Ginkgolic Acid as a carbapenem synergist against KPC-2 positive Klebsiella pneumoniae
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The successful evolution of KPC-2 in bacteria has limited the clinical practice of carbapenems. This dilemma deteriorated the prognosis of associated infections and hence attracted increasing attention from researchers to explore alternative therapeutic options. Here, the enzyme inhibition assay was first performed to screen for a potent KPC-2 inhibitor. The synergistic effect of the candidate with carbapenems was further confirmed by checkboard minimum inhibitory concentration (MIC) assay, time-killing assay, disk diffusion method, and live/dead bacteria staining analysis. The mechanisms by which the candidate acts were subsequently explored through molecular dynamics (MD) simulations, etc. Our study found that Ginkgolic Acid (C13:0) (GA) exhibited effective KPC-2 inhibitory activity in both laboratory strain and clinical strain containing KPC-2. It could potentiate the killing effect of carbapenems on KPC-2-positive Klebsiella pnenmoniae (K. pnenmoniae) . Further explorations revealed that GA could competitively bind to the active pocket of KPC-2 with meropenem (MEM) via residues Trp 104, Gly 235, and Leu 166 . The secondary structure and functional groups of KPC-2 were subsequently altered, which may be the main mechanism by which GA exerted its KPC-2 inhibitory effect. In addition, GA was also found to synergize with MEM to disrupt membrane integrity and increase membrane permeability, which may be another mechanism by which GA reinforced the bactericidal ability of carbapenems. Our study indicated that GA was a significant KPC-2 inhibitor that could prolong the lifespan of carbapenems and improve the prognosis of patients.Keywords:
Carbapenem
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We used meropenem to successfully treat a patient with bacteremia due to ceftazidime-avibactam-resistant, meropenem- susceptible Klebsiella pneumoniae that carried mutant blaKPC-3. Meropenem was bactericidal against ceftazidime-avibactam- resistant K pneumoniae isolates in vitro. Nevertheless, the role of carbapenems in treating such infections remains uncertain, because meropenem resistance is selected readily during passage experiments.
Ceftazidime/avibactam
Bacteremia
Carbapenem
Avibactam
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Carbapenem
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Serum sensitivity and surface hydrophobicity of two Klebsiella pneumoniae strains (internal strain No. 378 and 3259) exposed to imipenem (CAS 64221-86-9) and meropenem (CAS 96036-03-2) at subinhibitory concentrations (sub-MICs; 1/4, 1/8 and 1/16 of the MICs) were evaluated. Carbapenems at all sub-MICs tested (with the exception of 1/16 of the MICs in strain 378) decreased susceptibility of bacteria to serum bactericidal activity. All sub-MICs of the antibiotics tested also reduced the bacterial surface hydrophobicity. The surface hydrophobicity of strain 3259 was most effectively decreased after the exposure to imipenem and meropenem at 1/4 of the MICs (to 3% or 5.2% of the control values). The highest decrease of hydrophobicity in strain 378 was found after exposure to imipenem and meropenem at 1/16 of the MICs (19.2% or 32.3%).
Klebsiella
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Objective To evaluate the disk tests incorporating boracic acid inhibitor for the detection of Klebsiella pneumoniae carbopenem(KPC)-producing Klebsiella pneumoniae isolates.Methods A total of 36 genetically unrelated KPC-producing Klebsiella pneumoniae isolates were determined.The minimum inhibitory concentrations(MIC) of imipenem,meropenem and ertapenem were determined by agar dilution method.Polymerase chain reaction(PCR) and DNA sequencing were used for the identification of beta-lactamase genotypes.The modified Hodge test(MHT),using both standard and high inoculum of test organisms,was performed to detect carbopenem phenotype.The disk tests consisting of 8 antibiotics with and without boracic acid inhibitor were designed to detect KPC phenotype,and the diameter≥5 mm augmentation of inhibition zone was considered a positive result.Results All 36 KPC-producing Klebsiella pneumoniae isolates were resistant to at least one of the 3 carbopenems.The sensitivity and specificity of MHT were 97.2% and 91.0% for the detection of carbopenems,and they were 100.0% and 87.0% when a high inoculum was employed.For disk tests using cefepime,imipenem or meropenem with and without boracic acid detecting KPC phenotype in Klebsiella pneumoniae,the sensitivity and specificity were 100.0%.Conclusions Disk tests incorporating boracic acid inhibitor in combination with cefepime,imipenem or meropenem may help the phenotypic detection of KPC in Klebsiella pneumoniae,and are very easy to perform and interpret.
