Activity Of Meropenem Research Articles

A Retrospective Analysis of Intravenous Push versus Extended Infusion Meropenem in Critically Ill Patients.

Meropenem is a broad-spectrum antibiotic used for the treatment of multi-drug-resistant infections. Due to its pharmacokinetic profile, meropenem's activity is optimized by maintaining a specific time the serum concentration remains above the minimum inhibitory concentration (MIC) via extended infusion (EI), continuous infusion, or intermittent infusion dosing strategies. The available literature varies regarding the superiority of these dosing strategies. This study's primary objective was to determine the difference in time to clinical stabilization between intravenous push (IVP) and EI administration. We performed a retrospective pilot cohort study of 100 critically ill patients who received meropenem by IVP (n = 50) or EI (n = 50) during their intensive care unit (ICU) admission. There was no statistically significant difference in the overall achievement of clinical stabilization between IVP and EI (48% vs. 44%, p = 0.17). However, the median time to clinical stability was shorter for the EI group (20.4 vs. 66.2 h, p = 0.01). EI administration was associated with shorter hospital (13 vs. 17 days; p = 0.05) and ICU (6 vs. 9 days; p = 0.02) lengths of stay. Although we did not find a statistically significant difference in the overall time to clinical stabilization, the results of this pilot study suggest that EI administration may produce quicker clinical resolutions than IVP.

Fabrication and antimicrobial properties of novel meropenem-honey encapsulated chitosan nanoparticles against multiresistant and biofilm-forming Staphylococcus aureus as a new antimicrobial agent.

Honey exhibits a broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) ones. Chitosan (Cs) is a mucoadhesive polymer that also has antibacterial properties. Special attention has been paid to the design of polymeric nanoparticles (NPs) as new nano drug delivery systems to overcome bacterial resistance and its problems. The aim of the present study is to synthesize Cs-meropenem NPs with/without honey as an antibiofilm and antibacterial agent to inhibit Staphylococcus aureus. This study synthesized meropenem and honey-loaded Cs nanogels and subsequently characterized them by Field Emission Scanning Electron Microscopy (FESEM), Fourier Transform Infrared Spectroscopy (FTIR), and DLS-zeta potential. Using the broth microdilution and crystal violet assays, the antibacterial and antibiofilm activity of meropenem and honey-loaded Cs nanogel, free meropenem, free honey, and free Cs NPs were investigated in vitro against MRSA strains. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) was also used to test the cytotoxicity of several Cs-NPs compound against the HEK-293 regular cell line. The average size of meropenem and honey-Cs-NPs was reported to be 119.885nm, and encapsulation efficiency was 88.33 ± 0.97 with stability up to 60 days at 4°C. The NPs showed enhanced antibiofilm efficacy against S. aureus at sub-minimum inhibitory concentrations. Additionally, the cytotoxicity of meropenem and honey-encapsulated Cs against the HEK-293 normal cell line was insignificant. Our findings suggested that meropenem and honey-Cs-NPs might be potential antibacterial and antibiofilm materials.

Phenotypic, molecular, and in silico characterization of coumarin as carbapenemase inhibitor to fight carbapenem-resistant Klebsiella pneumoniae

BackgroundCarbapenems represent the first line treatment of serious infections caused by drug-resistant Klebsiella pneumoniae. Carbapenem-resistant K. pneumoniae (CRKP) is one of the urgent threats to human health worldwide. The current study aims to evaluate the carbapenemase inhibitory potential of coumarin and to test its ability to restore meropenem activity against CRKP. Disk diffusion method was used to test the antimicrobial susceptibility of K. pneumoniae clinical isolates to various antibiotics. Carbapenemase genes (NDM-1, VIM-2, and OXA-9) were detected using PCR. The effect of sub-MIC of coumarin on CRKP isolates was performed using combined disk assay, enzyme inhibition assay, and checkerboard assay. In addition, qRT-PCR was used to estimate the coumarin effect on expression of carbapenemase genes. Molecular docking was used to confirm the interaction between coumarin and binding sites within three carbapenemases.ResultsK. pneumoniae clinical isolates were found to be multi-drug resistant and showed high resistance to meropenem. All bacterial isolates harbor at least one carbapenemase-encoding gene. Coumarin significantly inhibited carbapenemases in the crude periplasmic extract of CRKP. The checkerboard assay indicated that coumarin-meropenem combination was synergistic exhibiting a fractional inhibitory concentration index ≤ 0.5. In addition, qRT-PCR results revealed that coumarin significantly decreased carbapenemase-genes expression. Molecular docking revealed that the binding energies of coumarin to NDM1, VIM-2, OXA-48 and OXA-9 showed a free binding energy of -7.8757, -7.1532, -6.2064 and − 7.4331 Kcal/mol, respectively.ConclusionCoumarin rendered CRKP sensitive to meropenem as evidenced by its inhibitory action on hydrolytic activity and expression of carbapenemases. The current findings suggest that coumarin could be a possible solution to overcome carbapenems resistance in CRKP.

