DEDICATÓRIA

Gostaria de agradecer ao Professor António Sarmento pelo empenho e

disponibilidade demonstrados ao longo da elaboração deste trabalho.

Gostaria também de agradecer aos meus pais e à minha família pelo apoio constante

ao longo dos anos e quilómetros.

FACULDADE DE MEDICINA DA UNIVERSIDADE DO PORTO

MESTRADO INTEGRADO EM MEDICINA

ANO LECTIVO 2017/18

DISSERTAÇÃO/ MONOGRAFIA

TRABALHO ELABORADO DE ACORDO COM AS NORMAS DA REVISTA

“INFECÇÃO E SEPSIS”

ORIENTADOR: PROF. ANTÓNIO SARMENTO

ALUNO: LUIS BICHEIRO

1

TITLE

A systematic review on serious infections by the intracellular bacterial pathogens

Legionella, Listeria, and Salmonella in patients receiving anti-TNF therapy

TÍTULO

Revisão sistemática das infecções graves pelas bactérias patogénicas intracelulares

Legionella, Listeria e Salmonella em doentes medicados com agentes anti-TNF

2

AUTHORS/ TITLES/ DEPARTMENT/ CONTACT INFO

Luis Bicheiro, PhD

Faculty of Medicine, University of Porto, Portugal

lbicheiro@igc.gulbenkian.pt

António Sarmento, MD, PhD

Department of Infectious Diseases, Hospital S. João, Portugal

Faculty of Medicine, University of Porto, Portugal

3

ABSTRACT

Anti-TNF- agents are widely used in inflammatory diseases and have been

associated with serious intracellular infections. This study is aimed at characterising the

clinical presentation, analysing the treatment options, and assessing the different outcomes

of infections by the intracellular bacteria Legionella, Listeria, and Salmonella in patients

treated with anti-TNFs.

PubMed/MEDLINE was used to search for peer-reviewed papers of relevance. This

study found 70 papers which fulfilled the criteria, in which 31 cases of serious infection by

Legionella, 57 cases of serious infection by Listeria, and 16 cases of serious infection by

Salmonella were described.

The overwhelming majority of the patients taking anti-TNFs with serious infection

were also receiving concomitant immunosuppressive drugs, especially steroids. The typical

patient is a male in his 50s, suffering from RA, and taking Infliximab. All of the patients

infected with Legionella had pneumonia and were treated with either a quinolone, or a

macrolide, or a combination involving at least one of them. The majority of patients

infected with Listeria had bacteremia and/ or meningitis and/ or CNS involvement; they

were mainly treated with ampicillin +/- gentamicin or amoxicillin +/- gentamicin. The

majority of patients infected with Salmonella had bacteremia, being septic arthritis also

very common; most were treated with fluoroquinolones. Altogether, 17 patients died, and

others developed complications.

A very important step towards successfully treating these patients is to achieve an

accurate diagnosis quickly; instituting effective empirical antibiotic therapy is also

paramount.

4

RESUMO

Os agentes anti-TNF- são muito usados em doenças inflamatórias e estão

associados a infecções intracelulares graves. Este trabalho tem por objectivo a

caracterização da apresentação clínica, a análise das opções de tratamento e a avaliação das

consequências das infecções pelas bactérias intracelulares Legionella, Listeria e Salmonella

em doentes tratados com anti-TNFs.

Neste trabalho recorreu-se ao PubMed/MEDLINE para a procura de artigos revistos

por pares relevantes, tendo sido encontrados 70 artigos que cumpriram os critérios e que

apresentavam 31 casos de infecção grave por Legionella, 57 casos de infecção grave por

Listeria e 16 casos de infecção grave por Salmonella.

A maioria dos doentes medicados com agentes anti-TNF e que sofreram infecção

grave estavam a tomar outros fármacos imunossupressores, especialmente esteróides. O

doente típico é homem, com mais de 50 anos de idade, com artrite reumatóide e medicado

com infliximab. Todos os doentes infectados com Legionella apresentaram pneumonia e

foram tratados com uma quinolona, ou um macrólido, ou uma combinação com pelo menos

um deles. A maioria dos doentes com infecção por Listeria apresentaram bacteremia e/ ou

meningite e/ ou envolvimento do SNC, tendo sido a maior parte das vezes tratados com

ampicilina +/- gentamicina ou amoxicilina +/- gentamicina. A maioria dos doentes com

infecção por Salmonella apresentou bacteremia, sendo a artrite séptica uma apresentação

também bastante comum; a maioria foi tratada com fluoroquinolonas. Ao todo, morreram

17 doentes, tendo outros desenvolvido complicações.

Um passo muito importante para o tratamento eficaz destes doentes é chegar ao

diagnóstico correcto rapidamente; igualmente importante é instituir terapêutica antibiótica

empírica adequada.

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KEYWORDS

Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab, Legionellosis,

Listeriosis, and Salmonellosis.

PALAVRAS-CHAVE

Adalimumab, Certolizumab, Etanercept, Golimumab, Infliximab, Legionelose,

Listeriose e Salmonelose.

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INTRODUCTION

Tumor necrosis factor alpha (TNF-) is a key regulator of Th1 responses to

intracellular pathogens, playing an equally important role in the regulation of innate

immunity and induction of the inflammatory response. TNF- is synthesized by activated

macrophages and T cells, being subsequently cleaved to form soluble TNF-. Biologically

active TNF- requires aggregation of three TNF- monomers, which then act by binding

TNFR1 or TNFR2, which stimulate production of inflammatory cytokines, chemokines and

endothelial adhesion molecules[1].

TNF- is important for recruitment of neutrophils and macrophages, differentiation

of monocytes into macrophages, activation of phagosome and macrophages, formation and

maintenance of granuloma integrity. Mycobacterium species, Histoplasma capsulatum and

other intracellular pathogens are not readily killed by the host’s immune system; they are

sequestered in granulomas, which are made of a central core of macrophages,

multinucleated giant cells and necrotic debris enveloped by macrophages and

lymphocytes[2].

In excess, TNF- leads to inadequate inflammation and tissue damage, thus,

dysregulated TNF- can contribute to several pathological conditions, namely rheumatoid

arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, Crohn’s disease

(CD) and ulcerative colitis (UC)[1]. Studies concerning the role of TNF- in these diseases

led to the development of therapies based on TNF- blockage.

Presently there are five TNF- inhibitors (anti-TNFs) approved for the treatment of

a variety of inflammatory diseases. Adalimumab is a human monoclonal anti-TNF

antibody; it binds both monomeric and trimeric TNF-. Certolizumab is the antigen-

binding fragment of a humanized monoclonal antibody coupled to polyethylene glycol; the

lack of a Fc portion means it does not induce apoptosis, complement activation or

7

antibody-dependent cellular cytotoxicity. Etanercept is a fusion protein consisting of two

TNFR2 coupled to the constant region of IgG1, acting as a soluble TNF- receptor,

binding to trimeric TNF- and lymphotoxin; it has the shortest half-life of the five (3 days

versus 8-14 days). Golimumab is a human monoclonal anti-TNF antibody. Infliximab is a

mouse-human chimeric monoclonal anti-TNF antibody; it binds both monomeric and

trimeric TNF-; it is the only of the five which is administered intravenously[3].

The five anti-TNFs bind both the soluble (sTNF) and transmembrane (mTNF)

bioactive forms of TNF-. Binding to mTNF can have an agonistic action, initiating

reverse signalling leading to cytokine suppression, cell cycle arrest and/ or apoptosis.

Binding to mTNF can also lead to complement-dependent-cytotoxicity and antibody-

dependent cell-mediated cytotoxicity (ADCC). It is thought the therapeutic consequences

of the anti-TNFs come from sequestration of sTNF, accelerated efflux of cells from target

sites, induction of apoptosis (but not with Certolizumab), ADCC (but not with

Certolizumab), or a mix of these. Etanercept has reduced potential to disrupt granuloma but

also reduces the number of memory B cells, comparing to the other four anti-TNFs; at least

in part, this is due to binding the mTNF with decreased affinity or avidity, unlike the other

anti-TNFs[3].

Skin reactions characterized by itching, pain, redness, irritation, bruising, or

swelling at the site of injection are common but usually minor problems with

subcutaneously administered agents (Adalimumab, Certolizumab, Etanercept and

Golimumab). Infliximab is associated with non-allergic acute (<24h) and delayed (1-14d)

infusion reactions such as skin rash, joint pain, myalgia and fatigue[2]. Other adverse effects

of the anti-TNFs include mild neutropenia, infections, demyelinating disease, heart failure,

malignancy and induction of autoimmunity[2].

8

The importance of TNF in host defense has led to an awareness of potential

infection risk. The incidence of serious infection (infection requiring intravenous

antibiotics or hospitalisation) has been reported to be significantly higher in patients taking

anti-TNFs when compared to patients taking glucocorticoids or other non-anti-TNF

immunosuppressors[4]. The risk of tuberculosis reactivation with anti-TNF therapy is well

established and the original findings led to the development of screening and prophylaxis

protocols before the start of anti-TNF therapy[5],[6]. As expected, there is an enhanced risk

of infection with other intracellular bacteria as well (such as Listeria, Salmonella,

Legionella, and Nocardia), with fungi (such as Candida albicans, Aspergillus fumigatus,

Pneumocystis jirovecii, Cryptococcus, Coccidioides, and Histoplasma capsulatum), and

with virus (such as hepatitis B and herpes zoster virus) [7],[8].

As TNF- is important for the maintenance of granuloma, TNF- inhibitors allow

the breakdown of granuloma and subsequent reactivation and dissemination of the

pathogens. Also, TNF- neutralization with monoclonal antibodies results in a reduced

synthesis of interferon (IFN)-γ, which leads to a reduced expression of Toll-like receptor 4

(TLR-4) and defective cellular immune response. As recognition of microorganisms by

TLR-4 and activation of macrophages by IFN-γ are fundamental mechanisms for the

defense against intracellular pathogens, their inhibition by anti-TNFs leads to increased

infections by these agents[9].

Pathogenic bacteria, which can cause disease, may be able to infect their host in an

acute or chronic fashion. Intracellular bacteria are characterised by entering host cells’,

usually macrophages, using this intracellular habitat in order to avoid antibody responses,

among others. Considering macrophages are notorious for their pathogen detection and

killing functions, this is somewhat of a paradox. In fact, living in such a hostile

9

environment requires the use of different strategies, namely influencing host processes such

as membrane trafficking, signalling pathways, metabolism, autophagy and apoptosis[10].

Among the obligatory intracellular pathogenic bacteria we find Chlamydia,

Ehrlichia, and Rickettsia. Among the facultative intracellular pathogenic bacteria we find

Legionella pneumophila (a Gram negative [G-]), Listeria (G+), Mycobacterium,

Salmonella (G-), Neisseria (G-), Brucella (G-), Nocardia (G+), Francisella (G-) and

Yersinia pestis (G-).

