Clinical, biological and genome-wide comparison of carbapenem-resistant Klebsiella pneumoniae with susceptibility transformation to polymyxin B during therapy.

OBJECTIVES: The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major clinical concern, and polymyxin B (PMB) is a 'last resort' antibiotic for its treatment. Understanding the effects of drug susceptibility transformation in CRKP-infected patients undergoing PMB treatment would be beneficial to optimize PMB treatment strategies. METHODS: We retrospectively collected data from patients infected with CRKP and treated with PMB from January 2018 to December 2020. CRKPs were collected before and after PMB therapy, and patients were classified into the 'transformation' group (TG) and 'non-transformation' group (NTG) by the shift of susceptibility to PMB. We compared clinical characteristics between these groups, and further analysed the phenotypic and genome variation of CRKP after PMB susceptibility transformation. RESULTS: A total of 160 patients (37 in the TG and 123 in the NTG) were included in this study. The duration of PMB treatment before PMB-resistant K. pneumoniae (PRKP) appearance in TG was even longer than the whole duration of PMB treatment in NTG (8 [8] vs. 7 [6] days; p 0.0496). Compared with isogenic PMB-susceptible K. pneumoniae (PSKP), most PRKP strains had missense mutations in mgrB (12 isolates), yciC (10 isolates) and pmrB (7 isolates). The competition index of 82.4% (28/34) of PRKP/PSKP pairs was <67.6% (23/34), and 73.5% (25/34) of PRKP strains showed a higher 7-day lethality in Galleria mellonella and a greater ability to resist complement-dependent killing than their corresponding PSKP, respectively. CONCLUSION: Low dose with longer PMB treatment durations may be associated with the emergence of polymyxin resistance. The evolution of PRKP is predominantly mediated by an accumulation of mutations, including those in mgrB, yciC, and pmrB. Lastly, PRKP exhibited reduced growth and increased virulence compared with parental PSKP.

[Heavy metal pollution and comprehensive ecological risk assessment of surface soil in diffe-rent functional areas of Shenzhen, China]. / æ·±åœ³å¸‚ä¸åŒåŠŸèƒ½åŒºåœŸå£¤è¡¨å±‚é‡é‡‘å±žæ±¡æŸ“åŠå ¶ç»¼åˆç”Ÿæ€é£Žé™©è¯„ä»·.

To explore the impact of urban functional zones on surface soil metal pollution, we analyzed the concentrations and pollution status of eight heavy metals (i.e., Mn, Ni, Cr, Pb, Cd, Zn, Cu, and As) in surface soils from various urban functional zones of Shenzhen City. Nemero index and potential ecological hazard indices were used to quantify the ecological risk levels of different heavy metals in different urban functional zones. Moreover, we spatially classified ecological risk zones for soil heavy metal pollution. Results showed that: 1) concentrations of Cd, Zn, Cu, and As in the surface soil were heavily impacted by human activities, while those of Mn, Ni, Cr, and Pb were not. High-intensity urbanization and industrialization with the constraints of physical environment were identified as the determining factors for regional and functional variation of heavy metal pollution. 2) Pb, Cd, Zn, and Cu had high pollution risks in the surface soils, with Pb having the highest risk, which necessitated further management and control of heavy metals. The overall level of heavy metal pollution risk in the surface soils of Shenzhen was higher than that of other cities in China. 3) Nemero index and potential ecological hazard indices had different emphases in terms of assessing the risk level of heavy metals. Those indices showed different performances in the risk assessment of single heavy metal, overall ecological risks in the different urban functional zones, and ecological risk classification of heavy metal pollution in the urban surface soils. We suggest that those indices should be combined to provide more holistic information about urban heavy metal pollution.

Characterization of Nine Compounds Isolated from the Acid Hydrolysate of Lonicera fulvotomentosa Hsu et S. C. Cheng and Evaluation of Their In Vitro Activity towards HIV Protease.

In this study, we isolated nine compounds from the acid hydrolysate of the flower buds of Lonicera fulvotomentosa Hsu et S. C. Cheng and characterized their chemical structures using 1H-NMR, 13C-NMR, and electron ionization mass spectroscopy (EI-MS). These compounds were identified as ß-sitosterol (1), 5,5'-dibutoxy-2,2'-bifuran (2), nonacosane-10-ol (3), ethyl (3ß)-3,23-dihydroxyolean-12-en-28-oate (4), oleanolic acid (5), ethyl caffeate (6), caffeic acid (7), isovanillin (8), and hederagenin (9), with 4 as a new triterpene compound. Inhibitory activity against human immunodeficiency virus (HIV) protease was also evaluated for the compounds, and only ethyl caffeate, caffeic acid, and isovanillin (6, 7, and 8) exhibited inhibitory effects, with IC50 values of 1.0 µM, 1.5 µM, and 3.5 µM, respectively. Molecular docking with energy minimization and subsequent molecular dynamic (MD) simulation showed that ethyl caffeate and caffeic acid bound to the active site of HIV protease, while isovanillin drifted out from the active site and dissociated into bulk water during MD simulations, and most of the binding residues of HIV protease have been previously identified for HIV protease inhibitors. These results suggest that caffeic acid derivatives may possess inhibitory activities towards HIV protease other than previously reported inhibitory activities against HIV integrase, and thus ethyl caffeate and caffeic acid could be used as lead compounds in developing potential HIV protease inhibitors, and possibly even dual-function inhibitors against HIV.

Comparison of Tigecycline or Cefoperazone/Sulbactam therapy for bloodstream infection due to Carbapenem-resistant Acinetobacter baumannii.

Background: We retrospectively analyzed the effect of tigecycline and cefoperazone/sulbactam therapies on the prognosis of patients with carbapenem-resistant Acinetobacter baumannii bloodstream infection (CRAB-BSI). Methods: CRAB-BSI patients receiving tigecycline therapy or cefoperazone/sulbactam therapy between January 2012 and December 2017 was enrolled, and strict exclusion criteria were followed. The 28-day mortality of patients was analyzed. The impact of cefoperazone/sulbactam therapy on prognosis was evaluated using Cox multivariate regression analysis. The 28-day mortality of patients receiving cefoperazone/sulbactam monotherapy and cefoperazone/sulbactam-based combination therapy was also compared. Results: Three hundred forty eight patients with CRAB-BSI were enrolled in the study. Two hundred ten patients were included after applying the exclusion criteria. Of these, 135 patients received tigecycline therapy and 75 patients received cefoperazone/sulbactam therapy. The 28-day mortality of patients in the latter group was, significantly lower than that of the tigecycline group [29.3% vs. 51.9%; P = 0.001]. Cox multivariate regression analysis revealed that cefoperazone/sulbactam therapy exerted a protective effect on the prognosis of patients [hazard ratio 0.566, 95% confidence interval (0.342-0.940); P = 0.028]. Kaplan-Meier survival curve analysis indicated that the 28-day mortality of patients receiving cefoperazone/sulbactam therapy was lower than that of patients receiving cefoperazone/sulbactam monotherapy, but the difference was not significant (22.2% vs. 40%; P = 0.074). However, the mortality of patients receiving cefoperazone/sulbactam with imipenem/cilastatin was significantly lower than that of patients receiving cefoperazone/sulbactam monotherapy (P = 0.048). Conclusions: Patients treated with cefoperazone/sulbactam therapy had a better clinical outcome. The mortality of patients receiving cefoperazone/sulbactam with imipenem/cilastatin seems to be the lowest.