The synergic and addictive activity of biogenic silver nanoparticle associated with meropenem against carbapenem-resistant Acinetobacter baumannii.

Antibiotic management of infections caused by Acinetobacter baumannii often fails due to antibiotic resistance (especially to carbapenems) and biofilm-forming strains. Thus, the objective here was to evaluate in vitro the antibacterial and antibiofilm activity of biogenic silver nanoparticle (Bio-AgNP) combined with meropenem, against multidrug-resistant isolates of A. baumannii. In this study, A. baumannii ATCC® 19606™ and four carbapenem-resistant A. baumannii (Ab) strains were used. The antibacterial activity of Bio-AgNP and meropenem was evaluated through broth microdilution. The effect of the Bio-AgNP association with meropenem was determined by the checkboard method. Also, the time-kill assay and the integrity of the bacterial cell membrane were evaluated. Furthermore, the antibiofilm activity of Bio-AgNP and meropenem alone and in combination was determined. Bio-AgNP has antibacterial activity with minimum inhibitory concentration (MIC) and minimum bactericidal concentration ranging from 0.46 to 1.87 μg ml-1. The combination of Bio-AgNP and meropenem showed a synergistic and additive effect against Ab strains, and Bio-AgNP was able to reduce the MIC of meropenem from 4- to 8-fold. Considering the time-kill of the cell, meropenem and Bio-AgNP when used in combination reduced bacterial load to undetectable levels within 10 min to 24 h after treatment. Protein leakage was observed in all treatments evaluated. When combined, meropenem/Bio-AgNP presents biofilm inhibition for Ab2 isolate and ATCC® 19606™, with 21% and 19%, and disrupts the biofilm from 22% to 50%, respectively. The increase in nonviable cells in the biofilm can be observed after treatment with Bio-AgNP and meropenem in carbapenem-resistant A. baumannii strains. The combination of Bio-AgNP with meropenem can be a therapeutic option in the treatment of infections caused by carbapenem-resistant A. baumannii.

Model-based learn and confirm: designing effective treatment regimens against multidrug resistant Gram-negative pathogens

Over the last decade, there has been a growing appreciation for the use of in vitro and in vivo infection models to generate robust and informative nonclinical PK/PD data to accelerate the clinical translation of treatment regimens. The objective of this study was to develop a model-based “learn and confirm” approach to help with the design of combination regimens using in vitro infection models to optimise the clinical utility of existing antibiotics. Static concentration time-kill studies were used to evaluate the PD activity of polymyxin B (PMB) and meropenem against two carbapenem-resistant Klebsiella pneumoniae (CRKP) isolates; BAA2146 (PMB-susceptible) and BRKP67 (PMB-resistant). A mechanism-based model (MBM) was developed to quantify the joint activity of PMB and meropenem. In silico simulations were used to predict the time-course of bacterial killing using clinically-relevant PK exposure profiles. The predictive accuracy of the model was further evaluated by validating the model predictions using a one-compartment PK/PD in vitro dynamic infection model (IVDIM). The MBM captured the reduction in bacterial burden and regrowth well in both the BAA2146 and BRKP67 isolate (R2 = 0.900 and 0.940, respectively). The bacterial killing and regrowth predicted by the MBM were consistent with observations in the IVDIM: sustained activity against BAA2146 and complete regrowth of the BRKP67 isolate. Differences observed in PD activity suggest that additional dose optimisation might be beneficial in PMB-resistant isolates. The model-based approach presented here demonstrates the utility of the MBM as a translational tool from static to dynamic in vitro systems to effectively perform model-informed drug optimisation.

