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The Journal of Antimicrobial... Dec 2022Molecular analysis of meropenem-resistant mechanisms in mutants emerging from long-term in vitro meropenem exposure to borderline meropenem-susceptible...
Full-length whole-genome sequencing analysis of emerged meropenem-resistant mutants during long-term in vitro exposure to meropenem for borderline meropenem-susceptible carbapenemase-producing and non-carbapenemase-producing Enterobacterales.
OBJECTIVES
Molecular analysis of meropenem-resistant mechanisms in mutants emerging from long-term in vitro meropenem exposure to borderline meropenem-susceptible carbapenemase-producing Enterobacterales (CPE) and non-CPE.
METHODS
Escherichia coli TUM13867 harbouring both blaIMP-6- and blaCTX-M-2-carrying IncN plasmid and Citrobacter koseri TUM13189 with blaCTX-M-2-carrying chromosome were used. Meropenem MIC was 1 mg/L against both strains. Each strain was cultured in the hollow-fibre infection model (HFIM) to approximately 1 × 106 colony formation unit (cfu)/mL, and meropenem 1 g q8h treatment was initiated. Then, changes in total and meropenem-resistant populations were observed for 124 h. Meropenem resistance mechanisms were analysed using full-length whole-genome sequencing (WGS), reverse-transcription quantitative PCR and digital PCR.
RESULTS
Meropenem reduced TUM13867 and TUM13189 to approximately 5 and 2 log10 cfu/mL, respectively, at 2 h after initiation, but regrowth was observed at 24 h. The meropenem-resistant mutant emergence frequency at 120 and 124 h was 4.4 × 10-4 for TUM13867 and 7.6 × 10-1 for TUM13189. Meropenem MIC of the mutants derived from TUM13867 (TUM20902) and TUM13189 (TUM20903) increased 4- and 16-fold, respectively. TUM20902, which harboured pMTY20902_IncN plasmid with a 27 505-bp deletion that included blaCTX-M-2, and blaIMP-6 showed 4.21-fold higher levels of transcription than the parental strain. TUM20903 had a 49 316-bp deletion that included ompC and a replicative increase of blaCTX-M-2 to three copies.
CONCLUSIONS
Molecular analysis including full-length WGS revealed that the resistance mechanisms of meropenem-resistant mutants that emerged during long-term in vitro meropenem exposure were increased blaIMP-6 transcripts in CPE and increased blaCTX-M-2 transcripts due to gene triplication and OmpC loss resulting from ompC deletion in non-CPE.
Topics: Meropenem; Anti-Bacterial Agents; Microbial Sensitivity Tests; Bacterial Proteins; beta-Lactamases; Escherichia coli; Plasmids
PubMed: 36374518
DOI: 10.1093/jac/dkac376 -
Antimicrobial Agents and Chemotherapy Dec 2023It is unclear whether plasma is a reliable surrogate for target attainment in the epithelial lining fluid (ELF). The objective of this study was to characterize...
It is unclear whether plasma is a reliable surrogate for target attainment in the epithelial lining fluid (ELF). The objective of this study was to characterize meropenem target attainment in plasma and ELF using prospective samples. The first 24-hour T was evaluated vs 1xMIC and 4xMIC targets at the patient (i.e., fixed MIC of 2 mg/L) and population [i.e., cumulative fraction of response (CFR) according to EUCAST MIC distributions] levels for both plasma and ELF. Among 65 patients receiving ≥24 hours of treatment, 40% of patients failed to achieve >50% T in plasma and ELF, and 30% of patients who achieved >50% T in plasma had <50% T in ELF. At 1xMIC and 4xMIC targets, 3% and 25% of patients with >95% T in plasma had <50% T in ELF, respectively. Those with a CRCL >115 mL/min were less likely to achieve >50%T in ELF ( < 0.025). In the population, CFR for at 1xMIC and 4xMIC was >97%. For , CFR was ≥90% in plasma and ranged 80%-85% in ELF at 1xMIC when a loading dose was applied. CFR was reduced in plasma (range: 75%-81%) and ELF (range: 44%-60%) in the absence of a loading dose at 1xMIC. At 4xMIC, CFR for was 60%-86% with a loading dose and 18%-62% without a loading dose. We found that plasma overestimated ELF target attainment inup to 30% of meropenem-treated patients, CRCL >115 mL/min decreased target attainment in ELF, and loading doses increased CFR in the population.
