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Antimicrobial Agents and Chemotherapy Jan 2021This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We...
This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM. Individual PK parameters were determined by a two-compartment analysis. The median (range) age and body weight were 1.4 (0.03 to 14.6) years and 8.9 (2.7 to 40.9) kg, respectively, and eight (23.5%) patients received continuous renal replacement therapy (CRRT), three of whom received extracorporeal membrane oxygenation. Renal function, the systemic inflammatory response syndrome (SIRS) score for the clearance (CL), and the use of CRRT for the central volume of distribution () were identified as significant covariates. The mean CL, , and peripheral volume of distribution () were 0.45 liters/kg/h, 0.49 liters/kg, and 0.34 liters/kg, respectively. The mean population CL of MEM increased by 35% in patients with SIRS and increased by 66% in patients on CRRT in the final model. Dosing simulations suggested that the standard dosing regimen provided insufficient PD exposures of a 100% free time above the MIC, and higher doses (40 to 80 mg/kg of body weight/dose every 8 h) with a prolonged 3-h infusion were required to ensure the appropriate PD exposures for patients with SIRS. Our PK model indicated that critically ill pediatric patients are at risk of subtherapeutic exposure under the standard dosing regimen of MEM. A larger, prospective investigation confirming the safety and efficacy of higher concentrations and prolonged infusion of MEM is necessary.
Topics: Anti-Bacterial Agents; Child; Critical Illness; Humans; Meropenem; Prospective Studies; Retrospective Studies
PubMed: 33199385
DOI: 10.1128/AAC.01909-20 -
The Journal of Antibiotics Dec 2022Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial and community-acquired infections. Klebsiella has developed resistance against antimicrobials...
Klebsiella pneumoniae is an opportunistic pathogen causing nosocomial and community-acquired infections. Klebsiella has developed resistance against antimicrobials including the last resort class; carbapenem. Currently, treatment options for carbapenem-resistant-Klebsiella (CRK) are very limited. This study aims to restore carbapenem effectiveness against CRK using celastrol and thymol. Clinical Klebsiella isolates were identified using biochemical and molecular methods. Antimicrobial susceptibility was determined using disk-diffusion method. Carbapenemase-production was tested phenotypically and genotypically. Celastrol and thymol-MICs were determined and the carbapenemase-inhibitory effect of sub-MICs was investigated. Among 85 clinical Klebsiella isolates, 72 were multi-drug-resistant and 43 were meropenem-resistant. Phenotypically, 39 isolates were carbapenemase-producer. Genotypically, bla was detected in 35 isolates, bla in 17 isolates, bla in 18 isolates, and bla was detected only in 6 isolates. Celastrol showed significant inhibitory effect against carbapenemase-hydrolytic activity. Meropenem-MIC did not decrease in presence of celastrol, only 2-fold decrease was observed with thymol, while 4-64 fold decrease was observed when meropenem was combined with both celastrol and thymol. Furthermore, thymol increased CRK cell wall-permeability. Molecular docking revealed that celastrol is superior to thymol for binding to KPC and VIM-carbapenemase. Our study showed that celastrol is a promising inhibitor of multiple carbapenemases. While meropenem-MIC were not affected by celastrol alone and decreased by only 2-folds with thymol, it decreased by 4-64 folds in presence of both celastrol and thymol. Thymol increases the permeability of CRK-envelope to celastrol. The triple combination (meropenem/celastrol/thymol) could be useful for developing more safe and effective analogues to restore the activity of meropenem and other β-lactams.
Topics: Humans; Klebsiella pneumoniae; Meropenem; Thymol; Molecular Docking Simulation; Anti-Bacterial Agents; beta-Lactamases; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; Microbial Sensitivity Tests; Bacterial Proteins; Klebsiella Infections
PubMed: 36167781
DOI: 10.1038/s41429-022-00566-y -
MSphere Oct 2023To evaluate the resistance mechanisms among clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). clinical isolates...