Assessing the in vivo impact of novel β-lactamase inhibitors on the efficacy of their partner β-lactams against serine carbapenemase-producing Pseudomonas aeruginosa using human-simulated exposures.

To evaluate the efficacy of human-simulated regimens (HSRs) of ceftazidime, ceftazidime/avibactam, imipenem, imipenem/relebactam, meropenem and meropenem/vaborbactam in a murine thigh infection model against serine carbapenemase-producing Pseudomonas aeruginosa. Nine P. aeruginosa clinical isolates harbouring GES-5 (n = 1), GES-20 (n = 1), GES-5/20 (n = 1), GES-19, GES-20 (n = 3) and KPC (n = 3) were evaluated. Six mice were administered HSRs of ceftazidime 2 g q8h (2 h infusion), ceftazidime/avibactam 2.5 g q8h (2 h infusion), meropenem 2 g q8h (3 h infusion), imipenem 0.5 g q6h (0.5 h infusion), imipenem/relebactam 1.25 g q6h (0.5 h infusion) and meropenem/vaborbactam 4 g q8h (3 h infusion). Change in bacterial burden relative to baseline and the percent of isolates meeting the 1 log10 kill endpoint were assessed. The addition of avibactam to ceftazidime increased the percentage of isolates meeting 1 log10 kill from 33% to 100% of GES- or KPC-harbouring isolates. Imipenem/relebactam HSR produced ≥1 log10 of kill against 83% and 100% of GES- and KPC-harbouring isolates, respectively, while imipenem alone failed to reach 1 log10 kill for any isolates. Vaborbactam resulted in variable restoration of meropenem activity as 1 log10 kill was achieved in only 33% and 66% of GES- and KPC-harbouring isolates, respectively, compared with no isolates for meropenem alone. Ceftazidime/avibactam and imipenem/relebactam were active against 100% and 89% of KPC- or GES-harbouring isolates tested in vivo. The activity of meropenem/vaborbactam was variable, suggesting this may be an inferior treatment option in this setting. Further studies to evaluate clinical outcomes in GES- and KPC-producing P. aeruginosa are warranted given their increasing prevalence worldwide.

Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.

Metallo-β-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic β-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance.

Profiling cell envelope-antibiotic interactions reveals vulnerabilities to β-lactams in a multidrug-resistant bacterium

The cell envelope of Gram-negative bacteria belonging to the Burkholderia cepacia complex (Bcc) presents unique restrictions to antibiotic penetration. As a consequence, Bcc species are notorious for causing recalcitrant multidrug-resistant infections in immunocompromised individuals. Here, we present the results of a genome-wide screen for cell envelope-associated resistance and susceptibility determinants in a Burkholderia cenocepacia clinical isolate. For this purpose, we construct a high-density, randomly-barcoded transposon mutant library and expose it to 19 cell envelope-targeting antibiotics. By quantifying relative mutant fitness with BarSeq, followed by validation with CRISPR-interference, we profile over a hundred functional associations and identify mediators of antibiotic susceptibility in the Bcc cell envelope. We reveal connections between β-lactam susceptibility, peptidoglycan synthesis, and blockages in undecaprenyl phosphate metabolism. The synergy of the β-lactam/β-lactamase inhibitor combination ceftazidime/avibactam is primarily mediated by inhibition of the PenB carbapenemase. In comparison with ceftazidime, avibactam more strongly potentiates the activity of aztreonam and meropenem in a panel of Bcc clinical isolates. Finally, we characterize in Bcc the iron and receptor-dependent activity of the siderophore-cephalosporin antibiotic, cefiderocol. Our work has implications for antibiotic target prioritization, and for using additional combinations of β-lactam/β-lactamase inhibitors that can extend the utility of current antibacterial therapies.

