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

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.

The effect of drug dose and timing of treatment on the emergence of drug resistancein vivoin a malaria model

“…For example, small differences in the growth rate between resistant mutants and wild type parasites can reduce genetic diversity over time [46]. The few in vivo tests of which we are aware [38,39,[47][48][49][50] involved early or late drug treatment or infections initiated with small or large inocula [39,49]. In these binary cases, resistance typically emerged less readily if infections were treated early or had fewer pathogens to begin with, consistent with the idea that larger populations are more likely to contain resistant mutants.…”

Can oral group medication be improved to reduce antimicrobial use?

“…It has been shown that metaphylactic treatments are associated with higher cure rates than curative treatments administered when animals are already exhibiting clinical signs of disease. 2,3 However, the European guidelines for the prudent use of antimicrobials in veterinary medicine 4 highlight treatment via feed and drinking water as a major concern in the development of antimicrobial resistance.…”

The pharmacokinetic/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: Recent advances and critical appraisal

“…When the delay between onset of bacteriological challenge and AMD treatment is reduced, the concentration–effect relationship is shifted to the left; drug potency is then increased with the lower bacterial load. This has been established both in rodent models (Ferran et al., 2011; Vasseur et al., 2014, 2017) and in target species studies such as the calf model of bacterial infection (Lhermie et al., 2016). Thus, lower AMD doses can be clinically more efficacious in the pre‐patent phase of infection than subsequently, when animals display clinical signs.…”