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Antibiotics (Basel, Switzerland) Apr 2023While the relevance of inter-ethnic differences to the pharmacokinetic variabilities of antimicrobials has been reported in studies recruiting healthy subjects,... (Review)
Review
While the relevance of inter-ethnic differences to the pharmacokinetic variabilities of antimicrobials has been reported in studies recruiting healthy subjects, differences in antimicrobial pharmacokinetics between Asian and non-Asian patients with severe pathologic conditions require further investigation. For the purpose of describing the potential differences in antimicrobial pharmacokinetics between Asian and non-Asian populations, a systematic review was performed using six journal databases and six theses/dissertation databases (PROSPERO record CRD42018090054). The pharmacokinetic data of healthy volunteers and non-critically ill and critically ill patients were reviewed. Thirty studies on meropenem, imipenem, doripenem, linezolid, and vancomycin were included in the final descriptive summaries. In studies recruiting hospitalised patients, inconsistent differences in the volume of distribution (V) and drug clearance (CL) of the studied antimicrobials between Asian and non-Asian patients were observed. Additionally, factors other than ethnicity, such as demographic (e.g., age) or clinical (e.g., sepsis) factors, were suggested to better characterise these pharmacokinetic differences. Inconsistent differences in pharmacokinetic parameters between Asian and non-Asian subjects/patients may suggest that ethnicity is not an important predictor to characterise interindividual pharmacokinetic differences between meropenem, imipenem, doripenem, linezolid, and vancomycin. Therefore, the dosing regimens of these antimicrobials should be adjusted according to patients' demographic or clinical characteristics that can better describe pharmacokinetic differences.
PubMed: 37237706
DOI: 10.3390/antibiotics12050803 -
Antimicrobial Agents and Chemotherapy Jun 2023The β-lactam antibiotics have been successfully used for decades to combat susceptible Pseudomonas aeruginosa, which has a notoriously difficult to penetrate outer...
The β-lactam antibiotics have been successfully used for decades to combat susceptible Pseudomonas aeruginosa, which has a notoriously difficult to penetrate outer membrane (OM). However, there is a dearth of data on target site penetration and covalent binding of penicillin-binding proteins (PBP) for β-lactams and β-lactamase inhibitors in intact bacteria. We aimed to determine the time course of PBP binding in intact and lysed cells and estimate the target site penetration and PBP access for 15 compounds in P. aeruginosa PAO1. All β-lactams (at 2 × MIC) considerably bound PBPs 1 to 4 in lysed bacteria. However, PBP binding in intact bacteria was substantially attenuated for slow but not for rapid penetrating β-lactams. Imipenem yielded 1.5 ± 0.11 log killing at 1h compared to <0.5 log killing for all other drugs. Relative to imipenem, the rate of net influx and PBP access was ~ 2-fold slower for doripenem and meropenem, 7.6-fold for avibactam, 14-fold for ceftazidime, 45-fold for cefepime, 50-fold for sulbactam, 72-fold for ertapenem, ~ 249-fold for piperacillin and aztreonam, 358-fold for tazobactam, ~547-fold for carbenicillin and ticarcillin, and 1,019-fold for cefoxitin. At 2 × MIC, the extent of PBP5/6 binding was highly correlated ( = 0.96) with the rate of net influx and PBP access, suggesting that PBP5/6 acted as a decoy target that should be avoided by slowly penetrating, future β-lactams. This first comprehensive assessment of the time course of PBP binding in intact and lysed P. aeruginosa explained why only imipenem killed rapidly. The developed novel covalent binding assay in intact bacteria accounts for all expressed resistance mechanisms.
Topics: Penicillin-Binding Proteins; Anti-Bacterial Agents; Pseudomonas aeruginosa; Bacterial Proteins; Network Pharmacology; Microbial Sensitivity Tests; beta-Lactams; Imipenem; Ceftazidime; beta-Lactamases
PubMed: 37199612
DOI: 10.1128/aac.01603-22 -
Journal of Clinical Medicine Apr 2023The high incidence of urinary tract infections (UTIs), often in nosocomial environments, is a major cause of antimicrobial resistance (AMR). The dissemination of...