Fluorescence Microscopy: Determination of Meropenem Activity against Klebsiella pneumoniae.

The development and implementation of diagnostic methods that allow rapid assessment of antibiotic activity against pathogenic microorganisms is an important step towards antibiotic therapy optimization and increase in the likelihood of successful treatment outcome. To determine whether fluorescence microscopy with acridine orange can be used for rapid assessment (≤8 h) of the meropenem activity against Klebsiella pneumoniae, six isolates including three OXA-48-carbapenemase-producers were exposed to meropenem at different levels of its concentration (0.5 × MIC, 1 × MIC, 8 or 16 µg/mL) and the changes in the viable counts within 24 h were evaluated using fluorescence microscopy and a control culture method. The approach was to capture the regrowth of bacteria as early as possible. Within the first 8 h fluorescence microscopy allowed to categorize 5 out of 6 K. pneumoniae strains by their meropenem susceptibility (based on the MIC breakpoint of 8 mg/L), but meropenem activity against three isolates, two of which were OXA-48-producers, could not be accurately determined at 8 h. The method proposed in our study requires improvement in terms of accelerating the bacterial growth and regrowth for early meropenem MIC determination. Volume-dependent elevation in meropenem MICs against OXA-48-producers was found and this phenomenon should be studied further.

The Impact of Copper Ions on the Activity of Antibiotic Drugs.

Copper (Cu) is an essential trace metal and its concentration in body plasma is tightly regulated. An increase in Cu concentration in body fluids is observed in numerous pathological conditions, including infections caused by microorganisms. Evidence shows that Cu ions can impact the activity of antibiotics by increasing efficiency or diminishing/neutralizing antibiotic activity, forming complexes which may lead to antibiotic structure degradation. Herein, we represent the evidence available on Cu-antibiotic interactions and their possible impact on antimicrobial therapy efficiency. So far, in vitro studies described interactions between Cu ions and the majority of antibiotics in clinical use: penicillins, cephalosporins, carbapenems, macrolides, aminoglycosides, tetracyclines, fluoroquinolones, isoniazid, metronidazole. In vitro-described degradation or lower antimicrobial activity of amoxicillin, ampicillin, cefaclor, ceftriaxone, and meropenem in the presence of Cu ions suggest caution when using prescribed antibiotics in patients with altered Cu levels. On the other hand, several Cu-dependent compounds with antibacterial activity including the drug-resistant bacteria were discovered, such as thiosemicarbazones, disulfiram, dithiocarbamates, 8-hydroxiquinoline, phenanthrolines, pyrithione. Having in mind that the development of new antibiotics is already marked as inadequate and does not meet global needs, the potential of Cu-antibiotic interactions to change the efficiency of antimicrobial therapy requires further investigation.

Assessing the in vivo efficacy of rational antibiotics and combinations against difficult-to-treat Pseudomonas aeruginosa producing GES β-lactamases.

We evaluated the in vivo efficacy of human-simulated regimens (HSRs) of cefiderocol, ceftazidime/avibactam, meropenem and ceftazidime/avibactam/meropenem combination against Guiana-extended spectrum (GES)-producing Pseudomonas aeruginosa isolates. Eighteen P. aeruginosa isolates producing GES-1 (n = 5), GES-5 (n = 5) or miscellaneous GESs (combinations of GES-19, GES-20 and/or GES-26; n = 8) were evaluated. In vitro MIC testing was determined using broth microdilution. In a validated murine thigh infection model, HSRs of cefiderocol 2 g q8h as a 3 h IV infusion, ceftazidime/avibactam 2.5 g q8h as a 2 h IV infusion, meropenem 2 g q8h as a 3 h IV infusion or ceftazidime/avibactam/meropenem were administered. Change in bacterial burden relative to baseline and the proportion of isolates in each genotypic group meeting 1-log10 kill endpoint were assessed. Modal MICs (mg/L) ranged from 0.125 to 1 for cefiderocol, 4 to >64 for ceftazidime/avibactam and 2 to >64 for meropenem. Cefiderocol produced >1-log10 of kill against all 18 tested isolates. Meropenem was active against all GES-1 isolates whereas activity against GES-5 and miscellaneous GESs was lacking, consistent with the MICs. Ceftazidime/avibactam was active against all GES-1 and GES-5 isolates and retained activity against 62.5% of miscellaneous GESs including isolates with elevated MICs. For isolates where ceftazidime/avibactam failed, the addition of meropenem restored the in vivo efficacy. As monotherapy, cefiderocol was active in vivo against all tested isolates. The activities of meropenem or ceftazidime/avibactam alone were variable; however, a combination of both was active against all isolates. Cefiderocol and ceftazidime/avibactam/meropenem could be valuable therapeutic options for GES-producing P. aeruginosa infections. Clinical confirmatory data are warranted.

