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Clinical Therapeutics Apr 2020The search for new agents to treat multidrug-resistant gram-negative bacterial infections has been ongoing. Specifically, carbapenem-resistant Enterobacteriaceae (CRE)... (Review)
Review
PURPOSE
The search for new agents to treat multidrug-resistant gram-negative bacterial infections has been ongoing. Specifically, carbapenem-resistant Enterobacteriaceae (CRE) infections often exhibit multiple resistance mechanisms, including alterations in drug structure, bacterial efflux pumps, and drug permeability. Vaborbactam, a cyclic boronic acid pharmacophore, has the highest potency in vitro with meropenem as an inhibitor of class A carbapenemases, including Klebsiella pneumoniae carbapenemase (KPC). This combination product was approved by the US Food and Drug Administration for complicated urinary tract infections (cUTIs) in August 2017, and recent Phase III trial data have expanded the literature available. This article aimed to describe the literature regarding spectrum of activity, dosing and administration, including pharmacokinetic and pharmacodynamics properties, safety profile, and efficacy end points.
METHODS
The terms meropenem, vaborbactam, RPX7009, and meropenem-vaborbactam were used to search for literature via PubMed, ClinicalTrials.gov, and published abstracts from 2013 to July 2019. Abstracts from IDWeek 2019 were also searched via these terms. Results were limited to availability in English.
FINDINGS
Meropenem-vaborbactam covers a spectrum of gram-negative bacterial pathogens, including K pneumoniae, Escherichia coli, and Enterobacter cloacae complex. Although the addition of vaborbactam to meropenem results in MIC lowering for KPC-positive Enterobacteriaceae, in vitro data reveal limited activity against resistant strains of Acinetobacter species and Pseudomonas aeruginosa. Data from 2 Phase III studies compare the drug with available therapies for the following indications: cUTIs, acute pyelonephritis, hospital-acquired and ventilator-acquired bacterial pneumonia, bacteremia, and complicated intra-abdominal infections. Outcomes include an improvement in clinical success when compared with piperacillin-tazobactam (98.4% vs 94%; 95% CI, 0.7%-9.1%; P < 0.001 for noninferiority) for overall treatment of cUTIs and acute pyelonephritis and clinical cure (64.3% vs 33.3%; P = 0.04) when compared with best available therapy for CRE infections in various sites of infection. Adverse events have been described as mild to moderate, with few events requiring discontinuation of the drug therapy.
IMPLICATIONS
Currently, meropenem-vaborbactam is approved for treatment of cUTIs and acute pyelonephritis; however, off-label use, in particular for CRE infections, appears beneficial. Clinical trials to date have found an improvement in clinical cure and potentially an improved tolerability compared with standard therapies. Most of the evidence for meropenem-vaborbactam activity and the role in therapy focuses on KPC-producing organisms; however, because in vitro activity has been found with some non-KPC-producing CRE, its role may be further described from upcoming in vivo cases and postmarketing research.
Topics: Anti-Bacterial Agents; Boronic Acids; Drug Combinations; Drug Interactions; Heterocyclic Compounds, 1-Ring; Humans; Meropenem
PubMed: 32147146
DOI: 10.1016/j.clinthera.2020.01.023 -
Expert Review of Anti-infective Therapy Jan 2022The emergence of carbapenemase resistant Gram-negative is designated as an 'urgent' priority of public health. Carbapenemase producing (CPKP) is linked with significant... (Review)
Review
INTRODUCTION
The emergence of carbapenemase resistant Gram-negative is designated as an 'urgent' priority of public health. Carbapenemase producing (CPKP) is linked with significant mortality. Conventionally used antibiotics (polymyxins, tigecycline, aminoglycosides, etc.) are associated with poor efficacy and toxicity profiles are quite worrisome.
AREAS COVERED
This article reviews mechanism of resistance and evidence regarding novel treatments of infections caused by CPKP, focusing mainly on currently approved new therapies and implications on future therapeutic strategies. A review of novel β-lactam/β-lactamase inhibitors (BLI) recently approved and in clinical development as well as cefiderocol, eravacycline and apramycin are discussed.