To evaluate the resistance mechanisms among clinical isolates exhibiting meropenem (MEM) MIC values higher than meropenem-vaborbactam (MEV). clinical isolates collected in US hospitals from 2014 to 2019 were susceptibility tested. Whole-genome and transcriptome sequencing were performed. Results were analyzed for strain typing, acquired β-lactamases, and mutations in chromosomal genes; gene expression was measured for known β-lactam resistance contributors. Results were compared to a control group of 10 . isolates displaying MIC values at 8 mg/L for meropenem ± vaborbactam (MEM = MEV). Out of 88 isolates displaying MEM > MEV, 33 (37.5%) isolates had reproducibly lower MIC values for meropenem-vaborbactam compared to meropenem when retested. The expression of , , , and was significantly greater among a higher percentage of the MEM > MEV isolates. Furthermore, the association of and overexpression was detected in 17/33 MEM > MEV isolates and only 1/10 MEM = MEV isolate. In addition, the -derived cephalosporinase amino acid substitution R79Q was detected among 33.3% of the isolates displaying MEM > MEV, and none of the isolates displayed MEM = MEV. Other resistance mechanisms were not observed or were equally observed in both groups. In rare cases, vaborbactam plays a role in lowering the meropenem MIC values in clinical isolates likely due to the inhibition of the AmpC gene that was overexpressed in the presence of upregulation of MexXY with or without alterations in the AmpC gene. IMPORTANCE isolates are intrinsically resistant to multiple antimicrobial agents and meropenem is an important therapeutic option to treat infections caused by this organism. Meropenem-vaborbactam activity is similar to that of meropenem alone against isolates. Isolates belonging to this species that display lower meropenem-vaborbactam compared to meropenem are rare. We initiated this study to understand the resistance mechanisms that could lead to lower meropenem-vaborbactam MIC values when compared to meropenem alone. We documented that isolates displaying lower meropenem-vaborbactam exhibited overexpression of MexXY and AmpC. In addition, isolates displaying the R79Q PDC (AmpC) mutation were more likely to display lower meropenem-vaborbactam when compared to isolates displaying the same MIC values for these agents.
Topics: Meropenem; Anti-Bacterial Agents; Pseudomonas aeruginosa; Up-Regulation; Bacterial Proteins
PubMed: 37768064
DOI: 10.1128/msphere.00162-23 -
Antimicrobial Agents and Chemotherapy Jan 2018This study investigated whether pulmonary surfactant has an effect on the antibacterial activity of either meropenem alone or meropenem in combination with vaborbactam...
This study investigated whether pulmonary surfactant has an effect on the antibacterial activity of either meropenem alone or meropenem in combination with vaborbactam at a fixed concentration of 8 μg/ml against several carbapenemase (KPC)-producing strains of Gram-negative bacteria. Results showed that the potency of meropenem alone and that of meropenem-vaborbactam were not affected when tested with pulmonary surfactant.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Boronic Acids; Drug Resistance, Bacterial; Enterobacteriaceae; Meropenem; Microbial Sensitivity Tests; Pulmonary Surfactants; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 29038266
DOI: 10.1128/AAC.01702-17 -
BMJ Case Reports Nov 2018A 63-year-old man admitted to hospital for the management of a frontal lobe abscess developed elevated liver enzymes within 48 hours of receiving meropenem. Liver...
A 63-year-old man admitted to hospital for the management of a frontal lobe abscess developed elevated liver enzymes within 48 hours of receiving meropenem. Liver enzymes reached a maximum at 5 days postadministration of meropenem, with alanine aminotransferase 1160 U/L, aspartate aminotransferase 787 U/L, alkaline phosphatase 297 U/L and gamma-glutamyltransferase 252 U/L. Meropenem was ceased and liver function normalised. Meropenem was administered for a second time later in the patient's admission and again the patient developed rapidly increasing liver enzymes, with a mixed hepatocellular/cholestatic pattern. Other possible causes of liver injury were excluded following extensive investigations, and the patient's liver enzymes continued to normalise following meropenem discontinuation. The patient was asymptomatic during the admission and was transferred to a rehabilitation facility. This case demonstrates that meropenem can cause severe liver injury and that early recognition of drug-induced liver injury is important.
Topics: Administration, Intravenous; Anti-Bacterial Agents; Brain Abscess; Chemical and Drug Induced Liver Injury; Early Diagnosis; Frontal Lobe; Humans; Liver; Liver Diseases; Male; Meropenem; Middle Aged
PubMed: 30567128
DOI: 10.1136/bcr-2018-227124 -
Antimicrobial Agents and Chemotherapy Mar 2018Vaborbactam is a member of a new class of β-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g., carbapenemase) that has been developed...
