Emergence of tigecycline-resistant Klebsiella pneumoniae ST11 clone in patients without exposure to tigecycline

Introduction: Tigecycline is a unique class of semi-synthetic glycylcyclines developed to treat infections caused by multidrug-resistant Klebsiella pneumoniae. In the past decades, eight tigecycline-resistant Acinetobacter baumannii isolates have been identified in Tehran and no Klebsiella pneumoniae has been reported. Methodology: To elucidate the mechanism of K. pneumoniae efflux pump-mediated resistance, the expression of efflux pump genes (oqxA, oqxB, acrA, acrB, tolC) and regulators (acrR, ramA, marA, soxS, rarA, rob) was investigated by real-time RT-PCR. Multilocus sequence typing (MLST) of tigecycline-resistant strains was also performed. Results: Compared to the tigecycline sensitive strain K32 (negative control), all resistant strains showed higher expression levels of efflux genes and regulatory factors. Three tigecycline-resistant strains (K53, K67, K79) showed higher levels of rarA expression (38.1-fold, 41-fold and 24-fold, respectively) and oqxB pump gene (48.2-fold, 60-fold and 58-fold, respectively). The increased expression of acrB was associated with the expression of ramA. However, to the best of our knowledge, studies on the mechanisms of resistance of K. pneumoniae strains to tigecycline are limited, especially in developing countries such as Iran. Conclusions: In the present study, we found that both AcrAB-TolC and OqxAB efflux pumps may play an important role in tigecycline resistance in K. pneumoniae isolates. Finally, the emergence of ST11 molecular type of resistant isolates should be monitored in hospitals to identify factors leading to tigecycline resistance.

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PUNICA GRANATUM RIND EXTRACT: ANTIBIOTIC POTENTIATOR AND EFFLUX PUMP INHIBITOR OF MULTIDRUG RESISTANT KLEBSIELLA PNEUMONIAE CLINICAL ISOLATES

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i3.16000 ◽

2017 ◽

Vol 10 (3) ◽

pp. 191 ◽

Cited By ~ 2

Author(s):

Zumaana Rafiq ◽

Sreevidya Narasimhan ◽

Magesh Haridoss ◽

Rosy Vennila ◽

Rama Vaidyanathan

Keyword(s):

Klebsiella Pneumoniae ◽

Efflux Pump ◽

Ethanol Extract ◽

Punica Granatum ◽

Multidrug Resistant ◽

Synergistic Activity ◽

Sequential Fractionation ◽

Efflux Pump Inhibitor ◽

Fold Reduction ◽

Significant Area

ABSTRACTObjective: With a rise in multidrug resistant (MDR) bacterial isolates, search for antibiotics or compounds that could act synergistically with themis a significant area of research. Efflux-mediated resistance, in particular, is a great hurdle that needs to be overcome. In an effort to identify suchsynergistic compounds and potential efflux pump inhibitors (EPI), we analyzed the rind of Punica granatum (pomegranate) against MDR clinicalKlebsiella pneumoniae isolates.Methods: Sequential fractionation of P. granatum rind ethanol (PGR) extract was carried out to obtain hexane, butanol and water fractions.Antibacterial activity of the plant extracts was confirmed, and synergistic interaction with antibiotics was determined by the checkerboard assay. Gaschromatography-mass spectrometry (GC-MS) analysis was performed to identify the phytochemical constituents of the hexane extract. To study EPIactivity of the extracts, norfloxacin accumulation assay was carried out.Results: PGR ethanol extract was found to have synergistic activity with ciprofloxacin, levofloxacin, ceftazidime, cefoxitin, meropenem, and gentamicinresulting in fold decrease of minimum inhibitory concentration (MIC) ranging from 2 to 32 fold. The hexane fraction was found to have maximumsynergistic activity resulting in a 32-fold reduction of ciprofloxacin MIC followed by butanol and water fractions. The PGR ethanol extract was alsofound to have efflux inhibition activity by the norfloxacin accumulation assay. Of the sequential fractions, the butanol fraction had maximum effluxinhibition activity.Conclusion: Therefore, our study shows that PGR extract can potentiate the effect of antibiotics on MDR bacteria, and the mode of action is likely tobe due to EPI.Keywords: Punica granatum rind, Pomegranate, Synergy with antibiotics, Multidrug resistant, Klebsiella pneumoniae, Efflux pump inhibition.

