-
European Journal of Medicinal Chemistry Mar 2023New 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...
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 Zn 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.
Topics: Animals; Mice; Meropenem; Escherichia coli; Anti-Bacterial Agents; beta-Lactamases; Enzyme Inhibitors; Microbial Sensitivity Tests; beta-Lactamase Inhibitors
PubMed: 36870273
DOI: 10.1016/j.ejmech.2023.115225 -
Clinical Pharmacokinetics Nov 2022We aimed to develop a meropenem population pharmacokinetic model in critically ill children receiving continuous renal replacement therapy and simulate dosing regimens...
BACKGROUND AND OBJECTIVE
We aimed to develop a meropenem population pharmacokinetic model in critically ill children receiving continuous renal replacement therapy and simulate dosing regimens to optimize patient exposure.
METHODS
Meropenem plasma concentration was quantified by high-performance liquid chromatography. Meropenem pharmacokinetics was investigated using a non-linear mixed-effect modeling approach. Monte Carlo simulations were performed to compute the optimal scheme of administration, according to the target of a 100% inter-dose interval time in which concentration is one to four times above the minimum inhibitory concentration (100% fT>1-4×MIC).
RESULTS
A total of 27 patients with a median age of 4 [interquartile range 0-11] years, a median body weight of 16 [range 7-35] kg receiving continuous renal replacement therapy were included. Concentration-time courses were best described by a one-compartment model with first-order elimination. Body weight (BW) produced significant effects on volume of distribution (V) and BW and continuous renal replacement therapy effluent flow rate (Q) produced significant effects on clearance (CL): [Formula: see text] and [Formula: see text], where V and CL estimates were 32.5 L and 5.88 L/h, respectively, normalized to a 70-kg BW and median Q at 1200 mL/h. Using this final model and Monte Carlo simulations, for patients with Q over 1200 mL/h, meropenem continuous infusion was adequate in most cases to attain 100% fT>-. For bacterial infections with a low minimum inhibitory concentration (≤2 mg/L), meropenem intermitent administration was appropriate for patients weighing more than 20 kg with Q <500 mL/h and for patients weighing more than 10 kg with Q <100 mL/h.
CONCLUSIONS
Meropenem exposure in critically ill children receiving continuous renal replacement therapy needs dosing adjustments to the minimum inhibitory concentration that take into account body weight and the continuous renal replacement therapy effluent flow rate.
Topics: Child; Humans; Infant, Newborn; Infant; Child, Preschool; Meropenem; Continuous Renal Replacement Therapy; Critical Illness; Anti-Bacterial Agents; Microbial Sensitivity Tests; Body Weight; Renal Replacement Therapy
PubMed: 36251162
DOI: 10.1007/s40262-022-01179-2 -
Antimicrobial Agents and Chemotherapy Nov 2022Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and...
Several pathophysiological changes can alter meropenem pharmacokinetics in critically ill patients, thereby increasing the risk of subtherapeutic concentrations and affecting therapeutic outcomes. This study aimed to characterize the population pharmacokinetic (PPK) parameters of meropenem, evaluate the relationship between the pharmacokinetic/pharmacodynamic index of meropenem and treatment outcomes, and evaluate the different dosage regimens that can achieve 40%, 75%, and 100% of the dosing interval for which the free plasma concentrations remain above the MIC of the pathogens () targets. Critically ill adult patients treated with meropenem were recruited for this study. Five blood samples were collected from each patient. PPK models were developed using a nonlinear mixed-effects modeling approach, and the final model was subsequently used for Monte Carlo simulations to determine the optimal dosage regimens. A total of 247 concentrations from 52 patients were available for analysis. The two-compartment model with linear elimination adequately described the data. The mean PPK parameters were clearance (CL) of 4.8 L/h, central volume of distribution (V) of 11.4 L, peripheral volume of distribution (V) of 14.6 L, and intercompartment clearance of 10.5 L/h. Creatinine clearance was a significant covariate affecting CL, while serum albumin level and shock status were factors influencing V and V, respectively. Although 75% of the drug-resistant infection patients had values of >40%, approximately 83% of them did not survive the infection. Therefore, 40% might not be sufficient for critically ill patients, and a higher target, such as 75 to 100% , should be considered for optimizing therapy. A 75% could be reached using approved doses administered via a 3-h infusion.
