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Journal of Global Antimicrobial... Sep 2022To report reference method antimicrobial susceptibility testing results for recent clinical isolates of Gram-negative bacilli from Morocco.
OBJECTIVES
To report reference method antimicrobial susceptibility testing results for recent clinical isolates of Gram-negative bacilli from Morocco.
METHODS
CLSI (Clinical and Laboratory Standards Institute) broth microdilution antimicrobial susceptibility testing was performed by a central laboratory for isolates of Enterobacterales (n = 810), Pseudomonas aeruginosa (n = 321), and Acinetobacter baumannii (n = 191) collected in 2018-2020 by three hospital laboratories in Morocco. MICs were interpreted using both CLSI (2021) and EUCAST (European Committee on Antimicrobial Susceptibility Testing) (2021) breakpoints. Molecular testing for β-lactamase genes was performed on isolates meeting defined screening criteria.
RESULTS
Most isolates of Enterobacterales were susceptible (CLSI/EUCAST breakpoints) to amikacin (98.0%/96.2%), ceftazidime-avibactam (94.8%/94.8%), and meropenem (92.5%/94.2%). Of Enterobacterales isolates eligible for β-lactamase gene screening (n = 210), 174 were ESBL-positive, 40 were metallo-β-lactamase-positive (all NDM), 39 were serine carbapenemase-positive (all OXA); and 7 isolates carried both OXA-48 and NDM-1. Amikacin (89.1%/89.1%) and ceftazidime-avibactam (88.2%/88.2%) were the most active agents tested against P. aeruginosa. Applying CLSI and EUCAST breakpoints, MDR rates were 21.9% and 29.3% for Enterobacterales and 18.4% and 21.8% for P. aeruginosa. Susceptible rates for amikacin, ceftazidime-avibactam, and meropenem were 93.2%/89.5%, 77.4%/82.3%, and 67.8%/80.2% for MDR Enterobacterales and 50.8%/57.1%, 40.7%/45.7%, and 27.1/32.9% for MDR P. aeruginosa. ≥70% of A. baumannii isolates were resistant to all agents tested (except colistin, EUCAST breakpoints only) including amikacin and meropenem.
CONCLUSION
Newer β-lactam/β-lactamase inhibitor combinations such as ceftazidime-avibactam warrant testing and reporting for Enterobacterales and P. aeruginosa in Morocco given the presence of significant resistance to first-line β-lactams and fluoroquinolones, pervasive ESBLs and carbapenemases, and toxicity concerns associated with some second-line agents.
Topics: Amikacin; Anti-Bacterial Agents; Gram-Negative Bacteria; Meropenem; Morocco; Pseudomonas aeruginosa; beta-Lactamase Inhibitors; beta-Lactamases
PubMed: 35447385
DOI: 10.1016/j.jgar.2022.04.011 -
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 -
BMC Pharmacology & Toxicology Apr 2022The mixing step after medication addition to the infusion bag is frequently omitted during the preparation of drug infusions. However, the importance of mixing when...
BACKGROUND
The mixing step after medication addition to the infusion bag is frequently omitted during the preparation of drug infusions. However, the importance of mixing when preparing antibiotic infusions is still unknown.
METHODS
The primary aim of this study was to assess the importance of the mixing step by comparing the concentrations of unmixed antibiotic infusions (cefuroxime, flucloxacillin, meropenem, and vancomycin) with the declared concentration at regular intervals during infusion. The secondary aim was to compare concentrations between preparation sites (hospital pharmacy versus clinical ward). Infusion bags were run through electronic infusion pumps. For cefuroxime, flucloxacillin, and meropenem, samples were collected 1, 15, and 20 min after starting the administration (infusion duration: 30 min). For vancomycin, samples were collected after 1, 60, and 110 min (infusion duration: 120 min). Vancomycin concentrations were measured using the Architect c4000 analyser and other concentrations using a validated UPC-MS-MS multimethod.
RESULTS
The median concentrations of the four antibiotics were comparable to the declared concentration at all three time points. No significant differences were found between preparation sites.
CONCLUSIONS
Spontaneous mixing occurred in the examined antibiotic solutions during normal handling.
