the fact that the rate of Listeria infection in infliximab-treated rheumatic patients (5 out of 82.000) may be higher than in CD patients (2 out of 104.500) receiving infliximab therapy; this difference might be correlated to a larger concomitant use of methotrexate in rheumatoid arthritis (RA) patients, the different dosage of infliximab in RA and CD, and a higher age of AR patients[17]. Dixon et al[18], in the British Society for Rheunatology Biologic Register (BSRBR), described 3 cases of Listeriosis out of 7664 patients treated by anti TNF-alpha agents, with this prevalence being higher compared to Listeriosis’s incidence in the general population, estimated to be 0.7 per 100.000 subjects[19]. In 2010, the FDA Adverse Event Reporting System identified 92 case of Listeriosis related to infliximab therapy[20]; 69 patients (75%) showed Listeria meningitis and 14 of these (20.3%) also had encephalitis. A mortality rate of 17.4% (16/92 cases) was reported, and 15 out of 16 patients (93.8%) died for meningitis. Three cases of Listeria were reported by the BSRBR in 1352-person treated by biologic therapy[21]; none was reported in patients non receiving biologic agents[21]. The Spanish BIODABASER found an incidence of serious infections of about 53 cases per 1000 persons-year[22], and 6 Listeria infections were identified. The French RATIO registry reported 4 cases of Listeriosis in patients receiving biologic therapy (etanercept, infliximab, adalimubab)[23]. The FDA Adverse Event Reporting, in a review of reports in patients treated with infliximab or etanercept from 1998 to 2002, reported 38 cases of Listeriosis[24]. Subsequently, a more comprehensive literature review from 2004 to 2011 reported 266 cases of Listeria infections associated with the use of biologic agents[25]. Most infections were related to the use of infliximab (77.1%), and the others to the use of etanercept (11.7%), adalimumab (9.8%), rituximab (4.1%), abatecept (0.4%), and golimumab (0.4%). Most patients (47.7%) received biological therapies for rheumatologic diseases, 38% for IBD, 10.5% for miscellaneous indications, and 3.4% for hematological conditions. 73% of all these patients were in concomitant immunosuppressive therapy (56% with Steroids and 31.6% with Methotrexate). The median time of the disease’s onset was 184 days. The mortality rate varied from about 11% (adalimumab) to about 30% (rituximab)[25].

More recently, a few more case have been described, related to high steroid dosage and also to other biological agents (certulizumab, alemtuzumab)[26,27].

The importance of an early diagnosis of Listeria infection should be stressed, particularly for meningitis due to its high mortality. Listeria meningitis may be less frequent in ulcerative colitis because Listeria organism are not transferred to the CNS by phagocytosis and are killed extracellulaly by antibiotic therapy[4]. Minami et al[4] described Listeria septicemia following colonscopy, and suggested to consider the prevention of bacteriemic complications in immunosuppressed patients before this procedure. Listeria species have been added to the “FDA Boxed Warning” for the entire class of anti TNF-alpha therapies[28].


Ampicillin is the first choice drug to treat Listeriosis infection and the Meningitis United Kingdom Guidelines recommend to prescribe ampicillin for all patients with suspected meningitis above the age of 55 years to cover Listeria[20]. At present, Listeria resistance to antibiotics of the penicillin family has not been found[29]. The effectiveness of the penicillin family is due to their high affinity for penicillin-binding protein 3 (PBP3), essential transpeptidase participating in the construction of peptidoglycan, a main constituent of the bacterial cell wall[30]. Cephalosporins are inactive against Listeria because they have only weak affinity for PBP3[3], even though this resistance may have more complex pathophysiologic grounds[31]. Aminoglycosides are also indicated for the treatment of Listeriosis[24]. The second-line drugs, used particularly in penicillin allergic patients, are trimethoprim/sulphamethoxazole, erythromycin, vancomycin and meropenem[32]. In immunocompromised patients, the therapy should always be prolonged for more than 2 weeks, due to a high risk of relapse[28].


It is very important to recognize that every patient during anti TNF-alpha therapy must be informed about the potential risk to contract Listeria monocytogenes infection in case of ingestion of high risk foods, and a list of such foods should be given when prescribing TNF-alpha therapy[20]. An early diagnosis determined by increased medical sensibilization for this infection could permit a reduction of mortality, especially that due to meningitis and septicemia.