The broad grouping of intracellular bacteria colonizes two topologically distinct

regions of the host cell, being thus subdivided into cytosolic and intravacuolar bacteria[11].

Cytosolic bacteria, such as Francisella tularensis and Listeria monocytogenes, escape from

the endocytic pathway and replicate in the host cytosol. Intravacuolar bacteria, such as

Brucella spp, L. pneumophila, Mycobacterium tuberculosis and Salmonella enterica, reside

and replicate within the host endomembrane system; this is accompanied by expansion of

the vacuolar membrane and has the added benefit of being protected from the host

cytosolic innate immune defenses[10].

Following entry, vacuoles containing invading bacteria diverge from the

phagolysosomal pathway; bacteria will then target multiple host’s components in order to

maintain the integrity of the vacuole. One of the main challenges intravacuolar bacteria

face is to exert actions beyond the vacuolar membrane; this is accomplished by secreting

effectors outside of it through secreting systems, such as Salmonella’s type III secretion

system (T3SS), and L. pneumophila’s type IV secretion system (T4SS). Furthermore,

secretion systems are also involved in invasion of the host’s cells and the evasion of the

phagolysosome. L. pneumophila segregates from the endocytic route, recruit endoplasmic

reticulum-derived vesicles, and form ribosome-studded specialized vacuoles in a T4SS-

dependent manner. S. enterica replicates in a late endosome-like compartment that

10

excludes lysosomal degradation enzymes; the S. enterica containing vacuole migrates to

the microtubule-organizing centre and forms Salmonella-induced filaments along

microtubules in a T3SS-dependent manner. Manipulation of autophagy and apoptosis

occurs[10].

For entry into host epithelial cells, L. monocytogenes, a cytosolic bacterium,

requires interaction between E-cadherin and internalin A (a bacterial surface protein). L.

monocytogenes escapes the phagolysosomal pathway using the type II secretion system

(T2SS) effectors listeriolysin and phospholipase C (PLC), which promote vacuolar

membrane disruption. In the cytosol, L. monocytogenes manipulates host sensing pathways

to avoid detection, autophagy and cell death, replicating rapidly and hijacking the host actin

polymerization machinery to move within and between cells[10].

A review of the Adverse Event Reporting System of the US Food and Drug

Administration (AERSUSFDA) between 1998-2002 revealed a high frequency of

granulomatous infections in patients taking Infliximab or Etanercept. On the

aforementioned period, there were 38 serious infections by Listeria and 11 by Salmonella

in patients receiving anti-TNFs reported to the AERSUSFDA[7]. Similarly, between 1999

and 2010, 80 cases of serious infection by Legionella in patients receiving anti-TNFs, were

reported to the AERSUSFDA. These three agents were found to be the top bacterial

pathogens, excluding Mycobacterium sp, in the population of anti-TNF takers, causing high

morbidity and mortality. In fact, perhaps more important than the numbers were the

uncommon presentations of these infections that soon after started to be described in the

peer-reviewed literature.

Given the increased risk of serious infection by the intracellular bacteria Legionella,

Listeria, and Salmonella, this study is aimed at characterising the clinical presentation,

11

analysing the treatment options, and assessing the different outcomes of these infections in

patients treated with anti-TNFs.

12

METHODS

PubMed/MEDLINE was used to search for records of relevance for this review. The

search queries included medical subject headings and keywords where appropriate; the

terms “anti-TNF”, “Adalimumab”, “Certolizumab”, “Etanercept”, “Golimumab”,

“Infliximab” were combined with each of the pathogenic agents or causative disease:

“Legionella” or “Legionellosis”, “Listeria” or “Listeriosis”, and “Salmonella” or

“Salmonellosis”. The last search was conducted on 30 September 2017. Some records were

identified through the reference section of previously query-identified papers. In short, after

identifying records of potential interest, these were put to a process of selection as indicated

in Figure 1: randomized controlled trials (RCTs), observational studies (OSs) and case

reports reporting infection with either Legionella, Listeria or Salmonella in humans

receiving anti-TNFs were to be retrieved and used in this systematic review, while records

without access to full text, without comprehensible language or without data on the patients

or data on the course of the infection were to be excluded. Altogether, 70 papers were

found that fulfilled the criteria: 19 papers reporting legionellosis in anti-TNF-treated

humans were included in this review (Table 1); 37 papers reporting listeriosis in anti-TNF-

treated humans were included in this review (Table 2); 15 papers reporting salmonellosis in

anti-TNF-treated humans were included in this review (Table 3) one paper is included in

both Table 2 and Table 3.

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RESULTS AND DISCUSSION

Legionellosis

Legionellosis refers to Pontiac fever (acute and self-limited illness) and

Legionnaire´s disease (pneumonia), which are the two human diseases caused by

Legionella sp; L. pneumophila is responsible for 80-90% of the cases[82].

This study has found 31 cases of serious infection by L. pneumophila in patients

taking anti-TNF medication published in the peer-reviewed literature (Table 1). Of these,

55% of the patients were male and 45% were female. The mean age of the patients was 54

years, while the youngest was 26 and the oldest 78 years old. Infliximab was associated to

55% of the cases, Adalimumab to 35% and Etanercept to 10%; Certolizumab and

Golimumab were not associated to any of the cases. Interestingly, a study which used the

national registry of France on biotherapies found there is a higher risk for legionellosis in

patients taking anti-TNFs than the general french population[5] and another study found

there is a higher risk for legionellosis in patients taking Infliximab or Adalimumab, versus

Etanercept[83]. The same study also found that patients taking anti-TNF medication in

general have a risk for L. pneumophila infection 13,1 times higher than the general

population. That study also found that patients taking anti-TNF medication who developed

Legionnaire’s disease were younger and had a lower mortality rate than the general

population who developed Legionnaire’s disease; in both populations there were more men

than women developing Legionnaire’s disease[83].

Of the 31 cases retrieved in this study, 17 (55%) had RA, 5 (16%) had CD, and the

remaining patients had either psoriasis, psoriatic arthritis, SLE, UC, Behcet’s disease or

pyoderma gangrenosum as indication for administration of the anti-TNF therapy. Only 4

patients were not taking any other immunosuppressive drug at the time of the infection. Of

those receiving concomitant immunosuppressive drugs, corticosteroids were the most

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common, with 58% taking them, either alone or with other immunosuppressive drugs; 48%

of the patients were taking MTX; and other patients were taking azathioprine,

sulphasalazine, 6-mercaptopurine and/ or others. The dosage, timing and duration of anti-

TNF and other immunosuppressive therapies has been discussed elsewhere[5],[7],[83],[84] and

is not the focus of this study.

Most of the patients identified had several co-morbidities, apart from the condition

which was the reason for anti-TNF treatment and apart from immunosuppression. The most

common issue with these patients is a long history of smoking, while some had COPD,

diverting colostomy, enterocutaneous fistula, and others. In fact, immunosuppression,

chronic lung disease, tobacco, >65 years old, and discharge from hospital around 10 days

before first pneumonia symptoms are risk factors for Legionnaire’s disease; in 28% of

cases with Legionnaire’s disease, these risk factors are not present[85].

At the time of legionellosis diagnosis none of the papers reported continuation of

anti-TNF therapy. Stopping anti-TNF therapy is a sound initial approach towards infection

treatment in these patients and should be recommended. Anti-TNF therapy was restarted in

5 patients[14],[26],[28],[29],[30], some 6 weeks, others one year after the end of the infection

treatment; two papers reported discontinuation of anti-TNF therapy[15],[21]; and the

remaining papers did not mention whether anti-TNF therapy was restarted or not. In one

case[26], the patient experienced a second episode of Legionnaire’s disease after re-

introduction of Infliximab. The decision to re-introduce anti-TNF should be worked out

case by case, measuring risk versus benefit, but this limited sample does not warrant

permanent absence of anti-TNF treatment based on legionellosis.

Most of the cases decribed here are community-acquired pneumonia, but there are

also three cases of hospital-acquired pneumonia[20],[23]. Legionella is in the top 4 causes of

microbial community-acquired pneumonia (2-13% of cases) and accounts for 10-50% of

15

patients with nosocomial pneumonia[82]. The natural habitats for L. pneumophila are

aquatic rivers and lakes, but they proliferate more after entering man-made aquatic

reservoirs. Legionella infection may occur through aspiration or inhalation of contaminated

aerosols produced by cooling towers, public baths, decorative fountains, humidifiers or

faucets[82]. In most cases here described, the origin of the infection was never identified; in

one case, the suspected source was a public bath. Guidelines for preventing legionellosis in

patients taking anti-TNFs are not available; however, reducing exposure to aerosolized

untreated water sources, such as fountains is reasonable; and also reasonable is minimizing

exposure to public baths.

After entering the lungs, L. pneumophila attaches to host cells via bacterial type IV

pili, heat-shock proteins, a major outer-membrane protein and complement. Macrophages

phagocytose L. pneumophila and enhance neutrophil recruitment. L. pneumophila evades

intracellular killing by inhibiting phagosome-lysosome fusion. The humoral immune

system is activated against Legionella, with IgM and IgG antibodies measurable in the first

weeks of infection[86]. In all cases retrieved by this study, the target organ was the lung, and

the disease of presentation was pneumonia. Fever was present in all patients while some

patients had shortness of breath, cough and chest pain. Many patients also developed

extrapulmonary symptoms such as vomiting, abdominal pain, diarrhea, headache, myalgia,

fatigue and others. All patients had abnormal chest radiograph’s showing pulmonary

infiltrates; 16 patients had unilateral pneumonia, 7 had bilateral pneumonia, and 4 pleural

effusion. CT chest scan revealed in many cases ground-glass opacity. Laboratory analysis

revealed in many, but all cases, elevated CRP and elevated leucocyte count. Crackles and/

wheezes could be heard in many, but not all patients. These findings are also present in

immunocompetent patients with Legionnaire’s disease and, as in such patients, are also

nonspecific, not allowing to distinguish from pneumonia of other etiologies; however,

16

temperature > 39ºC, diarrhea, neurologic findings and unresponsiveness to beta-lactamic

drugs (penicillins and cephalosporins) and aminoglycosides occur more frequently are thus

suggestive clues of Legionnaire’s disease.

