Purpose: Colistin heteroresistance mediates the failure of antibiotic treatments, is prone to lead to colistin resistance, and has been frequently reported in Klebsiella pneumoniae. This study investigated origins of the increase in colistin resistance following colistin exposure to colistin-heteroresistant K. pneumoniae. Methods: A modeled colistin-heteroresistant K. pneumoniae strain (i.e., mimicking colistin- heteroresistant [m-CLHR]) was generated using a susceptible K. pneumoniae strain ATCC 10031 and its resistance-induced mutant. Heteroresistance patterns were investigated through population analysis profiling (PAP), competition assays, and fluctuation and stability tests. An in vitro time-killing assay for colistin was performed for the m-CLHR to identify the change in susceptible and resistant populations before and after colistin exposure. Results: The generated m-CLHR strain showed a typical heteroresistance pattern for colistin in PAP, and its competition assay did not show fitness costs for any population. The ratio of resistant cells to susceptible cells did not deviate significantly from the range of heteroresistance in the fluctuation test, while the ratios of resistant cells preserved their stability. The in vitro time-killing assay thus showed that the resistant cells increased upon colistin exposure; sequencing analyses confirmed that the surviving resistant cells did not originate from susceptible cells by mutation. This study successfully modeled a colistin-heteroresistant K. pneumoniae strain, i.e., m-CLHR. Conclusion In this modeled heteroresistant strain, only the colistin-resistant population survived the colistin treatment—this suggests that the development of colistin resistance from heteroresistant strain is because of the selection of a resistant population and not by the induction of resistance through mutations in susceptible populations.

Purpose: Colistin heteroresistance mediates the failure of antibiotic treatments, is prone to lead to colistin resistance, and has been frequently reported in Klebsiella pneumoniae. This study investigated origins of the increase in colistin resistance following colistin exposure to colistin-heteroresistant K. pneumoniae. Methods: A modeled colistin-heteroresistant K. pneumoniae strain (i.e., mimicking colistin- heteroresistant [m-CLHR]) was generated using a susceptible K. pneumoniae strain ATCC 10031 and its resistance-induced mutant. Heteroresistance patterns were investigated through population analysis profiling (PAP), competition assays, and fluctuation and stability tests. An in vitro time-killing assay for colistin was performed for the m-CLHR to identify the change in susceptible and resistant populations before and after colistin exposure. Results: The generated m-CLHR strain showed a typical heteroresistance pattern for colistin in PAP, and its competition assay did not show fitness costs for any population. The ratio of resistant cells to susceptible cells did not deviate significantly from the range of heteroresistance in the fluctuation test, while the ratios of resistant cells preserved their stability. The in vitro time-killing assay thus showed that the resistant cells increased upon colistin exposure; sequencing analyses confirmed that the surviving resistant cells did not originate from susceptible cells by mutation. This study successfully modeled a colistin-heteroresistant K. pneumoniae strain, i.e., m-CLHR. Conclusion In this modeled heteroresistant strain, only the colistin-resistant population survived the colistin treatment—this suggests that the development of colistin resistance from heteroresistant strain is because of the selection of a resistant population and not by the induction of resistance through mutations in susceptible populations.

Purpose: Colistin heteroresistance mediates the failure of antibiotic treatments, is prone to lead to colistin resistance, and has been frequently reported in Klebsiella pneumoniae. This study investigated origins of the increase in colistin resistance following colistin exposure to colistin-heteroresistant K. pneumoniae. Methods: A modeled colistin-heteroresistant K. pneumoniae strain (i.e., mimicking colistin- heteroresistant [m-CLHR]) was generated using a susceptible K. pneumoniae strain ATCC 10031 and its resistance-induced mutant. Heteroresistance patterns were investigated through population analysis profiling (PAP), competition assays, and fluctuation and stability tests. An in vitro time-killing assay for colistin was performed for the m-CLHR to identify the change in susceptible and resistant populations before and after colistin exposure. Results: The generated m-CLHR strain showed a typical heteroresistance pattern for colistin in PAP, and its competition assay did not show fitness costs for any population. The ratio of resistant cells to susceptible cells did not deviate significantly from the range of heteroresistance in the fluctuation test, while the ratios of resistant cells preserved their stability. The in vitro time-killing assay thus showed that the resistant cells increased upon colistin exposure; sequencing analyses confirmed that the surviving resistant cells did not originate from susceptible cells by mutation. This study successfully modeled a colistin-heteroresistant K. pneumoniae strain, i.e., m-CLHR. Conclusion In this modeled heteroresistant strain, only the colistin-resistant population survived the colistin treatment—this suggests that the development of colistin resistance from heteroresistant strain is because of the selection of a resistant population and not by the induction of resistance through mutations in susceptible populations.

