Influence of tramadol on bacterial burden in the standard neutropenic thigh infection model

The neutropenic thigh infection model is one of the standard models in pharmacokinetic/ pharmacodynamic (PK/PD) characterization of novel antibacterials which are urgently needed due to the rise of antimicrobial resistance. The model enables to investigate PK/PD parameters crucial for translation of animal results towards humans. However, the neutropenic thigh infection model can result in moderate to severe discomfort of the animals, especially when high inocula are used. Tramadol has been proven to reduce pain effectively. This study investigates if tramadol influences the bacterial burden in the primary organ, the thighs, and organs affected by secondary seeding. Therefore, several strains of the ESKAPE pathogens, namely S. aureus, P. aeruginosa, K. pneumoniae, E. coli, A. baumannii and E. faecalis were examined. It was shown that tramadol did not influence the bacterial burden neither in thighs nor in organs affected by secondary seeding for the strains of E. faecalis, S. aureus, P. aeruginosa, K. pneumoniae and E.coli tested here, whereas secondary seeding seemed to be affected by tramadol for the tested strain of A. baumannii. Consequently, it was demonstrated that tramadol is an option to reduce discomfort in the untreated group for the strains of five out of the six tested ESKAPE pathogens and, thereby, contributes to the refinement of one of the standard PK/PD models.