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Association of Efflux Pump and OMPs with Antibiotic Susceptibility Among ESBL-Producing Klebsiella Pneumoniae Clinical Strains in Malaysia

10.21203/rs.3.rs-375267/v1 ◽

2021 ◽

Author(s):

Golnaz Mobasseri ◽

Thong Kwai Lin ◽

Cindy Shuan Ju Teh

Keyword(s):

Antibiotic Resistance ◽

Klebsiella Pneumoniae ◽

Antibiotic Susceptibility ◽

Efflux Pump ◽

Outer Membrane Proteins ◽

Multidrug Resistant ◽

Efflux Pump Inhibitor ◽

Pump System ◽

Extended Spectrum Beta Lactamases ◽

Amoxicillin Clavulanate

Abstract Multidrug-resistant (MDR) Klebsiella pneumoniae (K. pneumoniae) poses a serious public health threat. K. pneumoniae strains that produce extended-spectrum beta-lactamases (ESBL) are becoming increasingly reported in nosocomial and community-acquired infections. Besides resistance genes, integrons, and plasmids, altered membrane permeability caused by porin loss and energy-dependent efflux have also contributed to antibiotic resistance in K. pneumoniae. The objective of this study was to determine the correlation between the reduction of antibiotic susceptibility and overexpression of efflux pump as well as the lack of outer membrane proteins (OMPs) among clinical ESBLs resistant K. pneumoniae. The expression levels of ramA, acrA, ompK35 and ompK36 in 12 MDR K. pneumoniae strains with varying MICs levels were analyzed using quantitative real time-Polymerase Chain Reaction (qRT-PCR). The role of efflux pump on antibiotic resistance was also studied by using minimum inhibitory concentration (MICs) method with//without efflux pump inhibitor. The result indicated that the strains with highest resistance to cefotaxime showed the lowest level of ompK35 and ompK36 genes expression while the strains with lowest MIC level of resistance to cefotaxime showed the highest level of expression of acrA and ramA. Our finding also revealed the effect of efflux pump inhibitor phenyl-arginine-b-naphthylamide (PAβN) on the MIC levels of ceftazidime, amoxicillin-clavulanate and cefotaxime which were significantly reduced around 1–7 folds MIC levels. These results suggest that Efflux pump system and deficiently of OMPs contributing role in antibiotic susceptibility which should be taken seriously to prevent the treatment failure due to antimicrobial resistance.

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Persisting intrahospital transmission of multidrug-resistant Klebsiella pneumoniae and challenges for infection control

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2019.153 ◽

2019 ◽

Vol 40 (8) ◽

pp. 904-909 ◽

Cited By ~ 1

Author(s):

Isabelle Vock ◽

Sarah Tschudin-Sutter

Keyword(s):

Klebsiella Pneumoniae ◽

Infection Control ◽

Multidrug Resistant ◽

Global Scale ◽

Resistance Mechanisms ◽

Healthcare Associated Infections ◽

The Past ◽

Healthcare Settings ◽

Healthcare Associated ◽

Antibiotic Agents

AbstractIn the past several decades, the incidence of Klebsiella pneumoniae harboring resistance mechanisms against multiple antibiotic agents has increased on a global scale. We discuss reasons for ongoing transmission of multidrug-resistant K. pneumoniae in healthcare settings, which has resulted in the successful spread and establishment of this pathogen. It is now one of the most important causes of healthcare-associated infections worldwide.

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A Novel Cecropin D-Derived Short Cationic Antimicrobial Peptide Exhibits Antibacterial Activity Against Wild-Type and Multidrug-Resistant Strains of Klebsiella pneumoniae and Pseudomonas aeruginosa

Evolutionary Bioinformatics ◽

10.1177/1176934320936266 ◽

2020 ◽

Vol 16 ◽

pp. 117693432093626

Author(s):

Iván Darío Ocampo-Ibáñez ◽

Yamil Liscano ◽

Sandra Patricia Rivera-Sánchez ◽

José Oñate-Garzón ◽

Ashley Dayan Lugo-Guevara ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Antibacterial Activity ◽