Early diagnosis is important in the treatment of pneumonia by L. pneumophila. In

the papers analysed in this study, L. pneumophila was successfully identified in all but one

case, in which bacteria from the genus Legionella was without doubt identified,

nonetheless. Laboratory confirmation of legionellosis can be achieved by antigen detection

in urine, immunofluorescence testing, polymerase chain reaction, culture of respiratory

secretions and serology. The urine antigen test is rapid and has high sensibility and

specificity, making it the primary method for detection; however, it only works for

serogroup 1 (SG1), while there are 16 SGs[87]. The non-reactivity of the urine antigen test

towards other SGs markedly delays the diagnostic of pneumonia by Legionella as members

of the Legionellaceae do not grow on routine microbiologic media; growing them in

Wadowsky-Yee-Okuda medium (which allows the detection of the other SGs) is the

definitive method for diagnosis but requires a high degree of suspicion and takes 3-5 days.

If this translates in a delay in instituting the appropriate antibiotics for Legionella

pneumonia, the mortality increases significantly. In the papers analysed in this study, the

most used method of identification was the urinary antigen test (23 positively identified

cases), but culture in Wadowsky-Yee-Okuda medium was also widely used. Also in this

study, the main SG identified was SG1, with 74% of the reported cases; serogroups 2, 3, 4,

5, 6, 7, 8 and 10 were also identified; in 4 cases no data regarding the SG was reported.

SG1 is globally responsible for 80-86% of Legionnaire´s disease.

All of the patients retrieved by this study were treated for Legionnaire’s disease

with either a quinolone, or a macrolide, or a combination involving at least one of them.

Roughly speaking, the patients were subjected to either quinolone alone (5 patients), or

17

macrolide alone (4 patients), or macrolide and quinolone (4 patients), or quinolone and

rifampicin (7 patients), or macrolide and rifampicin (two patients), or quinolone and other

non-macrolide nor rifampicin (4 patients); 5 patient’s data on antibiotic treatment are

absent. Some of the quinolones used were levofloxacin, pazufloxacin, moxifloxacin and

ofloxacin. Some of the macrolides used were azithromycin, erythromycin and

clarithromycin. The preferred route to administer the antibiotics was the intravenous one

(IV) with a few patients receiving them orally (o). The majority of patients were treated for

three weeks; some successfully treated patients received their antibiotics for as little as 10

days while others for as long as 9 weeks.

Most of the papers did not state which empirical therapy (if any) was given. At least

5 patients received empirical antibiotic treatment for pneumonia (before Legionella was

identified as the pathogen). Four of these[17],[20],[21],[24] included a macrolide, and after

positive identification of Legionella were switched anyway to specific treatment, which is

listed in Table 1; one patient was initially treated with imipenem, which was switched two

days later for vancomycin + levofloxacin; however, at day 7, the patient died of septic

shock and multiorgan failure[27].

That particular case re-iterates the importance of a quick diagnosis of Legionnaire’s

disease and the importance of an expedient administration of appropriate antimicrobial

therapy. Since not always is possible to identify L. pneumophila (this was a case of SG4,10

hence the urinary antigen test came back negative), all patients with pneumonia who are

being treated with anti-TNFs should receive first-line antibiotic therapy that is active

against Legionella (such as a fluoroquinolone or a macrolide, as either is capable of

attaining high intracellular concentrations). For instance, for community-acquired

pneumonia in non-ICU inpatients: moxifloxacin 400mg/24h (IV) or ceftriaxone 2g/24h (IV)

+ azithromycin 500mg/24h (IV) (the first dose should be doubled) is recommended by the

18

Infectious Diseases Society of America. Upon identification of L. pneumophila as the

etiological agent, the antibiotic regimen should change to a macrolide, or a quinolone, or a

combination of both; rifampicin may also be used, but always in association with one the

first two. Initial therapy should be given by IV route. In the immunocompetent patient the

total duration of therapy is 10-14 days, with clinical response occurring within 3-5 days and

complete clearing of infiltrates requiring 1-4 months. For the immunosuppressed patient, as

we have seen, administering a longer course of antibiotics (three weeks) seems to be the

preferred alternative. Whether to administer monotherapy or a combination of antibiotics

depends largely on the clinician’s evaluation of the severity of the pneumonia; for critically

ill patients it is common practice to use combination regimens. Some of the recommended

dosages are as follows: azithromycin 500mg/24h (IV) (the first dose should be doubled),

levofloxacin 750mg/24h (IV), rifampicin 300-600mg/12h (o or IV)[86].

In the cases reviewed by this study, many patients developed acute respiratory

distress syndrome and a few developed pulmonary abscess, bacteremia, septic shock and

multiorgan failure. Those that survived, recovered fully. Altogether, 7 patients died (23%).

For instance, in immunocompetent patients, mortality rates from community-acquired

Legionnaire’s disease usually go no further than 11%[86], which makes the mortality in

patients treated with anti-TNFs a high mortality rate. Immunosuppression is a known risk

factor for negative outcome; however the timing of administration of appropriate

antimicrobial therapy, the patient’s underlying disease, and the severity of pneumonia also

influence prognosis[86].

Let’s take a closer look at other cases which also resulted in death. In the case

described by Hayashi et al[15], the patient was successfully treated with pazufloxacin 1g IV

daily for 10 days and discharged; however, the L. pneumophila pneumonia relapsed at day

55, this time with deep mycosis, and the patient died 24 days later. In the case described by

19

Kaku2013, the patient died within 24h after admission; post-mortem blood culture revealed

bacteremia as well. In the case of the 59 year old man described by Hofmann et al[20], the

pulmonary infiltrates found on the initial inspection evolved to abscess formation over the

next days (at this time he was being treated with piperacillin-tazobactam 3,375g IV every

6h and ciprofloxacin 400mg every 12h, the etiological agent of the pneumonia having not

yet been identified); the patient was indicated to open lung biopsy, although the

identification of L. pneumophila was achieved first through the urinary antigen test; while

staying in the ICU he developed candidemia, and cytomegalovirus, Pseudomonas

aeruginosa and vancomycin-resistant Enterococcus sp were also identified in the patient’s

samples; he was treated with azithromycin 500mg IV daily as well as adequate antibiotics

for the other pathogens; however the patient’s status worsened and he died. In the case

described by Kohn et al[23] the patient died 8 days after admission by septic shock; he had

developed pulmonary abscess. As we can see from these cases, death as an outcome of L.

pneumophila pneumonia seems to be more likely when Legionnaire’s disease is fulminant

or severe, complicated by concomitant infections, pulmonary abscess or bacteremia. This

further highlights the need to act preventively and act promptly.

Listeriosis

This study has found 57 cases of serious infection by Listeria in patients taking anti-

TNF medication published in the peer-reviewed literature (Table 2). Of these, 54% of the

patients were male and 46% were female. The mean age of the patients was 56 years, while

the youngest was 17 and the oldest 87 years old. Infliximab was associated with 79% of the

cases, Etanercept with 12%, Adalimumab with 7% and Certolizumab with 2%; Golimumab

was not associated with any of the cases. These percentages are very similar to the ones

found in a 2013 study which included case reports and adverse reaction databases data,

heralding 266 cases of Listeria infection in patients taking biologicals (anti-TNFs and

20

others)[88]: Infliximab was associated with 77% of the cases, Etanercept with 12% and

Adalimumab with 10%. Serious infection with Listeria does seem to be much more

common in Infliximab-treated patients than in patients taking any other anti-TNF.

Indications for the use of anti-TNFs in the 57 patients included in this study are as

follows: 25 (44%) had RA, 18 (32%) had CD, 6 (11%) had UC, 4 (7%) had psoriatic

arthritis, and the remaining patients had AS, Still’s disease, or unstated disease. Eighty-four

percent of these patients were receiving concomitant immunosuppressive drugs, especially

steroids (70%), MTX (40%) and/ or azathioprine (16%); fifty-six percent of patients were

taking two or more distinct immunosuppressors apart from the anti-TNF. The dosage,

timing and duration of anti-TNF and other immunosuppressive therapies and its relation

with the onset of infection has been approached elsewhere[42],[88] and is not the focus of this

study.

None of the papers report continuation of anti-TNF therapy during the severe

infection episode. Stopping anti-TNF therapy is a sound initial approach towards infection

treatment in these patients and should be recommended. There are 8 cases in which the fate

of anti-TNF therapy is clearly stated; of these, 5 authors opted for non-reintroducing anti-

TNF therapy while three patients received further anti-TNF therapy after finishing infection

treatment; none of these three were reported to suffer from infection recurrence. The

decision to re-introduce anti-TNF should be worked out case by case, measuring risk

versus benefit; this study does not warrant permanent exclusion of anti-TNF treatment

based on one episode of listeriosis.

L. monocytogenes can present as several clinical syndromes, such as gastroenteritis,

bacteremia, meningitis and/ or focal CNS infection. In this study, bacteremia was found to

be the most common type of serious infection, affecting 31 patients (54%); meningitis,

affecting 25 patients (44%), was the second most common; other patients had

21

meningoencephalitis, rhombencephalitis, brain abscess, encephalitis, hydrocephalus, septic

arthritis, cholecystitis, and/ or others; indeed, 17 patients (30%) had more than one

manifestation of Listeria infection. L. monocytogenes infection with involvement of the

meningeal membranes (meningitis or meningoencephalitis), rhombencephalitis or brain

abscess may occur in up to 47% of infected patients[89].

Symptoms of listeriosis overlap greatly with those of other infectious diseases.

However, immunocompetent patients frequently present with nonspecific flu-like

symptoms, lymphadenopathy, and gastrointestinal symptoms, while immunosuppressed

patients are more prone to develop bacteremia and/ or meningitis[90]. Bacteremic

presentation typically has fever, chills and myalgia/ arthralgia. Meningitic presentation is

more frequently subacute than in other bacterial etiologies, but CSF does show elevated

white blood cell count, elevated protein levels, and low glucose levels. Rhombencephalitis

caused by L. monocytogenes may affect equally healthy, immunocompetent patients; it

typically has a biphasic presentation with a prodrome of headache, nausea, vomiting, and

fever, although elderly and/ or immunosuppressed patients with meningoencephalitis may

not manifest a fever; neurologic signs signify the end of the prodrome[91]; CSF can be

normal or can more frequently show pleocytosis and elevation in protein; CT imaging can

demonstrate small brainstem abscesses, brainstem hypodensities, widening of the brainstem,

or hydrocephalus or can be normal; MR imaging can show increased intensities on T2

sequences[92].

Diagnosing in time requires considering the disease in the following risk

groups: >65 years old, pregnant women, neonates, immunosuppressed, and patients with

certain chronical conditions (diabetes, renal disease, etc.). Meningitis in those over 60 years

of age should trigger consideration of L. monocytogenes as the etiological agent, regardless

of immunosuppression. In UC or CD patients with active disease, fever may not result from

22

infection but from non-infectious inflammatory process, turning more difficult to tell apart

infection from a flare of the underlying illness; these patients provide additional diagnostic

challenge within the anti-TNF-treated population. Clinicians must be able to identify early

signs of this serious infection in patients taking anti-TNFs. If these patients show headache,

fever or new-onset neurological signs, clinicians should go for a thourough assessment;

immediate empirical antibiotic therapy should be started, and Listeria should be considered

as the possible etiological agent. The diagnosis is usually achieved by CSF or blood

culture[86].

