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European Journal of Clinical... Sep 2023Carbapenemase-producing in Enterobacterales (CPE) represent a critical health concern worldwide, including in Switzerland, leading to very limited therapeutic options....
Carbapenemase-producing in Enterobacterales (CPE) represent a critical health concern worldwide, including in Switzerland, leading to very limited therapeutic options. Therefore, our aim was to evaluate the susceptibility to the novel ß-lactam/ß-lactamase inhibitor combinations ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam of CPE isolates recovered in Switzerland from 2018 to 2020. A total of 150 clinical CPE were studied including mainly Klebsiella pneumoniae (n = 61, 40.3%) and Escherichia coli (n = 53, 35.3%). The distribution of carbapenemases was as follows: KPC-like (32%), OXA-48-like (32%), NDM-like (24%), combinations of carbapenemases (10%), VIM-1 producers (n = 2), and a single IMI-1 producer. Overall, 77% of the strains were susceptible to meropenem-vaborbactam, 63% was susceptible to ceftazidime-avibactam, and 62% susceptible to imipenem-relebactam. Those data may contribute to optimize the choice of first line therapy for treating infections due to CPE.
Topics: Humans; Meropenem; Switzerland; Anti-Bacterial Agents; Ceftazidime; beta-Lactamases; Bacterial Proteins; Drug Combinations; Imipenem; Microbial Sensitivity Tests; Klebsiella pneumoniae
PubMed: 37566365
DOI: 10.1007/s10096-023-04647-0 -
Antimicrobial Agents and Chemotherapy Nov 2022Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and...
Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and affecting therapeutic outcomes. This study aimed to characterize the population pharmacokinetic (PPK) parameters of meropenem, evaluate the relationship between the pharmacokinetic/pharmacodynamic index of meropenem and treatment outcomes, and evaluate the different dosage regimens that can achieve 40%, 75%, and 100% of the dosing interval for which the free plasma concentrations remain above the MIC of the pathogens () targets. Critically ill adult patients treated with meropenem were recruited for this study. Five blood samples were collected from each patient. PPK models were developed using a nonlinear mixed-effects modeling approach, and the final model was subsequently used for Monte Carlo simulations to determine the optimal dosage regimens. A total of 247 concentrations from 52 patients were available for analysis. The two-compartment model with linear elimination adequately described the data. The mean PPK parameters were clearance (CL) of 4.8 L/h, central volume of distribution (V) of 11.4 L, peripheral volume of distribution (V) of 14.6 L, and intercompartment clearance of 10.5 L/h. Creatinine clearance was a significant covariate affecting CL, while serum albumin level and shock status were factors influencing V and V, respectively. Although 75% of the drug-resistant infection patients had values of >40%, approximately 83% of them did not survive the infection. Therefore, 40% might not be sufficient for critically ill patients, and a higher target, such as 75 to 100% , should be considered for optimizing therapy. A 75% could be reached using approved doses administered via a 3-h infusion.
Topics: Humans; Adult; Meropenem; Critical Illness; Anti-Bacterial Agents; Monte Carlo Method; Microbial Sensitivity Tests
PubMed: 36226944
DOI: 10.1128/aac.00845-22 -
Diagnostic Microbiology and Infectious... Jun 2023A total of 35,360 Enterobacterales isolates were consecutively collected from 75 US medical centers in 2018-2022. Among these isolates, 2612 (7.4%) were categorized as...
Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam activities against multidrug-resistant Enterobacterales from United States Medical Centers (2018-2022).
A total of 35,360 Enterobacterales isolates were consecutively collected from 75 US medical centers in 2018-2022. Among these isolates, 2612 (7.4%) were categorized as multidrug-resistant (MDR). Isolates were susceptibility tested by reference broth microdilution methods. Carbapenem-resistant Enterobacterales (CRE) were screened for carbapenemase (CPE) genes by whole genome sequencing. The highest MDR rates was observed among Klebsiella pneumoniae (12.2%), followed by Raoultella spp. (10.9%) and Providencia stuartii (9.8%). Ceftazidime-avibactam and meropenem-vaborbactam were very active and showed identical susceptibility rates against MDR isolates (97.9%). Imipenem-relebactam (93.5% susceptible [S]) exhibited slightly lower susceptibility rates due to its limited activity against Morganellaceae family. The most active β-lactamase inhibitor combination (BLI) against CRE isolates (n = 310) was ceftazidime-avibactam (84.2%S), followed by meropenem-vaborbactam (81.9%S) and imipenem-relebactam (74.8%S). All 3 BLIs were very active against KPC producers and none were active against MBL producers. Ceftazidime-avibactam exhibited greater activity against OXA-48-type producers than meropenem-vaborbactam and imipenem-vaborbactam.
