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The Yale Journal of Biology and Medicine Dec 2022: Antibiotic resistance in cystic fibrosis (CF) is a well-known phenomenon. However, the comprehensive epidemiological impact of antibiotic resistance in CF is not... (Meta-Analysis)
Meta-Analysis Review
: Antibiotic resistance in cystic fibrosis (CF) is a well-known phenomenon. However, the comprehensive epidemiological impact of antibiotic resistance in CF is not clearly documented. So, this meta-analysis evaluated the proportion rates of carbapenem resistance (imipenem, meropenem, and doripenem) in CF based on publication date (1979-2000, 2001-2010, and 2011-2021), continents, pathogens, and antimicrobial susceptibility testing (AST). : We searched studies in PubMed, Scopus, and Web of Science (until April 2021). Statistical analyses were conducted using STATA software (version 14.0). : The 110 studies included in the analysis were performed in 25 countries and investigated 13,324 pathogens associated with CF. The overall proportion of imipenem, meropenem, and doripenem resistance in CF were 43% (95% CI 36-49), 48% (95% CI 40-57), 28% (95% CI 23-33), and 45% (95% CI 32-59), respectively. Our meta-analysis showed that trends of imipenem, meropenem, and doripenem-resistance had gradual decreases over time (1979-2021). This could be due to the limited clinical effectiveness of these antibiotics to treat CF cases over time. Among the opportunistic pathogens associated with CF, the highest carbapenem resistance rates were shown in , spp., , and . The highest and lowest carbapenem resistance rates among in CF patients were shown against meropenem (23%) and doripenem (39%). : We showed that trends of carbapenem resistance had decreased over time (1979-2021). This could be due to the limited clinical effectiveness of these antibiotics to treat CF cases over time. Plans should be directed to fight biofilm-associated infections and prevent the emergence of mutational resistance. Systematic surveillance for carbapenemase-producing pathogens in CF by molecular surveillance is necessitated.
Topics: Humans; Meropenem; Doripenem; Carbapenems; Cystic Fibrosis; Microbial Sensitivity Tests; Anti-Bacterial Agents; Imipenem; Pseudomonas aeruginosa
PubMed: 36568834
DOI: No ID Found -
Journal of Applied Microbiology Sep 2022Here, we investigate the impact of phage-antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in...
AIMS
Here, we investigate the impact of phage-antibiotic combinations (PAC) on bacterial killing, resistance development and outer membrane vesicle (OMV) production in multidrug-resistant (MDR) P. aeruginosa.
METHODS AND RESULTS
After screening 10 well-characterized MDR P. aeruginosa strains against three P. aeruginosa phages, representative strains, R10266 and R9316, were selected for synergy testing based on high phage sensitivity and substantial antibiotic resistance patterns, while phage EM was chosen based on host range. To understand the impact of phage-antibiotic combinations (PAC) against MDR P. aeruginosa, time-kill analyses, OMV quantification and phage/antibiotic resistance testing were performed. Phage and meropenem demonstrated synergistic activity against both MDR strains. Triple combination regimens, phage-meropenem-colistin and phage-ciprofloxacin-colistin, resulted in the greatest CFU reduction for strains R9316 (3.50 log CFU ml ) and R10266 (4.50 log CFU ml ) respectively. PAC resulted in regained and improved antibiotic susceptibility to ciprofloxacin (MIC 2 to 0.0625) and meropenem (MIC 32 to 16), respectively, in R9316. Phage resistance was prevented or reduced in the presence of several classes of antibiotics and OMV production was reduced in the presence of phage for both strains, which was associated with significantly improved bacterial eradication.
CONCLUSIONS
These findings support the potential of phage-antibiotic synergy (PAS) to augment killing of MDR P. aeruginosa. Systematic in vitro and in vivo studies are needed to better understand phage interactions with antipseudomonal antibiotics, to define the role of OMV production in P. aeruginosa PAC therapy and to outline pharmacokinetic and pharmacodynamic parameters conducive to PAS.
SIGNIFICANCE AND IMPACT OF STUDY
This study identifies novel bactericidal phage-antibiotic combinations capable of thwarting resistance development in MDR and XDR P. aeruginosa strains. Furthermore, phage-mediated OMV reduction is identified as a potential mechanism through which PAC potentiates bacterial killing.
Topics: Anti-Bacterial Agents; Bacteriophages; Ciprofloxacin; Colistin; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas Infections; Pseudomonas aeruginosa
PubMed: 35652690
DOI: 10.1111/jam.15647 -
Biomedical Chromatography : BMC Nov 2021An efficient and reliable method using LC-MS/MS was established and validated for the simultaneous quantification of meropenem and imipenem in rat plasma. An electronic...