Of the cases retrieved by this systematic review, thirty patients were treated with

ampicillin, either alone (11 patients) or in combination. Amoxicillin was given to 8 patients,

either alone or in combination. Gentamicin was given to 21 patients, but always in

combination with another antibiotic, mainly ampicillin (15 patients). Altogether, 10

patients received only the combination ampicillin + gentamicin. Meropenem,

benzylpenicillin, co-trimoxazole, and others were also used. The treatment of septic

arthritis was, in all cases, completed with arthroscopic lavage and debridement. Similarly,

the treatment of cholecystitis was, in all cases, completed with cholecystectomy. Most of

the papers do not state what, if any, empiric therapy was administered; meropenem was

given empirically to 3 patients with meningitis/ CNS involvement; one patient under 65

years old with meningitis received ceftriaxone, which was changed after identification of

Listeria; in fact, in all these cases, once the pathogen was identified, empirical therapy was

changed to the one stated in Table 2. All patients received their antibiotics via IV, at least

on the first days of specific treatment; while some later changed to oral antibiotics, others

finished the course with IV antibiotics as well. The duration of therapy varied from as little

as 10 days to as much as 18 weeks; typically, a patient with bacteremia was treated for two

23

weeks, a patient with meningitis for three weeks, and a patient with CNS involvement for

at least 4 weeks.

L. monocytogenes is susceptible to all common antibiotics (in vitro), but not to

cephalosporins. Antibiotic regimens used have included a combination of ampicillin 2g/6h

(IV) and gentamicin 80mg tds (IV), or amoxicillin 2g qds (IV) and gentamicin, although

optimal therapy has not been established in controlled clinical trials; the addition of an

aminoglycoside is recommended in serious infection because the penicillins alone are not

bactericidal against this organism; as such, gentamicin is usually added due to its

synergistic bactericidal effect. Meropenem and penicillin have good in vitro activity against

L. monocytogenes, and are occasionally used[93]. For the penicillin-allergic patient, the

bactericidal co-trimoxazole is an alternative, and erythromycin another[38],[39]. Treatment

takes two weeks for bacteremia, three weeks for meningitis, and 6-8 weeks for other types

of CNS involvement. For meningitis in the immunosuppressed, some suggest three weeks

of IV treatment plus three weeks of oral treatment[39]. Empirical treatment for meningitis in

all those over 60 years is ampicillin + cefotaxime or ceftriaxone, which covers L.

monocytogenes. In those taking anti-TNFs, L. monocytogenes should be considered as

possible etiological agent and, as such, these patients should also receive empirical

treatment that covers this agent, regardless of age. Optimal treatment of prosthetic joint

infection includes debridement and resection of infected tissues within the first weeks of

symptoms, prosthesis removal, antimicrobial therapy for 6 weeks, and re-implantation of a

new prosthesis[48].

Of the 57 patients with Listeria infection described in this systematic review, 8 died,

which corresponds to 14%. This percentage is very similar to the 16% mortality rate found

in the 2013 study with 266 cases of Listeria infection previously mentioned[88]. In the

present study, in 6 of the death cases, the patients were taking Infliximab, while in the other

24

two Etanercept was the anti-TNF. Although rarer occurrences, encephalitis,

rhombencephalitis and meningoencephalitis are associated with three deaths; meningitis is

associated with 4 deaths; and bacteremia, either alone or associated with one of the former

is also associated with fatalities. Furthermore, this study also shows that infections with

involvement of the CNS resulted in a few cases of survival with permanent neurological

sequelae. It has been shown that CNS involvement is an independent risk factor for

mortality in L. monocytogenes infections[94]. The development of CNS sequelae, which is

rare in the general population, is partially dependent on infected macrophages spreading the

intracellular bacterium cell-to-cell within neurons[95].

Human infections with L. monocytogenes occur mainly via ingestion of

contaminated processed and unprocessed foods of animal and plant origin. L.

monocytogenes induces its own internalization by cells that are not normally phagocytic.

An essential determinant of its pathogenicity is listeriolisin, which mediates the rupture of

the phagosomal membrane formed after phagocytosis. Bacteria that survive the bactericidal

activity of macrophages grow in the cytosol and spread from cell to cell. Another important

protein, ActA, allows the bacteria to move intra- and extra-cellularly via nucleation of the

host’s actin filaments. Neutrophils are fundamental to host defense during the first 24h of

infection; later on, migration of activated macrophages from the bone marrow is crucial.

DCs also play a role in the early steps of enteral L. monocytogenes infection; furthermore,

DCs, along with macrophages, are a major cellular constituent of the outer ring wall of

suppurative granulomas in human listeriosis. Immunity is cell-mediated (CD8+ T cells

doing the recognition and lysing the infected cells); humoral immunity plays no role[96]. L.

monocytogenes is reportedly capable of entering the CNS by: direct invasion of endothelial

cells, transport across the bloodbrain barrier within leukocytes, and migration into the brain

within the axons of cranial nerves[95].

25

Use of co-trimoxazole prophylaxis against Pneumocystis jirovecii is recommended

if patients are prescribed triple immunosuppression including either a calcineurin inhibitor

or an anti-TNF; in cases of dual immunosuppression, prophylaxis should still be considered,

particularly with use of a calcineurin inhibitor[97]. As co-trimoxazole may also be of use in

the prophylaxis against Listeria, Legionella and Toxoplasma[98], its use could potentially

reduce the number of cases of Listeria in high risk individuals. Furthermore, patients taking

anti-TNFs should be advised to avoid certain foods such as unpasteurized dairy products

and to reheat until steaming processed meats, as a way to minimise the risk of acquiring

this infection[32],[33].

Salmonellosis

This study has found 16 cases of serious infection by Salmonella in patients taking

anti-TNF medication published in the peer-reviewed literature (Table 3). Of these, 69% of

the patients were male and 31% were female. The mean age of the patients was 57 years,

while the youngest was 31 and the oldest 74 years old. Infliximab was associated with 63%

of the cases, Etanercept to 19%, Adalimumab to 12% and Certolizumab to 6%; Golimumab

was not associated with any of the cases.

Of the 16 cases retrieved in this study, 11 (69%) had RA, 3 (19%) had CD, and the

remaining patients had either psoriatic arthritis or IBD as indication for administration of

the anti-TNF therapy. Only 2 patients were not taking any other immunosuppressive drug

at the time of the infection. Of those receiving concomitant immunosuppressive drugs,

MTX was the most common, with 6 patients taking it, either alone or with other

immunosuppressive drugs; 5 patients were taking corticosteroids; and other patients were

taking azathioprine, 6-mercaptopurine and/ or hidroxichloroquine; 4 patients had no data

reporting to concomitant immunosuppressive therapy. The dosage, timing and duration of

anti-TNF and other immunosuppressive therapies is not the focus of this study.

26

Most of the patients had several co-morbidities, such as hypertension,

atherosclerosis, non-alcoholic steatohepatitis, total knee arthroplasty, cholecystectomy,

partial colectomy, loop ileostomy and anti-acid therapy, apart from the condition which

was the reason for anti-TNF treatment, and apart from immunosuppression. In fact,

conditions that are reported to increase susceptibility to Salmonella infection include

decreased stomach acidity and decreased intestinal integrity[86].

At the time of salmonellosis diagnosis none of the papers reported continuation of

anti-TNF therapy. Stopping anti-TNF therapy is a sound initial approach towards infection

treatment in these patients and should be recommended. Anti-TNF therapy was restarted in

two patients[50],[76], after the end of the infection treatment; these two patients did not suffer

from recurrence of Salmonella infection; three papers reported discontinuation of anti-TNF

therapy[71],[72],[73]; and the remaining papers did not mention whether anti-TNF therapy was

restarted or not. The decision to re-introduce anti-TNFs should be worked out case by case,

measuring risk versus benefit, but this limited sample does not warrant permanent absence

of anti-TNF treatment based on salmonellosis.

All members of Salmonella are now grouped into only two species: S. bongori and

S. enterica. S. enterica has 6 subspecies and each subspecies has associated serotypes. Most

of the human pathogenic Salmonella serotypes belong to the enterica subspecies; these

serotypes include S. Typhi, S. Paratyphi, and nontyphoidal Salmonella (NTS) serotypes: S.

Enteritidis, S. Typhimurium, S. Choleraesuis, and others. S. Typhi and S. Paratyphi, whose

growth only occurs in humans, cause enteric (aka typhoid) fever. The remaining serotypes,

which are able to colonize the gastrointestinal tracts of a wide range of animals, namely

humans, may cause nontyphoidal salmonellosis. Over 16 million cases of enteric fever

occur worldwide, with 500 000 fatalities per year, while NTS cases go up to 800 million,

with 3 million fatalities[99]. Identification of serotypes can be helped by agglutination

27

testing, which defines specific O-antigen serogroups: A, B, C1, C2, D and E; strains in

these serogroups cause nearly all Salmonella infections in humans; S. Enteritidis, S. Typhi

and others are serogroup D, for instance[86].

Only one patient out of the 16 cases retrieved by this study developed infection with

an enteric fever-causing serotype, S. Paratyphi. The most common serotype found in this

study was S. Enteritidis, affecting 6 patients. Other NTS serotypes found include S.

Typhimurium (2 patients), S. Choleraesuis (one patient) and one other NTS serotype; there

were also 3 patients with S. Group D, one patient with S. enterica and one patient with an

undetermined species of Salmonella. In the USA, S. Typhimurium is the main serotype

associated with salmonellosis, with 23% of infections, and S. Enteritidis is the second one,

with 16% of infections. S. Choleraesuis is extremely rare in the USA, although it’s the

second commonest Salmonella causing human disease in Taiwan[86],[69]. Enteric fever has

become rare in developed countries, being transmitted via water or food which has become

contaminated by feces from ill or asymptomatic chronic human carriers. NTS, on the other

hand, is quite common in developed and underdeveloped countries alike, and is mostly

associated with uncooked products of animal origin and other products contaminated with

animal waste.

Six of the patients retrieved by this study had travelled to a developing country

shortly before the onset of salmonellosis’ symptoms; many of these patients were also able

to confirm consumption of undercooked foods. One patient, who never left the UK,

confirmed consumption of partially cooked eggs from a local free range farm[50]. In 9

papers there was no data available on the possible source of Salmonella infection.