EXPERT OPINION
Newly approved and forthcoming antimicrobial agents are promising to combat infections caused by CPKP. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-cilastatin-relebactam are novel agents with favorable outcome and associated with improved mortality in KPC-producing infections. However, are inactive against metallo-β-lactamases (MBL). Novel BLI in later stage of development, i.e. aztreonam-avibactam, cefepime-zidebactam, cefepime-taniborbactam, and meropenem-nacubactam as well as cefiderocol are active against both KPC and MBL. Potential expectations of future therapeutic strategies are improved potency against CPKP, more tolerable safety profile, and capability of overcoming current resistance mechanism of multidrug-resistant .
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Proteins; Carbapenem-Resistant Enterobacteriaceae; Ceftazidime; Drug Combinations; Humans; Klebsiella pneumoniae; Meropenem; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 34033499
DOI: 10.1080/14787210.2021.1935237 -
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 -
Expert Review of Anti-infective Therapy Jul 2020infections due to carbapenem-resistant (CRE) constitute a worldwide threat and are associated with significant mortality, especially in fragile patients, and costs.... (Review)
Review
INTRODUCTION
infections due to carbapenem-resistant (CRE) constitute a worldwide threat and are associated with significant mortality, especially in fragile patients, and costs. Meropenem-vaborbactam (M/V) is a combination of a group 2 carbapenem with a novel cyclic boronic acid-based β-lactamase inhibitor which has shown good efficacy against KPC carbapenemase-producing , which are amongst the most prevalent types of CRE.
AREAS COVERED
This article reviews the microbiological and pharmacological profile and current clinical experience and safety of M/V in the treatment of infections caused by CRE.
EXPERT OPINION
M/V is a promising drug for the treatment of infections due to KPC-producing CRE (KPC-CRE). It exhibited an almost complete coverage of KPC-CRE isolates from large surveillance studies and a low propensity for resistance selection, retaining activity also against strains producing KPC mutants resistant to ceftazidime-avibactam. Both meropenem and vaborbactam have a favorable pharmacokinetic profile, with similar kinetic properties, a good intrapulmonary penetration, and are efficiently cleared during continuous venovenous hemofiltration (CVVH). According to available data, M/V monotherapy is associated with higher clinical cure rates and lower rates of adverse events, especially in terms of nephrotoxicity, if compared to 'older' combination therapies.
Topics: Animals; Anti-Bacterial Agents; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Drug Combinations; Enterobacteriaceae Infections; Hemofiltration; Heterocyclic Compounds, 1-Ring; Humans; Meropenem; Tissue Distribution; beta-Lactamase Inhibitors
PubMed: 32297801
DOI: 10.1080/14787210.2020.1756775 -
Nature Communications Jun 2023Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap...
Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.
Topics: Mice; Animals; Anti-Bacterial Agents; Proteome; Meropenem; Sepsis; Gram-Negative Bacterial Infections; Bacteremia
PubMed: 37330510
DOI: 10.1038/s41467-023-39269-9 -
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 -
Farmacia Hospitalaria : Organo Oficial... Sep 2021The literature has described the interaction between valproic acid and carbapenems. This interaction leads to decreases in plasma concentrations of valproic acid.... (Observational Study)
Observational Study
OBJECTIVE
The literature has described the interaction between valproic acid and carbapenems. This interaction leads to decreases in plasma concentrations of valproic acid. The main objectives of this study were to assess its relevance in clinical practice, to identify variables associated with increased seizure episode rates, and to analyse the impact of pharmaceutical intervention on avoiding the effects of this interaction.
METHOD
An observational retrospective study of inpatients with epilepsy admitted between 2016 and 2020. Their pharmacological treatment throughout admission was recorded, and the presence of other interactions leading to decreased plasma concentrations of valproic acid was reviewed. The seizure rate during the year prior to admission was compared to that during the interaction period. For every episode in which the interaction was detected, an intervention was conducted by providing the prescriber with information on the interaction and suggesting a change of antibiotherapy as well as the pharmacokinetic monitoring of valproic acid.