Efficacy of meropenem extended infusion vs intermittent bolus monotherapy and in combination with colistin against Pseudomonas aeruginosa biofilm

Device-related infections are difficult-to-treat due to biofilms. In this setting, optimizing the antibiotic efficacy is difficult since most PK/PD studies have been performed on planktonic cells, and therapies are limited when multidrug-resistant bacteria are involved. We aimed to analyze the PK/PD indices of meropenem predicting anti-biofilm efficacy againstmeropenem-susceptible and -resistantP. aeruginosastrains. Pharmacodynamics of meropenem dosages mimicking those of clinical practice (intermittent bolus of 2g every 8h; extended infusion of 2g over 4h every 8h), 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 pharmacokinetic/pharmacodynamic indices for meropenem. Concerning PAO1, both meropenem regimens were bactericidal, with higher killing for the extended infusion (∆log10 CFU/mL 54-0h=-4.66±0.93 and ∆log10 CFU/mL 54-0h=-3.4±0.41 for intermittent bolus; p<0.001). Concerning XDR-HUB3, meropenem by intermittent bolus was non-active whereas it showed bactericidal effect by extended infusion (∆log10 CFU/mL 54-0h=-3.65±0.29; p<0.001). Time above minimum inhibitory concentration (f%T>MIC) had the best correlation with efficacy for both strains. Adding colistin always improved meropenem activity and resistant-strains did not emerge. Thef%T>MIC was the PK/PD index that best correlated with the anti-biofilm efficacy of meropenem; it was better optimized when using extended infusion, allowing to recover bactericidal activity in monotherapy also against meropenem-resistantP. aeruginosa.Combining meropenemby extended infusionwith colistin offered the most effective therapy for both strains. Optimizing meropenem dosing by extended infusion should be encouraged when treating biofilm-related infections.

DUAL APPLICATION OF BACTERIOPHAGES AND MEROPENEM USING MICROBEAD-LOADED HYDROGEL FOR TREATMENT OF MULTIDRUG-RESISTANT PSEUDOMONAS AERUGINOSA IN A MOUSE MODEL OF BONE INFECTION

Fracture related infection remains a major challenge in musculoskeletal trauma surgery. Despite best practice, treatment strategies suffer from high failure rates due to antibiotic resistance and tolerance. Bacteriophages represent a promising alternative as they retain activity against such bacteria. However, optimal phage administration protocols remain unknown, although injectable hydrogels, loaded with phage and conventional antibiotics, may support conventional therapy.In this study we tested the activity of meropenem, and two newly isolated bacteriophages (ϕ9 and ϕ3) embedded within alginate-chitosan microbeads and a hydrogel. Antibiotic and phage stability and activity were monitored in vitro, over a period of 10 days. In vivo, the same material was tested in treatment of a 5-day old Pseudomonas aeruginosa infection of a tibial plate osteotomy in mice. Treatment involved debridement and 5 days of systemic antibiotic therapy plus: i- saline, ii-phages in saline, iii-phages and antibiotics loaded into a hydrogel (n=7 mice/group). To assess the efficacy of the treatments, the infection load was monitored during revision surgery with debridement of the infected tissue after 5,10 and 13 days (euthanasia) by CFU and PFU quantification.In vitro testing confirmed that the stability of meropenem and activity of ϕ9 and ϕ3, was not affected within the alginate beads or hydrogel over 10 days. The in vivo study showed that all mice receiving phages and antibiotics loaded into a hydrogel survived the infection with a reduction of the bacterial load in the soft tissue. Active phages could be recovered from the infected site at euthanasia (104 PFU/g).The hydrogel loaded with bacteriophages and meropenem showed a positive result in locally reducing the infection load indicating a synergistic effect of the selected antimicrobials. Overall, our new strategy shows encouraging results for improving the treatment of antibiotic-resistant biofilm infections that are related to medical implants.