Travellers to developing countries are advised to monitor their food and water intake and

consider immunisation against S. Typhi. Patients under anti-TNF therapy should take extra

care when travelling abroad, specially to developing countries. Although quality control of

28

food is an area of growing concern and improvement worldwide, these patients should take

extra measures, such as avoid eating raw eggs, or undercooked meat products. Some

authors have proposed screening for Salmonella fecal colonization[71], others considering

even the possibility of routine co-trimoxazole prophylaxis[98].

Enteric fever serotypes, after reaching the small intestine, penetrate the mucus layer

and traverse through M cells that reside within Peyer’s patches; after crossing the epithelial

layer, they are phagocytosed by macrophages; they may disseminate throughout the body

in macrophages via the lymphatics and colonize the reticuloendothelial system[86].

Comparatively, NTS gastroenteritis is characterized by polymorphonuclear leukocyte

infiltration into the large- and small-bowel mucosa, while in enteric fever infiltration of

mononuclear cells into the small-bowel mucosa occurs. Both enteric fever and NTS

serotypes can lie dormant in the reticuloendothelial system and eventually reactivating after

immunosuppression. Salmonellosis can present in 5 major forms: enteric fever,

gastroenteritis, bacteremia, focal disease, and a carrier state. Enteric fever is a systemic

disease characterized by abdominal pain and fever, being caused by dissemination of S.

Typhi or S. Paratyphi; other common symptoms include headache, anorexia, chills, cough,

diarrhea, sweating, nausea, myalgia, vomiting and others. Infection with NTS usually leads

to gastroenteritis indistinguishable from that caused by other enteric pathogens,

characterized by nausea, vomiting, diarrhea, abdominal cramping and fever[86]. Bacteremia

occurs in as much as 8% of patients with NTS gastroenteritis and up to 10% of these

develop localized infections; both these complications are more common in the young, the

old, and the immunocompromised. Chronic asymptomatic carriers occur with both enteric

and NTS serotypes, in as up to 0,6% of patients previously infected with Salmonella,

carriage being more common in females, the young, and persons with biliary

abnormalities[86].

29

In the present study, bacteremia was found to be the most common type of serious

infection, affecting 9 patients (56%); septic arthritis was the second most common,

affecting 8 patients (two patients were found with septic arthritis and bacteremia). Other

patients had urosepsis, pleural empyema and/ or soft tissue infection. The most affected

joint in the septic arthritis subgroup was the knee, with 5 cases; other sites include the

elbow, pubic symphysis and a Baker’s cyst. Whereas most NTS cause self-limited

gastroenteritis with only 5% of patients developing bacteremia, some serotypes are

particularly aggressive; for instance, S. Choleraesuis has the higheest predilection among

Salmonella serotypes to cause primary bacteremia (which it does in up to 70% of patients),

focal invasive extra intestinal disease (which it does in up to 50% of patients) and

recurrence; and this with little or no gastrointestinal symptoms; these manifestations occur

especially in the immunosuppressed (the most significant risk factor for invasive

salmonellosis, others being age over 50 years, liver cirrhosis, IBD, SLE, and diabetes

mellitus); mycotic aneurysms, osteomyelitis, and pleuropulmonary infections are the

commonest focal infections reported[100]. Salmonella septic arthritis comes by way of

haematogenous spread instead of direct inoculation into the joint; still, septic arthritis is an

uncommon complication of Salmonella bacteremia (<1% of patients); joint infections that

occur over three months after joint arthroplasty are haematogenous in origin[71]. The risk of

septic arthritis in Salmonella infection is associated with young and old age, RA, CD, SLE,

HIV, diabetes mellitus, prosthetic joint transplant, and others[70]. It was also shown that

anti-TNF therapy poses a higher risk of septic arthritis than non-biological DMARD

therapy, and that Etanercept poses a higher risk of septic arthritis than Adalimumab or

Infliximab[101].

Most of the patients found by this systematic review showed non-specific

symptoms of infection such as fever and chills. Also, the majority of patients evidenced,

30

either some time before the severe infection episode, or concomitant to it, symptoms that

are consistent with gastroenteritis, such as nausea, vomiting, abdominal pain and diarrhea;

interestingly, three patients showed no gastrointestinal symptoms at all. On the other hand,

many patients showed extra-abdominal symptoms, such as headache, somnolence,

tachycardia, acute renal failure, sweating, cough, shortness of breath, myalgia; all the

patients who presented with septic arthritis showed, if not all, at least some symptoms of

joint inflammation, such as joint pain, swelling, stiffness, erythema and increased warmth.

On ultrasound, septic arthritis showed itself via synovial thickening and excessive fluid in

most of patients. Laboratory analysis revealed in many, but not all of the 16 cases of

serious infection by Salmonella, elevated CRP, elevated erythrocyte sedimentation rate and

elevated leukocyte count with neutrophilia. Although joint infection is a rheumatology

emergency that requires early diagnosis, the onset of septic arthritis in RA patients is more

insidious and may be mistaken for a flare of RA; the presentation may be even more subtle

in patients on immunosuppressor therapy. This may account for a delay in diagnosis, when

a quick diagnosis is essential to prevent joint destruction; as such, for patient’s on anti-TNF

therapy one must consider the possibility of septic arthritis. The identification of

Salmonella, and subsequent diagnosis of salmonellosis is based on isolation of the bacteria

from stool, blood or synovial fluid. All cases retrieved by this systematic review identified

Salmonella via culture and most of them followed that with serotyping. Gram staining was

also widely used. It is not enough to stress out that because the rates of morbidity and

mortality associated with salmonellosis are highest among the old, the young, and the

immunosuppressed, while the clinical presentation is relatively non-specific, taking the

necessary steps to identify the pathogen quickly is fundamental to implement successful

therapy to quench the infection. Also important is assessing antibiotic susceptibility as

multidrug resistant strains of Salmonella have been emerging since the 1980s, with some

31

being resistant to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracyclines,

trimethoprim-sulfamethoxazole (TMP-SMZ, TMP-SMX, co-trimoxazole) or ciprofloxacin;

assessing antibiotic susceptibility was also undertaken in the vast majority of cases here

reported.

Although antibiotic treatment is usually not recommended in NTS gastroenteritis

(fluid and electrolyte replacement is, if dehydration is an issue), pre-emptive antibiotic

treatment should be considered for patients with increased risk of invasive salmonellosis

(such as patients younger than three months, patients older than 50 years with

atherosclerosis, immunosuppressed patients, patients with endovascular abnormalities, and

patients with joint prosthesis); treatment should consist of ciprofloxacin 500mg bid (o) or

ofloxacin 400mg bid (o); immunocompromised patients may require 7-14 days of therapy,

while non-immunocompromised patients 2-3 days. Because of the increasing antibiotic

resistance, empirical treatment for focal disease or bacteremia should include a third

generation cephalosporin or a fluoroquinolone. In case of bacteremia, ceftriaxone 2g/d (IV)

or ciprofloxacin 400mg q12h (IV) are recommended for 7-14 days. In case of arteritis,

ceftriaxone 2g/d (IV) or ciprofloxacin 400mg q8h (IV) are recommended for 42 days, plus

surgical resection; ampicillin is suggested by some. In case of septic arthritis, the same

antibiotics of arteritis are recommended, plus surgical drainage of the affected area. In case

of enteric fever, the empiric treatment is ceftriaxone 2g/d (IV) for 10-14 days, or another

third-generation cephalosporin, or azithromycin; for treatment of fully-susceptible enteric

fever, fluoroquinolones (such as ciprofloxacin) are the most effective class of agents, but

azithromycin, amoxicillin, chloramphenicol or co-trimoxazole can also be used; for

treatment of multidrug- and quinolone-resistant strains, ceftriaxone, azithromycin or

ciprofloxacin are used. In case of chronic carriage, treatment for 4-6 weeks with oral

ciprofloxacin, oral amoxicillin, or others is advised[86].

32

In this systematic review 10 patients were found to be treated with fluoroquinolones,

ciprofloxacin being the one most used (in 7 patients); levofloxacin (in two patients) and

ofloxacin (in one patient) were also used. Ceftriaxone was given to 5 patients. Amoxiclav,

oxacillin, minocycline and amoxicillin were also used to treat salmonellosis. Furthermore,

other antibiotics were used as well, either empirically, or after complications emerged.

Most of the papers do not state what, if any empiric therapy was administered. For instance,

out of the 8 cases of septic arthritis, only three authors reported the empiric treatment: two

patients received vancomycin and levofloxacin, while one patient received meropenem.

Once the pathogen was identified and/ or antibiotic susceptibility ascertained, antibiotic

was changed as indicated in Table 3. The treatment of septic arthritis was, in all cases,

completed with non-antibiotic therapy, including arthroscopic lavage and debridement;

continuous closed irrigation suction; open arthrotomy and synovectomy (with retention or

reconstruction of prosthesis). Most patients received their antibiotics via IV while admitted

and, after discharge, would continue with oral therapy. The duration of therapy varied

widely; of the papers which report its length, there are patients who received antibiotics for

as little as 10 days, and others for as many as 6 months; the septic arthritis cases were the

ones which required the longest course of action (from one to 6 months), while bacteremia,

unless complicated by mycotic aneurism, required usually under one month.

In the cases retrieved by this study, 4 patients developed mycotic

aneurism[9],[72],[75],[79], while three patients experienced recurrence of Salmonella

infection[69],[71],[79], and only one patient had to go through joint reconstruction[80]. Two of

the patients that eventually developed mycotic aneurism were initially not given

fluoroquinolones or cephalosporins; in one of these cases, and despite later changing the

antibiotic treatment to ceftriaxone, the patient died. Similar to septic arthritis, treatment of

mycotic aneurism included non-antibiotic therapy, such as surgical resection with or

33

without placement of bypass, or placement of endovascular prosthesis. Antibiotic treatment

after identification of mycotic aneurism complication involved ciprofloxacin and a long

course therapy with co-trimoxazole, in one successful case.

Altogether, two patients died (12%), and both of them had developed mycotic

aneurism. Mycotic aneurism development is facilitated by atherosclerosis and

immunosuppression, which are common in the 16 patients retrieved by this study.

Recurrence after appropriate and adequate antimicrobial therapy is a feared complication in

patients with infection by some serotypes of Salmonella; some of the risk factors for

recurrence include atherosclerotic plaques, diseased joints, and diseased bones. In patients

with mycotic aneurysms, in addition to antibiotics, surgery may prevent recurrence[100].