1 Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum 2003; 48: 319-324 [PMID: 15468359]

2 Camargo AC, Woodward JJ, Nero LA. The continuous challenge of characterizing the foodborne pathogen Listeria monocytogenes. Foodborne Pathog Dis 2016 (in press) [PMID: 27162388]; [DOI: 10.1007/513197-015-2126-3]

3 Lebreton A, Stavru F, Brisse S, Cossart P. 926-2016: 90 years of Listeriology. Microbes and Infection 2016; 1-13 [DOI: 10.1016/j.micinf.2016.10.009], [PMID: 27876526]

4 Minami M, Hasegawa T, Ando T, Maeda O., Ohkura T., Ohta M., Goto H. . Post-colonoscopic Listeria septicemia in ulcerative colitis during immunosuppressive therapy. Intern Med 2007; 46: 2023-2027 [PMID: 18084128]

5 Nyfeldt A. Etiologie de la mononucleose infectiuse. C R Sciences Soc Biol (Paris) 1929; 101: 590-595

6 Izbéki F, Nagy F, Szepes Z, Kiss I, Lonovics J, Molnár T. Severe Listeria meningoencephalitis in an infliximab-treated patient with Crohn’s disease. Inflamm Bowel Dis 2008; 14(3) :429-431 [PMID: 17973302]

7 Southwick FS, Purich DL. Intracellular pathogenesis of listeriosis. N Engl J Med 1996; 334:770-776 [PMID: 8592552]

8 Soulat D, Bürckstümmer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A, Hantschel O, Bennett KL, Decker T, Superti-Furga G. The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. Embo J. 2008; 27: 2135-46 [DOI: 10.1038/emboj.2008.126]; [PMID: 18583960]

9 Morelli J, Wilson FA. Does administration of Infliximab increase susceptibility to Listeriosis? Am J Gastroenterol 2000; 95: 841-842 [PMID: 10710107]

10 Ramos JM, García-Sepulcre MF, Masiá M, Brotons A, Grau MC, Gutiérrez F. Listeria monocytogenes infection in patients with inflammatory bowel diseases receiving anti-tumor necrosis factor therapy. Rev Esp Enferm Dig 2010; 102(10): 614-616 [PMID: 21039077]

11 Zachar Z, Savage DC. Microbial interference and colonization of the murine gastro-intestinal tract by Listeria Monocytogenes. Infect Immun 1979; 23(1):168-174 [PMID: 106003]

12 Charlier C, Leclercq A, Cazenave B, Travier L, Cantinelli T, Lortholary O, Goulet V, Lemonnier A, Lecuit M. Listeria monocytogenes Joint and Bone Infections Study Group. Listeria monocytogenes-associated joint and bone infections: a study of 43 consecutive cases. Clin Infect Dis 2012; 54: 240-248 [DOI: 10.1093/cid/cir803]; [PMID: 22100574]

13 Goulet V, Marchetti P. Listeriosis in 225 non-pregnant patients in 1992: clinical aspects and outcome in relation to predisposing conditions. Scand J Infect Dis 1996; 28(4): 367-374 [PMID: 8893400]

14 Bierhoff M, Krufwagen E, Van Bommel EF, Verburgh CA. Listeria Peritonitis in patients on peritoneal dialysis: 2 cases and review of the literature. Neth. J. Med. 2011; 63(10): 461-4 [PMID: 22058269]

15 MacGowan AP, Bowker K, McLauchlin J, Bennett PM, Reeves J. The occurrence and seasonal changes in the isolation of Listeria spp. in shop bought food stuffs, human feces, sewage and soil from urban sources. Int J Food Microbiol 1994; 21(4):325-334 [PMID: 8043351]

16 Al-Harbi TM, Al-Muammar SA, Ellis RJ. Brain Abscess following Rituximab infusion in a patients with Pemphigus Vulgaris. Am. J. Case Report 2016; 16: 65-8 [DOI: 10.12659/AJCR.892635]

17 Aparicio AG, Munoz-Fernandez S, Bonilla G, Miralles A, Cerdeno V, Martin-Mola E. Report of an additional case of anti tumor necrosis factor therapy and Listeria monocytogenes infection: comment on the letter by Gluck et al. Arthritis Rheum 2003; 48: 1764-1765 Author Reply 1765-6 [PMID: 12794847]