Vaborbactam is a member of a new class of β-lactamase inhibitors with inhibitory activity against serine carbapenemases (e.g., carbapenemase) that has been developed in combination with meropenem. The pharmacokinetics of the combination was evaluated in 41 subjects with chronic renal impairment in a phase 1, open-label, single-dose study. Subjects were assigned to one of five groups based on renal function: normal (creatinine clearance of ≥90 ml/min), mild (estimated glomerular filtration rate [eGFR] of 60 to 89 ml/min/1.73 m), moderate (eGFR of 30 to <60), or severe (eGFR of <30) impairment plus end-stage renal disease (ESRD) patients on hemodialysis. Subjects received a single intravenous dose of 1 g of meropenem plus 1 g of vaborbactam by 3-h infusion. The ESRD group received two doses (on and off dialysis) separated by a washout. Pharmacokinetic parameters were estimated by standard noncompartmental methods. For both meropenem and vaborbactam, the area under the concentration-time curve was larger and the elimination half-life was longer with decreasing renal function. Meropenem and vaborbactam total plasma clearance (CLt) rates were similar and decreased with decreasing renal function. Slopes of the linear relationship between eGFR and CLt were similar, indicating a similar proportional reduction in CLt with decreasing renal function. Hemodialysis significantly increased drug clearance of meropenem (mean of 2.21-fold increase in CLt, < 0.001) and vaborbactam (mean of 5.11-fold increase, = 0.0235) relative to drug administration off dialysis, consistent with dose recovery rates of 38.3% and 52.9% for meropenem and vaborbactam, respectively, in dialysate. Plasma clearance of meropenem and vaborbactam is reduced with renal impairment, requiring dose adjustment. Hemodialysis removes both drugs. (This study has been registered at ClinicalTrials.gov under identifier NCT02020434.).
Topics: Adult; Aged; Anti-Bacterial Agents; Area Under Curve; Boronic Acids; Creatinine; Drug Administration Schedule; Drug Combinations; Female; Glomerular Filtration Rate; Half-Life; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Meropenem; Middle Aged; Renal Dialysis; Renal Insufficiency, Chronic
PubMed: 29311069
DOI: 10.1128/AAC.02103-17 -
Antimicrobial Agents and Chemotherapy Apr 2024Increasing evidence supports the repositioning of beta-lactams for tuberculosis (TB) therapy, but further research on their interaction with conventional anti-TB agents...
Increasing evidence supports the repositioning of beta-lactams for tuberculosis (TB) therapy, but further research on their interaction with conventional anti-TB agents is still warranted. Moreover, the complex cell envelope of () may pose an additional obstacle to beta-lactam diffusion. In this context, we aimed to identify synergies between beta-lactams and anti-TB drugs ethambutol (EMB) and isoniazid (INH) by assessing antimicrobial effects, intracellular activity, and immune responses. Checkerboard assays with H37Rv and eight clinical isolates, including four drug-resistant strains, exposed that only treatments containing EMB and beta-lactams achieved synergistic effects. Meanwhile, the standard EMB and INH association failed to produce any synergy. In -infected THP-1 macrophages, combinations of EMB with increasing meropenem (MEM) concentrations consistently displayed superior killing activities over the individual antibiotics. Flow cytometry with BODIPY FL vancomycin, which binds directly to the peptidoglycan (PG), confirmed an increased exposure of this layer after co-treatment. This was reinforced by the high IL-1β secretion levels found in infected macrophages after incubation with MEM concentrations above 5 mg/L, indicating an exposure of the host innate response sensors to pathogen-associated molecular patterns in the PG. Our findings show that the proposed impaired access of beta-lactams to periplasmic transpeptidases is counteracted by concomitant administration with EMB. The efficiency of this combination may be attributed to the synchronized inhibition of arabinogalactan and PG synthesis, two key cell wall components. Given that beta-lactams exhibit a time-dependent bactericidal activity, a more effective pathogen recognition and killing prompted by this association may be highly beneficial to optimize TB regimens containing carbapenems.IMPORTANCEAddressing drug-resistant tuberculosis with existing therapies is challenging and the treatment success rate is lower when compared to drug-susceptible infection. This study demonstrates that pairing beta-lactams with ethambutol (EMB) significantly improves their efficacy against (). The presence of EMB enhances beta-lactam access through the cell wall, which may translate into a prolonged contact between the drug and its targets at a concentration that effectively kills the pathogen. Importantly, we showed that the effects of the EMB and meropenem (MEM)/clavulanate combination were maintained intracellularly. These results are of high significance considering that the time above the minimum inhibitory concentration is the main determinant of beta-lactam efficacy. Moreover, a correlation was established between incubation with higher MEM concentrations during macrophage infection and increased IL-1β secretion. This finding unveils a previously overlooked aspect of carbapenem repurposing against tuberculosis, as certain strains suppress the secretion of this key pro-inflammatory cytokine to evade host surveillance.