34

GENERAL DISCUSSION AND CONCLUSIONS

The discussion on whether anti-TNFs pose an elevated risk of infection is far from

being over; for instance, in IBD, biological drugs, even when taken in combination with

other immunosuppressive drugs, were not found to confer a higher risk of serious infection

than other treatment options[102]. Similarly, in psoriasis, no increased risk of infection was

observed in patients taking anti-TNFs[103]. However, in RA, standard-dose biological drugs

were associated with an increase in serious infections compared with traditional

immunosuppressive drugs[104],[105]. Curiously, the magnitude of the risk of serious infection

in RA patients was not determined by the type of biological agents, having patient-specific

risk factors more impact[106]. Perhaps these reports reflect more of a difference in

methodology, (with clinical trials concluding that biological drugs do not increase serious

infections, while registries, which include the typical patients, showing different results)

than of fundamental differences between RA-patients versus IBD- and psoriasis-patients.

Regardless, it is clear that infection in patients taking anti-TNFs poses additional

challenges, both in terms of diagnosis and treatment.

Between the different anti-TNFs, Infliximab seems to present a higher risk of

infection. For instance, the previously mentioned review of the AERSUSFDA showed

there was a 3,25-fold greater risk of developing granulomatous infections in patients under

Infliximab than in those under Etanercept; for Listeria, there were 15,5 infections per 100

000 patients on Infliximab versus 1,8 infections per 100 000 patients on Etanercept; while

for Salmonella there were 3 infections per 100 000 patients on Infliximab and 3,5

infections per 100 000 patients on Etanercept[7]. Comparing between different anti-TNFs

should take in consideration that they have been in use for different periods and in different

diseases. In RA, the FDA approved Etanercept in 1998, Infliximab in 1998, Adalimumab in

35

2002, Certolizumab in 2009, and Golimumab in 2009[105]. Infliximab and Adalimumab are

also approved for CD and UC, Certolizumab for CD, and Golimumab for UC[107].

The infection risk should not forbid anti-TNF treatment. The risk of serious

infections in patients taking anti-TNF therapy can be managed by testing and treating

existing latent infections; adequate precautions prior and during treatment should also be

undertaken. In IBD, it is recommended to discontinue anti-TNF treatment during infection

with Legionella, Listeria, and Salmonella[97]. The American College of Rheumatology also

recommends that anti-TNF therapy be withheld when active bacterial infections or bacterial

infections requiring antibiotic therapy are present; it further recommends RA patients who

have a history of serious infections to use combination of DMARDs over anti-TNFs[108].

However, in these patients, treatment may continue if the risk/benefit ratio is favourable;

the decision to continue treatment should be personalized and based on the medical history

of the patient, causality of the adverse event, and whether the adverse event is a recurrence

of a prior similar event, among others.

In this study, we searched the peer-reviewed literature and found 104 cases of

serious infection by Legionella, Listeria, and Salmonella in patients who were under anti-

TNF therapy. In the overwhelming majority of these cases the patients were receiving

concomitant immunosuppressive drugs, especially steroids. The typical patient is a male in

his 50s, suffering from RA, and taking Infliximab. All of the patients infected with

Legionella had pneumonia and were treated with either a quinolone, or a macrolide, or a

combination involving at least one of them. The majority of patients infected with Listeria

had bacteremia and/ or meningitis and/ or CNS involvement; they were mainly treated with

ampicillin +/- gentamicin or amoxicillin +/- gentamicin. The majority of patients infected

with Salmonella had bacteremia, being septic arthritis also very common; most were

treated with fluoroquinolones. Altogether, 17 patients died. Others experienced

36

complications, namely recurrence of infection, a rare event nonetheless, occurring after

resuming anti-TNF therapy; many patients never did resume it. Patients can minimize the

risk of infection with these agents by taking care with what they eat, and where they go. A

very important step towards successfully treating these patients is to achieve an accurate

diagnosis quickly; instituting effective empirical antibiotic therapy is also paramount.

This study has relied mainly on case reports; however, some cases were taken from

RCTs and OSs as well. Case reports inform on which particular issues arise while treating

specific patients, allowing emphasis on the narrative aspect, and detecting novelties;

however, they lack the ability to generalize and suffer from publication bias. RCTs provide

balanced groups for analysis of conditions; however, they usually involve a small number

of patients and selected populations. OSs such as clinical registries capture the long-term

benefit of drugs in routine care although lacking controls and randomization. However,

both OSs and RCTs most often don’t show the information this study required for

characterising the patients and their clinical evolution; while case reports may have sketchy

data, and collecting it turns to a laborious process, a deeper understanding of the issue at

hand may emerge.

Finally, as biologic therapies are increasing in use, one should be aware of the

potential challenges they pose and how to best overcome them.

37

ACKNOWLEDGEMENTS

We thank Elsa Sousa and Inge De Landtsheer for their insightful takes on RA and

flemish/dutch papers, respectively.

38

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51

FIGURES AND TABLES

Figure 1: Schematic representation of the process of identification, selection and inclusion

of papers followed in this systematic revision. Adapted from Moher et al[12].

52

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tR

AM

TXL.

pn

eum

op

hila

SG2

-8P

neu

mo

nia

Levo

flo

xaci

n,

eryt

hro

myc

in3

wR

eco

very

Man

cin

i[25]

200

73

0M

Infl

ixim

abB

ehce

t’s

dis

eas

eM

TXL.

pn

eum

op

hila

SG1

Pn

eum

on

iaLe

vofl

oxa

cin

, ri

fam

pic

inR

eco

very

Tab

le1

: Pu

blis

he

dse

rio

us

infe

ctio

ns

by

Leg

ion

ella

inp

atie

nts

taki

ng

anti

-TN

Fd

rugs

Re

fere

nce

Ye

arA

geSe

xA

nti

-TN

FIn

dic

atio

nC

on

com

itan

tIS

dru

gsIn

fect

iou

sag

en

tTy

pe

of

infe

ctio

nTr

eat

me

nt

Ou

tco

me

Ku

nim

oto

[13]

201

64

7M

Ad

alim

um

abP

sori

atic

arth

riti

sM

TX, p

red

nis

olo

ne

L. p

neu

mo

ph

ila S

G1

Pn

eum

on

iaLe

vofl

oxa

cin

2w

(o)

Rec

ove

ry

Gia

ssi[1

4]2

014

50

MIn

flix

imab

RA

Lefl

un

om

ide

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Azi

thro

myc

in,

levo

flo

xaci

nR

eco

very

Hay

ash

i[15]

201

37

8F

Ad

alim

um

abR

AM

TX, p

red

nis

olo

ne,

su

lph

asal

azin

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaP

azu

flo

xaci

n1

0d

(IV

)R

eco

very

, re

lap

sean

dd

eat

h

Kak

u[1

6]2

013

65

MA

dal

imu

mab

RA

MTX

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Levo

flo

xaci

n,

mer

op

enem

Dea

th

Wu

erz[1

7]2

012

67

FA

dal

imu

mab

RA

Aza

thio

pri

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Levo

flo

xaci

n(I

V)

and

rifa

mp

icin

3w

A

zith

rom

ycin

6w

Rec

ove

ry

Ari

nge

r[18]

200

9n

dF

Infl

ixim

abSL

E-

Leg

ion

ella

spP

neu

mo

nia

nd

Dea

th

Bei

gel[1

9]2

009

58

MIn

flix

imab

CD

Aza

thio

pri

ne,

p

red

nis

olo

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Pip

erac

illin

/ ta

zob

acta

man

dm

oxi

flo

xaci

n

Rec

ove

ry

Ho

fman

n[2

0]2

009

26

MIn

flix

imab

CD

6-m

erca

pto

pu

rin

e,

pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Azi

thro

myc

in2

1d

Rec

ove

ry

59

MIn

flix

imab

CD

Met

hyl

pre

dn

iso

lon

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaA

zith

rom

ycin

21

dD

eath

Jin

no

[21]

200

96

7F

Ad

alim

um

abR

AM

TXL.

pn

eum

op

hila

SG1

Pn

eum

on

iaM

oxi

flo

xaci

n(I

V)

and

rifa

mp

icin

3w

Rec

ove

ry

Vin

ter[2

2]2

009

59

FIn

flix

imab

CD

-L.

pn

eum

op

hila

Pn

eum

on

ian

dD

eath

48

MIn

flix

imab

Pso

rias

is-

L. p

neu

mo

ph

ilaP

neu

mo

nia

nd

Rec

ove

ry

Ko

hn

[23]

200

77

1M

Infl

ixim

abU

CIV

ste

roid

s,

mes

alaz

ine

L. p

neu

mo

ph

ilaP

neu

mo

nia

An

tib

ioti

csD

eath

Lagi

er[2

4]2

007

60

MEt

aner

cep

tR

AM

TXL.

pn

eum

op

hila

SG2

-8P

neu

mo

nia

Levo

flo

xaci

n,

eryt

hro

myc

in3

wR

eco

very

Man

cin

i[25]

200

73

0M

Infl

ixim

abB

ehce

t’s

dis

eas

eM

TXL.

pn

eum

op

hila

SG1

Pn

eum

on

iaLe

vofl

oxa

cin

, ri

fam

pic

inR

eco

very

54

Ta

ble

1 (

con

tin

uat

ion

): P

ub

lish

ed

seri

ou

sin

fect

ion

sb

yLe

gio

nel

lain

pat

ien

tsta

kin

gan

ti-T

NF

dru

gs

Re

fere

nce

Ye

arA

geSe

xA

nti

-TN

FIn

dic

atio

nC

on

com

itan

tIS

dru

gsIn

fect

iou

sag

en

tTy

pe

of

infe

ctio

nTr

eat

me

nt

Ou

tco

me

Tub

ach

[26]

200

64

3M

Ad

alim

um

abR

AM

TX, p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaFl

uo

roq

uin

olo

ne

Rec

ove

ry

55

FA

dal

imu

mab

RA

MTX

, pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e,

rifa

mp

icin

Rec

ove

ry

67

MEt

aner

cep

tR

AM

TX, p

red

nis

olo

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Rif

amp

icin

, fl

uo

roq

uin

olo

ne

Rec

ove

ry

46

FIn

flix

imab

Pyo

der

ma

gan

gren

o-

sum

Pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e,

rifa

mp

icin

Rec

ove

ry

58

MIn

flix

imab

Pso

rias

is-

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e,

flu

oro

qu

ino

lon

eR

eco

very

40

MA

dal

imu

mab

RA

Sulf

alaz

ine,

b

etam

eth

aso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Rif

amp

icin

, fl

uo

roq

uin

olo

ne

Rec

ove

ry

45

FA

dal

imu

mab

RA

MTX

, pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e Fl

uo

roq

uin

olo

ne

Rec

ove

ry

66

FA

dal

imu

mab

RA

MTX

L. p

neu

mo

ph

ilaSG

6P

neu

mo

nia

Flu

oro

qu

ino

lon

e,

ceft

riax

on

eR

eco

very

47

MA

dal

imu

mab

RA

Pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Rif

amp

icin

, fl

uo

roq

uin

olo

ne

Rec

ove

ry

69

FEt

aner

cep

tR

AM

TX, p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaFl

uo

roq

uin

olo

ne

Rec

ove

ry

27

FIn

flix

imab

CD

Aza

thio

pri

ne,

p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaR

ifam

pic

in,

flu

oro

qu

ino

lon

eR

eco

very

Eise

nd

le[2

7]2

005

56

MIn

flix

imab

Pso

rias

isP

red

nis

olo

ne

L. p

neu

mo

ph

ila S

G4

,10

Pn

eum

on

iaIm

ipen

em 2

d(I

V)