An efficient and reliable method using LC-MS/MS was established and validated for the simultaneous quantification of meropenem and imipenem in rat plasma. An electronic spray ion source in the positive multiple reaction monitoring mode was used for the detection and the transitions were m/z 384.6 → m/z 141.2 for meropenem, m/z 300.1 → m/z 141.8 for imipenem and m/z 423.4 → m/z 207.1 for matrine (IS). The calibration curves of meropenem and imipenem were linear in the range of 0.50-200 μg/mL. Satisfactory separation was achieved with a total run time of 3.0 min, the injection volume was 3 μl. The retention times of meropenem, imipenem and IS were 1.19, 1.14 and 1.13 min, respectively. Meropenem and imipenem are easily hydrolyzed in plasma. HEPES was used as a stabilizer and added to the plasma samples immediately after centrifugation. Extractions of meropenem, imipenem and IS were carried out by protein precipitation with acetonitrile. The specificity, precision and accuracy, stability, recovery and matrix effects were within acceptance limits. This method was successfully applied to investigate the pharmacokinetics of intravenous injection of meropenem and imipenem single administration or combined with sulbactam in rats. We found that sulbactam has no influence on the pharmacokinetics behavior of meropenem or imipenem.
Topics: Animals; Chromatography, Liquid; Imipenem; Linear Models; Male; Meropenem; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry
PubMed: 34060114
DOI: 10.1002/bmc.5185 -
Clinical Therapeutics Apr 2020Antibiotic dosing is challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD)... (Observational Study)
Observational Study
PURPOSE
Antibiotic dosing is challenge in critically ill patients undergoing renal replacement therapy. Our aim was to evaluate the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of meropenem and vancomycin in patients undergoing SLED.
METHODS
Consecutive ICU patients undergoing SLED and receiving meropenem and/or vancomycin were prospectively evaluated. Serial blood samples were collected before, during, and at the end of SLED sessions. Antimicrobial concentrations were determined using a validated HPLC method. Noncompartmental PK analysis was performed. AUC was determined for vancomycin. For meropenem, time above MIC was calculated.
FINDINGS
A total of 24 patients receiving vancomycin and 21 receiving meropenem were included; 170 plasma samples were obtained. Median serum vancomycin and meropenem concentrations before SLED were 24.5 and 28.0 μg/mL, respectively; after SLED, 14 and 6 μg/mL. Mean removal was 42% with vancomycin and 78% with meropenem. With vancomycin, 19 (83%), 16 (70%), and 15 (65%) patients would have achieved the target (AUC >400) considering MICs of 1, 2, and 4 mg/L, respectively. With meropenem, 17 (85%), 14 (70%), and 10 (50%) patients would have achieved the target (100% of time above MIC) if infected with isolates with MICs of 1, 4, and 8 mg/L, respectively.
IMPLICATIONS
SLED clearances of meropenem and vancomycin were 3-fold higher than the clearance described by continuous methods. Despite this finding, overall high PK/PD target attainments were obtained, except for at higher MICs. We suggest a maintenance dose of 1 g TID or BID of meropenem. With vancomycin, a more individualized approach using therapeutic drug monitoring should be used, as commercial assays are available.
Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Critical Illness; Female; Humans; Hybrid Renal Replacement Therapy; Intensive Care Units; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Vancomycin; Young Adult
PubMed: 32199609
DOI: 10.1016/j.clinthera.2020.02.011 -
Pharmaceutical Research Jul 2021Skin and soft tissue infections are increasingly prevalent and often complicated by potentially fatal therapeutic hurdles, such as poor drug perfusion and antibiotic...
PURPOSE
Skin and soft tissue infections are increasingly prevalent and often complicated by potentially fatal therapeutic hurdles, such as poor drug perfusion and antibiotic resistance. Delivery vehicles capable of versatile loading may improve local bioavailability and minimize systemic toxicities yet such vehicles are not clinically available. Therefore, we aimed to expand upon the use of glutathione-conjugated poly(ethylene glycol) GSH-PEG hydrogels beyond protein delivery and evaluate the ability to deliver traditional therapeutic molecules.
METHODS
PEG and GSH-PEG hydrogels were prepared using ultraviolet light (UV)-polymerization. Hydrogel loading and release of selected drug candidates was examined using UV-visible spectrometry. Therapeutic molecules and GST-fusion protein loading was examined using UV-visible and fluorescent spectrometry. Efficacy of released meropenem was assessed against meropenem-sensitive and -resistant P. aeruginosa in an agar diffusion bioassay.
