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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 -
Expert Review of Anti-infective Therapy Dec 2018Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat... (Review)
Review
Complicated urinary tract infections are increasingly caused by multidrug-resistant organisms. Carbapenem-resistant Enterobacteriaceae (CRE) constitute a rising threat among uropathogens with significant morbidity and mortality. Meropenem-vaborbactam is a novel carbapenem and cyclic boronic acid-based beta-lactamase inhibitor combination with potent activity against subtypes of CRE. Areas covered: This article reviews mechanisms of carbapenem resistance, existing treatment options for CRE, and the current evidence to support the use of meropenem-vaborbactam for the treatment of infections caused by subtypes of CRE including complicated urinary tract infections. Expert commentary: Meropenem-vaborbactam is a superior treatment option for infections secondary to Klebsiella pneumoniae carbapenemase (KPC)-producing CRE. It is associated with higher rates of treatment success and lower rates of toxicity than traditional agents and demonstrates a potentially higher barrier to acquired antimicrobial resistance than ceftazidime-avibactam. At present, meropenem-vaborbactam should be regarded as a preferred treatment option for invasive infections secondary to KPC-producing CRE.
Topics: Adult; Animals; Anti-Bacterial Agents; Boronic Acids; Carbapenem-Resistant Enterobacteriaceae; Drug Combinations; Drug Resistance, Multiple, Bacterial; Enterobacteriaceae Infections; Humans; Klebsiella pneumoniae; Meropenem; Urinary Tract Infections
PubMed: 30372359
DOI: 10.1080/14787210.2018.1542300 -
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 -
Antimicrobial Agents and Chemotherapy Aug 2021Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated...
Meropenem-vaborbactam is a broad-spectrum carbapenem-beta-lactamase inhibitor combination approved in the United States and Europe to treat patients with complicated urinary tract infections and in Europe for other serious bacterial infections, including hospital-acquired and ventilator-associated pneumonia. Population pharmacokinetic (PK) models were developed to characterize the time course of meropenem and vaborbactam using pooled data from two phase 1 and two phase 3 studies. Multicompartment disposition model structures with linear elimination processes were fit to the data using NONMEM 7.2. Since both drugs are cleared primarily by the kidneys, estimated glomerular filtration rate (eGFR) was evaluated as part of the base structural models. For both agents, a two-compartment model with zero-order input and first-order elimination best described the pharmacokinetic PK data, and a sigmoidal Hill-type equation best described the relationship between renal clearance and eGFR. For meropenem, the following significant covariate relationships were identified: clearance (CL) decreased with increasing age, CL was systematically different in subjects with end-stage renal disease, and all PK parameters increased with increasing weight. For vaborbactam, the following significant covariate relationships were identified: CL increased with increasing height, volume of the central compartment () increased with increasing body surface area, and CL, , and volume of the peripheral compartment were systematically different between phase 1 noninfected subjects and phase 3 infected patients. Visual predictive checks demonstrated minimal bias, supporting the robustness of the final models. These models were useful for generating individual PK exposures for pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy and Monte Carlo simulations to evaluate PK-PD target attainment.
Topics: Anti-Bacterial Agents; Boronic Acids; Drug Combinations; Heterocyclic Compounds, 1-Ring; Humans; Meropenem
PubMed: 34097490
DOI: 10.1128/AAC.02606-20 -
Microbiology Spectrum Jun 2022Debate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied the extent of bacterial killing by...
Debate continues as to the role of combination antibiotic therapy for the management of Pseudomonas aeruginosa infections. We studied the extent of bacterial killing by and the emergence of resistance to meropenem and amikacin as monotherapies and as a combination therapy against susceptible and resistant P. aeruginosa isolates from bacteremic patients using the dynamic hollow-fiber infection model. Three P. aeruginosa isolates (meropenem MICs of 0.125, 0.25, and 64 mg/L) were used, simulating bacteremia with an initial inoculum of ~1 × 10 CFU/mL and the expected pharmacokinetics of meropenem and amikacin in critically ill patients. For isolates susceptible to amikacin and meropenem (isolates 1 and 2), the extent of bacterial killing was increased with the combination regimen compared with the killing by monotherapy of either antibiotic. Both the combination and meropenem monotherapy were able to sustain bacterial killing throughout the 7-day treatment course, whereas regrowth of bacteria occurred with amikacin monotherapy after 12 h. For the meropenem-resistant P. aeruginosa isolate (isolate 3), only the combination regimen demonstrated bacterial killing. Given that tailored antibiotic regimens can maximize potential synergy against some isolates, future studies should explore the benefit of combination therapy against resistant P. aeruginosa. Current guidelines recommend that aminoglycosides should be used in combination with β-lactam antibiotics as initial empirical therapy for serious infections, and otherwise, patients should receive β-lactam antibiotic monotherapy. Given the challenges associated with studying the clinical effect of different antibiotic strategies on patient outcomes, useful data for subsequent informed clinical testing can be obtained from models like the hollow-fiber infection model (HFIM). Based on the findings of our HFIM, we propose that the initial use of combination therapy with meropenem and amikacin provides some bacterial killing against carbapenem-resistant P. aeruginosa isolates. For susceptible isolates, combination therapy may only be of benefit in specific patient populations, such as critically ill or immunocompromised patients. Therefore, clinicians may want to consider using the combination therapy for the initial management and ceasing the aminoglycosides once antibiotic susceptibility results have been obtained.
