Within-host spatiotemporal dynamics of systemic Salmonella infection during and after antimicrobial treatment.

O Rossi,A J Grant,D J Maskell,P Mastroeni,O Restif,R Dybowski

doi:10.1093/jac/dkx294

O Rossi, A J Grant + Show 4 more

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https://doi.org/10.1093/jac/dkx294

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Abstract

ObjectivesWe determined the interactions between efficacy of antibiotic treatment, pathogen growth rates and between-organ spread during systemic Salmonella infections.MethodsWe infected mice with isogenic molecularly tagged subpopulations of either a fast-growing WT or a slow-growing ΔaroC Salmonella strain. We monitored viable bacterial numbers and fluctuations in the proportions of each bacterial subpopulation in spleen, liver, blood and mesenteric lymph nodes (MLNs) before, during and after the cessation of treatment with ampicillin and ciprofloxacin.ResultsBoth antimicrobials induced a reduction in viable bacterial numbers in the spleen, liver and blood. This reduction was biphasic in infections with fast-growing bacteria, with a rapid initial reduction followed by a phase of lower effect. Conversely, a slow and gradual reduction of the bacterial load was seen in infections with the slow-growing strain, indicating a positive correlation between bacterial net growth rates and the efficacy of ampicillin and ciprofloxacin. The viable numbers of either bacterial strain remained constant in MLNs throughout the treatment with a relapse of the infection with WT bacteria occurring after cessation of the treatment. The frequency of each tagged bacterial subpopulation was similar in the spleen and liver, but different from that of the MLNs before, during and after treatment.ConclusionsIn Salmonella infections, bacterial growth rates correlate with treatment efficacy. MLNs are a site with a bacterial population structure different to those of the spleen and liver and where the total viable bacterial load remains largely unaffected by antimicrobials, but can resume growth after cessation of treatment.

Highlights

Bacterial diseases pose a grave threat for humankind, causing approximately six million deaths per year.[1]
Ampicillin showed a more marked effect on the overall reduction in viable bacterial numbers in the liver as compared with the spleen, while the effect of treatment with ciprofloxacin was similar in both organs (Table S7)
We showed that antimicrobial treatment fails to reduce viable bacterial numbers in mesenteric lymph nodes (MLNs) in contrast with the reduction in bacterial loads seen in the spleen, liver and blood

Summary

Introduction

Bacterial diseases pose a grave threat for humankind, causing approximately six million deaths per year.[1] Antibiotics are key weapons against bacterial infections. Antimicrobial treatment does not always result in the complete resolution of acute bacterial infections even when the pathogen retains susceptibility to the drugs used.[2,3] Post-treatment persistence of antibiotic-susceptible bacteria is increasingly being recognized as a situation of great medical importance and can lead to disease reservoirs, continued transmission and in some cases within-host relapses, especially in immune-deficient individuals.[2,4,5,6,7,8,9] The reasons why many antimicrobials are far less effective in vivo than in in vitro are difficult to explain. It is likely that key parameters of in vivo pathogen behaviour, such as location, division and spread within and between different organs, would have an impact on the therapeutic potential offered by antimicrobials.[10,11,12,13,14,15,16,17,18]

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