Heteroresistance to cefepime in Pseudomonas aeruginosa bacteraemia

Heteroresistance to antibiotic agents can lead to diagnostic and therapeutic failures; however, to date, cefepime heteroresistance (FEP-HR) in Pseudomonas aeruginosa (P. aeruginosa) bacteraemia has not been characterised. The primary goal of this study was to investigate the molecular epidemiology, mechanisms and risk factors for cefepime-heteroresistant P. aeruginosa bacteraemia over approximately 6 years in Southwest China. A high prevalence (57.3%) of heteroresistance to cefepime was observed during the study period, and these FEP-HR isolates were not clonally related. Mechanistic studies revealed that AmpC hyperproduction contributed to the development of this phenomenon. In addition, patients with advanced age, haematological malignancies, central venous catheters, and previous cephalosporin therapy were identified as independent risk factors for acquiring FEP-HR P. aeruginosa bacteraemia. Furthermore, patients infected with FEP-HR were generally at a greater risk for an adverse prognosis compared with those with non-FEP-HR. More importantly, characterisation of three successive P. aeruginosa isolates recovered from the same patient revealed that heteroresistance can act as an intermediate stage during the evolution from susceptibility to full resistance in patients undergoing antibiotic therapy for prolonged periods. These findings emphasised the necessity of antimicrobial stewardship programs in clinical settings, as well as the need for some rapid screening methods for detecting this phenomenon.