Corticosteroid-Induced Immunosuppression Ultimately Does Not Compromise the Efficacy of Antibiotherapy in Murine Mycobacterium ulcerans Infection

Abstract

BackgroundBuruli ulcer (BU) is a necrotizing disease of the skin, subcutaneous tissue and bone caused by Mycobacterium ulcerans. It has been suggested that the immune response developed during the recommended rifampicin/streptomycin (RS) antibiotherapy is protective, contributing to bacterial clearance. On the other hand, paradoxical reactions have been described during or after antibiotherapy, characterized by pathological inflammatory responses. This exacerbated inflammation could be circumvented by immunosuppressive drugs. Therefore, it is important to clarify if the immune system contributes to bacterial clearance during RS antibiotherapy and if immunosuppression hampers the efficacy of the antibiotic regimen.Methodology/Principal FindingsWe used the M. ulcerans infection footpad mouse model. Corticosteroid-induced immunosuppression was achieved before experimental infection and maintained during combined RS antibiotherapy by the administration of dexamethasone (DEX). Time-lapsed analyses of macroscopic lesions, bacterial burdens, histology and immunohistochemistry were performed in M. ulcerans-infected footpads. We show here that corticosteroid-immunosuppressed mice are more susceptible to M. ulcerans, with higher bacterial burdens and earlier ulceration. Despite this, macroscopic lesions remised during combined antibiotic/DEX treatment and no viable bacteria were detected in the footpads after RS administration. This was observed despite a delayed kinetics in bacterial clearance, associated with a local reduction of T cell and neutrophil numbers, when compared with immunocompetent RS-treated mice. In addition, no relapse was observed following an additional 3 month period of DEX administration.Conclusions/SignificanceThese findings reveal a major role of the RS bactericidal activity for the resolution of M. ulcerans experimental infections even during immunosuppression, and support clinical investigation on the potential use of corticosteroids or other immunosuppressive/anti-inflammatory drugs for the management of BU patients undergoing paradoxical reactions.

Microbiological, Histological, Immunological, and Toxin Response to Antibiotic Treatment in the Mouse Model of Mycobacterium ulcerans Disease

“…This suggests either that viable organisms persisted for more than 5 weeks after antibiotics were started or that mycolactone could still be detected some time after M. ulcerans had been killed. The latter is supported by the observations that no viable M. ulcerans were detected in mouse footpads after antibiotic treatment, similar to that used here, followed by a course of corticosteroid therapy [24], [38] but we did not use the very recently described 16S rRNA assay to determine if viable organisms were still present [39].…”

ProgressiveMycobacterium abscessuslung infection in C3HeB/FeJ mice associated with corticosteroid administration

“…Corticosteroid regimens and study design for Study 1 and Study 2 are outlined in Tables 1 and 2, respectively. Cortisone (Sigma-Aldrich C2755) and dexamethasone (Sigma-Aldrich D1756) were dissolved in sterile 1x phosphate buffered saline, pH 7.4 (Quality Biological, 114-058-101) and administered by sub-cutaneous injection, 200 µL bolus using 26 gauge syringe, as described previously 34,36,38,39 .…”

“…This hypothesis of the use of corticosteroids for immune suppression was based on epidemiological studies describing corticosteroid use as a risk factor for development of invasive infections with rapidly-growing mycobacteria 31–33 . Of note in in vivo studies, a study evaluating efficacy of antibiotic treatment against M. ulcerans , another nontuberculous mycobacteria, in mice in the setting of concurrent dexamethasone use found that corticosteroid use prior to infection resulted in increased bacterial burdens and higher degrees of pathology compared to control 34 . Additionally, studies using the Cornell model of latent tuberculosis 35 have assessed rates of reactivation of latent tuberculosis in the setting of corticosteroid use 36 .…”

Problematic Management of Buruli Ulcer and HIV Co-infection in Tropical Regions

“…The use of corticosteroid agents to reduce these paradoxical reactions was reported by several authors, and evidence from mouse model suggested that cortisteroids use does not lead to BU treatment failure [8].…”