Topics: Humans; Adult; Meropenem; Critical Illness; Anti-Bacterial Agents; Monte Carlo Method; Microbial Sensitivity Tests
PubMed: 36226944
DOI: 10.1128/aac.00845-22 -
Antimicrobial Agents and Chemotherapy May 2023Dissemination of hypervirulent and carbapenem-resistant Klebsiella pneumoniae (CRKP) has been reported worldwide, posing a serious threat to antimicrobial therapy and...
Dissemination of hypervirulent and carbapenem-resistant Klebsiella pneumoniae (CRKP) has been reported worldwide, posing a serious threat to antimicrobial therapy and public health. Outer membrane vesicles (OMVs) act as vectors for the horizontal transfer of virulence and resistance genes. However, K. pneumoniae OMVs that transfer carbapenem resistance genes into hypervirulent K. pneumoniae (hvKP) have been insufficiently investigated. Therefore, this study investigates the transmission of the gene encoding resistance via OMVs released from CRKP and the potential mechanism responsible for the carbapenem-resistant hypervirulent K. pneumoniae (CR-hvKP) emergence. OMVs were isolated via ultracentrifugation from CRKP with or without meropenem selective pressure. OMVs were then used to transform classical K. pneumoniae (ckp) ATCC 10031, extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae ATCC 700603, and hvKP NTUH-K2044. Our results showed that meropenem treatment resulted in changes in the number and diameter of OMVs secreted by CRKP. OMVs derived from CRKP mediated the transfer of to ckp and hvKP, thereby increasing the carbapenem MIC of transformants. Further experiments confirmed that NTUH-K2044 transformants exhibited hypervirulence. Our study demonstrates, for the first time, that OMVs derived from CRKP can carry and deliver resistance genes to other K. pneumoniae strains, even hvKP. The transfer of carbapenem genes into hypervirulent strains may promote the emergence and dissemination of CR-hvKP. This study elucidates a new mechanism underlying the formation of CR-hvKP.
Topics: Humans; Klebsiella pneumoniae; Meropenem; Klebsiella Infections; Carbapenems; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae
PubMed: 37052502
DOI: 10.1128/aac.01444-22 -
MBio Jun 2022β-Lactam antibiotics exploit the essentiality of the bacterial cell envelope by perturbing the peptidoglycan layer, typically resulting in rapid lysis and death. Many...
