Infection-stage adjusted dose of beta-lactams for parsimonious and efficient antibiotic treatments: A Pasteurella multocida experimental pneumonia in mice.

Maleck V. Vasseur,Marlene Z. Lacroix,Pierre-Louis Toutain,Alain Bousquet-Melou,Aude A. Ferran,Brenda A Wilson

doi:10.1371/journal.pone.0182863

Abstract

In this study, the impact of infection stage on clinically and microbiologically efficacious doses and on antibiotic consumption was assessed during a naturally evolving infectious disease, using an original mouse model of pulmonary infection produced by air-borne contamination. When Pasteurella multocida was administered as pathogenic agent to immunocompetent mice, 60% of the animals exhibited clinical symptoms of pneumonia 2 to 4 days after bacterial contamination of the lungs. Two beta-lactam antibiotics were evaluated: amoxicillin and cefquinome, a fourth generation cephalosporin developed for food animals. First, a pharmacokinetic study was performed in infected mice to determine the exposure to amoxicillin or cefquinome required to treat clinically affected animals, based on the targeted values of PK/PD indices for beta-lactams. We then confirmed that these doses resulted in a 100% clinical cure rate in animals exhibiting clinical signs of infection and harboring a high pathogenic inoculum. More interestingly, we also showed that the same 100% clinical cure could be obtained in our model with 10-fold lower doses in animals at pre-patent stages of infection i.e. when harboring a low pathogenic inoculum. At the group level, antimicrobial drug consumption was reduced by treating animals at an early stage of the infection course with a pre-patent tailored dose. These results suggest that early treatment with a dose suitably adjusted to the stage of infection might help to reduce both overall antibiotic consumption and resistance selection pressure in the animals and in the environment.

Highlights

Bacterial resistance to antimicrobials has become a worldwide problem and an increasing threat to human health
We have already shown that the low doses of cefquinome, a fourth generation cephalosporin, sufficient to eradicate a low inoculum of Klebsiella pneumoniae in a rat model of infection led to lower selection of intestinal E. coli carrying Extended Spectrum Beta-Lactamase (ESBL) [12]
We assessed the effects of different infection-stage adjusted doses on clinical and microbiological outcomes by developing an original model of pneumonia in immunocompetent mice using Pasteurella multocida, which is one of the main pathogens responsible for respiratory diseases and pneumonia in cattle, swine and poultry

Summary

Introduction

Bacterial resistance to antimicrobials has become a worldwide problem and an increasing threat to human health. We have already shown that the low doses of cefquinome, a fourth generation cephalosporin, sufficient to eradicate a low inoculum of Klebsiella pneumoniae in a rat model of infection led to lower selection of intestinal E. coli carrying Extended Spectrum Beta-Lactamase (ESBL) [12] These results support the hypothesis that, in the case of a low bacterial pathogen load, reducing the dose could simultaneously ensure a cure of the infection and avoid the selection and amplification of ESBL-carrying Enterobacteria in the gut microbiota. Metaphylaxis, the second approach, is more frequently adopted as an early BRD treatment and consists of treating the entire cohort of animals when only a few express clinical signs of BRD [18,19] This approach has the advantages of ensuring both a good survival rate of the cohort and ease of use [18] but, compared to the first individual approach, has the disadvantage of exposing animals to antibiotic consumption even when this is not required. This means that, with the metaphylaxis approach, drug consumption is probably higher than required to eradicate the pathogens

Objectives

Methods

Results

Conclusion