Topics: Amikacin; Aminoglycosides; Anti-Bacterial Agents; Bacteremia; Critical Illness; Humans; Meropenem; Microbial Sensitivity Tests; Pseudomonas Infections; Pseudomonas aeruginosa
PubMed: 35442072
DOI: 10.1128/spectrum.00525-22 -
The Journal of Antimicrobial... Apr 2022To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter...
OBJECTIVES
To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii.
METHODS
Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time-kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice.
RESULTS
Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time-kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 μM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy.
CONCLUSIONS
These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.
Topics: Animals; Female; Mice; Acinetobacter baumannii; Anti-Bacterial Agents; beta-Lactamases; Carbapenems; Disulfiram; Meropenem; Microbial Sensitivity Tests
PubMed: 35199158
DOI: 10.1093/jac/dkac057 -
Enfermedades Infecciosas Y... Dec 2023Prolonged intravenous infusion of beta-lactams increase the clinical cure rate compared to conventional administration in critical or septic patients. This study aimed...
INTRODUCTION
Prolonged intravenous infusion of beta-lactams increase the clinical cure rate compared to conventional administration in critical or septic patients. This study aimed to determine chemical stability and physical compatibility of meropenem at conditions used in clinical practice to evaluate the stability of the preparation during its administration and the possibility of anticipated preparation.
METHODS
Admixtures in study were: (i) meropenem 6g in 0.9% sodium chloride (NS) in infusor of 2mL/h 50mL or 10mL/h 240mL; (ii) meropenem 1 or 2g in NS in infusion bag of 250mL. Temperatures of study were: (i) infusor: 4.5°C, 32°C or 12h at 4.5°C followed by 32°C; (ii) Infusion bag: 4.5°C, 24.5°C or 6h at 4.5°C followed by 24.5°C. Time of study was 5-6 days in infusor and 1 day in infusion bag. Chemical stability was evaluated by high performance liquid chromatography and physical compatibility by measuring pH and visual inspection.
RESULTS
Chemical stability and physical compatibility of meropenem in admixtures in infusors were reduced at high meropenem concentration and high temperature. Admixtures in infusion bag show chemical stability and physical compatibility for at least 1 day.
CONCLUSION
Administration of meropenem 6g in infusion of 24h in 240mL of 0.9% NaCl in infusor of 10mL/h could be possible if the admixture is infused at 4.5°C. Extended infusion of meropenem 1 or 2g in 0.9% NaCl in infusion bag (250mL) in 3-4h is also feasible. Anticipated preparation of the admixtures in infusion bag is possible with a stability of 24h.
Topics: Humans; Infusions, Intravenous; Meropenem; Saline Solution
PubMed: 36707284
DOI: 10.1016/j.eimce.2022.07.010 -
International Journal of Antimicrobial... Aug 2023Device-related infections are difficult to treat due to biofilms. In this setting, optimizing antibiotic efficacy is difficult as most pharmacokinetic/pharmacdynamic...
INTRODUCTION
Device-related infections are difficult to treat due to biofilms. In this setting, optimizing antibiotic efficacy is difficult as most pharmacokinetic/pharmacdynamic (PK/PD) studies have been performed on planktonic cells, and therapies are limited when multi-drug-resistant bacteria are involved. This study aimed to analyse the PK/PD indices of meropenem predicting anti-biofilm efficacy against meropenem-susceptible and meropenem-resistant strains of Pseudomonas aeruginosa.
MATERIALS AND METHODS
Pharmacodynamics of meropenem dosages mimicking those of clinical practice (intermittent bolus of 2 g every 8 h; extended infusion of 2 g over 4 h every 8 h), with and without colistin, were evaluated with the CDC Biofilm Reactor in-vitro model for susceptible (PAO1) and extensively-drug-resistant (XDR-HUB3) P. aeruginosa. Efficacy was correlated with the PK/PD indices for meropenem.
RESULTS
For PAO1, both meropenem regimens were bactericidal, with higher killing for extended infusion [∆log colony-forming units (CFU)/mL 54-0h=-4.66±0.93 for extended infusion vs ∆log CFU/mL 54-0h=-3.4±0.41 for intermittent bolus; P<0.001]. For XDR-HUB3, the intermittent bolus regimen was non-active, but extended infusion showed bactericidal effect (∆log CFU/mL 54-0h=-3.65±0.29; P<0.001). Time above minimum inhibitory concentration (f%T) had the best correlation with efficacy for both strains. The addition of colistin always improved meropenem activity, and resistant strains did not emerge.
CONCLUSION
f%T was the PK/PD index that best correlated with the anti-biofilm efficacy of meropenem; it was better optimized when using the extended infusion regimen, allowing recovery of bactericidal activity in monotherapy, including activity against meropenem-resistant P. aeruginosa. Combining meropenem by extended infusion with colistin offered the most effective therapy for both strains. Optimizing meropenem dosing by extended infusion should be encouraged when treating biofilm-related infections.
Topics: Humans; Meropenem; Colistin; Pseudomonas aeruginosa; Pseudomonas Infections; Anti-Bacterial Agents; Microbial Sensitivity Tests
PubMed: 37211260
DOI: 10.1016/j.ijantimicag.2023.106856