Van

com

ycin

, le

vofl

oxa

cin

5d

Dea

th

Go

bb

i[28]

200

53

8F

Infl

ixim

abR

AM

TXL.

pn

eum

op

hila

SG1

Pn

eum

on

iaC

lari

thro

myc

inR

eco

very

Alb

ert[2

9]2

004

73

FIn

flix

imab

RA

MTX

, pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Ofl

oxa

cin

3w

Rec

ove

ry

Wo

nd

erge

m[3

0]2

004

43

FIn

flix

imab

RA

Aza

thio

pri

ne,

p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaEr

yth

rom

ycin

1

7d

(IV

)R

eco

very

Kro

esen

[31]

200

34

9M

Infl

ixim

abP

sori

asis

MTX

L. p

neu

mo

ph

ilaP

neu

mo

nia

nd

Rec

ove

ry

Tab

le1

(co

nti

nu

atio

n):

Pu

blis

he

dse

rio

us

infe

ctio

ns

by

Leg

ion

ella

inp

atie

nts

taki

ng

anti

-TN

Fd

rugs

Re

fere

nce

Ye

arA

geSe

xA

nti

-TN

FIn

dic

atio

nC

on

com

itan

tIS

dru

gsIn

fect

iou

sag

en

tTy

pe

of

infe

ctio

nTr

eat

me

nt

Ou

tco

me

Tub

ach

[26]

200

64

3M

Ad

alim

um

abR

AM

TX, p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaFl

uo

roq

uin

olo

ne

Rec

ove

ry

55

FA

dal

imu

mab

RA

MTX

, pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e,

rifa

mp

icin

Rec

ove

ry

67

MEt

aner

cep

tR

AM

TX, p

red

nis

olo

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Rif

amp

icin

, fl

uo

roq

uin

olo

ne

Rec

ove

ry

46

FIn

flix

imab

Pyo

der

ma

gan

gren

o-

sum

Pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e,

rifa

mp

icin

Rec

ove

ry

58

MIn

flix

imab

Pso

rias

is-

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e,

flu

oro

qu

ino

lon

eR

eco

very

40

MA

dal

imu

mab

RA

Sulf

alaz

ine,

b

etam

eth

aso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Rif

amp

icin

, fl

uo

roq

uin

olo

ne

Rec

ove

ry

45

FA

dal

imu

mab

RA

MTX

, pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Mac

rolid

e Fl

uo

roq

uin

olo

ne

Rec

ove

ry

66

FA

dal

imu

mab

RA

MTX

L. p

neu

mo

ph

ilaSG

6P

neu

mo

nia

Flu

oro

qu

ino

lon

e,

ceft

riax

on

eR

eco

very

47

MA

dal

imu

mab

RA

Pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Rif

amp

icin

, fl

uo

roq

uin

olo

ne

Rec

ove

ry

69

FEt

aner

cep

tR

AM

TX, p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaFl

uo

roq

uin

olo

ne

Rec

ove

ry

27

FIn

flix

imab

CD

Aza

thio

pri

ne,

p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaR

ifam

pic

in,

flu

oro

qu

ino

lon

eR

eco

very

Eise

nd

le[2

7]2

005

56

MIn

flix

imab

Pso

rias

isP

red

nis

olo

ne

L. p

neu

mo

ph

ila S

G4

,10

Pn

eum

on

iaIm

ipen

em 2

d(I

V)

Van

com

ycin

, le

vofl

oxa

cin

5d

Dea

th

Go

bb

i[28]

200

53

8F

Infl

ixim

abR

AM

TXL.

pn

eum

op

hila

SG1

Pn

eum

on

iaC

lari

thro

myc

inR

eco

very

Alb

ert[2

9]2

004

73

FIn

flix

imab

RA

MTX

, pre

dn

iso

ne

L. p

neu

mo

ph

ilaSG

1P

neu

mo

nia

Ofl

oxa

cin

3w

Rec

ove

ry

Wo

nd

erge

m[3

0]2

004

43

FIn

flix

imab

RA

Aza

thio

pri

ne,

p

red

nis

on

eL.

pn

eum

op

hila

SG1

Pn

eum

on

iaEr

yth

rom

ycin

1

7d

(IV

)R

eco

very

Kro

esen

[31]

200

34

9M

Infl

ixim

abP

sori

asis

MTX

L. p

neu

mo

ph

ilaP

neu

mo

nia

nd

Rec

ove

ry

Age

inye

ars.

CD

: Cro

hn’s

dis

ease

. d: d

ays.

F: f

emal

e. IS

: im

mu

no

sup

pre

ssiv

e. IV

: in

trav

eno

us.

M: m

ale.

MTX

: met

ho

trex

ate.

nd

: no

dat

a. o

: ora

l. R

A: r

heu

mat

oid

arth

riti

s. S

LE: s

yste

mic

lup

us

eryt

hem

ato

sus.

U

C: u

lcer

ativ

eco

litis

. w: w

eeks

.

55

Ta

ble

2: P

ub

lish

ed

seri

ou

sin

fect

ion

sb

yLi

ster

iain

pat

ien

tsta

kin

gan

ti-T

NF

dru

gs

Re

fere

nce

Ye

arA

geSe

xA

nti

-TN

FIn

dic

atio

nC

on

com

itan

tIS

dru

gsIn

fect

iou

sag

en

tTy

pe

of

infe

ctio

nTr

eat

me

nt

Ou

tco

me

Stra

tto

n[3

2]2

016

69

MIn

flix

imab

CD

Aza

thio

pri

ne,

p

red

nis

olo

ne

List

eria

mo

no

cyto

gen

esR

ho

mb

en

cep

hal

itis

Gen

tam

icin

3w

, am

oxi

cilli

n 6

wN

o n

euro

-lo

gica

lre

cove

ry

Par

ihar

[33]

201

53

7M

Infl

ixim

abU

C5

-ASA

, h

ydro

cort

iso

ne

List

eria

mo

no

cyto

gen

esM

enin

giti

sG

enta

mic

in,

amo

xici

llin

10

dR

eco

very

Mat

hew

s[34]

201

48

7F

Etan

erce

pt

RA

Hyd

roxy

chlo

roq

uin

eLi

ster

ia m

on

ocy

tog

enes

Rh

om

be

nce

ph

alit

is-

Dea

th

Mir

and

a-B

auti

sta[3

5]2

014

47

MC

erto

lizu

mab

CD

Co

rtic

ost

ero

ids

List

eria

mo

no

cyto

gen

esB

acte

rem

iaG

enta

mic

in,

amp

icill

inR

eco

very

Ran

a[36]

201

47

5M

Infl

ixim

abU

C-

List

eria

mo

no

cyto

gen

esB

acte

rem

ia

Men

ingi

tis

Gen

tam

icin

, m

ero

pen

em,

rifa

mp

icin

Rec

ove

ry

Ab

reu

[37]

201

35

1F

Infl

ixim

abU

CSt

ero

ids

List

eria

mo

no

cyto

gen

esM

enin

goen

cep

hal

i-ti

s B

acte

rem

iaA

mp

icill

in 2

8d

Rec

ove

ry

69

MIn

flix

imab

UC

Pre

dn

iso

lon

eLi

ster

ia m

on

ocy

tog

enes

Bac

tere

mia

M

enin

giti

sG

enta

mic

in 7

d,

amp

icill

in 2

1d

Rec

ove

ry

Bru

min

hen

t[38]

201

35

6M

Etan

erce

pt

RA

nd

List

eria

mo

no

cyto

gen

esC

ho

lecy

stit

isA

mp

icill

in 5

d(I

V)

Am

oxi

clav

4w

(o)

Rec

ove

ry

Will

son

[39]

201

25

8M

Ad

alim

um

abC

D6

-mer

cap

top

uri

ne,

p

red

nis

on

eLi

ster

ia m

on

ocy

tog

enes

Men

ingi

tis

Ben

zylp

enic

illin

14

d(I

V)

Co

-tri

mo

xazo

le6

w(o

)

Rec

ove

ry

Ch

uan

g[40]

201

01

7M

Infl

ixim

abU

C6

-mer

cap

top

uri

ne,

p

red

nis

olo

ne

List

eria

mo

no

cyto

gen

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acte

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ia

Men

ingi

tis

Mer

op

enem

, ge

nta

mic

in,

rifa

mp

icin

21

d

Rec

ove

ry

Kat

san

os[4

1]2

010

76

MIn

flix

imab

UC

Met

hyl

pre

dn

iso

lon

eLi

ster

ia m

on

ocy

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enes

Bac

tere

mia

Gen

tam

icin

10

d,

amp

icill

in 1

4d

(IV

)R

eco

very

Kel

esid

is[4

2]2

010

47

FIn

flix

imab

Pso

riat

icar

thri

tis

nd

List

eria

mo

no

cyto

gen

esB

acte

rem

ia

End

oca

rdit

isA

mp

icill

in 2

8d

Rec

ove

ry

Ram

os[4

3]2

010

50

FIn

flix

imab

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Men

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tis

Co

-tri

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wR

eco

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Slif

man

[64]

200

38

0M

Infl

ixim

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red

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on

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on

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M

enin

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74

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List

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73

FIn

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74

FIn

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73

MIn

flix

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64

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39

FIn

flix

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Dea

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le2

(co

nti

nu

atio

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ctio

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List

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atie

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anti

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rugs

Re

fere

nce

Ye

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fect

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of

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7]2

005

65

MEt

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red

nis

on

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on

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enes

Sep

tic

arth

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nti

bio

tics

Join

td

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8]2

005

54

FEt

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A-

List

eria

mo

no

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car

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tis

Am

pic

illin

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very

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iam

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Etan

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28

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2]2

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57

MIn

flix

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200

34

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Infl

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-tri

mo

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[64]

200

38

0M

Infl

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on

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on

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M

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flix

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List

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flix

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FIn

flix

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MIn

flix

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72

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on

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Dea

th

58

Ta

ble

2 (

con

tin

uat

ion

III):

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he

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rio

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ctio

ns

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List

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atie

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rugs

Re

fere

nce

Ye

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of

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nt

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Twee

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Zaks

[65]