Klebsiella Pneumoniae ◽

Multidrug Resistant ◽

Clinical Isolates ◽

Health Concern ◽

Wild Type ◽

Cationic Antimicrobial Peptide ◽

Promising Alternative ◽

Resistant Strains

Infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa and Klebsiella pneumoniae are a serious worldwide public health concern due to the ineffectiveness of empirical antibiotic therapy. Therefore, research and the development of new antibiotic alternatives are urgently needed to control these bacteria. The use of cationic antimicrobial peptides (CAMPs) is a promising candidate alternative therapeutic strategy to antibiotics because they exhibit antibacterial activity against both antibiotic susceptible and MDR strains. In this study, we aimed to investigate the in vitro antibacterial effect of a short synthetic CAMP derived from the ΔM2 analog of Cec D-like (CAMP-CecD) against clinical isolates of K pneumoniae (n = 30) and P aeruginosa (n = 30), as well as its hemolytic activity. Minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of CAMP-CecD against wild-type and MDR strains were determined by the broth microdilution test. In addition, an in silico molecular dynamic simulation was performed to predict the interaction between CAMP-CecD and membrane models of K pneumoniae and P aeruginosa. The results revealed a bactericidal effect of CAMP-CecD against both wild-type and resistant strains, but MDR P aeruginosa showed higher susceptibility to this peptide with MIC values between 32 and >256 μg/mL. CAMP-CecD showed higher stability in the P aeruginosa membrane model compared with the K pneumoniae model due to the greater number of noncovalent interactions with phospholipid 1-Palmitoyl-2-oleyl-sn-glycero-3-(phospho-rac-(1-glycerol)) (POPG). This may be related to the boosted effectiveness of the peptide against P aeruginosa clinical isolates. Given the antibacterial activity of CAMP-CecD against wild-type and MDR clinical isolates of P aeruginosa and K pneumoniae and its nonhemolytic effects on human erythrocytes, CAMP-CecD may be a promising alternative to conventional antibiotics.

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Fighting Antibiotic-Resistant Klebsiella pneumoniae with “Sweet” Immune Targets

mBio ◽

10.1128/mbio.00874-18 ◽

2018 ◽

Vol 9 (3) ◽

Cited By ~ 4

Author(s):

Roberto Adamo ◽

Immaculada Margarit

Keyword(s):

Klebsiella Pneumoniae ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Therapeutic Approaches ◽

Antibiotic Resistant ◽

Content Type ◽

Carbapenem Resistant ◽

Surface Polysaccharides ◽

Resistant Strains ◽

Murine Monoclonal Antibodies

ABSTRACT Antibiotics and vaccines have greatly impacted human health in the last century by dramatically reducing the morbidity and mortality associated with infectious diseases. The recent challenge posed by the emergence of multidrug-resistant bacteria could possibly be addressed by novel immune prophylactic and therapeutic approaches. Among the newly threatening pathogens, Klebsiella pneumoniae is particularly worrisome in the nosocomial setting, and its surface polysaccharides are regarded as promising antigen candidates. The majority of Klebsiella carbapenem-resistant strains belong to the sequence type 158 (ST258) lineage, with two main clades expressing capsular polysaccharides CPS1 and CPS2. In a recent article, S. D. Kobayashi and colleagues (mBio 9:e00297-18, 2018, https://doi.org/10.1128/mBio.00297-18) show that CPS2-specific IgGs render ST258 clade 2 bacteria more sensitive to human serum and phagocytic killing. E. Diago-Navarro et al. (mBio 9:e00091-18, 2018, https://doi.org/10.1128/mBio.00091-18) generated two murine monoclonal antibodies recognizing distinct glycotopes of CPS2 that presented functional activity against multiple ST258 strains. These complementary studies represent a step toward the control of this dangerous pathogen.

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Complete Genome Sequence of Klebsiella pneumoniae Myophage May

Microbiology Resource Announcements ◽

10.1128/mra.00252-19 ◽

2019 ◽

Vol 8 (19) ◽

Author(s):

Katherine T. Nguyen ◽

Rachele Bonasera ◽

Garret Benson ◽

Adriana C. Hernandez-Morales ◽

Jason J. Gill ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Genome Sequence ◽

Complete Genome Sequence ◽

Complete Genome ◽

Multidrug Resistant ◽

Antibiotic Resistant ◽

Content Type ◽

Resistant Strains

May is a newly isolated myophage that infects multidrug-resistant strains of Klebsiella pneumoniae, a pathogen that is associated with antibiotic-resistant infections in humans. The genome of May has been shown to be similar to that of phage Vi01.