Neutralizing Carbapenem Resistance by Co-Administering Meropenem with Novel β-Lactam-Metallo-β-Lactamase Inhibitors.

Virulent Enterobacterale strains expressing serine and metallo-β-lactamases (MBL) genes have emerged responsible for conferring resistance to hard-to-treat infectious diseases. One strategy that exists is to develop β-lactamase inhibitors to counter this resistance. Currently, serine β-lactamase inhibitors (SBLIs) are in therapeutic use. However, an urgent global need for clinical metallo-β-lactamase inhibitors (MBLIs) has become dire. To address this problem, this study evaluated BP2, a novel beta-lactam-derived β-lactamase inhibitor, co-administered with meropenem. According to the antimicrobial susceptibility results, BP2 potentiates the synergistic activity of meropenem to a minimum inhibitory concentration (MIC) of ≤1 mg/L. In addition, BP2 is bactericidal over 24 h and safe to administer at the selected concentrations. Enzyme inhibition kinetics showed that BP2 had an apparent inhibitory constant (Kiapp) of 35.3 µM and 30.9 µM against New Delhi Metallo-β-lactamase (NDM-1) and Verona Integron-encoded Metallo-β-lactamase (VIM-2), respectively. BP2 did not interact with glyoxylase II enzyme up to 500 µM, indicating specific (MBL) binding. In a murine infection model, BP2 co-administered with meropenem was efficacious, observed by the >3 log10 reduction in K. pneumoniae NDM cfu/thigh. Given the promising pre-clinical results, BP2 is a suitable candidate for further research and development as an (MBLI).

Rational Design of Stapled Antimicrobial Peptides to Enhance Stability and In Vivo Potency against Polymicrobial Sepsis.

In this work, we sought to develop a TP4-based stapled peptide that can be used to counter polymicrobial sepsis. First, we segregated the TP4 sequence into hydrophobic and cationic/hydrophilic zones and substituted the preferred residue, lysine, as the sole cationic amino acid. These modifications minimized the intensity of cationic or hydrophobic characteristics within small segments. Then, we incorporated single or multiple staples into the peptide chain, bracketing the cationic/hydrophilic segments to improve pharmacological suitability. Using this approach, we were able to develop an AMP with low toxicity and notable in vivo efficacy. IMPORTANCE In our in vitro studies, one dual stapled peptide out of the series of candidates (TP4-3: FIIXKKSXGLFKKKAGAXKKKXIKK) showed significant activity, low toxicity, and high stability (in 50% human serum). When tested in cecal ligation and puncture (CLP) mouse models of polymicrobial sepsis, TP4-3 improved survival (87.5% on day 7). Furthermore, TP4-3 enhanced the activity of meropenem against polymicrobial sepsis (100% survival on day 7) compared to meropenem alone (37.5% survival on day 7). Molecules such as TP4-3 may be well suited for a wide variety of clinical applications.

The activity and mechanism of vidofludimus as a potent enzyme inhibitor against NDM-1-positive E. coli