Topics: Anti-Bacterial Agents; Cefuroxime; Floxacillin; Infusions, Intravenous; Meropenem; Vancomycin
PubMed: 35395823
DOI: 10.1186/s40360-022-00562-w -
Computational and Mathematical Methods... 2022To summarize the clinical characteristics and drug sensitivity analysis of children with Salmonella enteritis in our hospital, explore the characteristics and drug...
OBJECTIVE
To summarize the clinical characteristics and drug sensitivity analysis of children with Salmonella enteritis in our hospital, explore the characteristics and drug resistance of Salmonella infection, and guide the rational clinical use of drugs.
METHODS
The clinical data of 90 pediatric Salmonella enteritis patients treated in our hospital from January 2015 to January 2020 were selected as the observation group of this retrospective study, and 90 patients with non-Salmonella enteritis were selected at the same time as a control group. Discuss the clinical characteristics of Salmonella, drug sensitivity analysis, infection characteristics, and drug resistance and guide the rational clinical use of drugs.
RESULTS
The susceptibility rates of 15 antibiotics from high to low were imipenem and meropenem, piperacillin, cefoperazone, compound trimethoprim, chloramphenicol, and ceftazidime. Salmonella strains were both resistant to imipenem and meropenem. Salmonella is sensitive and has a low rate of resistance to quinolones (ciprofloxacin) and a high rate of resistance to cephalosporins (ceftriaxone, cefotaxime, ceftazime, and cefpiramide), both reached more than 28%. Salmonella has the highest resistance to penicillin and erythromycin, both at 85.00% and above. Among 90 children with Salmonella enteritidis food poisoning, 32 were hospitalized, 21 cases were hospitalized less than 7 days, and 11 cases were 7-14 days. The longest hospital stay was 12 days, the shortest was 1 day, and the average was 6.1 days. Seven people stayed for observation and 51 people were discharged after treatment. All the children recovered without death.
CONCLUSION
In clinical practice, antibiotics should be used rationally based on drug susceptibility results. In the case of poor efficacy of cephalosporins, amoxicillin and potassium clavulanate, piperacillin, tazobactam, or imipenem, cephalosporin antibiotics can be considered the first choice for clinical empiric medication.
Topics: Anti-Bacterial Agents; Case-Control Studies; Cephalosporins; Child; Drug Resistance; Enteritis; Humans; Imipenem; Meropenem; Microbial Sensitivity Tests; Piperacillin; Retrospective Studies
PubMed: 35966239
DOI: 10.1155/2022/5091945 -
Journal of Orthopaedic Research :... May 2022There has been increasing interest in the use of a synthetic absorbable calcium sulfate (CaSO ) for local antibiotic delivery in orthopaedic infections. The purpose of...
There has been increasing interest in the use of a synthetic absorbable calcium sulfate (CaSO ) for local antibiotic delivery in orthopaedic infections. The purpose of this study was to quantify elution kinetics of six antibiotics (amikacin, meropenem, fosfomycin, minocycline, cefazolin, and dalbavancin) from a clinically relevant CaSO bead model and compare elution and antimicrobial activity to the current clinical gold standards: vancomycin and tobramycin. Antibiotic-loaded synthetic CaSO beads were immersed in phosphate buffered saline and incubated at 37°C. Eluent was harvested at eight time points over 28 days. Antibiotic concentrations were measured by high performance liquid chromatography to quantify elution rates. CaSO beads demonstrated burst release kinetics. Dalbavancin, cefazolin, and minocycline all demonstrated similar elution profiles to vancomycin. Amikacin and meropenem demonstrated favorable elution profiles and durations of above-minimum inhibitory concentration when compared to tobramycin. Clinical Significance: This study provides important novel data regarding the utility of amikacin, meropenem and dalbavancin as alternative choices to place in CaSO carriers when treating orthopaedic infections.
Topics: Amikacin; Anti-Bacterial Agents; Calcium Sulfate; Cefazolin; Meropenem; Minocycline; Tobramycin; Vancomycin
PubMed: 34191350
DOI: 10.1002/jor.25135 -
European Journal of Medicinal Chemistry May 2022Linear and cyclic amphiphilic peptides, (WKR) and [WKR], were evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including four...