18 Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmonds DP. British Society for Report Biologic Register. Rates of serious infection, including site specific and Bacterial intracellular infection, in rheumatoid arthritis patients receiving anti TNF-Alpha therapy: results from the British Society of Rheumatology Register. Arthritis Rheum 2006; 54: 2368-2376 [PMID: 16868999]

19 Kelesidis T, Salhotra A, Fleisher J, Ushan DZ. Listeria endocarditis in a patient with psoriatic arthritis on infliximab: are Biologic Agent as treatment for Inflammatory Arthritis increasing the incidence of Listeria Infection? J. Infect 2010; 60: 386-396 [DOI: 10.1016/ J.Jinf 2010.02-009], [PMID: 20176052]

20 Rana F, Shaikh MM, Bowles J. Listeria meningitis and resultant symptomatic hydrocephalus complicating infliximab treatment for ulcerative colitis. JRSM Open 2014; 5: 2054270414522223 [DOI: 16.1177/2054270414522223], [PMID: 25057381]

21 Heyderman RS. British Infection Society. Early management of suspected bacterial meningitis and meningococcal septicaemia in immunocompetent adults-second edition. J Infect 2005; 50: 373-374 [PMID: 15991345]

22 Perez-Sola MJ, Torre-Cisneros J, Perez-Zafrilla B, Carmona L, Descalzo MA, Gomez-Reino JJ. Infections in patients treated with tumor necrosis factor antagonists: incidence, etiology and mortality in the BIOBADASER registry. Med Clin (Barc) 2011; 137(12): 533-540 [DOI: 10.1016/J.medcli.2010.11.032], [PMID: 21514606]

23 Salmon-Ceron D, Tubach F, Lortholary O, Chosidow O, Bretagne S, Nicolas N, Cuillerier E, Fautrel B, Michelet C, Morel J, Puéchal X, Wendling D, Lemann M, Ravaud P, Mariette X; RATIO group. Drug-specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3-year prospective French RATIO registry. Ann Rheum Dis 2011; 70: 616-623 [PMID: 21177290]

24 Witlox MA, Klinkenberg-Knol EC, Meuwissen SG. Listeria sepsis as a complication of endoscopy. Gastrointest Endosc 2000; 51: 235-236 [PMID: 10650280]

25 Bodro M, Paterson DL. Listeriosis in patients receiving biologic therapies. Eur J Microbiol Infect Dis 2013; 32(9):1225-1230 [DOI: 10.1007/S 10096-013-1873-1]; [PMID: 23568606]

26 Miranda-Bautista J, Padilla-Suárez C, Bouza E, Muñoz P, Menchén L, Marín-Jiménez I. Listeria monocytogenes infection in inflammatory bowel disease patients: case series and review of the literature. Eur J Gastroenterol Hepatol 2014; 26(11): 1247-1252 [DOI: 10.1097/MEG.000000000000188]; [PMID: 25171025

27 Rau D, Lang M, Harth A, Naumann M, Weber F, Tumani H, Bayas A. Listeria meningitis complicating alemtuzumab treatment in multiple sclerosis--report of two cases. Int J Mol Sci 2015 Jun 29; 16(7): 14669-14676 [PMID: 26132570]

28 Bodro M, Paterson DL. Has the time come for routine trimethoprim-sulfamethoxazole prophylaxis in patients taking biologic therapies? Clin Infect Dis 2013; 56(11): 1621-1628 [DOI: 10.1093/cid/cit071];[PMID: 23392396]

29 Hof H. Listeriosis: therapeutic options. FEMS Immunol Med Microbiol 2003; 35(3): 203-205 [PMID: 12677961]

30 Hof H, Nichterlein T, Kretschmar M. Management of Listeriosis. Clin Microbiol Rev 1997; 10(2): 345-357 [PMID: 9105758]

31 Krawczyk-Balska A, Markiewicz Z. The intrinsic cephalosporin resistome of Listeria monocytogenes in the context of stress response, gene regulation, pathogenesis and therapeutics. J Appl Microbiol 2016; 120(2): 251-265 [DOI: 10.1111/jam 12989]; [PMID: 26509460]

32 Temple ME, Nahata MC. Treatment of Listeriosis. Ann Pharmacother 2000; 34: 656-661 [PMID: 10852095]

Peer reviewer: Monowar Aziz


  • There are currently no refbacks.

Creative Commons License
This work is licensed under a Creative Commons Attribution 3.0 License.