PURPOSE
The high incidence of urinary tract infections (UTIs), often in nosocomial environments, is a major cause of antimicrobial resistance (AMR). The dissemination of antibiotic-resistant infections results in very high health and economic burdens for patients and healthcare systems, respectively. This study aims to determine and present the antibiotic resistance profiles of the most common pathogens in a urology department in Greece.
METHODS
During the period 2019-2020, we included 12,215 clinical samples of blood and urine specimens that tested positive for the following pathogens: , , , , , or , as these are the most commonly encountered microbes in a urology department.
RESULTS
The analysis revealed a 22.30% mean resistance rate of strains with a 76.42% resistance to ampicillin and a 54.76% resistance rate to ciprofloxacin in the two-year period. It also showed an approximately 19% resistance rate of strains and a mean resistance rate of 46.205% of strains, with a decreasing trend during the four semesters (-value < 0.001), which presented an 80% resistance rate to ampicillin/sulbactam and 73.33% to ciprofloxacin. The resistance to carbapenems was reported to be 39.82%. The analysis revealed a 24.17% mean resistance rate of with a declining rate over the two-year period (-value < 0.001). The strains were 38% resistant to fluoroquinolones and presented varying resistance against carbapenems (31.58% against doripenem and 19.79% against meropenem). Regarding the strains, a 46.91% mean resistance was noted for with 100% resistance to ampicillin, and a 24.247% mean resistance rate for strains that were 41% resistant to ciprofloxacin. Both types showed 100% sensitivity to linezolid.
CONCLUSIONS
The dissemination of antibiotic-resistant pathogens poses the need to implement surveillance programs and, consequently, to develop strategies to prevent the emergence of such pathogens in order to optimize patient outcomes.
PubMed: 37176622
DOI: 10.3390/jcm12093180 -
Data in Brief Jun 2023The dataset reported in this article describes the adsorption isotherms of amoxicillin, ampicillin, and doripenem onto bentonite. Batch adsorption experiments were...
The dataset reported in this article describes the adsorption isotherms of amoxicillin, ampicillin, and doripenem onto bentonite. Batch adsorption experiments were carried out on single antibiotic solutions with various dosage of bentonite across temperatures from 30 to 50 °C. The adsorbent loading dataset was later obtained by measuring the concentration of antibiotic solution at adsorption equilibrium UV-Vis spectrophotometer. The dataset was also fitted using various isotherm models including Freundlich, Langmuir, Toth, Hill, and Dubinin-Radushkevich models to further analyze the adsorption behavior. On top of that, orthogonal regression was applied to avoid fitting biasness, whereby the fitting results revealed the highest adsorption capacities of 82.259 mg g for amoxicillin, 78.851 mg g for ampicillin, and 93.278 mg g for doripenem using Langmuir model, which gave an accurate representation of the adsorption isotherm dataset that was consistent with the results of Toth and Hill model.
PubMed: 37168600
DOI: 10.1016/j.dib.2023.109159 -
The Journal of Antimicrobial... May 2023We found a carbapenem-resistant Escherichia coli without known carbapenemase-encoding genes and performed a study to identify the possible new carbapenemase.
BACKGROUND
We found a carbapenem-resistant Escherichia coli without known carbapenemase-encoding genes and performed a study to identify the possible new carbapenemase.
METHODS
The production of carbapenemase was examined using the modified carbapenem inactivation method. The strain was subjected to short- and long-read genome sequencing and the complete genome was obtained by hybrid assembly. The gene encoding a potential new OXA-type carbapenemase was cloned. The enzyme was purified and was then subjected to kinetic assays. Molecular docking analysis of the enzyme was performed using the MOE software suite. Mating experiments were attempted to obtain the plasmid carrying the corresponding gene.