Topics: Humans; Meropenem; Anti-Bacterial Agents; Prospective Studies; Pseudomonas Infections; Plasma; Microbial Sensitivity Tests
PubMed: 37975660
DOI: 10.1128/aac.00727-23 -
F1000Research 2022Carbapenems are the treatment of choice for multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections, but the emergence of...
Carbapenems are the treatment of choice for multidrug-resistant (MDR) and extensively drug-resistant (XDR) infections, but the emergence of carbapenem-resistant (CRAB) has rendered it ineffective in the vast majority of cases. Combination therapy has grown in popularity over the last decade; this study aims to analyze growth kinetics after exposure to meropenem and ampicillin-sulbactam compared with meropenem and amikacin antibiotic combinations in clinically relevant concentrations. This experimental laboratory study was conducted on the ATCC 19606 isolate and three clinical isolates that were intermediate or resistant to tested antibiotics. Meropenem and ampicillin-sulbactam, as well as meropenem and amikacin, were tested at four different concentrations against isolates. Turbidity measurements were taken at predetermined time points of 0, 1, 2, 4, 6, 8, and 24 hours following exposure; bacterial concentration was enumerated using the agar plate method, with the results plotted in a time-kill curve. A bactericidal effect was achieved in isolates that were intermediate to ampicillin-sulbactam and resistant to meropenem after the administration of meropenem and ampicillin-sulbactam combination with a concentration of 4 µg/ml and 16/8 µg/ml, respectively. The combination of meropenem and ampicillin-sulbactam demonstrated bacteriostatic activity against isolates that were resistant to both antibiotics. Isolates treated with resistant antibiotics showed an increased growth rate compared to the growth control. The combination of meropenem and ampicillin-sulbactam could be a promising combination therapy in treating CRAB infections. The mechanism and degree of antibiotic resistance in the isolates affect the efficacy of antibiotic combinations; further research is needed to corroborate the findings of this study.
Topics: Humans; Meropenem; Acinetobacter baumannii; Amikacin; Kinetics; Anti-Bacterial Agents; Carbapenems; Acinetobacter Infections
PubMed: 36531260
DOI: 10.12688/f1000research.122221.2 -
Journal of Chemotherapy (Florence,... May 2023Anti-microbial resistance is an escalating worldwide threat. Thus, there is an utmost necessity for the introduction of novel anti-microbial agents. This research aimed...
Anti-microbial resistance is an escalating worldwide threat. Thus, there is an utmost necessity for the introduction of novel anti-microbial agents. This research aimed to evaluate the in-vitro activity of plazomicin, meropenem-vaborbactam, and omadacycline against carbapenem-resistant Gram-negative isolates gathered from one Egyptian University group of Hospitals. 210 intensive care units (ICU) and 113 non-ICU samples were included. Resistance to carbapenems was reported in 37.5% and 21.05% of the isolated Gram-negative ICU and non-ICU organisms respectively (P < 0.001). Via disc diffusion, the sensitivity rates for carbapenem-resistant non-ICU and ICU strains were 68.8% & 64.4% for plazomicin, 68.8% & 48.9% for meropenem-vaborbactam, and 56.25% & 44.5% for omadacycline, respectively. Regarding MIC/ it was 1/16 μg/mL for plazomicin and 4/32 μg/mL for both meropenem-vaborbactam and omadacycline separately. In conclusion, plazomicin displayed potent activity against carbapenem-resistant strains. Moreover, meropenem-vaborbactam and omadacycline demonstrated satisfactory results.