New Delhi metallo-β-lactamase-1 (NDM-1) is the most important and prevalent enzyme among all metallo-β-lactamases. NDM-1 can hydrolyze almost all-available β-lactam antibiotics including carbapenems, resulting in multidrug resistance, which poses an increasing clinical threat. However, there is no NDM-1 inhibitor approved for clinical treatment. Therefore, identifying a novel and potential enzyme inhibitor against NDM-1-mediated infections is an urgent need. In this study, vidofludimus was identified as a potential NDM-1 inhibitor by structure-based virtual screening and an enzyme activity inhibition assay. Vidofludimus significantly inhibited NDM-1 hydrolysis activity with a significant dose-dependent effect. When the vidofludimus concentration was 10 μg/ml, the inhibition rate and 50% inhibitory concentration were 93.3% and 13.8 ± 0.5 μM, respectively. In vitro, vidofludimus effectively restored the antibacterial activity of meropenem against NDM-1-positive Escherichia coli (E. coli), and the minimum inhibitory concentration of meropenem was decreased from 64 μg/ml to 4 μg/ml, a 16-fold reduction. The combination of vidofludimus and meropenem showed a significant synergistic effect with a fractional inhibitory concentration index of 0.125 and almost all the NDM-1-positive E. coli were killed within 12 h. Furthermore, the synergistic therapeutic effect of vidofludimus and meropenem in vivo was evaluated in mice infected with NDM-1 positive E. coli. Compared with the control treatment, vidofludimus combined with meropenem significantly improved the survival rate of mice infected with NDM-1-positive E. coli (P < 0.05), decreased the white blood cell count, the bacterial burden and inflammatory response induced by NDM-1-positive E. coli (P < 0.05), and alleviated histopathological damage in infected mice. It was demonstrated by molecular dynamic simulation, site-directed mutagenesis and biomolecular interaction that vidofludimus could interact directly with the key amino acids (Met67, His120, His122 and His250) and Zn2+ in the active site of NDM-1, thereby competitively inhibiting the hydrolysis activity of NDM-1 on meropenem. In summary, vidofludimus holds promise as anNDM-1 inhibitor, and the combination of vidofludimus and meropenem has potential as a therapeutic strategy for NDM-1-mediated infections.

In Vitro and In Vivo Synergism of Fosfomycin in Combination with Meropenem or Polymyxin B against KPC-2-Producing Klebsiella pneumoniae Clinical Isolates.

Fosfomycin disodium is a potential therapeutic option to manage difficult-to-treat infections, especially when combined with other antimicrobials. In this study, we evaluated the activity of fosfomycin in combination with meropenem or polymyxin B against contemporaneous KPC-2-producing K. pneumoniae clinical isolates (KPC-KPN). Synergistic activity was assessed by checkerboard (CKA) and time-kill (TKA) assays. TKA was performed using serum peak and trough concentrations. The activity of these combinations was also assessed in the Galleria mellonella model. Biofilm disruption was assessed by the microtiter plate technique. CKA resulted in an 8- to 2048-fold decrease in meropenem MIC, restoring meropenem activity for 82.4% of the isolates when combined with fosfomycin. For the fosfomycin + polymyxin B combination, a 2- to 128-fold reduction in polymyxin B MIC was achieved, restoring polymyxin B activity for 47% of the isolates. TKA resulted in the synergism of fosfomycin + meropenem (3.0-6.7 log10 CFU/mL decrease) and fosfomycin + polymyxin B (6.0-6.2 log10 CFU/mL decrease) at peak concentrations. All larvae treated with fosfomycin + meropenem survived. Larvae survival rate was higher with fosfomycin monotherapy (95%) than that observed for fosfomycin + polymyxin B (75%) (p-value < 0.0001). Finally, a higher biofilm disruption was observed under exposure to fosfomycin + polymyxin B (2.4-3.4-fold reduction). In summary, we observed a synergistic effect of fosfomycin + meropenem and fosfomycin + polymyxin B combinations, in vitro and in vivo, against KPC-KPN, as well as biofilm disruption.

Antibacterial composite: polymeric mesoporous silica nanoparticles and combination of imipenem/meropenem.

Using nanomaterials is a novel strategy to eliminate drug resistance against bacteria. Nanoparticles with metal sites show antimicrobial activities that counteract or obstruct antibiotic-resistant mechanisms expressed by the pathogens. Here, a nanocomposite based on mesoporous silica nanoparticles with active sites of silver, and a combination of imipenem and meropenem as antibiotic drugs, was synthesized and characterized using different physicochemical methods. The antibacterial assessments exhibited sensitivity by Staphylococcus aureus (S. aureus), Klebsiella pneumoniae (K. pneumoniae) and Escherichia coli (E. coli) toward the synthesized composite, which showed a suitable safety profile in human cells. This composite has an excellent synergic mechanism based on reactive oxygen species (ROS) to kill bacteria due to penetrating the microbial membrane. In addition, this composite is resistant to hydrolysis by plasmids and chromosomally mediated β-lactamases. This nanocomposite showed extraordinary antiseptic power against Gram-positive and Gram-negative microbes.