Topics: United States; Humans; Meropenem; Anti-Bacterial Agents; Ceftazidime; Azabicyclo Compounds; Drug Combinations; Imipenem; beta-Lactamases; Carbapenems; Microbial Sensitivity Tests
PubMed: 37060707
DOI: 10.1016/j.diagmicrobio.2023.115945 -
BMC Infectious Diseases Apr 2023Which antimicrobial agents provide the optimal efficacy, safety, and tolerability for the empirical treatment of complicated intra-abdominal infection (cIAI) remains... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Which antimicrobial agents provide the optimal efficacy, safety, and tolerability for the empirical treatment of complicated intra-abdominal infection (cIAI) remains unclear but is paramount in the context of evolving antimicrobial resistance. Therefore, updated meta-analyses on this issue are warranted.
METHODS
We systematically searched four major electronic databases from their inception through October 2022. Randomized controlled trials examining antimicrobial agents for cIAI treatment were included. Two reviewers independently assessed the quality of included studies utilizing the Cochrane Collaboration's risk of bias tool as described in the updated version 1 of the Cochrane Collaboration Handbook and extracted data from all manuscripts according to a predetermined list of topics. All meta-analyses were conducted using R software. The primary outcome was clinical success rate in patients with cIAIs.
RESULTS
Forty-five active-controlled trials with low to medium methodological quality and involving 14,267 adults with cIAIs were included in the network meta-analyses. The vast majority of patients with an acute physiology and chronic health evaluation II score < 10 had low risk of treatment failure or death. Twenty-one regimens were investigated. In the network meta-analyses, cefepime plus metronidazole was more effective than tigecycline and ceftolozane/tazobactam plus metronidazole (odds ratio [OR] = 1.96, 95% credibility interval [CrI] 1.05 ~ 3.79; OR = 3.09, 95% CrI 1.02 ~ 9.79, respectively). No statistically significant differences were found among antimicrobial agents regarding microbiological success rates. Cefepime plus metronidazole had lower risk of all-cause mortality than tigecycline (OR = 0.22, 95% CrI 0.05 ~ 0.85). Statistically significant trends were observed favoring cefotaxime plus metronidazole, which exhibited fewer discontinuations because of adverse events (AEs) when compared with eravacycline, meropenem and ceftolozane/tazobactam plus metronidazole (OR = 0.0, 95% CrI 0.0 ~ 0.8; OR = 0.0, 95% CrI 0.0 ~ 0.7; OR = 0.0, 95% CrI 0.0 ~ 0.64, respectively). Compared with tigecycline, eravacycline was associated with fewer discontinuations because of AEs (OR = 0.17, 95% CrI 0.03 ~ 0.81). Compared with meropenem, ceftazidime/avibactam plus metronidazole had a higher rate of discontinuation due to AEs (OR = 2.09, 95% CrI 1.0 ~ 4.41). In pairwise meta-analyses, compared with ceftriaxone plus metronidazole, ertapenem and moxifloxacin (one trial, OR = 1.93, 95% CI 1.06 ~ 3.50; one trial, OR = 4.24, 95% CI 1.18 ~ 15.28, respectively) were associated with significantly increased risks of serious AEs. Compared with imipenem/cilastatin, tigecycline (four trials, OR = 1.57, 95%CI 1.07 ~ 2.32) was associated with a significantly increased risk of serious AEs. According to the surface under the cumulative ranking curve, Cefepime plus metronidazole was more likely to be optimal among all treatments in terms of efficacy and safety, tigecycline was more likely to be worst regimen in terms of tolerability, and eravacycline was more likely to be best tolerated.
CONCLUSION
This study suggests that cefepime plus metronidazole is optimal for empirical treatment of patients with cIAIs and that tigecycline should be prescribed cautiously considering the safety and tolerability concerns. However, it should be noted that data currently available on the effectiveness, safety, and tolerability of antimicrobial agents pertain mostly to lower-risk patients with cIAIs.
Topics: Adult; Humans; Metronidazole; Meropenem; Network Meta-Analysis; Tigecycline; Cefepime; Anti-Bacterial Agents; Intraabdominal Infections; Tazobactam; Anti-Infective Agents
PubMed: 37085768
DOI: 10.1186/s12879-023-08209-9 -
Journal of Medical Microbiology Dec 2021Carbapenems are potent members of the β-lactam family that inhibit bacterial cell-wall biosynthesis inhibitors . They are highly effective against Gram-negative and... (Review)
Review
Carbapenems are potent members of the β-lactam family that inhibit bacterial cell-wall biosynthesis inhibitors . They are highly effective against Gram-negative and Gram-positive drug-resistant infections . As such, carbapenems are typically reserved as an antibiotic of last resort. The WHO lists meropenem as an essential medicine. Nausea and vomiting are reported in ≤20% of carbapenem recipients, with 1.5% suffering seizures. Enzymatic hydrolysis of the βlactam ring is the main driver of clinical resistance. These enzymes can be classified as Class A, B and D. Classes A and D are serine βlactamases, whereas Class B rely on metal-mediated hydrolysis, typically through zinc.