β-Lactam antibiotics exploit the essentiality of the bacterial cell envelope by perturbing the peptidoglycan layer, typically resulting in rapid lysis and death. Many Gram-negative bacteria do not lyse but instead exhibit "tolerance," the ability to sustain viability in the presence of bactericidal antibiotics for extended periods. Antibiotic tolerance has been implicated in treatment failure and is a stepping-stone in the acquisition of true resistance, and the molecular factors that promote intrinsic tolerance are not well understood. Acinetobacter baumannii is a critical-threat nosocomial pathogen notorious for its ability to rapidly develop multidrug resistance. Carbapenem β-lactam antibiotics (i.e., meropenem) are first-line prescriptions to treat A. baumannii infections, but treatment failure is increasingly prevalent. Meropenem tolerance in Gram-negative pathogens is characterized by morphologically distinct populations of spheroplasts, but the impact of spheroplast formation is not fully understood. Here, we show that susceptible A. baumannii clinical isolates demonstrate tolerance to high-level meropenem treatment, form spheroplasts upon exposure to the antibiotic, and revert to normal growth after antibiotic removal. Using transcriptomics and genetic screens, we show that several genes associated with outer membrane integrity maintenance and efflux promote tolerance, likely by limiting entry into the periplasm. Genes associated with peptidoglycan homeostasis in the periplasm and cytoplasm also answered our screen, and their disruption compromised cell envelope barrier function. Finally, we defined the enzymatic activity of the tolerance determinants penicillin-binding protein 7 (PBP7) and ElsL (a cytoplasmic ld-carboxypeptidase). These data show that outer membrane integrity and peptidoglycan recycling are tightly linked in their contribution to A. baumannii meropenem tolerance. Carbapenem treatment failure associated with "superbug" infections has rapidly increased in prevalence, highlighting the urgent need to develop new therapeutic strategies. Antibiotic tolerance can directly lead to treatment failure but has also been shown to promote the acquisition of true resistance within a population. While some studies have addressed mechanisms that promote tolerance, factors that underlie Gram-negative bacterial survival during carbapenem treatment are not well understood. Here, we characterized the role of peptidoglycan recycling in outer membrane integrity maintenance and meropenem tolerance in A. baumannii. These studies suggest that the pathogen limits antibiotic concentrations in the periplasm and highlight physiological processes that could be targeted to improve antimicrobial treatment.
Topics: Acinetobacter baumannii; Anti-Bacterial Agents; Carbapenems; Gram-Negative Bacteria; Meropenem; Microbial Sensitivity Tests; Peptidoglycan
PubMed: 35638738
DOI: 10.1128/mbio.01001-22 -
Acta Microbiologica Et Immunologica... Jun 2023The incidence of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) is increasing worldwide, and very limited number of effective antibiotics are...
The incidence of infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKP) is increasing worldwide, and very limited number of effective antibiotics are available for therapy. In our study, the in vitro efficacy of meropenem/polymyxin B and meropenem/fosfomycin combinations against CRKP strains was investigated. The efficiency of meropenem/polymyxin B and meropenem/fosfomycin combinations was tested by checkerboard microdilution and checkerboard agar dilution methods, respectively, against 21 CRKP strains containing major carbapenem resistant genes (7 blaKPC, 7 blaOXA-48 gene, and 7 blaOXA-48+ blaNDM), and seven additional CRKP strains without carbapenemase genes.Among the 28 CRKP strains, the meropenem/polymyxin B combination was synergistic in ten (35.7%), partially synergistic in 12 (42.8%), and indifferent in six (21.4%) isolates. The meropenem/fosfomycin combination was found to be synergistic in three isolates (10.7%), partially synergistic in 20 (71.4%), and indifferent in five (17.8%). In 21 strains containing carbapenem resistance genes, meropenem/polymyxin B and meropenem/fosfomycin combinations exhibited synergistic/partial synergistic effects in 15 (71.4%) and 16 (76.2%) strains, respectively, compared to 100% synergistic/partial synergistic efficiency in both combinations in seven strains free of carbapenemase genes. No antagonistic effect was detected in either combination.Regardless of presence or absence of carbapenem resistance genes, meropenem/polymyxin B and meropenem/fosfomycin combinations both demonstrated high synergistic and partial synergistic activity against 78.4% and 82.1% of CRKP strains, respectively. Also, they have no antagonistic effects and can be used successfully to prevent therapeutic failure with monotherapy, according to our in vitro studies.
Topics: Humans; Meropenem; Fosfomycin; Polymyxin B; Klebsiella pneumoniae; Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Carbapenems; beta-Lactamases; Microbial Sensitivity Tests; Klebsiella Infections
PubMed: 37133999
DOI: 10.1556/030.2023.02015 -
Molecular Immunology Aug 2022Multi-drug resistant Pseudomonas aeruginosa is a gram-negative bacillus responsible for nosocomial infections. Immunoglobulin Y (IgY) is a chicken immunoglobulin used...