Topics: Humans; Ethambutol; Mycobacterium tuberculosis; Meropenem; Clavulanic Acid; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Tuberculosis; Carbapenems; beta-Lactams; Microbial Sensitivity Tests
PubMed: 38411952
DOI: 10.1128/aac.01586-23 -
Antimicrobial Agents and Chemotherapy Oct 2022Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required...
Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required for beta-lactamase inhibition, xeruborbactam has direct antibacterial activity against some Gram-negative bacteria, with MIC/MIC values of 16/32 μg/mL and 16/64 μg/mL against carbapenem-resistant and carbapenem-resistant Acinetobacter baumannii, respectively (the MIC/MIC values against Pseudomonas aeruginosa are >64 μg/mL). In Klebsiella pneumoniae, inactivation of OmpK36 alone or in combination with OmpK35 resulted in 2- to 4-fold increases in the xeruborbactam MIC. In A. baumannii and P. aeruginosa, AdeIJK and MexAB-OprM, respectively, affected xeruborbactam's antibacterial potency (the MICs were 4- to 16-fold higher in efflux-proficient strains). In Escherichia coli and K. pneumoniae, the 50% inhibitory concentrations (ICs) of xeruborbactam's binding to penicillin-binding proteins (PBPs) PBP1a/PBP1b, PBP2, and PBP3 were in the 40 to 70 μM range; in A. baumannii, xeruborbactam bound to PBP1a, PBP2, and PBP3 with ICs of 1.4 μM, 23 μM, and 140 μM, respectively. Treating K. pneumoniae and P. aeruginosa with xeruborbactam at 1× and 2× MIC resulted in changes of cellular morphology similar to those observed with meropenem; the morphological changes observed after treatment of A. baumannii were consistent with inhibition of multiple PBPs but were unique to xeruborbactam compared to the results for control beta-lactams. No single-step xeruborbactam resistance mutants were obtained after selection at 4× MIC of xeruborbactam using wild-type strains of E. coli, K. pneumoniae, and A. baumannii; mutations selected at 2× MIC in K. pneumoniae did not affect antibiotic potentiation by xeruborbactam through beta-lactamase inhibition. Consistent with inhibition of PBPs, xeruborbactam enhanced the potencies of beta-lactam antibiotics even against strains that lacked beta-lactamase. In a large panel of KPC-producing clinical isolates, the MIC values of meropenem tested with xeruborbactam (8 μg/mL) were at least 4-fold lower than those in combination with vaborbactam at 64 μg/mL, the concentration of vaborbactam that is associated with complete inhibition of KPC. The additional enhancement of the potency of beta-lactam antibiotics beyond beta-lactamase inhibition may contribute to the potentiation of beta-lactam antibiotics by xeruborbactam.
Topics: Meropenem; Penicillin-Binding Proteins; Escherichia coli; Anti-Bacterial Agents; beta-Lactamases; beta-Lactams; Microbial Sensitivity Tests; Klebsiella pneumoniae; Carbapenems; Monobactams; Pseudomonas aeruginosa; Serine
PubMed: 36102663
DOI: 10.1128/aac.00879-22 -
Clinical Pharmacokinetics May 2022A quantitative evaluation of the PK of meropenem, a broad-spectrum β-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of... (Clinical Trial)
Clinical Trial
Comparative Plasma and Interstitial Tissue Fluid Pharmacokinetics of Meropenem Demonstrate the Need for Increasing Dose and Infusion Duration in Obese and Non-obese Patients.
BACKGROUND AND OBJECTIVES
A quantitative evaluation of the PK of meropenem, a broad-spectrum β-lactam antibiotic, in plasma and interstitial space fluid (ISF) of subcutaneous adipose tissue of obese patients is lacking as of date. The objective of this study was the characterisation of meropenem population pharmacokinetics in plasma and ISF in obese and non-obese patients for identification of adequate dosing regimens via Monte-Carlo simulations.
METHODS
We obtained plasma and microdialysate concentrations after administration of meropenem 1000 mg to 15 obese and 15 non-obese surgery patients from a prospective clinical trial. After characterizing plasma- and microdialysis-derived ISF pharmacokinetics via population pharmacokinetic analysis, we simulated thrice-daily (TID) meropenem short-term (0.5 h), prolonged (3.0 h), and continuous infusions. Adequacy of therapy was assessed by the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment (PTA) analysis based on time unbound concentrations exceeded minimum inhibitory concentrations (MIC) on treatment day 1 (%fT) and the sum of PTA weighted by relative frequency of MIC values for infections by pathogens commonly treated with meropenem. To avoid interstitial tissue fluid concentrations below MIC for the entire dosing interval during continuous infusions, a more conservative PK/PD index was selected (%fT).