Topics: Anti-Bacterial Agents; Carbapenems; Meropenem; beta-Lactamases; beta-Lactams
PubMed: 34889726
DOI: 10.1099/jmm.0.001462 -
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 -
Scientific Reports Nov 2022Understanding the response of bacteria to environmental stress is hampered by the relative insensitivity of methods to detect growth. This means studies of antibiotic...
Understanding the response of bacteria to environmental stress is hampered by the relative insensitivity of methods to detect growth. This means studies of antibiotic resistance and other physiological methods often take 24 h or longer. We developed and tested a scattered light and detection system (SLIC) to address this challenge, establishing the limit of detection, and time to positive detection of the growth of small inocula. We compared the light-scattering of bacteria grown in varying high and low nutrient liquid medium and the growth dynamics of two closely related organisms. Scattering data was modelled using Gompertz and Broken Stick equations. Bacteria were also exposed meropenem, gentamicin and cefoxitin at a range of concentrations and light scattering of the liquid culture was captured in real-time. We established the limit of detection for SLIC to be between 10 and 100 cfu mL in a volume of 1-2 mL. Quantitative measurement of the different nutrient effects on bacteria were obtained in less than four hours and it was possible to distinguish differences in the growth dynamics of Klebsiella pneumoniae 1705 possessing the Bla betalactamase vs. strain 1706 very rapidly. There was a dose dependent difference in the speed of action of each antibiotic tested at supra-MIC concentrations. The lethal effect of gentamicin and lytic effect of meropenem, and slow bactericidal effect of cefoxitin were demonstrated in real time. Significantly, strains that were sensitive to antibiotics could be identified in seconds. This research demonstrates the critical importance of improving the sensitivity of bacterial detection. This results in more rapid assessment of susceptibility and the ability to capture a wealth of data on the growth dynamics of bacteria. The rapid rate at which killing occurs at supra-MIC concentrations, an important finding that needs to be incorporated into pharmacokinetic and pharmacodynamic models. Importantly, enhanced sensitivity of bacterial detection opens the possibility of susceptibility results being reportable clinically in a few minutes, as we have demonstrated.
Topics: Anti-Bacterial Agents; Meropenem; Cefoxitin; Klebsiella pneumoniae; Gentamicins; Microbial Sensitivity Tests
PubMed: 36371444
DOI: 10.1038/s41598-022-22671-6 -
BMC Microbiology Dec 2022Acinetobacter baumannii (A. baumannii) is one of the members of ESKAPE bacteria which is considered multidrug resistant globally. The objective of this study is to...
Acinetobacter baumannii (A. baumannii) is one of the members of ESKAPE bacteria which is considered multidrug resistant globally. The objective of this study is to determine the protein docking of different antibiotic resistance gene (ARGs) in A. baumannii. In silico analysis of antibiotic resistance genes against carbapenem are the blaOXA-51, blaOXA-23, blaOXA-58, blaOXA-24, blaOXA-143, NMD-1 and IMP-1 in A. baumannii. The doripenem, imipenem and meropenem were docked to blaOXA-51 and blaOXA-23 using PyRx. The top docking energy was -5.5 kcal/mol by imipenem and doripenem and meropenem showed a binding score of -5. 2 kcal/mol each and blaOXA-23 energy was -4.3 kcal/mol by imipenem and meropenem showed a binding score of -2.3 kcal/mol, while doripenem showed the binding score of -3.4 kcal/mol. Similarly, doripenem imipenem and meropenem were docked to blaOXA-58, IMP-1, Rec A and blaOXA-143, with docking energy was -8.8 kcal/mol by doripenem and meropenem each while imipenem showed a binding score of -4.2 kcal/mol and with IMP-1 demonstrated their binding energies. was -5.7 kcal/mol by meropenem and doripenem showed a binding score of -5.3 kcal/mol, while imipenem showed a binding score of -4.5 kcal/mol. And docking energy was -4.9 kcal/mol by imipenem and meropenem showed binding energy of -3.6 kcal/mol each while doripenem showed a binding score of -3.9 kcal/mol in RecA and with blaOXA-143 docking energy was -3.0 kcal/mol by imipenem and meropenem showed a binding score of -1.9 kcal/mol, while doripenem showed the binding score of -2.5 kcal/mol respectively. Doripenem, imipenem, and meropenem docking findings with blaOXA-24 confirmed their binding energies. Doripenem had the highest docking energy of -5.5 kcal/mol, meropenem had a binding score of -4.0 kcal/mol, and imipenem had a binding score of -3.9 kcal/mol. PyRx was used to dock the doripenem, imipenem, and meropenem to NMD-1. Docking energies for doripenem were all - 4.0 kcal/mol, whereas meropenem had docking energy of -3.3 kcal/mol and imipenem was -1.50 kcal/mol. To the best of our knowledge the underlying mechanism of phenotypic with genotypic resistance molecular docking regarding carbapenem resistance A. baumannii is unclear. Our molecular docking finds the possible protein targeting mechanism for carbapenem-resistant A.baumannii.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Carbapenems; Doripenem; Imipenem; Meropenem; Molecular Docking Simulation