200

35

5F

Infl

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TX, p

red

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ster

ia m

on

ocy

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Bac

tere

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Gen

tam

icin

, am

pic

illin

Rec

ove

ry

48

MIn

flix

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-Li

ster

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on

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Sp

len

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sces

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Gen

tam

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pic

illin

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etro

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Rec

ove

ry

Glü

ck[6

6]2

002

60

FIn

flix

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MTX

, pre

dn

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e,

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List

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mo

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ia

Men

ingo

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cyst

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ron

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Dea

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62

FIn

flix

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, CsA

List

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rem

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Bra

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, am

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illin

18

wR

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ath

[67]

200

21

7F

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p

red

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on

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tere

mia

M

enin

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in, c

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)R

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very

Mo

relli

[68]

200

06

7M

Infl

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DA

zath

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e,

pre

dn

iso

ne

List

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mo

no

cyto

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acte

rem

iaB

road

-sp

ectr

um

anti

bio

tics

2d

(IV

) A

mo

xicl

av2

w(o

)

Rec

ove

ry

Tab

le2

(co

nti

nu

atio

nIII

): P

ub

lish

ed

seri

ou

sin

fect

ion

sb

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ster

iain

pat

ien

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kin

gan

ti-T

NF

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gs

Re

fere

nce

Ye

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FIn

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on

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of

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200

35

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red

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ster

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on

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Gen

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icin

, am

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Rec

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48

MIn

flix

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ster

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sces

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etro

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6]2

002

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flix

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List

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Men

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Dea

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62

FIn

flix

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, CsA

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Gen

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18

wR

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[67]

200

21

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red

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ster

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on

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enes

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mia

M

enin

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sA

mp

icill

in, c

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trim

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zole

(IV

)R

eco

very

Mo

relli

[68]

200

06

7M

Infl

ixim

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DA

zath

iop

rin

e,

pre

dn

iso

ne

List

eria

mo

no

cyto

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acte

rem

iaB

road

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ectr

um

anti

bio

tics

2d

(IV

) A

mo

xicl

av2

w(o

)

Rec

ove

ry

Age

inye

ars.

5-A

SA: 5

-am

ino

salic

ylic

aci

d. A

S: a

nky

losi

ng

spo

nd

ylit

is. C

D: C

roh

n’s

dis

ease

. CsA

: cic

losp

ori

nA

. d: d

ays.

F: f

emal

e. IS

: im

mu

no

sup

pre

ssiv

e. IV

: in

trav

eno

us.

M: m

ale.

MTX

: met

ho

trex

ate.

n

d: n

o d

ata.

o: o

ral.

RA

: rh

eum

ato

idar

thri

tis.

UC

: ulc

erat

ive

colit

is. w

: wee

ks.

59

Tab

le3

: Pu

blis

he

dse

rio

us

infe

ctio

ns

by

Salm

on

ella

inp

atie

nts

taki

ng

anti

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rugs

Re

fere

nce

Ye

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geSe

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nti

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FIn

dic

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nC

on

com

itan

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dru

gsIn

fect

iou

sag

en

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pe

of

infe

ctio

nTr

eat

me

nt

Ou

tco

me

Eke[6

9]2

014

52

MA

dal

imu

mab

CD

6-m

erca

pto

pu

rin

eSa

lmo

nel

laC

ho

lera

esu

isB

acte

rem

iaC

eftr

iaxo

ne

1m

(IV

)R

eco

very

Nan

dag

ud

i[70]

201

44

3M

Cer

toliz

um

abR

A-

Salm

on

ella

Ente

riti

dis

Sep

tic

arth

riti

sC

ipro

flo

xaci

n1

w(o

) A

mo

xicl

av3

wR

eco

very

Bu

bo

nja

-So

nje

[71]

201

36

2F

Infl

ixim

abR

AM

TX, p

red

nis

on

eSa

lmo

nel

laEn

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tid

isSe

pti

car

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tis

Cef

tria

xon

e(I

V)

Rec

ove

ry

Co

rber

and

[72]

201

36

7M

Infl

ixim

abIB

D-

Salm

on

ella

ente

rica

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tere

mia

Ofl

oxa

cin

14

dR

eco

very

Sky[7

3]2

013

69

FEt

aner

cep

tR

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ydro

xich

loro

qu

ine

Salm

on

ella

Gro

up

DB

acte

rem

ia

Sep

tic

arth

riti

sC

ipro

flo

xaci

n3

m(o

)R

eco

very

Stei

neb

run

ner

[74]

201

33

1M

Infl

ixim

abC

DA

zath

iop

rin

eSa

lmo

nel

laen

teri

caN

TSU

rose

psi

sC

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ne

(IV

)R

eco

very

Qu

tre[7

5]2

012

48

MEt

aner

cep

tR

An

dSa

lmo

nel

laTy

ph

imu

riu

mB

acte

rem

iaO

xaci

llin

3w

Rec

ove

ry

Oe[7

6]2

011

61

MEt

aner

cep

tR

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TX,

met

hyl

pre

dn

iso

lon

eSa

lmo

nel

laEn

teri

tid

isSe

pti

car

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tis

Levo

flo

xaci

n2

w(o

) M

ino

cycl

ine

3m

(o)

Rec

ove

ry

Bas

sett

i[77]

201

05

4M

Infl

ixim

abR

AM

TX, p

red

nis

on

eSa

lmo

nel

laP

arat

yph

iB

acte

rem

ia

So

ftti

ssu

ein

fect

ion

Cef

tria

xon

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V)

Rec

ove

ry

Rim

[78]

201

06

8M

Infl

ixim

abC

Dn

dSa

lmo

nel

laEn

teri

tid

isSe

pti

car

thri

tis

Cef

tria

xon

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d(I

V)

Levo

flo

xaci

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mR

eco

very

Rijk

eb

oer

[79]

200

77

4M

Infl

ixim

abR

AM

TX, p

red

nis

on

eSa

lmo

nel

laEn

teri

tid

isB

acte

rem

ia

Ple

ura

l em

pye

ma

Am

oxi

cilli

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wD

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Mak

kun

i[50]

200

66

7F

Infl

ixim

abR

AM

TX, p

red

nis

olo

ne

Salm

on

ella

spSe

pti

car

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cin

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Rec

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0]2

005

52

FIn

flix

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nd

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1]2

004

39

MIn

flix

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tis

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him

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um

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cin

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Rec

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Net

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]2

003

62

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RA

nd

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Gro

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60

MIn

flix

imab

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nd

Salm

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Gro

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Dea

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Re

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9]2

014

52

MA

dal

imu

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CD

6-m

erca

pto

pu

rin

eSa

lmo

nel

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ho

lera

esu

isB

acte

rem

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eftr

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ne

1m

(IV

)R

eco

very

Nan

dag

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i[70]

201

44

3M

Cer

toliz

um

abR

A-

Salm

on

ella

Ente

riti

dis

Sep

tic

arth

riti

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mo

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very

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bo

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[71]

201

36

2F

Infl

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red

nis

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nel

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V)

Rec

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and

[72]

201

36

7M

Infl

ixim

abIB

D-

Salm

on

ella

ente

rica

Bac

tere

mia

Ofl

oxa

cin

14

dR

eco

very

Sky[7

3]2

013

69

FEt

aner

cep

tR

AH

ydro

xich

loro

qu

ine

Salm

on

ella

Gro

up

DB

acte

rem

ia

Sep

tic

arth

riti

sC

ipro

flo

xaci

n3

m(o

)R

eco

very

Stei

neb

run

ner

[74]

201

33

1M

Infl

ixim

abC

DA

zath

iop

rin

eSa

lmo

nel

laen

teri

caN

TSU

rose

psi

sC

eftr

iaxo

ne

(IV

)R

eco

very

Qu

tre[7

5]2

012

48

MEt

aner

cep

tR

An

dSa

lmo

nel

laTy

ph

imu

riu

mB

acte

rem

iaO

xaci

llin

3w

Rec

ove

ry

Oe[7

6]2

011

61

MEt

aner

cep

tR

AM

TX,

met

hyl

pre

dn

iso

lon

eSa

lmo

nel

laEn

teri

tid

isSe

pti

car

thri

tis

Levo

flo

xaci

n2

w(o

) M

ino

cycl

ine

3m

(o)

Rec

ove

ry

Bas

sett

i[77]

201

05

4M

Infl

ixim

abR

AM

TX, p

red

nis

on

eSa

lmo

nel

laP

arat

yph

iB

acte

rem

ia

So

ftti

ssu

ein

fect

ion

Cef

tria

xon

e(I

V)

Rec

ove

ry

Rim

[78]

201

06

8M

Infl

ixim

abC

Dn

dSa

lmo

nel

laEn

teri

tid

isSe

pti

car

thri

tis

Cef

tria

xon

e2

d(I

V)

Levo

flo

xaci

n6

mR

eco

very

Rijk

eb

oer

[79]

200

77

4M

Infl

ixim

abR

AM

TX, p

red

nis

on

eSa

lmo

nel

laEn

teri

tid

isB

acte

rem

ia

Ple

ura

l em

pye

ma

Am

oxi

cilli

n3

wD

eath

Mak

kun

i[50]

200

66

7F

Infl

ixim

abR

AM

TX, p

red

nis

olo

ne

Salm

on

ella

spSe

pti

car

thri

tis

Cip

rofl

oxa

cin

3w

(o)

Rec

ove

ry

Kat

saro

lis[8

0]2

005

52

FIn

flix

imab

RA

nd

Salm

on

ella

Ente

riti

dis

Sep

tic

arth

riti

sC

ipro

flo

xaci

n6

m(o

)R

eco

very

Fu[8

1]2

004

39

MIn

flix

imab

Pso

riat

icar

thri

tis

MTX

Salm

on

ella

Typ

him

uri

um

Bac

tere

mia

Cip

rofl

oxa

cin

10

d(I

V)

Rec

ove

ry

Net

ea[9

]2

003

62

FA

dal

imu

mab

RA

nd

Salm

on

ella

Gro

up

DB

acte

rem

ia

Sep

tic

arth

riti

sC

ipro

flo

xaci

nR

eco

very

60

MIn

flix

imab

RA

nd

Salm

on

ella

Gro

up

DB

acte

rem

iaC

ipro

flo

xaci

n(I

V)

Dea

th

Age

inye

ars.

CD

: Cro

hn’s

dis

ease

. d: d

ays.

F: f

emal

e. IB

D: i

nfl

amm

ato

ryb

ow

eld

isea

se. I

S: im

mu

no

sup

pre

ssiv

e. IV

: in

trav

eno

us.

m: m

on

ths.

M: m

ale.

MTX

: met

ho

trex

ate.

nd

: no

dat

a. o

: ora

l.

R

A: r

heu

mat

oid

arth

riti

s. w

: wee

ks.

ANEXOS