RESULTS
For all tested agents, GSH-PEG hydrogels demonstrated time-dependent loading whereas PEG hydrogels did not. GSH-PEG hydrogels released meropenem over 24 h. Co-loading of biologic and traditional therapeutics into a single vehicle was successfully demonstrated. Meropenem-loaded GSH-PEG hydrogels inhibited the growth of meropenem-sensitive and resistant P. aeruginosa isolates.
CONCLUSION
GSH ligands within GSH-PEG hydrogels allow loading and effective delivery of charged therapeutic agents, in addition to biologic therapeutics.
Topics: Anti-Bacterial Agents; Biological Availability; Biological Products; Delayed-Action Preparations; Drug Delivery Systems; Drug Liberation; Drug Resistance, Bacterial; Drug Therapy, Combination; Glutathione; Humans; Hydrogels; Meropenem; Microbial Sensitivity Tests; Polyethylene Glycols; Pseudomonas Infections; Pseudomonas aeruginosa; Skin Diseases, Bacterial
PubMed: 34117588
DOI: 10.1007/s11095-021-03057-1 -
The Journal of Antibiotics May 2022The emergence of bacterial resistance poses a serious threat to public health. One of the most important resistance mechanisms against β-lactam antibiotics is the...
The emergence of bacterial resistance poses a serious threat to public health. One of the most important resistance mechanisms against β-lactam antibiotics is the production of metallo-β-lactamases (MBLs). In this study, α-lipoic acid (LA) and methimazole (MMI), which have been used in clinical practice as non-antibacterial drugs and as a supplement, were chosen to explore their potential to be metallo-β-lactamases inhibitors (MBLIs). Enzyme inhibition assays showed that LA and MMI had moderate inhibitory activity against NDM-1 but no activity against VIM-2 and IMP-7. Antibacterial assays to determine synergy, demonstrated that the combination of LA or MMI with meropenem (MER) reduced the MIC value of MER against NDM-1 producing E. coli 16 times and 4 times, respectively, lower than that of MER alone. The fractional inhibitory concentration index (FICI) values were calculated to be less than 0.5, indicating that both LA and MMI had synergistic antibacterial effects with MER against all three MBLs expressing E. coli strains. The time-kill studies also suggested that LA and MMI were effective in restoring the antibacterial effect of MER. These findings revealed that LA and MMI are potential carbapenem enhancers, and provide a starting point for the development of potent MBLIs.
Topics: Anti-Bacterial Agents; Escherichia coli; Meropenem; Methimazole; Microbial Sensitivity Tests; Thioctic Acid; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35197545
DOI: 10.1038/s41429-022-00513-x -
Therapeutic Drug Monitoring Jun 2022This therapeutic drug monitoring (TDM) grand round describes a patient with serious valproic acid intoxication. A total valproic acid level of 844 mg/L and an unbound...
This therapeutic drug monitoring (TDM) grand round describes a patient with serious valproic acid intoxication. A total valproic acid level of 844 mg/L and an unbound valproic acid level of 604 mg/L were observed. Meropenem was administered to enhance the clearance of valproic acid. This off-label usage of meropenem is based on the drug-drug interaction between carbapenems and valproic acid, which reduced the level of valproic acid within 24 hours after administration.
Topics: Anti-Bacterial Agents; Anticonvulsants; Drug Interactions; Humans; Meropenem; Valproic Acid
PubMed: 35170557
DOI: 10.1097/FTD.0000000000000973 -
Indian Journal of Pharmacology 2021Meropenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are the two most common nosocomial pathogens causing ventilator-associated pneumonia. To combat...
BACKGROUND
Meropenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa are the two most common nosocomial pathogens causing ventilator-associated pneumonia. To combat this resistance, different combinations of antibiotics have been evaluated for their efficacy in laboratories as well as in clinical situations.
AIM
The aim of the study was to investigate the effect of combined colistin and meropenem against meropenem-resistant isolates of A. baumannii and P. aeruginosa by checkerboard method.
MATERIALS AND METHODS
Fifty meropenem-resistant isolates of A. baumannii (n = 25) and P. aeruginosa (n = 25) from endotracheal aspirates were studied. The MIC of colistin and meropenem was found using the microbroth dilution method. The fractional inhibitory concentration was calculated for the combination of antibiotics by checkerboard assay and the antibiotic interactions were assessed. Fisher's exact test was carried out for statistical comparison of categorical variables.
RESULTS
A synergistic effect between colistin and meropenem was observed in 18/25 (72%) and 6/25 (24%) isolates of Acinetobacter baumannnii and P. Aeruginosa, respectively, with fractional inhibitory concentration indices of ≤0.5. None of the tested isolates exhibited antagonism.