PubMed: 36463105
DOI: 10.1186/s12866-022-02706-8 -
Drugs Aug 2018The global threat of the spread of carbapenem resistance in Enterobacteriaceae has led to the search for new antibacterials. Intravenous meropenem/vaborbactam... (Review)
Review
The global threat of the spread of carbapenem resistance in Enterobacteriaceae has led to the search for new antibacterials. Intravenous meropenem/vaborbactam (Vabomere™) is the first carbapenem/β-lactamase inhibitor combination approved in the USA for use in patients with complicated urinary tract infections (cUTIs), including pyelonephritis. Vaborbactam is a potent inhibitor of class A serine carbapenemases, which, when combined with the antibacterial meropenem, restores the activity of meropenem against β-lactamase producing Enterobacteriaceae, particularly Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae. Meropenem/vaborbactam demonstrated excellent in vitro activity against Gram-negative clinical isolates, including KPC- and extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. In the phase 3, noninferiority TANGO I trial in patients with cUTIs, intravenous meropenem/vaborbactam was noninferior to intravenous piperacillin/tazobactam for overall success (composite of clinical cure and microbial eradication; FDA primary endpoint) and microbial eradication (EMA primary endpoint). In subsequent superiority testing, meropenem/vaborbactam was superior to piperacillin/tazobactam for overall success. Meropenem/vaborbactam was generally well tolerated, with a tolerability profile generally similar to that of piperacillin/tazobactam. TANGO I did not assess the efficacy of meropenem/vaborbactam for the treatment of infections caused by carbapenem-resistant Enterobacteriaceae and meropenem/vaborbactam is currently not indicated for these patients. Available evidence indicates that meropenem/vaborbactam is a useful treatment option for patients with cUTIs.
Topics: Anti-Bacterial Agents; Boronic Acids; Drug Approval; Drug Combinations; Drug Resistance, Bacterial; Enterobacteriaceae; Humans; Meropenem; Piperacillin, Tazobactam Drug Combination; Treatment Outcome; United States; Urinary Tract Infections; beta-Lactamase Inhibitors
PubMed: 30128699
DOI: 10.1007/s40265-018-0966-7 -
Antimicrobial Agents and Chemotherapy Feb 2022Biofilms colonize medical devices and are often recalcitrant to antibiotics. Interkingdom biofilms, where at least a bacterium and a fungus are present, increase the...
Biofilms colonize medical devices and are often recalcitrant to antibiotics. Interkingdom biofilms, where at least a bacterium and a fungus are present, increase the likelihood of therapeutic failures. In this work, a three-species biofilm model including Staphylococcus aureus, Escherichia coli, and Candida albicans was used to study the activity of the antibiotics moxifloxacin and meropenem, the antifungal caspofungin, and combinations of them against interkingdom biofilms. The culturable cells and total biomass were evaluated to determine the pharmacodynamic parameters of the drug response for the incubation with the drugs alone. The synergic or antagonistic effects (increased/decreased effects) of the combination of drugs were analyzed with the highest-single-agent method. Biofilms were imaged in confocal microscopy after live/dead staining. The drugs had limited activity when used alone against single-, dual-, and three-species biofilms. When used in combination, additive effects against single- and dual-species biofilms and increased effects (synergy) against biomass of three-species biofilms were observed. In addition, the two antibiotics showed different patterns, moxifloxacin being more active when targeting S. aureus and meropenem when targeting E. coli. All these observations were confirmed by confocal microscopy images. Our findings highlight the interest in combining caspofungin with antibiotics against interkingdom biofilms.
Topics: Antifungal Agents; Biofilms; Candida albicans; Caspofungin; Escherichia coli; Meropenem; Microbial Sensitivity Tests; Moxifloxacin; Staphylococcus aureus
PubMed: 34930026
DOI: 10.1128/AAC.02149-21