Multi-drug resistant Pseudomonas aeruginosa is a gram-negative bacillus responsible for nosocomial infections. Immunoglobulin Y (IgY) is a chicken immunoglobulin used for research, immunodiagnosis, and immunotherapy. IgY presents antimicrobial properties and it is under investigation for use as an adjunct to prophylactic therapies. The current study aimed to assess the synergistic action between anti-P aeruginosa IgY and the beta-lactams ceftazidime, imipenem, and meropenem. IgY antibodies were obtained from laying hens immunized with SPM-1 producing P. aeruginosa (Pa48) or VIM-2 producing P. aeruginosa (Pa23). The antimicrobial activity of IgY antibodies was evaluated by the growth inhibition test, and the synergistic effect was assessed by determination of the fractional inhibitory concentration index. Anti-Pa48 IgY shows antimicrobial activity at 1.25 mg/ml and anti-Pa23 IgY shows antimicrobial activity at 2.5 mg/ml. The fractional inhibitory concentration indices of anti-Pa48 IgY and ceftazidime, or imipenem, or meropenem at 72 h of experiment were 0.189, 0.209, and 0.440, respectively. For anti-Pa23 IgY, the fractional inhibitory concentration indices were 0.440 with ceftazidime, 0.453 with imipenem, and 0.441 with meropenem at 72 h. We conclude that there is a synergistic action between anti-P. aeruginosa IgY and the antimicrobials tested. Further studies are necessary to investigate the mechanisms associated with this action.
Topics: Animals; Anti-Bacterial Agents; Ceftazidime; Chickens; Female; Imipenem; Immunoglobulins; Meropenem; Microbial Sensitivity Tests; Pseudomonas Infections; Pseudomonas aeruginosa
PubMed: 35640520
DOI: 10.1016/j.molimm.2022.05.010 -
Future Microbiology Jan 2023Meropenem-vaborbactam and delafloxacin activities were not assessed against spp. (), complex () and (). A total of 106 , 57 and 100 were tested with gradient...
Meropenem-vaborbactam and delafloxacin activities were not assessed against spp. (), complex () and (). A total of 106 , 57 and 100 were tested with gradient diffusion test of meropenem-vaborbactam, delafloxacin and comparators. Meropenem-vaborbactam MIC were 4 μg/ml for , 1 μg/ml for , 2 μg/ml for and , and 32 μg/ml for . Delafloxacin MIC were 4 μg/ml for , 0.25 μg/ml for and , 2 μg/ml for , and 0.5 μg/m for . meropenem-vaborbactam MICs were fourfold lower than meropenem for 28.3% , 77.2% , 53.8% and 77.2% . Meropenem-vaborbactam and delafloxacin are active against and .
Topics: Meropenem; Anti-Bacterial Agents; Gram-Negative Bacteria; Stenotrophomonas maltophilia; Burkholderia cepacia complex; Microbial Sensitivity Tests
PubMed: 36722304
DOI: 10.2217/fmb-2021-0278 -
The Journal of Antimicrobial... Nov 2021To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance.
OBJECTIVES
To investigate the increase in the rates of OXA-48-like-producing isolates during 3 years of global surveillance.
METHODS
Among 55?>162 Enterobacterales isolates, 354 carbapenem-resistant isolates carried genes encoding OXA-48-like enzymes. Isolates were susceptibility tested for ceftazidime/avibactam and comparators by broth microdilution methods. Analysis of β-lactam resistance mechanisms and MLST was performed in silico using WGS data.