Clinical Evaluation of Meropenem-Vaborbactam Combination for the Treatment of Urinary Tract Infection: Evidence to Date.

As antimicrobial resistance continues to grow, one of the biggest threats includes the members of the Enterobacterales order presenting with carbapenem resistance (CRE). Meropenem-vaborbactam, along with other beta-lactam/beta-lactamase agents, has been developed to help combat this growing concern and is currently approved to treat complicated urinary tract infections (cUTI), as well as acute pyelonephritis (AP), in the USA. Vaborbactam is a novel beta-lactamase inhibitor designed specifically to optimize and restore the activity of meropenem against resistant Enterobacterales. Vaborbactam inhibits a number of beta-lactamases, including in vitro activity against extended-spectrum beta-lactamases (ESBL) and the Klebsiella pneumoniae carbapenemase (KPC) group. KPC represents one of the most clinically relevant carbapenemase in the USA, accounting for the majority of carbapenemase-producing CRE. Meropenem-vaborbactam has been studied in the two Phase 3, noninferiority trials, TANGO I and TANGO II. TANGO I compared meropenem-vaborbactam against piperacillin-tazobactam in patients with cUTIs and was found to be noninferior for overall success and microbial eradication. TANGO II expanded to other disease states (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia [HAP/VAP], complicated intra-abdominal infection [cIAI], cUTI/AP) and was found to be noninferior against best available therapy (BAT) with respect to clinical cure at the end of treatment and the test of cure. Meropenem-vaborbactam maintained the established safety profile of meropenem alone, with headache as the most common adverse event in both phase 3 studies. Overall, clinical efficacy has been demonstrated and suggests the use of meropenem-vaborbactam for the treatment of cUTI is an option.

Cytotoxicity and anti-biofilm activities of biogenic cadmium nanoparticles and cadmium nitrate: a preliminary study.

Wild-type microorganisms have become tolerant to higher antibiotic and antimicrobial agent concentrations due to the global increase in antibiotic consumption. Green-synthesized nanoparticles (NPs) have been proposed as potential antimicrobial agents to overcome the problem. This research prepared cadmium nanoparticles (Cd NPs) using Artemisia persica extract. To clarify the biological behavior of Cd NPs and Cd (NO3)2, cytotoxicity, antibacterial, anti-biofilm, and biocompatible experiments were performed. Since Cd toxicity is associated with liver, kidney damage, and other deficits, HepG2 and HUVEC cell lines were employed as the in vitro cytotoxicity models. Cd NPs had a lower cytotoxic effect than Cd (NO3)2 against both HepG2 and HUVEC cells. The Cd NPs exhibited no hemolysis activity. The antibacterial and anti-biofilm studies were conducted using gram-positive Staphylococcus aureus and gram-negative Proteus mirabilis and Pseudomonas aeruginosa with the ability to form severe adherent biofilms. The antibacterial activity of Cd NPs against clinically isolated S. aureus, P. mirabilis, and P. aeruginosa was above 2560µg mL- 1. The Cd NPs (640µg mL- 1) decreased the biofilm formation of S. aureus, P. mirabilis, and P. aeruginosa by 24.6%, 31.6%, and 26.4%, respectively.Moreover, adding Cd NPs (100µg/disc) to antibiotic discs increased the antibacterial activity of vancomycin, gentamicin, tetracycline, streptomycin, meropenem, and kanamycin against Methicillin-resistant S. aureus, significantly. Due to the emergence of resistant microorganisms, Cd NPs can be used as an exciting material to counterattack global health problems. Further research is needed to clarify the molecular mechanisms underlying Cd NPs' pharmacological and toxicological effects.