RESULTS
Adjusted body weight (ABW) and calculated creatinine clearance (CLCR) of all patients (body mass index [BMI] = 20.5-81.5 kg/m) explained a considerable proportion of the between-patient pharmacokinetic variability (15.1-31.0% relative reduction). The ISF:plasma ratio of %fT was relatively similar for MIC ≤ 2 mg/L but decreased for MIC = 8 mg/L over ABW = 60-120 kg (0.50-0.20). Steady-state concentrations were 2.68 times (95% confidence interval [CI] = 2.11-3.37) higher in plasma than in ISF, supporting PK/PD targets related to four times the MIC during continuous infusions to avoid suspected ISF concentrations constantly below the MIC. A 3000 mg/24 h continuous infusion was sufficient at MIC = 2 mg/L for patients with CLCR ≤ 100 mL/min and ABW < 90 kg, whereas 2000 mg TID prolonged infusions were adequate for those with CLCR ≤ 100 mL/min and ABW > 90 kg. For MIC = 2 mg/L and %fT = 95, PTA was adequate in patients over the entire investigated range of body mass and renal function using a 6000 mg continuous infusion. A prolonged infusion of meropenem 2000 mg TID was sufficient for MIC ≤ 8 mg/L and all investigated ABW and CLCR when employing the PK/PD target %fT = 40. Short-term infusions of 1000 mg TID were sufficient for CLCR ≤ 130 mL/min and distributions of MIC values for Escherichia coli, Citrobacter freundii, and Klebsiella pneumoniae but not for Pseudomonas aeruginosa.
CONCLUSIONS
This analysis indicated a need for higher doses (≥ 2000 mg) and prolonged infusions (≥ 3 h) for obese and non-obese patients at MIC ≥ 2 mg/L. Higher PTA was achieved with prolonged infusions in obese patients and with continuous infusions in non-obese patients.
TRIAL REGISTRATION
EudraCT: 2012-004383-22.
Topics: Anti-Bacterial Agents; Humans; Meropenem; Microbial Sensitivity Tests; Monte Carlo Method; Obesity; Prospective Studies
PubMed: 34894344
DOI: 10.1007/s40262-021-01070-6 -
Clinical Microbiology and Infection :... Nov 2022New antibiotics have been developed to treat multidrug-resistant Enterobacterales. We evaluated the impact of the inoculum size on minimal inhibitory concentrations...
OBJECTIVES
New antibiotics have been developed to treat multidrug-resistant Enterobacterales. We evaluated the impact of the inoculum size on minimal inhibitory concentrations (MICs) of recently commercialized antibiotics.
METHODS
We focused on 40 clinical carbapenemase-producing Enterobacterales and evaluated the impact of the inoculum size on the MICs to cefiderocol and to new β-lactams/β-lactamase inhibitors (ceftolozane-tazobactam, ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) at usual and high inocula (10 and 10 CFU/mL, respectively).
RESULTS
At usual inoculum, 15% were resistant to cefiderocol (n = 6), 30% to meropenem-vaborbactam (n = 12), 42.5% to ceftazidime-avibactam (n = 17), 55% to imipenem-relebactam (n = 22), and 90% to ceftolozane-tazobactam (n = 36). At higher inoculum, a switch from susceptible to resistant category was observed for 88% (n = 30/34; CI, 71.6-96.2), 75% (n = 3/4; CI, 21.9-98.7), 72% (n = 13/18; CI, 46.4-89.3), 50% (n = 14/28; CI, 31.1-68.9), and 8.7% (n = 2/23; CI, 1.5-29.5) isolates regarding cefiderocol, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam, respectively.
DISCUSSION
Cefiderocol and meropenem-vaborbactam were the most efficient against carbapenemase-producing Enterobacterales at usual inoculum. When increasing inoculum to 10 CFU/mL, all of the molecules were impacted, particularly cefiderocol and imipenem-relebactam, while others, such as ceftazidime-avibactam, remain mildly affected. Our in vitro results deserved to be confirmed in vivo.
Topics: Humans; Anti-Bacterial Agents; Meropenem; beta-Lactamase Inhibitors; Carbapenems; Tazobactam; Imipenem; Cefiderocol
PubMed: 35777602
DOI: 10.1016/j.cmi.2022.06.018