Impact of the ST101 clone on fatality among patients with colistin-resistant Klebsiella pneumoniae infection

Can, Füsun; Menekşe, Şirin; Ispir, Pelin; Ataç, Nazlı; Albayrak, Özgür; Demir, Tuana; Karaaslan, Doruk; Karahan, Salih Nafiz; Kapmaz, Mahir; Azap, Özlem Kurt; Timurkaynak, Funda; Yavuz, Serap Şimşek; Başaran, Seniha; Yörük, Fügen; Azap, Alpay; Koçulu, Safiye; Benzonana, Nur; Lack, Nathan A.; Gönen, Mehmet; Ergönül, Önder

doi:10.1093/jac/dkx532

Cited by 46 publications

(33 citation statements)

References 36 publications

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“…The predominant ST observed was ST101, an emerging highrisk clone detected worldwide and associated with different carbapenemases and high mortality (Navon-Venezia et al, 2017;Can et al, 2018). In a recent European survey of CRKP isolates, including 244 hospitals in 32 countries, four major clonal lineages accounted for roughly 70% of the carbapenemaseproducing isolates, including ST 11, 15, 101, 258/512 and their derivatives (David et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Genomic Epidemiology of Carbapenem- and Colistin-Resistant Klebsiella pneumoniae Isolates From Serbia: Predominance of ST101 Strains Carrying a Novel OXA-48 Plasmid

et al. 2020

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Klebsiella pneumoniae is a major cause of severe healthcare-associated infections and often shows MDR phenotypes. Carbapenem resistance is frequent, and colistin represents a key molecule to treat infections caused by such isolates. Here we evaluated the antimicrobial resistance (AMR) mechanisms and the genomic epidemiology of clinical K. pneumoniae isolates from Serbia. Consecutive non-replicate K. pneumoniae clinical isolates (n = 2,298) were collected from seven hospitals located in five Serbian cities and tested for carbapenem resistance by disk diffusion. Isolates resistant to at least one carbapenem (n = 426) were further tested for colistin resistance with Etest or Vitek2. Broth microdilution (BMD) was performed to confirm the colistin resistance phenotype, and colistin-resistant isolates (N = 45, 10.6%) were characterized by Vitek2 and whole genome sequencing. Three different clonal groups (CGs) were observed: CG101 (ST101, N = 38), CG258 (ST437, N = 4; ST340, N = 1; ST258, N = 1) and CG17 (ST336, N = 1). mcr genes, encoding for acquired colistin resistance, were not observed, while all the genomes presented mutations previously associated with colistin resistance. In particular, all strains had a mutated MgrB, with MgrB C28S being the prevalent mutation and associated with ST101. Isolates belonging to ST101 harbored the carbapenemase OXA-48, which is generally encoded by an IncL/M plasmid that was no detected in our isolates. MinION sequencing was performed on a representative ST101 strain, and the obtained long reads were assembled together with the Illumina high quality reads to decipher the bla OXA-48 genetic background.

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Section: Discussionmentioning

confidence: 99%

Genomic Epidemiology of Carbapenem- and Colistin-Resistant Klebsiella pneumoniae Isolates From Serbia: Predominance of ST101 Strains Carrying a Novel OXA-48 Plasmid

et al. 2020

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“…were identi ed among the CPE-infected patients, something previously reported in South and Southeast Asia (46,51).…”

Section: Discussionmentioning

confidence: 56%

Genomic and clinical characterisation of multidrug-resistant carbapenemase-producing ST231 and ST16 Klebsiella pneumoniae isolates colonising and causing disease in hospitalised patients at Siriraj Hospital, Bangkok, Thailand from 2015 to 2017

Boonyasiri¹,

Jauneikaite²,

Brinkac³

et al. 2020

Preprint

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Background: Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) have continually grown as a global public health threat, with significant mortality rates observed across the world. We examined the clinical data from patients with CPE infections and their outcomes, concentrating on Klebsiella pneumoniae isolates. We analysed the clinical information, performed antimicrobial susceptibility testing, and conducted molecular epidemiological and genomic analyses on the isolates to identify patterns in the data.Methods: The clinical characteristics of 33 hospitalised patients with confirmed CPE, including patient-related factors associated with the development of CPE infections, were examined. Patients were divided according to whether they were “colonised” or “infected” with CPE and by the timing and frequency of their rectal swab collections, from which 45 swabs were randomly selected for analysis. CPE isolates were purified, and antimicrobial susceptibility tests performed. Whole genome sequences of these isolates were determined and analysed to compute bacterial multilocus sequence types and plasmid replicon types, infer phylogenetic relationships, and identify antimicrobial resistance and virulence genes.Results: Altogether, 88.9% (40/45) of the CPE isolates were K. pneumoniae. The most abundant carbapenemase gene family in the K. pneumoniae isolates (33/39) was blaOXA-232, with blaNDM-1 additionally identified in 19 of them. All CPE isolates carrying either blaOXA-232 or blaNDM-1 were resistant to meropenem, but only 40 from 45 were susceptible to colistin. Among the CPE-infected patients (n=18) and CPE-colonised patients who developed CPE infections during the study (n=3), all but one received standard colistin-based combination therapy. Phylogenetic analysis revealed the polyclonal spread of carbapenemase-producing K. pneumoniae (CPKP) within the patient population, with the following two major subclades identified: ST16 (n=15) and ST231 (n=14). CPKP-ST231 had the highest virulence score of 4 and was associated with primary bacteraemia. The siderophores yersiniabactin and aerobactin, considered to be important virulence factors, were only identified in the CPKP-ST231 genomes.Conclusions: This study has revealed the genomic features of disease-causing or colonising CPE isolates, focusing on antimicrobial resistance and virulence determinants. This type of multi-layered analysis can be further exploited in Thailand and elsewhere to modify the regimes used for empirical antibiotic treatment and improve the management strategies for CPE infections in hospitalised patients.