RESULTS
OXA-48-like-producing isolates increased from 0.5% (94/18 656) in 2016 to 0.9% (169/18?>808) in 2018. OXA-48 was the most common variant; isolates primarily were Klebsiella pneumoniae (318/354 isolates) from Europe and adjacent countries. MLST analysis revealed a diversity of STs, but K. pneumoniae belonging to ST395, ST23 and ST11 were observed most frequently. Thirty-nine isolates harboured MBLs and were resistant to most agents tested. The presence of blaCTX-M-15 (258 isolates), OmpK35 nonsense mutations (232) and OmpK36 alterations (316) was common among OXA-48 producers. Ceftazidime, cefepime and aztreonam susceptibility rates, when applying CLSI breakpoints, were 12%-15% lower for isolates carrying ESBLs alone and with either or both OmpK35 stop codons and OmpK36 alterations. Meropenem and, remarkably, meropenem/vaborbactam were affected by specific OmpK36 alterations when a deleterious mutation also was observed in OmpK35. These mechanisms caused a decrease of 12%-42% in the susceptibility rates for meropenem and meropenem/vaborbactam. Ceftazidime/avibactam susceptibility rates were >98.9%, regardless of the presence of additional β-lactam resistance mechanisms.
CONCLUSIONS
Guidelines for the treatment of infections caused by OXA-48-producing isolates are scarce and, as the dissemination of these isolates continues, studies are needed to help physicians understand treatment options for these infections.
Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Boronic Acids; Ceftazidime; Drug Combinations; Enterobacteriaceae; Heterocyclic Compounds, 1-Ring; Meropenem; Microbial Sensitivity Tests; Multilocus Sequence Typing; beta-Lactamases
PubMed: 34459890
DOI: 10.1093/jac/dkab306 -
Injury Aug 2022Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical...
Concentrations of co-administered vancomycin and meropenem in the internal dead space of a cannulated screw and in cancellous bone adjacent to the screw - Evaluated by microdialysis in a porcine model.
BACKGROUND
Cannulated screws are often used in the management of open lower extremity fractures. These fractures exhibit broad contamination profiles, necessitating empirical Gram-positive and Gram-negative antibiotic coverage. To ensure full antibiotic protection of the cannulated screw and the bone tissue, it is generally accepted that target tissue antibiotic concentrations, as a minimum, reach and remain above relevant epidemiological cut-off minimal inhibitory concentrations (T>MIC) for a sufficient amount of time.
METHODS
8 female pigs were included. Microdialysis catheters were placed in the internal dead space of a cannulated screw placed in tibial cancellous bone, in tibial cancellous bone adjacent to the screw (mean distance to the screw: 3 mm), and in cancellous bone on the contralateral tibia. Following single-dose simultaneous intravenous administrations of vancomycin (1000 mg) and meropenem (1000 mg), microdialysates and plasma were dynamically sampled over 8 h. The applied MIC targets ranged from 1 to 4 µg/mL for vancomycin and 0.125-2 µg/mL for meropenem RESULTS: For both drugs, and for all MIC targets investigated (except for the high vancomycin target: 4 µg/mL), the internal dead space of the cannulated screw had the shortest T>MIC. At the low MIC targets T>MIC ranged between 88 and 449 min across sampling sites for vancomycin (1 µg/mL), and 148-406 min for meropenem (0.125 µg/mL). For the high MIC targets, T>MIC ranged between 3 and 446 min for vancomycin (4 μg/mL) and 17-181 min for meropenem (2 μg/mL). Vancomycin displayed longer T>MIC (2 and 4 μg/mL), higher area under the concentration time curve (AUC) and peak drug concentration in the proximal tibial cancellous bone without a screw nearby. For meropenem, only the cancellous bone AUC was significantly higher on the side with no screw.
CONCLUSION
We found short T>MIC, particularly for the high MIC targets for vancomycin and meropenem, both inside the cannulated screw and in cancellous bone adjacent to the screw. The presence of a cannulated screw impaired the penetration of especially vancomycin into cancellous bone adjacent to the screw. More aggressive or different vancomycin and meropenem approaches may be considered to encompass contaminating differences and to ensure a theoretically more sufficient antibiotic protection of cannulated screws when used in the management of open lower extremity fractures.
Topics: Animals; Anti-Bacterial Agents; Cancellous Bone; Female; Meropenem; Microdialysis; Swine; Vancomycin
PubMed: 35710595
DOI: 10.1016/j.injury.2022.06.008