Tebipenem as an oral alternative for the treatment of typhoid caused by XDR Salmonella Typhi.

Elli Mylona,Judd Walson,Lluis Ballell,Stephen Baker,Abhilasha Karkey,Farah Qamar,Sonia Qureshi,Elena Fernández Álvaro,Sabina Dongol,Tuyen Ha Thanh,Phat Voong Vinh

doi:10.1093/jac/dkab326

Elli Mylona, Judd Walson + Show 9 more

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https://doi.org/10.1093/jac/dkab326

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Abstract

BackgroundAntimicrobial therapy is essential for the treatment of enteric fever, the infection caused by Salmonella serovars Typhi and Paratyphi A. However, an increase in resistance to key antimicrobials and the emergence of MDR and XDR in Salmonella Typhi poses a major threat for efficacious outpatient treatments.ObjectivesWe recently identified tebipenem, an oral carbapenem licensed for use for respiratory tract infections in Japan, as a potential alternative treatment for MDR/XDR Shigella spp. Here, we aimed to test the in vitro antibacterial efficacy of this drug against MDR and XDR typhoidal Salmonella.MethodsWe determined the in vitro activity of tebipenem in time–kill assays against a collection of non-XDR and XDR Salmonella Typhi and Salmonella Paratyphi A (non-XDR) isolated in Nepal and Bangladesh. We also tested the efficacy of tebipenem in combination with other antimicrobials.ResultsWe found that both XDR and non-XDR Salmonella Typhi and Salmonella Paratyphi A are susceptible to tebipenem, exhibiting low MICs, and were killed within 8–24 h at 2–4×MIC. Additionally, tebipenem demonstrated synergy with two other antimicrobials and could efficiently induce bacterial killing.Conclusions Salmonella Paratyphi A and XDR Salmonella Typhi display in vitro susceptibility to the oral carbapenem tebipenem, while synergistic activity with other antimicrobials may limit the emergence of resistance. The broad-spectrum activity of this drug against MDR/XDR organisms renders tebipenem a good candidate for clinical trials.

Highlights

Antimicrobial resistance poses a major threat for enteric fever treatment, as well as infections caused by other Gramnegative bacteria, such as Shigella spp. and pathogenic Escherichia coli.[1]
To determine the repurposing potential of tebipenem for typhoidal Salmonella, we measured the inhibitory activity of this compound against a collection of 100 clinical non-XDR and XDR Salmonella Typhi and non-XDR Salmonella Paratyphi A from Pakistan and Nepal
Identifying that all organisms were susceptible to tebipenem, we selected two isolates (Salmonella Typhi 01TY257 and Salmonella Paratyphi A 02TY224) to further investigate the bactericidal effect of tebipenem on typhoidal Salmonella

Summary

Introduction

Antimicrobial resistance poses a major threat for enteric (typhoid) fever treatment, as well as infections caused by other Gramnegative bacteria, such as Shigella spp. and pathogenic Escherichia coli.[1] Enteric fever is a life-threatening systemic disease caused by Salmonella enterica serovar Typhi and the various pathovars of Salmonella Paratyphi (A, B and C). Enteric fever remains a public health problem in many countries in South Asia and sub-Saharan Africa with poor sanitation, resulting in an estimated global incidence of >14 million cases and >135 000 deaths annually.[2]. Antimicrobial therapy is essential for the treatment of enteric fever, the infection caused by Salmonella serovars Typhi and Paratyphi A. An increase in resistance to key antimicrobials and the emergence of MDR and XDR in Salmonella Typhi poses a major threat for efficacious outpatient treatments

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