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“…In our study, ColR-HvKP ST101 isolates were found to be associated with VAP infections (p=0.009). In one of our previous studies, 30 day fatality of infections with ST101 K.pneumoniae was found to be 72% (30). The ST395 clone is known as a potentially high-risk clone (32), and recent studies pointed out the emergence of carbapenem-resistant ST395 in France and Italy (33, 34).…”

Section: Discussionmentioning

confidence: 89%

“…K.pneumoniae ST101 is known as hypervirulent clone mostly responsible for pneumonia and bacteremia in intensive care units. (30, 31). In our study, ColR-HvKP ST101 isolates were found to be associated with VAP infections (p=0.009).…”

Section: Discussionmentioning

confidence: 99%

“…Colistin resistant hypervirulent Klebsiella pneumonia (HvKp) infections are one of the emerging threats in public health because of high fatality rates (1–3). The ST101 and ST395 clones of K.pneumonia are known as hypervirulent clones (4–7), and reported to be significant predictors of the mortality (8). The leading virulence factors of HvKp are mostly associated with capsular serotype, muco-viscosity, iron uptake systems and allantoin metabolism (9–11).…”

Section: Introductionmentioning

confidence: 99%

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The role of iron uptake systems in the pathogenesis of colistin-resistant hypervirulent K.pneumoniae infections

Doğan

Vatansever

Ataç

et al. 2019

Preprint

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16Here we proposed the hypothesis that hypervirulent colistin resistant K.pneumoniae (ColR-Kp) exhibit 17 high number of virulence factors and have enhanced survival capacity against neutrophil activity. 18We studied virulence genes of ColR-Kp isolates and neutrophil response in 142 patients with invasive 19 infections. 20The patients infected with hypervirulent ST101 and ST395 ColR-Kp had higher 30-day mortality (58%, 21 p=0.005 and 75%, p=0.003, respectively. The yersiniabactin biosynthesis gene (ybtS) and ferric uptake 22 operon associated gene (kfu) were significantly higher in ST101 (99%, p=<0.001) and in ST395 23 (94%,p<0.012). Being in ICU (OR: 7.9; CI: 1.43-55.98; p=0.024), kfu (OR:27.0; CI:5.67-179.65; p<0.001) 24 and ST101 (OR: 17.2; CI: 2.45-350.40; p=0.01) were found to be predictors of 30-day mortality. The 25 uptake of kfu + -ybtS + ColR-Kp by neutrophils was significantly higher than kfu --ybtS -ColR-Kp (78% vs 26 65%, p<0.001). However, kfu + -ybtS + ColR-Kp were more resistant to the killing activity of neutrophils 27 than negative ones (7.90 vs 4.22; p=0.001). The kfu + -ybtS + ColR-Kp stimulated excessive NET formation 28 while the NET's against kfu --ybtS -ColR-Kp were weak and rare. 29Iron uptake systems enhance successful survival of K.pneumoniae against neutrophil phagocytic 30 defense, and stimulate excessive NET formation. The drugs targeted to iron uptake systems would be 31 a promising approach for treatment of hypervirulent K.pneumoniae infections. 32 33 34 35 39 40 41 65 diseases, type of infection, isolation site, blood biochemical parameters, predisposing factors such as 66 having operation within last one month, intensive care unit admission (ICU), type of antimicrobial 67 agents used for empirical and agent-specific therapy, duration of colistin therapy before isolation of 68 colistin-resistant isolates, and carbapenem resistance was used. The patients were followed up for 157 13.13) vs 4.22 (range:0.36-5.64), respectively (p=0.001). The survival index of S.epidermidis and 158 K.pneumoniae controls were 0.64 and 1.89, respectively (Figure2). The survival index of two ybtSkfu + 159isolates were 12.04 and 12.13, and it was 5.13 in one ybtS + kfuisolate. 161Among 21 isolates, four was in ST101 clone. The median phagocytosis rate 80% was found to be and 162 the survival index was 8.51. 164After NETosis, the mean colony count of two kfu + -ybtS + isolates was 5.50X10 6 and it was 4.05x10 6 for 165 kfu --ybtSstrains. The colony count of ATCC K.pneumoniae was 4.3x10 6 . Confocal microscopy study 166 showed that the kfu + -ybtS + isolate stimulated abundant NET formation with excessive release of 167 chromatin granular content to the extracellular area. However, the NET's against kfu --ybtSnegative 168 ColR-Kp were weak and seen only in few areas (Figure 3). 169 170 Discussion 171 ColR-HvKP infections are usually fatal because of limited therapeutic options due to extensive drug 172 resistance and successful immune escape mechanisms of these pathogens. Alternative approaches are

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Impact of the ST101 clone on fatality among patients with colistin-resistant Klebsiella pneumoniae infection

Cited by 46 publications

References 36 publications

Genomic Epidemiology of Carbapenem- and Colistin-Resistant Klebsiella pneumoniae Isolates From Serbia: Predominance of ST101 Strains Carrying a Novel OXA-48 Plasmid

Genomic Epidemiology of Carbapenem- and Colistin-Resistant Klebsiella pneumoniae Isolates From Serbia: Predominance of ST101 Strains Carrying a Novel OXA-48 Plasmid

Genomic and clinical characterisation of multidrug-resistant carbapenemase-producing ST231 and ST16 Klebsiella pneumoniae isolates colonising and causing disease in hospitalised patients at Siriraj Hospital, Bangkok, Thailand from 2015 to 2017

The role of iron uptake systems in the pathogenesis of colistin-resistant hypervirulent K.pneumoniae infections

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