RESULTS
We identified and characterized a novel class D carbapenem-hydrolysing β-lactamase, OXA-1041, in a carbapenem-resistant E. coli clinical strain. OXA-1041 had 89.77% (237/264) amino acid identity with OXA-427, a known carbapenemase. By cloning in an E. coli laboratory strain, blaOXA-1041 was found to reduce susceptibility to ertapenem by 16 times (MIC 0.25 versus 0.016 mg/L) and meropenem by four times (MIC 0.06 versus 0.016 mg/L) but did not significantly reduce susceptibility to imipenem and doripenem. Enzyme kinetic measurement of purified OXA-1041 showed that OXA-1041 could hydrolyse ertapenem and meropenem with a turnover number (kcat)/Michaelis constant (KM) of 8.57 and 3.63 mM-1s-1, respectively. The complete genome contained a single plasmid (223 341 bp, IncF, containing five replicons), which was self-transmissible. blaOXA-1041 was downstream of insertion sequence ISCR1 and there were three tandem copies of ISCR1-blaOXA-1041-creDΔ (encoding an envelope protein) on this plasmid.
CONCLUSIONS
The above findings suggest OXA-1041 is a new plasmid-encoded carbapenemase with preferential activity against ertapenem.
Topics: Carbapenems; Escherichia coli; Anti-Bacterial Agents; Meropenem; Ertapenem; Molecular Docking Simulation; beta-Lactamases; Bacterial Proteins; Microbial Sensitivity Tests
PubMed: 36995982
DOI: 10.1093/jac/dkad091 -
Journal of Global Antimicrobial... Jun 2023Both ertapenem and other carbapenems, including imipenem, meropenem, and doripenem, are recommended in the treatment of extended-spectrum-β-lactamase (ESBL)-producing... (Meta-Analysis)
Meta-Analysis
Clinical efficacy of ertapenem vs. other carbapenems for the treatment of extended-spectrum-β-lactamase-producing Enterobacterales infection: A systematic review and meta-analysis.
OBJECTIVE
Both ertapenem and other carbapenems, including imipenem, meropenem, and doripenem, are recommended in the treatment of extended-spectrum-β-lactamase (ESBL)-producing Enterobacterales infection. However, whether ertapenem is as effective as other carbapenems for ESBL-producing Enterobacterales remains unclear. Therefore, this meta-analysis was conducted to compare the clinical efficacy of ertapenem versus other carbapenems in the treatment of ESBL-producing Enterobacterales infection.
METHODS
PubMed, Web of Science, and Cochrane Library were searched from their inception to 29 November 2022. Only studies comparing ertapenem and other carbapenems in the treatment of patients with ESBL-producing Enterobacterales infections were included.
RESULTS
A total of six studies meeting selection criteria were identified. Overall, ertapenem was associated with a significantly lower 30-d mortality when compared with other carbapenems (10.7% [46/431] vs. 17.7% [104/586]; risk ratio [RR], 0.61; 95% CI: 0.40-0.91). The ertapenem group exhibited a significantly shorter length of hospital stay than the other carbapenem groups (mean differences, -6.02 d; 95% CI, -9.39 to -2.64). No significant differences were noted between ertapenem and other carbapenem groups in terms of rates of clinical cure or improvement (RR, 1.11; 95% CI: 0.97-1.25) and microbiological eradication (RR, 1.01; 95% CI: 0.97-1.06).
CONCLUSIONS
Ertapenem could be as effective as other carbapenems in the treatment of patients with ESBL-producing Enterobacterales infections.
Topics: Humans; Ertapenem; Carbapenems; Anti-Bacterial Agents; beta-Lactams; beta-Lactamases; Treatment Outcome; Gammaproteobacteria
PubMed: 36944409
DOI: 10.1016/j.jgar.2023.03.003 -
The Journal of Biological Chemistry May 2023L1 is a dizinc subclass B3 metallo-β-lactamase (MBL) that hydrolyzes most β-lactam antibiotics and is a key resistance determinant in the Gram-negative pathogen...