CONCLUSION
Our results showed that combinations of colistin and meropenem are associated with improvement in minimum inhibitory concentration and may be a promising strategy in treating meropenem-resistant A. baumannii respiratory tract infections.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Colistin; Cross-Sectional Studies; Drug Combinations; Drug Resistance, Multiple, Bacterial; Drug Synergism; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas aeruginosa
PubMed: 34169905
DOI: 10.4103/ijp.ijp_1013_20 -
Clinical Therapeutics Apr 2020Meropenem and vaborbactam is an intravenous beta-lactam/beta-lactamase inhibitor combination antibiotic active against multidrug resistant gram-negative bacteria. It may...
PURPOSE
Meropenem and vaborbactam is an intravenous beta-lactam/beta-lactamase inhibitor combination antibiotic active against multidrug resistant gram-negative bacteria. It may be a suitable treatment for inpatient and outpatient management of infections, and the intravenous admixture stability is therefore important for optimal utilization. The purpose of this study was to determine the stability of meropenem and vaborbactam in polyvinyl chloride (PVC) infusion bags and elastomeric pumps at room and refrigerated temperatures.
METHODS
Meropenem and vaborbactam vials were reconstituted according to manufacturer instructions and diluted in PVC infusion bags to final concentrations of 4, 8, and 16 mg/mL and in elastomeric pumps to 11.4 mg/mL (n = 5 replicates per concentration and per temperature). PVC bags and elastomeric pumps were stored at room temperature (~24 °C) or in the refrigerator (~4 °C) and sampled over 12 and 144 h, respectively. Stability was defined as the duration that meropenem and vaborbactam concentrations remained ≥90% of the original concentrations.
FINDINGS
All room temperature replicates across the tested concentrations retained meropenem and vaborbactam stability over 12 h and displayed concentration-dependent degradation. Refrigerated studies resulted in meropenem and vaborbactam stability at all tested concentrations up to 120 h.
IMPLICATIONS
Meropenem and vaborbactam in PVC bags (4, 8, and 16 mg/mL) and elastomeric pumps (11.4 mg/mL) were stable for 12 h at room temperature and 120 h when refrigerated. These stability data allow for enhanced flexibility in the preparation, storage, wastage, and administration of meropenem and vaborbactam in the hospital and outpatient setting.
Topics: Anti-Bacterial Agents; Boronic Acids; Drug Combinations; Drug Stability; Elastomers; Heterocyclic Compounds, 1-Ring; Infusion Pumps; Infusions, Intravenous; Meropenem; Polyvinyl Chloride; Refrigeration; Temperature
PubMed: 32139176
DOI: 10.1016/j.clinthera.2020.01.021 -
The Journal of Antimicrobial... Oct 2023The rise of MDR Gram-negative bacteria (GNB), especially those resistant to last-resort drugs such as carbapenems and colistin, is a global health risk and calls for...
OBJECTIVES
The rise of MDR Gram-negative bacteria (GNB), especially those resistant to last-resort drugs such as carbapenems and colistin, is a global health risk and calls for increased efforts to discover new antimicrobial compounds. We previously reported that polyimidazolium (PIM) compounds exhibited significant antimicrobial activity and minimal mammalian cytotoxicity. However, their mechanism of action is relatively unknown. We examined the efficacy and mechanism of action of a hydrophilic PIM (PIM5) against colistin- and meropenem-resistant clinical isolates.
METHODS
MIC and time-kill testing was performed for drug-resistant Escherichia coli and Klebsiella pneumoniae clinical isolates. N-phenyl-1-naphthylamine and propidium iodide dyes were employed to determine membrane permeabilization. Spontaneous resistant mutants and single deletion mutants were generated to understand potential resistance mechanisms to the drug.
RESULTS
PIM5 had the same effectiveness against colistin- and meropenem-resistant strains as susceptible strains of GNB. PIM5 exhibited a rapid bactericidal effect independent of bacterial growth phase and was especially effective in water. The polymer disrupts both the outer and cytoplasmic membranes. PIM5 binds and intercalates into bacterial genomic DNA upon entry of cells. GNB do not develop high resistance to PIM5. However, the susceptibility and uptake of the polymer is moderately affected by mutations in the two-component histidine kinase sensor BaeS. PIM5 has negligible cytotoxicity on human cells at bacterial-killing concentrations, comparable to the commercial antibiotics polymyxin B and colistin.
CONCLUSIONS
PIM5 is a potent broad-spectrum antibiotic targeting GNB resistant to last-resort antibiotics.
Topics: Animals; Humans; Anti-Bacterial Agents; Colistin; Meropenem; Gram-Negative Bacteria; Anti-Infective Agents; Escherichia coli; Microbial Sensitivity Tests; Drug Resistance, Multiple, Bacterial; Mammals
PubMed: 37671807
DOI: 10.1093/jac/dkad274