Detection and characterization of tigecycline heteroresistance in <i>E. cloacae</i>: clinical and microbiological findings

Tigecycline is regarded as a last-resort treatment for carbapenem-resistant Enterobacteriaceae (CRE), however, the emergence of tigecycline heteroresistance has posted the therapeutic challenge to combat this “nightmare bacteria”. The primary purpose of this study was to demonstrate the existence of tigecycline heteroresistance in carbapenem-resistant E. cloacae (TH-CRECL) and further to explore the epidemiological characteristics and underlying molecular mechanisms. Our study identified a relative low prevalence of carbapenem-resistant E. cloacae (CRECL) isolates, about 20.0% (28/140), as heteroresistance to tigecycline. Molecular genetic relatedness of these heteroresistant isolates were characterized epidemiologically sporadic. In addition, mechanistic analysis revealed that Phe-Arg-β-naphthylamide (PAβN) significantly reversed tigecycline MIC levels of resistant colonies in heteroresistant strains, as primarily related to the marked overproduction of efflux pump genes acrAB and oqxAB, as well as overexpression of transcriptional regulators (soxS and ramA). Moreover, logistic regression analysis showed that previous fluoroquinolone therapy was identified as the only potential independent risk factor for the acquisition of TH-CRECL. Most importantly, our data indicated that patients with TH-CRECL infection might lead to a remarkably prolonged hospital stay and deterioration in functional status. These findings emphasized the necessity of timely detection and intervention of patients infected with TH-CRECL.