Low or High Doses of Cefquinome Targeting Low or High Bacterial Inocula Cure Klebsiella pneumoniae Lung Infections but Differentially Impact the Levels of Antibiotic Resistance in Fecal Flora

Abstract

ABSTRACTThe combination of efficacious treatment against bacterial infections and mitigation of antibiotic resistance amplification in gut microbiota is a major challenge for antimicrobial therapy in food-producing animals. In rats, we evaluated the impact of cefquinome, a fourth-generation cephalosporin, on bothKlebsiella pneumoniaelung infection and intestinal flora harboring CTX-M-producingEnterobacteriaceae. Germfree rats received a fecal flora specimen from specific-pathogen-free pigs, to which a CTX-M-producingEscherichia colistrain had been added.K. pneumoniaecells were inoculated in the lungs of these gnotobiotic rats by using either a low (105CFU) or a high (109CFU) inoculum. Without treatment, all animals infected with the low or highK. pneumoniaeinoculum developed pneumonia and died before 120 h postchallenge. In the treated groups, the low-inoculum rats received a 4-day treatment of 5 mg/kg of body weight cefquinome beginning at 24 h postchallenge (prepatent phase of the disease), and the high-inoculum rats received a 4-day treatment of 50 mg/kg cefquinome beginning when the animals expressed clinical signs of infection (patent phase of the disease). The dose of 50 mg/kg targeting the highK. pneumoniaeinoculum cured all the treated rats and resulted in a massive amplification of CTX-M-producingEnterobacteriaceae. A dose of 5 mg/kg targeting the lowK. pneumoniaeinoculum cured all the rats and averted an outbreak of clinical disease, all without any amplification of CTX-M-producingEnterobacteriaceae. These findings might have implications for the development of new antimicrobial treatment strategies that ensure a cure for bacterial infections while avoiding the amplification of resistance genes of human concern in the gut microbiota of food-producing animals.