Topics: Humans; Meropenem; Carbapenems; Anti-Bacterial Agents; Egypt; Bacterial Proteins; Microbial Sensitivity Tests; beta-Lactamases
PubMed: 35822495
DOI: 10.1080/1120009X.2022.2095156 -
International Journal of Antimicrobial... Oct 2022To evaluate the activity of meropenem-amikacin and meropenem-colistin combinations with checkerboard broth microdilution (CKBM) compared with isothermal microcalorimetry...
Isothermal microcalorimetry vs checkerboard assay to evaluate in-vitro synergism of meropenem-amikacin and meropenem-colistin combinations against multi-drug-resistant Gram-negative pathogens.
OBJECTIVES
To evaluate the activity of meropenem-amikacin and meropenem-colistin combinations with checkerboard broth microdilution (CKBM) compared with isothermal microcalorimetry (ITMC) assays against a multi-centric collection of multi-drug-resistant Gram-negative clinical isolates; and to compare the fractional inhibitory concentration (FIC) index and time to results of CKBM and ITMC.
METHODS
A collection of 333 multi-drug-resistant Gram-negative clinical isolates showing reduced susceptibility to meropenem (121 Klebsiella pneumoniae, 14 Escherichia coli, 130 Pseudomonas aeruginosa and 68 Acinetobacter baumannii) isolated from different centres (Florence, Madrid, Rotterdam and Stockholm) was included in the study. The antimicrobial activity of meropenem-amikacin and meropenem-colistin combinations was evaluated with CKBM and ITMC. FIC index results were interpreted as synergistic/additive and indifferent for values ≤0.5/0.5
1, respectively. Whole-genome sequencing data of a subset of strains were used to evaluate their clonality. RESULTS
In total, 254 and 286 strains were tested with meropenem-colistin and meropenem-amikacin combinations with ITMC and CKBM, respectively. Synergistic/additive effects were observed for 46 strains (20 K. pneumoniae, four E. coli, 22 P. aeruginosa) and 20 strains (three K. pneumoniae, 11 P. aeruginosa and six A. baumannii) with meropenem-amikacin and meropenem-colistin combinations, respectively, with CKBM. ITMC showed good concordance with CKBM, with 89.5% and 92.2% of cases interpreted within the same FIC index category for meropenem-amikacin and meropenem-colistin combinations, respectively. Most of the synergistic/additive effects were detected within 6 h by ITMC.
CONCLUSIONS
ITMC showed very good concordance with CKBM against a large collection of multi-drug-resistant Gram-negative clinical isolates, and could be implemented for the rapid evaluation of in-vitro activity of antimicrobial combinations.
Topics: Amikacin; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Escherichia coli; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests
PubMed: 36038097
DOI: 10.1016/j.ijantimicag.2022.106668 -
Nanomedicine (London, England) Sep 2023We hypothesized that simultaneous administration of two antibiotics loaded into a nanopolymer matrix would augment their synergistic bactericidal interaction....
We hypothesized that simultaneous administration of two antibiotics loaded into a nanopolymer matrix would augment their synergistic bactericidal interaction. Nanoplatforms of chitosan/Pluronic loaded with ciprofloxacin/meropenem (CS/Plu-Cip/Mer) were prepared by the ionic gelation method, using Plu at concentrations in the range 0.5-4% w/v. CS/Plu-Cip/Mer was evaluated for antibacterial synergistic activity and . CS/Plu-Cip and CS/Plu-Mer with Plu concentrations of 3% w/v and 2% w/v, respectively, exhibited ∼80% encapsulation efficiency. The MICs of pathogens were fourfold to 16-fold lower for CS/Plu-Cip/Mer than for Cip/Mer. Synergy was evidenced for CS/Plu-Cip/Mer with a bactericidal effect (at 1× MIC and sub-MICs), and it significantly decreased bacterial load and rescued infected rats. This study illustrates the ability of CS/Plu nanopolymer to intensify synergy between antibiotics, thereby providing a promising potential to rejuvenate antibiotics considered ineffective against resistant pathogens.