L1 is a dizinc subclass B3 metallo-β-lactamase (MBL) that hydrolyzes most β-lactam antibiotics and is a key resistance determinant in the Gram-negative pathogen Stenotrophomonas maltophilia, an important cause of nosocomial infections in immunocompromised patients. L1 is not usefully inhibited by MBL inhibitors in clinical trials, underlying the need for further studies on L1 structure and mechanism. We describe kinetic studies and crystal structures of L1 in complex with hydrolyzed β-lactams from the penam (mecillinam), cephem (cefoxitin/cefmetazole), and carbapenem (tebipenem, doripenem, and panipenem) classes. Despite differences in their structures, all the β-lactam-derived products hydrogen bond to Tyr33, Ser221, and Ser225 and are stabilized by interactions with a conserved hydrophobic pocket. The carbapenem products were modeled as Δ-imines, with (2S)-stereochemistry. Their binding mode is determined by the presence of a 1β-methyl substituent: the Zn-bridging hydroxide either interacts with the C-6 hydroxyethyl group (1β-hydrogen-containing carbapenems) or is displaced by the C-6 carboxylate (1β-methyl-containing carbapenems). Unexpectedly, the mecillinam product is a rearranged N-formyl amide rather than penicilloic acid, with the N-formyl oxygen interacting with the Zn-bridging hydroxide. NMR studies imply mecillinam rearrangement can occur nonenzymatically in solution. Cephem-derived imine products are bound with (3R)-stereochemistry and retain their 3' leaving groups, likely representing stable endpoints, rather than intermediates, in MBL-catalyzed hydrolysis. Our structures show preferential complex formation by carbapenem- and cephem-derived species protonated on the equivalent (β) faces and so identify interactions that stabilize diverse hydrolyzed antibiotics. These results may be exploited in developing antibiotics, and β-lactamase inhibitors, that form long-lasting complexes with dizinc MBLs.
Topics: Humans; Anti-Bacterial Agents; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams; Carbapenems; Crystallography; Kinetics; Stenotrophomonas maltophilia; Gram-Negative Bacterial Infections
PubMed: 36924941
DOI: 10.1016/j.jbc.2023.104606 -
Journal of Infection and Chemotherapy :... Jul 2023Information regarding carbapenem-induced liver injury is limited, and the rate of liver injury caused by meropenem (MEPM) and doripenem (DRPM) remains unknown. Decision...
INTRODUCTION
Information regarding carbapenem-induced liver injury is limited, and the rate of liver injury caused by meropenem (MEPM) and doripenem (DRPM) remains unknown. Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of liver injury. Thus, we aimed to compare the rate of liver injury between MEPM and DRPM and construct a flowchart that can be used to predict carbapenem-induced liver injury.
METHODS
We investigated patients treated with MEPM (n = 310) or DRPM (n = 320) and confirmed liver injury as the primary outcome. We used a chi-square automatic interaction detection algorithm to construct DT models. The dependent variable was set as liver injury from a carbapenem (MEPM or DRPM), and factors including alanine aminotransferase (ALT), albumin-bilirubin (ALBI) score, and concomitant use of acetaminophen were used as explanatory variables.
RESULTS
The rates of liver injury were 22.9% (71/310) and 17.5% (56/320) in the MEPM and DRPM groups, respectively; no significant differences in the rate were observed (95% confidence interval: 0.710-1.017). Although the DT model of MEPM could not be constructed, DT analysis showed that the incidence of introducing DRPM in patients with ALT >22 IU/L and ALBI scores > -1.87 might be high-risk.
CONCLUSIONS
The risk of developing liver injury did not differ significantly between the MEPM and DRPM groups. Since ALT and ALBI score are evaluated in clinical settings, this DT model is convenient and potentially useful for medical staff in assessing liver injury before DRPM administration.
Topics: Humans; Carbapenems; Anti-Bacterial Agents; Chemical and Drug Induced Liver Injury, Chronic; Doripenem; Meropenem
PubMed: 36914094
DOI: 10.1016/j.jiac.2023.03.007 -
Water Research Apr 2023Carbapenems are last-resort antibiotics used to treat bacterial infections unsuccessfully treated by most common categories of antibiotics in humans. Most of their...