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IS5Element Integration, a Novel Mechanism for RapidIn VivoEmergence of Tigecycline Nonsusceptibility in Klebsiella pneumoniae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03053-14 ◽

2014 ◽

Vol 58 (10) ◽

pp. 6151-6156 ◽

Cited By ~ 24

Author(s):

Lindsey E. Nielsen ◽

Erik C. Snesrud ◽

Fatma Onmus-Leone ◽

Yoon I. Kwak ◽

Ricardo Avilés ◽

...

Keyword(s):

Klebsiella Pneumoniae ◽

Efflux Pump ◽

Multidrug Resistant ◽

Resistance Mechanisms ◽

Insertion Element ◽

Content Type ◽

Reverse Transcription Quantitative Pcr ◽

Antimicrobial Susceptibility Tests ◽

Susceptibility Tests

ABSTRACTTigecycline nonsusceptibility is concerning because tigecycline is increasingly relied upon to treat carbapenem- or colistin-resistant organisms. InEnterobacteriaceae, tigecycline nonsusceptibility is mediated by the AcrAB-TolC efflux pump, among others, and pump activity is often a downstream effect of mutations in their transcriptional regulators, cognate repressor genes, or noncoding regions, as demonstrated inEnterobacteriaceaeandAcinetobacterisolates. Here, we report the emergence of tigecycline nonsusceptibility in a longitudinal series of multidrug-resistant (MDR) and extensively drug-resistant (XDR)Klebsiella pneumoniaeisolates collected during tigecycline therapy and the elucidation of its resistance mechanisms. Clinical isolates were recovered prior to and during tigecycline therapy of a 2.5-month-old Honduran neonate. Antimicrobial susceptibility tests to tigecycline determined that the MIC increased from 1 to 4 μg/ml prior to the completion of tigecycline therapy. Unlike other studies, we did not find increased expression oframA,ramR,oqxA,acrB,marA, orrarAgenes by reverse transcription-quantitative PCR (qRT-PCR). Whole-genome sequencing revealed an IS5insertion element in nonsusceptible isolates 85 bp upstream of a putative efflux pump operon, here namedkpgABC, previously unknown to be involved in resistance. Introduction of thekpgABCgenes in a non-kpgABCbackground increased the MIC of tigecycline 4-fold and is independent of a functional AcrAB-TolC pump. This is the first report to propose a function forkpgABCand identify an insertion element whose presence correlated with thein vivodevelopment of tigecycline nonsusceptibility inK. pneumoniae.

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Inhibitors of Antibiotic Efflux in Resistant Enterobacter aerogenes and Klebsiella pneumoniae Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.48.3.1043-1046.2004 ◽

2004 ◽

Vol 48 (3) ◽

pp. 1043-1046 ◽

Cited By ~ 54

Author(s):

Jacqueline Chevalier ◽

Jérôme Bredin ◽

Abdallah Mahamoud ◽

Monique Malléa ◽

Jacques Barbe ◽

...

Keyword(s):

Multidrug Resistance ◽

Klebsiella Pneumoniae ◽

Efflux Pump ◽

Enterobacter Aerogenes ◽

Drug Susceptibility ◽

Multidrug Resistant ◽

Resistance Phenotype ◽

Pump Mechanism ◽

Energy Dependent ◽

Antibiotic Efflux

ABSTRACT In Enterobacter aerogenes and Klebsiella pneumoniae, efflux provides efficient extrusion of antibiotics and contributes to the multidrug resistance phenotype. One of the alkoxyquinoline derivatives studied here, 2,8-dimethyl-4-(2′-pyrrolidinoethyl)-oxyquinoline, restores noticeable drug susceptibility to resistant clinical strains. Analyses of energy-dependent chloramphenicol efflux indicate that this compound inhibits the efflux pump mechanism and improves the activity of structurally unrelated antibiotics on multidrug-resistant E. aerogenes and K. pneumoniae isolates.

