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Future Microbiology Jan 2023Meropenem-vaborbactam and delafloxacin activities were not assessed against spp. (), complex () and (). A total of 106 , 57 and 100 were tested with gradient...
Meropenem-vaborbactam and delafloxacin activities were not assessed against spp. (), complex () and (). A total of 106 , 57 and 100 were tested with gradient diffusion test of meropenem-vaborbactam, delafloxacin and comparators. Meropenem-vaborbactam MIC were 4 μg/ml for , 1 μg/ml for , 2 μg/ml for and , and 32 μg/ml for . Delafloxacin MIC were 4 μg/ml for , 0.25 μg/ml for and , 2 μg/ml for , and 0.5 μg/m for . meropenem-vaborbactam MICs were fourfold lower than meropenem for 28.3% , 77.2% , 53.8% and 77.2% . Meropenem-vaborbactam and delafloxacin are active against and .
Topics: Meropenem; Anti-Bacterial Agents; Gram-Negative Bacteria; Stenotrophomonas maltophilia; Burkholderia cepacia complex; Microbial Sensitivity Tests
PubMed: 36722304
DOI: 10.2217/fmb-2021-0278 -
The Journal of Antimicrobial... Nov 2021To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance.
OBJECTIVES
To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance.
METHODS
Among 55?>162 Enterobacterales isolates, 354 carbapenem-resistant isolates carried genes encoding OXA-48-like enzymes. Isolates were susceptibility tested for ceftazidime/avibactam and comparators by broth microdilution methods. Analysis of β-lactam resistance mechanisms and MLST was performed in silico using WGS data.
RESULTS
OXA-48-like-producing isolates increased from 0.5% (94/18 656) in 2016 to 0.9% (169/18?>808) in 2018. OXA-48 was the most common variant; isolates primarily were Klebsiella pneumoniae (318/354 isolates) from Europe and adjacent countries. MLST analysis revealed a diversity of STs, but K. pneumoniae belonging to ST395, ST23 and ST11 were observed most frequently. Thirty-nine isolates harboured MBLs and were resistant to most agents tested. The presence of blaCTX-M-15 (258 isolates), OmpK35 nonsense mutations (232) and OmpK36 alterations (316) was common among OXA-48 producers. Ceftazidime, cefepime and aztreonam susceptibility rates, when applying CLSI breakpoints, were 12%-15% lower for isolates carrying ESBLs alone and with either or both OmpK35 stop codons and OmpK36 alterations. Meropenem and, remarkably, meropenem/vaborbactam were affected by specific OmpK36 alterations when a deleterious mutation also was observed in OmpK35. These mechanisms caused a decrease of 12%-42% in the susceptibility rates for meropenem and meropenem/vaborbactam. Ceftazidime/avibactam susceptibility rates were >98.9%, regardless of the presence of additional β-lactam resistance mechanisms.
CONCLUSIONS
Guidelines for the treatment of infections caused by OXA-48-producing isolates are scarce and, as the dissemination of these isolates continues, studies are needed to help physicians understand treatment options for these infections.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Ceftazidime; Drug Combinations; Enterobacteriaceae; Heterocyclic Compounds, 1-Ring; Meropenem; Microbial Sensitivity Tests; Multilocus Sequence Typing; beta-Lactamases
PubMed: 34459890
DOI: 10.1093/jac/dkab306 -
Injury Aug 2022Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical...
Concentrations of co-administered vancomycin and meropenem in the internal dead space of a cannulated screw and in cancellous bone adjacent to the screw - Evaluated by microdialysis in a porcine model.
BACKGROUND
Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical Gram-positive and Gram-negative antibiotic coverage. To ensure full antibiotic protection of the cannulated screw and the bone tissue, it is generally accepted that target tissue antibiotic concentrations, as a minimum, reach and remain above relevant epidemiological cut-off minimal inhibitory concentrations (T>MIC) for a sufficient amount of time.
METHODS
8 female pigs were included. Microdialysis catheters were placed in the internal dead space of a cannulated screw placed in tibial cancellous bone, in tibial cancellous bone adjacent to the screw (mean distance to the screw: 3 mm), and in cancellous bone on the contralateral tibia. Following single-dose simultaneous intravenous administrations of vancomycin (1000 mg) and meropenem (1000 mg), microdialysates and plasma were dynamically sampled over 8 h. The applied MIC targets ranged from 1 to 4 µg/mL for vancomycin and 0.125-2 µg/mL for meropenem RESULTS: For both drugs, and for all MIC targets investigated (except for the high vancomycin target: 4 µg/mL), the internal dead space of the cannulated screw had the shortest T>MIC. At the low MIC targets T>MIC ranged between 88 and 449 min across sampling sites for vancomycin (1 µg/mL), and 148-406 min for meropenem (0.125 µg/mL). For the high MIC targets, T>MIC ranged between 3 and 446 min for vancomycin (4 μg/mL) and 17-181 min for meropenem (2 μg/mL). Vancomycin displayed longer T>MIC (2 and 4 μg/mL), higher area under the concentration time curve (AUC) and peak drug concentration in the proximal tibial cancellous bone without a screw nearby. For meropenem, only the cancellous bone AUC was significantly higher on the side with no screw.
CONCLUSION
We found short T>MIC, particularly for the high MIC targets for vancomycin and meropenem, both inside the cannulated screw and in cancellous bone adjacent to the screw. The presence of a cannulated screw impaired the penetration of especially vancomycin into cancellous bone adjacent to the screw. More aggressive or different vancomycin and meropenem approaches may be considered to encompass contaminating differences and to ensure a theoretically more sufficient antibiotic protection of cannulated screws when used in the management of open lower extremity fractures.