Linear and cyclic amphiphilic peptides, (WKR) and [WKR], were evaluated as antibacterial agents against Gram-positive and Gram-negative bacteria, including four multi-drug resistant strains and the corresponding four non-resistant strains. Cyclic peptide [WKR] showed higher antibacterial activity than the linear (WKR) counterpart. Cyclic [WKR] was subjected to combination (physical mixture or covalent conjugation) with meropenem as a model antibiotic to study the impact of the combination on antimicrobial activity. A physical mixture of meropenem and [WKR] showed synergistic antibacterial activity against Gram-negative P. aeruginosa (ATCC BAA-1744) and P. aeruginosa (ATCC 27883) strains. [WKR] was further subjected to extensive antibacterial studies against additional 10 bacteria strains, showing significant antibacterial efficacy against Gram-positive bacteria strains. Combinations studies of [WKR] with an additional 9 commercially available antibiotics showed significant enhancement in antibacterial activity for all tested combinations, especially with tetracycline, tobramycin, levofloxacin, clindamycin, daptomycin, polymyxin, kanamycin, and vancomycin. Time-kill kinetics assay and flow cytometry results exhibited that [WKR] had a time-dependent synergistic effect and membrane disruption property. These data indicate that [WKR] improves the antibacterial activity, presumably by facilitating the internalization of antibiotics and their interaction with the intracellular targets. This study introduces a potential strategy for treating multidrug-resistant pathogens by combining [WKR] and a variety of classical antibiotics to improve the antibacterial effectiveness.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Gram-Negative Bacteria; Gram-Positive Bacteria; Meropenem; Microbial Sensitivity Tests; Peptides, Cyclic; Pseudomonas aeruginosa
PubMed: 35339840
DOI: 10.1016/j.ejmech.2022.114278 -
American Journal of Respiratory and... May 2020
Topics: Administration, Intravenous; Administration, Oral; Adult; Aged; Aged, 80 and over; Amoxicillin; Anti-Bacterial Agents; Clavulanic Acid; Drug Combinations; Female; Humans; Male; Meropenem; Microbial Sensitivity Tests; Middle Aged; Mycobacterium tuberculosis; Practice Guidelines as Topic; Tuberculosis; World Health Organization; beta-Lactamase Inhibitors
PubMed: 31922901
DOI: 10.1164/rccm.201911-2149LE -
International Journal of Infectious... Jul 2022To compare the unbound plasma meropenem concentrations at mid-dosing intervals (C, 50%fT), end-dosing intervals (C, 100%fT), and proportions of patients achieving 50%fT... (Observational Study)
Observational Study
Therapeutic drug monitoring of meropenem and pharmacokinetic-pharmacodynamic target assessment in critically ill pediatric patients from a prospective observational study.
OBJECTIVES
To compare the unbound plasma meropenem concentrations at mid-dosing intervals (C, 50%fT), end-dosing intervals (C, 100%fT), and proportions of patients achieving 50%fT and 100%fT above minimum inhibitory concentration (MIC) (50%fT and 100%fT) between extended infusion (EI) and intermittent bolus (IB) administration in a therapeutic drug monitoring (TDM) program in children.
METHODS
A prospective observational study was conducted in children aged 1 month to 18 years receiving meropenem every 8 hours by either EI or IB. Meropenem C, C, and proportions of patients achieving 50%fT and 100%fT were compared.
RESULTS
TDM data from 72 patients with a median age (interquartile range [IQR]) of 12 months (3-37) were used. Meropenem dose was 120 and 60 mg/kg/day in EI and IB groups, respectively. Geometric mean (95% confidence interval [CI]) C of EI versus IB was 17.3 mg/L (13.7-21.8) versus 3.4 mg/L (1.7-6.7) (P <0.001). Geometric mean (95% CI) C of EI versus IB was 2.3 mg/L (1.6-3.4) versus 0.8 mg/L (0.4-1.5) (P=0.005). Greater proportions of patients achieving 50%fT and 100%fT were observed in the EI group.
CONCLUSIONS
A meropenem dose of 20 mg/kg/dose given by IB should not be used in critically ill children, even if they are not suspected of having a central nervous system infection. A dose of 40 mg/kg/dose given by EI resulted in higher C, C, and proportions of patients achieving 50%fT and 100%fT.