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Clinical challenges with hypervirulent Klebsiella pneumoniae (hvKP) in China

Journal of Translational Internal Medicine ◽

10.2478/jtim-2021-0004 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Yanzhu Chen ◽

Yi Chen

Keyword(s):

Antimicrobial Resistance ◽

Klebsiella Pneumoniae ◽

Published Data ◽

Clinical Microbiology Laboratory ◽

Consensus Definition ◽

Antibiotic Resistant ◽

Resistance Determinants ◽

The Past ◽

Resistant Strains ◽

Definition Of

AbstractHypervirulent Klebsiella pneumoniae (hvKp) is an evolving pathotype with higher virulence than classical K. pneumoniae (cKp) and is characterized by community-acquired, multiple sites of infections and young and healthy hosts. hvKP infections were primarily found in East Asia and have been increasingly reported worldwide over the past few decades. To better understand the clinical challenges faced by China with hvKP, this review will provide a summary and discussion focused on recognizing hvKP strains and prevalence of antibiotic-resistant hypervirulent strains in China and the mechanisms of acquiring antimicrobial resistance. Compared with cKP, hvKP is likely to cause serious disseminated infections, leading to a higher mortality. However, sensitive and specific clinical microbiology laboratory tests are still not available. Given the limited published data due to the clinical difficulty in differentiating hvKP from cKP, extrapolation of the previous data may not be applicable for the management of hvKP. A consensus definition of hvKP is needed. Furthermore, an increasing number of reports have described hvKp strains with antimicrobial resistance acquisition, increasing the challenges for management of hvKP. China, as an epidemic country, is also facing these challenges. Quite a number of studies from China have reported antibiotic-resistant hvKP strains, including extended-spectrum β-lactamase (ESBL), and carbapenem-, tigecycline-, and colistin-resistant strains. hvKP infections, especially those of antimicrobial-resistant strains, pose to be a great threat for public health in China. Therefore, an immediate response to recognize the hypervirulent strains and provide optimal treatments, especially those with resistance determinants, is an urgent priority for China.

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EVALUATION OF EFFLUX PUMP ACTIVITY AND BIOFILM FORMATION IN MULTIDRUG RESISTANT KLEBSIELLA PNEUMONIAE ISOLATES IN TANTA, EGYPT

International Research Journal of Pharmacy ◽

10.7897/2230-8407.1203123 ◽

2021 ◽

Vol 12 (3) ◽

pp. 1-5

Author(s):

Tarek El-Said El-Banna ◽

Fatma Ibrahim Sonbol ◽

Heba M El-Dawy ◽

Lamiaa A Al-Madboly

Keyword(s):

Drug Resistance ◽

Klebsiella Pneumoniae ◽

Biofilm Formation ◽

Efflux Pump ◽

Treatment Options ◽

Multidrug Resistant ◽

High Morbidity ◽

Biochemical Tests ◽

Antibiotic Resistance Profile ◽

Pump Activity

Nosocomial and community acquired infections that caused by multidrug-resistant (MDR) Klebsiella pneumoniae isolates are widespread recently resulting in high morbidity and mortality due to limited number of treatment options with effective antibiotics. The aim of this study is to evaluate the antibiotic resistance profile, biofilm formation and efflux pump activity of MDR K. pneumoniae isolates collected from different hospitals in Tanta, Egypt. A total of 70 K. pneumoniae isolates characterized by standard biochemical tests and confirmed by MALDI-TOF/MS were screened for antibiotic susceptibility, efflux pump activity and biofilm formation. Isolates displayed high resistance to penicillins, cephalosporins, trimethoprim-sulfamethoxazole and the majority of tested fluoro/-quinolones and decreased resistance to imipenem, amikacin, chloramphenicol, tigecycline and colistin. Out of 70 K. pneumoniae isolates, 2 isolates exhibited Pan Drug-Resistance (PDR) profile while 57 (81.4%) and 11 (15.7%) exhibited MDR and Extensively drug-resistance (XDR) profiles, respectively. Sixty-four (91.4%) isolates exhibited efflux pump activity while all tested isolates had the ability to form biofilm with varied degrees as 40 (57.1%), 26 (37.1%), and 4 (5.7%) isolates were strong, moderate and weak biofilm producers, respectively. Also, a strong relation between efflux pump activity and biofilm formation per isolate was detected. In conclusion, Multidrug resistance, biofilm formation and efflux pump capabilities in K. pneumoniae have serious public health implications in the management and control of infections caused by this bacterium. Therefore, a multifaceted approach and precise planning are recommended in controlling these infections

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