Purpose: Colistin heteroresistance mediates the failure of antibiotic treatments, is prone to lead to colistin resistance, and has been frequently reported in Klebsiella pneumoniae. This study investigated origins of the increase in colistin resistance following colistin exposure to colistin-heteroresistant K. pneumoniae. Methods: A modeled colistin-heteroresistant K. pneumoniae strain (i.e., mimicking colistin- heteroresistant [m-CLHR]) was generated using a susceptible K. pneumoniae strain ATCC 10031 and its resistance-induced mutant. Heteroresistance patterns were investigated through population analysis profiling (PAP), competition assays, and fluctuation and stability tests. An in vitro time-killing assay for colistin was performed for the m-CLHR to identify the change in susceptible and resistant populations before and after colistin exposure. Results: The generated m-CLHR strain showed a typical heteroresistance pattern for colistin in PAP, and its competition assay did not show fitness costs for any population. The ratio of resistant cells to susceptible cells did not deviate significantly from the range of heteroresistance in the fluctuation test, while the ratios of resistant cells preserved their stability. The in vitro time-killing assay thus showed that the resistant cells increased upon colistin exposure; sequencing analyses confirmed that the surviving resistant cells did not originate from susceptible cells by mutation. This study successfully modeled a colistin-heteroresistant K. pneumoniae strain, i.e., m-CLHR. Conclusion In this modeled heteroresistant strain, only the colistin-resistant population survived the colistin treatment—this suggests that the development of colistin resistance from heteroresistant strain is because of the selection of a resistant population and not by the induction of resistance through mutations in susceptible populations.

Purpose: This study aimed to evaluate the effects of bladder cuff method on oncological outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma. Materials and Methods: The records of 1,095 patients treated with RNU performed at our hospital between 1994 and 2018 were retrospectively reviewed; 856 patients with no bladder tumor history were enrolled in the present study. The management of bladder cuff was divided into two categories: extravesical ligation (EL) or transvesical resection (TR). Survival was analyzed using the Kaplan-Meier method and Cox regression analyses were performed to determine which factors were associated with intravesical recurrence (IVR)–free survival (IVRFS), cancer-specific survival (CSS), and overall survival (OS). Results: The mean patient age was 64.8 years and the median follow-up was 37.7 months. Among the 865 patients, 477 (55.7%) underwent the TR and 379 (44.3%) the EL. Significantly higher IVRFS (p=0.001) and OS (p=0.013) were observed in the TR group. In multivariable analysis, IVR, CSS, and OS were independently associated with the EL. Among 379 patients treated with the EL, eight underwent remnant ureterectomy. Based on radical cystectomy–free survival, significant difference was not observed between the two groups. However, significantly higher IVRFS was observed in the TR group when the tumor was located in the renal pelvis. Conclusion Intramural complete excision of the distal ureter during RNU should be the gold standard approach compared with EL for the management of distal ureter in terms of oncological outcomes.

Purpose: This study aimed to evaluate the effects of bladder cuff method on oncological outcomes in patients who underwent radical nephroureterectomy (RNU) for upper tract urothelial carcinoma. Materials and Methods: The records of 1,095 patients treated with RNU performed at our hospital between 1994 and 2018 were retrospectively reviewed; 856 patients with no bladder tumor history were enrolled in the present study. The management of bladder cuff was divided into two categories: extravesical ligation (EL) or transvesical resection (TR). Survival was analyzed using the Kaplan-Meier method and Cox regression analyses were performed to determine which factors were associated with intravesical recurrence (IVR)–free survival (IVRFS), cancer-specific survival (CSS), and overall survival (OS). Results: The mean patient age was 64.8 years and the median follow-up was 37.7 months. Among the 865 patients, 477 (55.7%) underwent the TR and 379 (44.3%) the EL. Significantly higher IVRFS (p=0.001) and OS (p=0.013) were observed in the TR group. In multivariable analysis, IVR, CSS, and OS were independently associated with the EL. Among 379 patients treated with the EL, eight underwent remnant ureterectomy. Based on radical cystectomy–free survival, significant difference was not observed between the two groups. However, significantly higher IVRFS was observed in the TR group when the tumor was located in the renal pelvis. Conclusion Intramural complete excision of the distal ureter during RNU should be the gold standard approach compared with EL for the management of distal ureter in terms of oncological outcomes.