Topics: Rats; Animals; Meropenem; Ciprofloxacin; Anti-Bacterial Agents; Gram-Negative Bacteria; Sepsis; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 37933674
DOI: 10.2217/nnm-2022-0314 -
Therapeutic Drug Monitoring Feb 2020The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the...
BACKGROUND
The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the available therapeutic options is required. Beta-lactams are time-dependent antibiotics and their efficacy is determined by the amount of time the free concentration remains above the minimum inhibitory concentration. Therefore, the aim of this study was to assess the extent and variability of protein binding for meropenem, cefepime, and piperacillin.
METHODS
Plasma samples for the analysis of meropenem, cefepime, and piperacillin were collected from patients admitted to a tertiary care hospital as part of the standard care. The bound and unbound drug fractions in the samples were separated by ultrafiltration. Validated liquid chromatography-tandem mass spectrometry assays were used to quantify the total and free plasma concentrations, and the protein binding was determined.
RESULTS
Samples from 95 patients were analyzed. The median (range) age of patients was 56 years (17-87) and the median (range) body mass index was 25.7 kg/m (14.7-74.2). Approximately 59% of the patients were men. The median (range) unbound fraction (fu) was 62.5% (41.6-99.1) for meropenem, 61.4% (51.6-99.2) for cefepime, and 48.3% (39.4-71.3) for piperacillin. In the bivariate analysis, as the total meropenem concentration increased, the fu increased (r = 0.37, P = 0.045). A decrease in piperacillin fu was observed as the albumin concentration increased (r = -0.56, P = 0.005).
CONCLUSIONS
The average fu values were lower than those reported in the literature. There was also a large variability in fu; hence, it should be considered when managing patients administered with these drugs through direct measurements of free drug concentrations.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacterial Infections; Cefepime; Drug Monitoring; Female; Humans; Male; Meropenem; Middle Aged; Piperacillin; Protein Binding; Young Adult
PubMed: 31318843
DOI: 10.1097/FTD.0000000000000675 -
Pediatrics International : Official... Dec 2021Prospective audit and feedback is a method that allows the antimicrobial stewardship program (ASP) team to interact with attending physicians to tailor antibiotic...
BACKGROUND
Prospective audit and feedback is a method that allows the antimicrobial stewardship program (ASP) team to interact with attending physicians to tailor antibiotic therapy, including de-escalation, as appropriate. This study aimed to evaluate the acceptance and outcomes of ASP de-escalation recommendations in children who received meropenem.
METHODS
A prospective cohort study was conducted in children aged 1 month to 18 years who received meropenem in a tertiary-care teaching hospital. The ASP team gave recommendation between 72 and 120 h after initiating meropenem therapy. Acceptance of de-escalation recommendations among primary physicians was evaluated within 24 h of recommendation. Outcomes included clinical success rate on the 7th day and incidence rate of acquisition of carbapenem-resistant gram-negative bacteria (CR-GNB) within 30 days.
RESULTS
From March to December 2019, 217 children with a median (interquartile range) age of 2.1 (0.6, 9.5) years received meropenem. The ASP team gave recommendations in 127 (58.5%) of cases for continuation of meropenem therapy and 90 (41.5%) of cases for de-escalation. The overall acceptance of ASP de-escalation recommendations was 57.8% (95%CI: 46.9-68.1%). Clinical success rates were 85.2% in the accepted group compared to 77.5% in the rejected group (P = 0.06). The incidence rate of acquisition of CR-GNB within 30 days after treatment was 5.8% in the accepted group and 15.8% in the rejected group (P = 0.03).
CONCLUSIONS
About half of the recommendations to de-escalate meropenem prescriptions were accepted through the ASP intervention. Carbapenem-resistant gram-negative bacteria acquisitions was less likely in the de-escalation group. A robust de-escalation strategy 72 h following carbapenem initiation should be encouraged to combat multidrug-resistant organisms.