RESULTS
37 episodes were included. 58.1% of the patients were male and median age was 70 years. In total, 56.8% of the patients received meropenem and 43.2% received ertapenem. The median duration of concomitant treatment with valproic acid and carbapenem was 4 days. The incidence rate ratio was 2.60 (95% confidence interval: 1.61-4.21). Thus, this interaction was associated with a higher seizure rate. A statistically significant association was found between higher seizure rates and patients treated with more than one anti-epileptic drug. Hospital pharmacists detected 24 episodes (64.9%). In total, 17 interventions (70.8%) were accepted and 13 combinations were discontinued. Pharmacokinetic monitoring was conducted in 13 episodes (35.1%) and infratherapeutic levels were found in all of them.
CONCLUSIONS
The interaction between valproic acid and meropenem or ertapenem is clinically relevant. It is recommended that this combination should be avoided provided that a viable alternative is available. Pharmaceutical intervention may contribute to preventing seizures associated with this combination.
Topics: Aged; Anti-Bacterial Agents; Anticonvulsants; Drug Interactions; Epilepsy; Ertapenem; Humans; Male; Meropenem; Pharmaceutical Preparations; Retrospective Studies; Valproic Acid
PubMed: 34806574
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Oct 2023Cefmetazole is active against extended-spectrum β-lactamase-producing (ESBLEC) and is a potential candidate for carbapenem-sparing therapy. This multicenter,... (Observational Study)
Observational Study
Cefmetazole is active against extended-spectrum β-lactamase-producing (ESBLEC) and is a potential candidate for carbapenem-sparing therapy. This multicenter, observational study included patients hospitalized for invasive urinary tract infection due to ESBLEC between March 2020 and November 2021 at 10 facilities in Japan, for whom either cefmetazole or meropenem was initiated as a definitive therapy within 96 h of culture collection and continued for at least 3 d. Outcomes included clinical and microbiological effectiveness, recurrence within 28 d, and all-cause mortality (14 d, 30 d, in-hospital). Outcomes were adjusted for the inverse probability of propensity scores for receiving cefmetazole or meropenem. Eighty-one and forty-six patients were included in the cefmetazole and meropenem groups, respectively. Bacteremia accounted for 43% of the cefmetazole group, and 59% of the meropenem group. The crude clinical effectiveness, 14 d, 30 d, and in-hospital mortality for patients in the cefmetazole and meropenem groups were 96.1% vs 90.9%, 0% vs 2.3%, 0% vs 12.5%, and 2.6% vs 13.3%, respectively. After propensity score adjustment, clinical effectiveness, the risk of in-hospital mortality, and the risk of recurrence were similar between the two groups ( = 0.54, = 0.10, and = 0.79, respectively). In all cases with available data (cefmetazole : = 61, meropenem : = 22), both drugs were microbiologically effective. In all isolates, was detected as the extended-spectrum β-lactamase gene. The predominant CTX-M subtype was CTX-M-27 (47.6%). Cefmetazole showed clinical and bacteriological effectiveness comparable to meropenem against invasive urinary tract infection due to ESBLECs.
Topics: Humans; Cefmetazole; Meropenem; beta-Lactamases; Escherichia coli; Urinary Tract Infections; Escherichia coli Infections; Anti-Bacterial Agents
PubMed: 37702483
DOI: 10.1128/aac.00510-23 -
The Journal of Antimicrobial... Mar 2022In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be... (Randomized Controlled Trial)
Randomized Controlled Trial
Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia.
OBJECTIVES
In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated.
METHODS
Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7-14 days after the end of therapy) in the microbiological ITT (mITT) population.
RESULTS
The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: -4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: -18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: -4.51 to 19.38], respectively, were also comparable.
CONCLUSIONS
In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.
Topics: Anti-Bacterial Agents; Cephalosporins; Hospitals; Humans; Meropenem; Microbial Sensitivity Tests; Pneumonia, Bacterial; Prospective Studies; Pseudomonas aeruginosa; Tazobactam; Ventilators, Mechanical
PubMed: 35022730
DOI: 10.1093/jac/dkab494 -
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