Carbapenems are last-resort antibiotics used to treat bacterial infections unsuccessfully treated by most common categories of antibiotics in humans. Most of their dosage is secreted unchanged as waste, thereby making its way into the urban water system. There are two major knowledge gaps addressed in this study to gain a better understanding of the effects of their residual concentrations on the environment and environmental microbiome: development of a UHPLC-MS/MS method of detection and quantification from raw domestic wastewater via direct injection and study of their stability in sewer environment during the transportation from domestic sewers to wastewater treatment plants. The UHPLC-MS/MS method was developed for four carbapenems: meropenem, doripenem, biapenem and ertapenem, and validation was performed in the range of 0.5-10 μg/L for all analytes, with limit of detection (LOD) and limit of quantification (LOQ) values ranging from 0.2-0.5 μg/L and 0.8-1.6 μg/L respectively. Laboratory scale rising main (RM) and gravity sewer (GS) bioreactors were employed to culture mature biofilms with real wastewater as the feed. Batch tests were conducted in RM and GS sewer bioreactors fed with carbapenem-spiked wastewater to evaluate the stability of carbapenems and compared against those in a control reactor (CTL) without sewer biofilms, over a duration of 12 h. Significantly higher degradation was observed for all carbapenems in RM and GS reactors (60 - 80%) as opposed to CTL reactor (5 - 15%), which indicates that sewer biofilms play a significant role in the degradation. First order kinetics model was applied to the concentration data along with Friedman's test and Dunn's multiple comparisons analysis to establish degradation patterns and differences in the degradation observed in sewer reactors. As per Friedman's test, there was a statistically significant difference in the degradation of carbapenems observed depending on the reactor type (p = 0.0017 - 0.0289). The results from Dunn's test indicate that the degradation in the CTL reactor was statistically different from that observed in either RM (p = 0.0033 - 0.1088) or GS (p = 0.0162 - 0.1088), with the latter two showing insignificant difference in the degradation rates observed (p = 0.2850 - 0.5930). The findings contribute to the understanding about the fate of carbapenems in urban wastewater and the potential application of wastewater-based epidemiology.
Topics: Humans; Wastewater; Sewage; Carbapenems; Tandem Mass Spectrometry; Bioreactors; Biofilms; Anti-Bacterial Agents
PubMed: 36863281
DOI: 10.1016/j.watres.2023.119796 -
Microbial Pathogenesis Apr 2023The multidrug-resistant Acinetobacter baumannii is an emerging nosocomial pathogen in the healthcare sector. Intrinsic resistance in A. baumannii is a significant...
The multidrug-resistant Acinetobacter baumannii is an emerging nosocomial pathogen in the healthcare sector. Intrinsic resistance in A. baumannii is a significant problem framing a perfect treatment regimen. Also, this organism showed more resistance towards the carbapenem antibiotics, especially for imipenem and meropenem. The development of carbapenem-resistant Acinetobacter baumannii is mainly due to the alteration or loss of the porin region in the outer membrane. The most well-known porin in Acinetobacter baumannii is CarO (carbapenem-associated outer membrane protein). The CarO protein, which functions as a porin channel for carbapenem inflow, may contribute to carbapenem resistance. The current study identifies a potent drug candidate with a better binding affinity to the carbapenem-resistant outer membrane protein. We investigated the specificity of carbapenems such as imipenem, meropenem, ertapenem, biapenem, doripenem, and fluoroquinolone drugs such as sitafloxacin against the imipenem-resistant CarO protein was demonstrated using the computational approaches molecular docking and dynamic simulation for 50 ns. As a result, the high to low enzyme-ligand complex's binding affinity exhibited a greater binding affinity for ertapenem -7.76 kcal·mol and sitafloxacin -7.75 kcal·mol than biapenem, doripenem, meropenem, and imipenem. The molecular dynamic simulation and the MMPBSA analysis depicted ertapenem -55.431±25.908 kJ/mol and sitafloxacin -47.154 ± 11.052 kJ/mol with better binding affinity and more stability against the imipenem resistant CarO protein when it compared to other antibiotics.
Topics: Imipenem; Acinetobacter baumannii; Meropenem; Ertapenem; Molecular Docking Simulation; Doripenem; Porins; Bacterial Outer Membrane Proteins; Anti-Bacterial Agents; Carbapenems; Microbial Sensitivity Tests
PubMed: 36858184
DOI: 10.1016/j.micpath.2023.106049