Recent Advances in Understanding the Clinical Implications of Heterogeneous Drug Resistance in Klebsiella pneumoniae

Jianhua Fang,1,2,* Hongyi Lai,3,* Huade Chen,1,2,* Zhibo Tao,4 Na Cheng,1,2 Tianxin Xiang1,2,5 1Infectious Disease Department, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330052, People’s Republic of China; 2Jiangxi Provincial Key Laboratory of Prevention and Treatment of Infectious Diseases, First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330052, People’s Republic of China; 3The First Clinical Medical College, Jiangxi Medical College, Nanchang University, Nanchang, 330006, People’s Republic of China; 4Clinical Laboratory Section, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330052, People’s Republic of China; 5Jiangxi Medical Center for Critical Public Health Events, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330052, People’s Republic of China*These authors contributed equally to this workCorrespondence: Tianxin Xiang, Email [email protected] Na Cheng, Email [email protected]: Klebsiella pneumoniae (KP), a clinically significant Gram-negative opportunistic pathogen, has emerged as one of the predominant causative agents of hospital-acquired infections (HAIs). This bacterium is responsible for various severe clinical manifestations, including pneumonia, urinary tract infections, bloodstream infections, and sepsis. In recent years, the global prevalence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) K. pneumoniae strains has been escalating rapidly. Epidemiological surveillance data reveal a persistent upward trend in infections caused by MDR microorganisms worldwide, a phenomenon disproportionately prevalent in resource-limited developing countries. This trend presents formidable challenges to clinical infection management and constitutes a critical threat to global public health security. In the context of bacterial antibiotic resistance, the phenomenon of heteroresistance (HR) has attracted growing scientific attention due to its unique clinical significance. HR is characterized by the coexistence of subpopulations within a clonal (ie, genetically similar) bacterial population that exhibit divergent susceptibility profiles to an antimicrobial agent. This subtle phenotypic heterogeneity is considered a crucial precursor to the development of stable, high-level antibiotic resistance, representing a pivotal transitional phase in the evolution of MDR. The clinical importance of HR is twofold: first, the resistant subpopulations are often missed by conventional antimicrobial susceptibility testing, potentially leading to unexpected treatment failure. Second, HR serves as an early warning indicator for the impending emergence of complete resistance.Keywords: heterogeneous drug resistance, Klebsiella pneumoniae, clinical research