Ertapenem
Cefepime
Klebsiella
Agar dilution
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Meropenem heteroresistance was investigated in six apparently meropenem-susceptible, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) clinical isolates, compared with that in carbapenemase-negative, meropenem-susceptible controls. In population analyses, the KPC-KP isolates grew at meropenem concentrations of 64 to 256 microg/ml. Heteroresistant colonies had significantly elevated expression of the bla(KPC) gene compared with the native populations but did not retain heteroresistance when subcultured in drug-free media. Time-kill assays indicated that meropenem alone was not bactericidal against KPC-KP but efficiently killed the control strains.
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Abstract Objectives To evaluate the in vivo efficacy of a dual carbapenem combination containing imipenem plus meropenem against carbapenem-resistant Acinetobacter baumannii producing carbapenemases OXA-23 or OXA-58. Methods An experimental model of peritonitis using C57BL/6J female mice was developed and the minimum lethal doses were calculated for infections due to OXA-23 or OXA-58 producers of A. baumannii clinical isolates. The efficacies of the carbapenems in monotherapy and in combination were tested. Results Meropenem was better than imipenem in mice infected with either of the carbapenem-resistant A. baumannii (CRAb) strains. The combination of meropenem plus imipenem significantly improved the clearance of CRAbs from spleen compared with non-treated groups. The carbapenem-containing combination was better than imipenem for treating mice infected with both carbapenemase producers. In blood, the carbapenem combination significantly decreased the bacterial load of the OXA-23 producers compared with imipenem or meropenem used in monotherapy. Conclusions These results suggest that dual carbapenem combination could be an option for the treatment of infections due to carbapenemase-producing A. baumannii such as OXA-23 and OXA-58 producers.
Acinetobacter baumannii
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Tigecycline
Carbapenem
Ertapenem
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Klebsiella
Carbapenem
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Carbapenem
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OXA-48 carbapenemases are frequently expressed by Klebsiella pneumoniae clinical isolates; they decrease the effectiveness of carbapenem therapy, particularly with meropenem. Among these isolates, meropenem-susceptible carbapenemase-producers may show decreased meropenem effectiveness. However, the probability of the emergence of resistance in susceptible carbapenemase-producing isolates and its dependence on specific K . pneumoniae meropenem MICs is not completely known. It is also not completely clear what resistance patterns will be exhibited by these bacteria exposed to meropenem, if they would follow the patterns of non-beta-lactamase-producing bacteria and other than beta-lactams antibiotics. These issues might be clarified if patterns of meropenem resistance related to the mutant selection window (MSW) hypothesis. To test the applicability of the MSW hypothesis to meropenem, OXA-48-carbapenemase-producing K . pneumoniae clinical isolates with MICs in a 64-fold range (from susceptible to resistant) were exposed to meropenem in a hollow-fiber infection model; epithelial lining fluid meropenem pharmacokinetics were simulated following administration of 2 grams every 8 hours in a 3-hour infusion. Strong bell-shaped relationships between the meropenem daily dose infused to the model as related to the specific isolate MIC and both the antimicrobial effect and the emergence of resistance were observed. The applicability of the MSW hypothesis to meropenem and carbapenemase producing K . pneumoniae was confirmed. Low meropenem efficacy indicates very careful prescribing of meropenem to treat K . pneumoniae infections when the causative isolate is confirmed as an OXA-48-carbapenemase producer.
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