Molecular Epidemiologic Factors Contributing to Guinolone Resistance in Clinical Multidrug-resistant Klebsiella Pneumoniae Isolates from Shanghai, China

Yan Wang,Guoping Cai, Jinan Zhang,Xiaogang Xu,Hongzhou Lu

semanticscholar（2021）

Fudan University | Fudan University Jinshan Hospital | Shanghai Jiankang Medical University | Fudan University Huashan Hospital Institute of Antibiotics | Fudan University Affiliated Public Health Clinical Center: Shanghai Public Health Clinical Center

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Abstract

Abstract Background : The soaring quinolone-resistance rate of Klebsiella pneumoniae , a common pathogen in immunocompromised individuals, has seriously undermined the wide applications of antimicrobials of this class. This study aimed to investigate the emerging key contributors to quinolone resistance in multidrug resistant K. pneumoniae (MDR-KP) isolates from a clinical setting with continuing point-source infection outbreaks. Methods : A total of 34 K. pneumoniae isolates, including 30 carbapenem-resistant K. pneumoniae (CRKP) isolates were randomly selected from a teaching hospital participating in an ongoing Bacterial Resistance Surveillance Project in Shanghai, China. Investigations included antimicrobial susceptibility tests, MLST and wzi -genotyping, PCR and DNA sequencing for identification of resistance determinants, sequence analyses using MEGA7.0 software, and clinical information retrieving through electronic medical records. Results : Two predominant high-risk resistant clones, ST11- wzi 64 and ST15- wzi 19/ wzi 24, from 30 CRKP isolates caused three point-source nosocomial outbreaks in intensive care unit and neurosurgery department potentially by respiratory-route, promoting the co-selection and evolution of multidrug resistant determinants. Multiple quinolone resistance-determining region (QRDR) mutations occurred in isolates of ST15 (S83F, D87A; S80I), ST11 (S83I, D87G; S80I), and ST218 (D87A; S80I). Plasmid-mediated quinolone resistance determinants, qnrS1 , aac(6’)-Ib-cr , oqxAB , were detected in 32 (94.1%) isolates alone or in combination, accompanied with β-lactamases, 16S rRNA methylases, and putrescine ABC permeases. AcrR, AcrAB transcriptional repressor, was insertion-inactivated by IS5-transposase in isolates of ST11. Thirteen ompK36 variants associated with specific ST (n=7) and wzi -allele (n=9) clustered into 10 (sub)lineages in the phylogenetic tree possibly affecting the MDR phenotype and infection outcome of isolates. Isolates of ST11, ST15, and ST218 had frameshift disruptions in OmpK35 coupled with specific GD-insertion at position 134-135 in OmpK36, all showing distinct microevolution clusters of ompK36 genotypes. Seven quinolone-susceptible isolates kept the porin genes integral, including two each CRKPs of ST13- wzi74 (carbapenemase KPC-2 and NDM-1-coproducers) and ST65- wzi72 . Conclusions : Under multiple selective pressures, accumulation of mutations of three types (QRDR, AcrR, OmpK36/OmpK35) and acquisition of resistance-conferring genes contribute to quinolone-resistance in clinical MDR-KP isolates, reinforcing the importance of continued epidemiologic surveillance on the evolution and transmission of these isolates. Our findings provided detailed mechanistic analyses and epidemiologic implications for further infection control and antibiotic stewardship initiatives.

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