Topics: Animals; Anti-Bacterial Agents; Cancellous Bone; Female; Meropenem; Microdialysis; Swine; Vancomycin
PubMed: 35710595
DOI: 10.1016/j.injury.2022.06.008 -
Antimicrobial Agents and Chemotherapy Aug 2022Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this...
Morbidity and mortality related to ventriculitis in neurocritical care patients remain high. Antibiotic dose optimization may improve therapeutic outcomes. In this study, a population pharmacokinetic model of meropenem in infected critically ill patients was developed. We applied the final model to determine optimal meropenem dosing regimens required to achieve targeted cerebrospinal fluid exposures. Neurocritical care patients receiving meropenem and with a diagnosis of ventriculitis or extracranial infection were recruited from two centers to this study. Serial plasma and cerebrospinal fluid samples were collected and assayed. Population pharmacokinetic modeling and Monte Carlo dosing simulations were performed using Pmetrics. We sought to determine optimized dosing regimens that achieved meropenem cerebrospinal fluid concentrations above pathogen MICs for 40% of the dosing interval, or a higher target ratio of meropenem cerebrospinal fluid trough concentrations to pathogen MIC of ≥1. In total, 53 plasma and 34 cerebrospinal fluid samples were obtained from eight patients. Meropenem pharmacokinetics were appropriately described using a three-compartment model with linear plasma clearance scaled for creatinine clearance and cerebrospinal fluid penetration scaled for patient age. Considerable interindividual pharmacokinetic variability was apparent, particularly in the cerebrospinal fluid. Percent coefficients of variation for meropenem clearance from plasma and cerebrospinal fluid were 41.7% and 89.6%, respectively; for meropenem, the volume of distribution in plasma and cerebrospinal fluid values were 63.4% and 58.3%, respectively. High doses (up to 8 to 10 g/day) improved attainment of meropenem cerebrospinal fluid target exposures, particularly for less susceptible organisms (MICs, ≥0.25 mg/L). Standard meropenem doses of 2 g every 8 h may not achieve effective concentrations in cerebrospinal fluid in all critically ill patients. Higher doses, or alternative dosing methods (e.g., loading dose followed by continuous infusion) may be required to optimize cerebrospinal fluid exposures. Doses of up to 8 to 10 g/day either as intermittent boluses or continuous infusion would be suitable for patients with augmented renal clearance; lower doses may be considered for patients with impaired renal function as empirical suggestions. Ongoing dosing should be tailored to the individual patient circumstances. Notably, the study population was small and dosing recommendations may not be generalizable to all critically ill patients.
Topics: Anti-Bacterial Agents; Cerebral Ventriculitis; Critical Illness; Humans; Meropenem; Prospective Studies; Renal Insufficiency; Thienamycins
PubMed: 35862757
DOI: 10.1128/aac.00142-22 -
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 -
Microbiology Spectrum Feb 2024Carbapenem-resistant (CRKP) is an important multidrug resistance (MDR) pathogen that threatens human health and is the main source of hospital-acquired infection. Outer...
Carbapenem-resistant (CRKP) is an important multidrug resistance (MDR) pathogen that threatens human health and is the main source of hospital-acquired infection. Outer membrane vesicles (OMVs) are extracellular vesicles derived from Gram-negative bacteria and contain materials involved in bacterial survival and pathogenesis. They also contribute to cellular communication to nearby or distant recipient cells and influence their functions and phenotypes. In this study, we sought to understand the mechanism of bacterial response to meropenem pressure and explore the relationship between pathogenic proteins and the high pathogenicity of bacteria. We performed whole-genome PacBio sequencing on a clinical CRKP strain, and its OMVs were characterized using nanoparticle tracking analysis, transmission electron microscopy, and proteomic analysis. Thousands of vesicle proteins have been identified in mass spectrometry-based high-throughput proteomics analyses of OMVs. Protein functionality analysis showed that the OMVs were predominantly involved in metabolic, intracellular compartments, nucleic acid binding, survival, defense, and antibiotic resistance, such as Chromosome partition protein MukB, 3-methyl-2-oxobutanoate hydroxymethyltransferase, methionine-tRNA ligase, Heat shock protein 60 family chaperone GroEL, and Gamma-glutamyl phosphate reductase. Additionally, a protein-protein interaction network demonstrated that OMVs from meropenem-treated showed the highest connectivity in DNA polymerase I, phenylalanine-tRNA ligase beta subunit, DNA-directed RNA polymerase subunit beta, methionine-tRNA ligase, DNA-directed RNA polymerase subunit beta, and DNA-directed RNA polymerase subunit alpha. The OMVs proteome expression profile indicates increased secretion of stress proteins released from meropenem-treated , which provides clues for revealing the biogenesis and pathophysiological functions of Gram-negative bacteria OMVs. The significant differentially expressed proteins identified in this study are of great significance for exploring effective control strategies for CRKP infection.IMPORTANCEMeropenem is one of the main antibiotics used in the clinical treatment of carbapenem-resistant (CRKP). This study demonstrated that some important metabolic changes occurred in meropenem-induced CRKP-outer membrane vesicles (OMVs), The OMVs proteome expression profile indicates increased secretion of stress proteins released from meropenem-induced . Furthermore, this is the first study to discuss the protein-protein interaction network of the OMVs released by CRKP, especially under antibiotic stress.
Topics: Humans; Meropenem; Klebsiella pneumoniae; Proteome; Proteomics; Methionine-tRNA Ligase; Anti-Bacterial Agents; Heat-Shock Proteins; DNA-Directed RNA Polymerases; Klebsiella Infections; Microbial Sensitivity Tests
PubMed: 38236023
DOI: 10.1128/spectrum.02917-23 -
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