Topics: Anti-Bacterial Agents; Child; Critical Illness; Drug Monitoring; Humans; Infant; Meropenem; Microbial Sensitivity Tests
PubMed: 35489632
DOI: 10.1016/j.ijid.2022.04.052 -
Letters in Applied Microbiology Sep 2022Pseudomonas aeruginosa is one of the most worrisome infectious bacteria due to its intrinsic and acquired resistance against several antibiotics and the recalcitrance of...
Pseudomonas aeruginosa is one of the most worrisome infectious bacteria due to its intrinsic and acquired resistance against several antibiotics and the recalcitrance of its infections; hence, the development of novel antimicrobials effective against multidrug-resistant P. aeruginosa is mandatory. In this work, silver nanoparticles obtained by green synthesis using a leaf extract and fungi were tested against a battery of clinical strains from cystic fibrosis, pneumonia and burnt patients, some of them with multidrug resistance. Both nanoparticles showed a potent antibacterial effect, causing severe damage to the cell wall, membrane and DNA, and inducing the production of reactive oxygen species. Moreover, the nanoparticles derived from fungi showed synergistic antibacterial effects with the antibiotics meropenem and levofloxacin for some clinical strains and both kinds of nanoparticles were nontoxic for larvae of the moth Galleria mellonella, encouraging further research for their implementation in the treatment of P. aeruginosa infections.
Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Humans; Levofloxacin; Meropenem; Metal Nanoparticles; Microbial Sensitivity Tests; Plant Extracts; Pseudomonas Infections; Pseudomonas aeruginosa; Reactive Oxygen Species; Silver
PubMed: 35687297
DOI: 10.1111/lam.13759 -
Frontiers in Immunology 2021Recently, there has been a growing interest in applying immune checkpoint blockers (ICBs), so far used to treat cancer, to patients with bacterial sepsis. We aimed to...
Recently, there has been a growing interest in applying immune checkpoint blockers (ICBs), so far used to treat cancer, to patients with bacterial sepsis. We aimed to develop a method for predicting the personal benefit of potential treatments for sepsis, and to apply it to therapy by meropenem, an antibiotic drug, and nivolumab, a programmed cell death-1 (PD-1) pathway inhibitor. We defined an optimization problem as a concise framework of treatment aims and formulated a fitness function for grading sepsis treatments according to their success in accomplishing the pre-defined aims. We developed a mathematical model for the interactions between the pathogen, the cellular immune system and the drugs, whose simulations under diverse combined meropenem and nivolumab schedules, and calculation of the fitness function for each schedule served to plot the fitness landscapes for each set of treatments and personal patient parameters. Results show that treatment by meropenem and nivolumab has maximum benefit if the interval between the onset of the two drugs does not exceed a dose-dependent threshold, beyond which the benefit drops sharply. However, a second nivolumab application, within 7-10 days after the first, can extinguish a pathogen which the first nivolumab application failed to remove. The utility of increasing nivolumab total dose above 6 mg/kg is contingent on the patient's personal immune attributes, notably, the reinvigoration rate of exhausted CTLs and the overall suppression rates of functional CTLs. A baseline pathogen load, higher than 5,000 CFU/μL, precludes successful nivolumab and meropenem combination therapy, whereas when the initial load is lower than 3,000 CFU/μL, meropenem monotherapy suffices for removing the pathogen. Our study shows that early administration of nivolumab, 6 mg/kg, in combination with antibiotics, can alleviate bacterial sepsis in cases where antibiotics alone are insufficient and the initial pathogen load is not too high. The study pinpoints the role of precision medicine in sepsis, suggesting that personalized therapy by ICBs can improve pathogen elimination and dampen immunosuppression. Our results highlight the importance in using reliable markers for classifying patients according to their predicted response and provides a valuable tool in personalizing the drug regimens for patients with sepsis.
Topics: Algorithms; Anti-Bacterial Agents; Biomarkers; Combined Modality Therapy; Disease Susceptibility; Humans; Immune Checkpoint Inhibitors; Immune Checkpoint Proteins; Leukocytes; Meropenem; Models, Biological; Nivolumab; Prognosis; Sepsis; T-Lymphocytes, Cytotoxic; Treatment Outcome
PubMed: 33732241
DOI: 10.3389/fimmu.2021.616881