Effect of in vivo neutralization of tumor necrosis alpha on the efficacy of antibiotic treatment in systemic Salmonella enterica infections.

Omar Rossi,Pietro Mastroeni,Andrew J Grant

doi:10.1093/femspd/ftx002

Abstract

Immunity can co-operate with antibiotics, but can also antagonize drug efficacy by segregating the bacteria to areas of the body that are less accessible to antimicrobials, and by selecting for subpopulations with low division rates that are often difficult to eradicate. We studied the effect of an anti-inflammatory/immunosuppressive anti-TNFα treatment, which accelerates bacterial growth in the tissues and inhibits or reverses the formation of granulomas, on the efficacy of ampicillin and ciprofloxacin during a systemic Salmonella enterica infection of the mouse. The anti-TNFα treatment neither precluded nor enhanced the efficacy of antibiotic treatment. However, the anti-TNFα treatment rendered the animals susceptible to the rapid relapse of the infection seen after cessation of the antibiotic treatment. Reactivation of an established infection, due to late administration of anti-TNFα antibodies, could be successfully controlled by antibiotics, but full clearance of the bacterial load from the tissues was not achieved. We conclude that the lack of TNFα does not preclude the efficacy of antibiotic treatment and must be monitored with care due to post-treatment relapses. Combinations of anti-cytokine compounds and antibiotic molecules may not be the best way to treat persistent infections with intracellular bacteria like Salmonella.

Highlights

Salmonella enterica causes enteric systemic diseases, gastroenteritis and non-typhoidal septicaemia in humans and other animals worldwide and some serovars have zoonotic potential (Crump and Mintz 2010; Crump and Heyderman 2014; Crump et al 2015).Salmonella infections can be difficult to treat
We show that exacerbation or reactivation of Salmonella infections by anti-inflammatory/immunosuppressant treatment with anti-TNFα antibodies does not impair the ability of ampicillin or ciprofloxacin to reduce bacterial numbers in the tissues to levels similar to the ones obtained after treatment of immunocompetent animals
In anti-TNFα-treated animals, ampicillin or ciprofloxacin could prevent the escalation of the infection, which in the absence of antibiotic treatment would reach lethal bacterial numbers in the organs

Summary

Introduction

Salmonella enterica causes enteric systemic diseases (typhoid and paratyphoid fever), gastroenteritis and non-typhoidal septicaemia in humans and other animals worldwide and some serovars have zoonotic potential (Crump and Mintz 2010; Crump and Heyderman 2014; Crump et al 2015).Salmonella infections can be difficult to treat. Persistence of the bacteria in the tissues and relapses can occur upon cessation of the treatment, especially in immunodeficient individuals (Crump, Luby and Mintz 2004; Gordon 2011; Okoro et al 2012; Klemm et al 2016). This is a grave medical problem especially in areas of the world where comorbidities such as malaria, HIV and malnutrition impair the immune system leading to higher incidence of both acute and recurrent bacterial infections, despite appropriate antimicrobial therapy (Gordon et al 2002). Better approaches to clear chronic infections are needed as these lead to disease reservoirs that are detrimental to human and veterinary medicine and can favor the selection of antimicrobial-resistant populations.

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