Effect of achieving bone sterilisation on bone architecture and bone marrow, in an experimental rabbit model of osteomyelitis caused by carbapenemase-producing Enterobacterales

Abstract

Natural history and treatment of bone infections caused by carbapenemase-producing Enterobacterales (CPE) are poorly defined. We evaluated the effect of treatment on the progression of subacute osteomyelitis in a rabbit model. Two isolates were used: a KPC-producing Klebsiella pneumoniae and an Escherichia coli harbouring blaOXA-48 and blaCTX-M15 inserts, both susceptible to gentamicin, colistin, fosfomycin, and ceftazidime-avibactam. Osteomyelitis was induced in rabbits by tibial injection of 2×108 colony-forming units/mL. Antibiotics were started 14 d later, for 7 d, in 6 groups of 12 rabbits. Three days after treatment completion (D24), rabbits were euthanised and bones were cultured. Bone marrow and bone architecture macroscopic changes were evaluated through analysis of pictures by investigators unaware of the rabbit treatment group and microbiological outcome, using scales ranging from 0 (normal) to 3 (severe lesions) depending on modifications. Bone marrow modifications induced by local infection were similar between prematurely deceased animals and non-sterilised animals (P=0.14) but differed significantly from animals that achieved bone sterilisation after treatment (P=0.04). Conversely, when comparing bone deformity, rabbits who died early (n=13) had similar bone architecture as those achieving bone sterilisation (P=0.12), as opposed to those not sterilised after treatment (P=0.04). After a multivariate logistic regression, bone marrow scale ≤2 was associated with bone sterilisation (P < 0.001), and bone architecture scale ≤2 was associated with bone sterilisation (adjusted odds ratio=2.7; 95% confidence interval 1.14-6.37) and KPC infection (adjusted odds ratio=5.1; 95% confidence interval 2.17-12.13). Effective antibacterial treatment reduces bone architecture distortion and bone marrow changes. These variables may be used as proxy for bone sterilisation.