Topics: Anti-Bacterial Agents; Antimicrobial Stewardship; Carbapenems; Child; Humans; Meropenem; Pediatrics; Prospective Studies
PubMed: 33740838
DOI: 10.1111/ped.14703 -
Journal of Mass Spectrometry : JMS Jun 2024Numerous studies have suggested that intra-articular administration of antibiotics following primary revision surgery may be one of the methods for treating prosthetic...
Numerous studies have suggested that intra-articular administration of antibiotics following primary revision surgery may be one of the methods for treating prosthetic joint infection (PJI). Vancomycin and meropenem are the two most commonly used antibiotics for local application. Determining the concentrations of vancomycin and meropenem in the serum and synovial fluid of patients with PJI plays a significant role in further optimizing local medication schemes and effectively eradicating biofilm infections. This study aimed to establish a rapid, sensitive, and accurate ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determining the concentrations of vancomycin and meropenem in human serum and synovial fluid. Serum samples were processed using acetonitrile precipitation of proteins and dichloromethane extraction, while synovial fluid samples were diluted before analysis. Chromatographic separation was achieved in 6 min on a Waters Acquity UPLC BEH C18 column, with the mobile phase consisting of 0.1% formic acid in water (solvent A) and acetonitrile (solvent B). Quantification was carried out using a Waters XEVO TQD triple quadrupole mass spectrometer with an electrospray ionization (ESI) source in positive ion mode. The multiple reaction monitoring (MRM) mode was employed to detect the following quantifier ion transitions: 717.95-99.97 (norvancomycin), 725.90-100.04 (vancomycin), 384.16-67.99 (meropenem). The method validation conformed to the guidelines of the FDA and the Chinese Pharmacopoeia. The method demonstrated good linearity within the range of 0.5-50 μg/ml for serum and 0.5-100 μg/ml for synovial fluid. Selectivity, intra-day and inter-day precision and accuracy, extraction recovery, matrix effect, and stability validation results all met the required standards. This method has been successfully applied in the pharmacokinetic/pharmacodynamic (PK/PD) studies of patients with PJI.
Topics: Humans; Tandem Mass Spectrometry; Vancomycin; Synovial Fluid; Meropenem; Chromatography, High Pressure Liquid; Prosthesis-Related Infections; Anti-Bacterial Agents; Reproducibility of Results; Male; Limit of Detection; Middle Aged; Liquid Chromatography-Mass Spectrometry
PubMed: 38751321
DOI: 10.1002/jms.5041 -
Antimicrobial Agents and Chemotherapy Jan 2018Vaborbactam (formerly RPX7009) is a novel inhibitor of serine β-lactamases, including Ambler class A carbapenemases, such as KPCs. The current study evaluated the...
Vaborbactam (formerly RPX7009) is a novel inhibitor of serine β-lactamases, including Ambler class A carbapenemases, such as KPCs. The current study evaluated the activity of the combination agent meropenem-vaborbactam against a global collection of 991 isolates of KPC-positive collected in 2014 and 2015 using the Clinical and Laboratory Standards Institute (CLSI) standard broth microdilution method. The MIC of meropenem (when tested with a fixed concentration of 8 μg/ml of vaborbactam) for isolates of KPC-positive was 1 μg/ml, and MIC values ranged from ≤0.03 to >32 μg/ml; 99.0% (981/991) of isolates had meropenem-vaborbactam MICs of ≤4 μg/ml, the U.S. FDA-approved MIC breakpoint for susceptibility to meropenem-vaborbactam (Vabomere). Vaborbactam lowered the meropenem MIC from 32 to 0.06 μg/ml and the MIC from >32 to 1 μg/ml. There were no differences in the activity of meropenem-vaborbactam when the isolates were stratified by KPC variant type. We conclude that meropenem-vaborbactam demonstrates potent activity against a worldwide collection of clinical isolates of KPC-positive collected in 2014 and 2015.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Boronic Acids; Enterobacteriaceae; Heterocyclic Compounds, 1-Ring; Humans; Meropenem; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 29084745
DOI: 10.1128/AAC.01904-17