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The Journal of Veterinary Medical... Jun 2024One of the most significant research areas in veterinary medicine is the search for carbapenem substitutes for the treatment of extended-spectrum β-lactamase...
Estimation of latamoxef (moxalactam) dosage regimens against β-lactamase-producing Enterobacterales in dogs: a pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulation.
One of the most significant research areas in veterinary medicine is the search for carbapenem substitutes for the treatment of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E). This study applied a pharmacokinetic/pharmacodynamic (PK/PD) strategy in validating optimal latamoxef (LMX) therapeutic regimens against canine ESBL-E infections. Five dogs were administered a bolus dose of 40 mg/kg LMX intravenously to measure serum drug concentrations and determine PK indices using the noncompartmental model. The highest minimum inhibitory concentration (MIC) with a probability of target attainment ≥90% was used to compute the PK/PD cutoff values for bacteriostatic (time for which the unbound drug concentration was above the MIC [fTAM] ≥40%) and bactericidal (fTAM ≥70%) effects when administered at 20, 30, 50, and 60 mg/kg, in addition to 40 mg/kg. The cumulative fraction of response (CFR) was determined using the MIC distribution of wild-type ESBL-E in companion animals. The PK/PD cutoff values can be increased by reducing the dosing interval rather than increasing the dose per time. Based on the calculated CFRs for ESBL-producing Escherichia coli and Klebsiella pneumoniae, all LMX regimens in this study and those administered at 30-60 mg/kg every 8 and 6 hr were found to be optimal (CFR ≥90%) for exerting bacteriostatic and bactericidal effects, respectively. However, the regimens of 50 and 60 mg/kg every 6 hr may merely exert bacteriostatic effects on ESBL-producing Enterobacter cloacae. Further clinical trials are required to confirm the clinical efficacy of LMX.
PubMed: 38897952
DOI: 10.1292/jvms.24-0197 -
Journal of Biomolecular Structure &... Oct 2023Antimicrobial resistance poses a significant challenge to public health, especially in developing countries, due to a substantial rise in bacterial resistance. This...
Antimicrobial resistance poses a significant challenge to public health, especially in developing countries, due to a substantial rise in bacterial resistance. This situation has become so concerning that we are now at risk of losing the effectiveness of antibiotics altogether. Recent research has firmly established that bacteria engage in a process called quorum sensing (QS). QS regulates various functions, including nutrient scavenging, immune response suppression, increased virulence, biofilm formation and mobility. , an opportunistic bacterial pathogen, plays a significant role in various medical conditions such as chronic wounds, corneal infections, burn wounds and cystic fibrosis. While antibiotics are effective in killing bacteria, only a few antibiotics, particularly those from the β-lactam group, have been studied for their impact on the quorum sensing of . Given the lack of concentrated efforts in this area, we have investigated the role of β-lactam antibiotics on various potential targets of . Based on their toxicological profiles and the average binding energy obtained through molecular docking, azlocillin and moxalactam have emerged as lead antibiotics. The binding energy for the docking of azlocillin and moxalactam with LasA was determined to be -8.2 and -8.6 kcal/mol, respectively. Molecular simulation analysis has confirmed the stable interaction of both these ligands with all three target proteins (LasI, LasA and PqsR) under physiological conditions. The results of this research underscore the effectiveness of azlocillin and moxalactam. These two antibiotics may be repurposed to target the quorum sensing of .Communicated by Ramaswamy H. Sarma.
PubMed: 37904338
DOI: 10.1080/07391102.2023.2275181 -
Journal of Biomolecular Structure &... Aug 2023The β-lactamase of is known to degrade β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an...
The β-lactamase of is known to degrade β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an extended-spectrum β-lactamase in a clinical isolate of , the bacterium has become multi-drug resistant. In this study, we aim to identify new β-lactamase inhibitors by virtually screening a total of 43 phytocompounds from two Indian medicinal plants. In the molecular docking studies, pinocembrin-7--β-D-glucopyranoside (P7G) (-9.6 kcal/mol) from and ellagic acid (EA) (-9.2 kcal/mol) from had lower binding energy than moxalactam (-8.4 kcal/mol). P7G and EA formed 5 ( and ) and 4 ( and ) conventional hydrogens bonds with the active site residues. 100 ns MD simulations revealed that moxalactam and P7G (but not EA) were able to form a stable complex. The binding free energy calculations further revealed that P7G (-59.6526 kcal/mol) formed the most stable complex with β-lactamase when compared to moxalactam (-46.5669 kcal/mol) and EA (-28.4505 kcal/mol). The HOMO-LUMO and other DFT parameters support the stability and chemical reactivity of P7G at the active site of β-lactamase. P7G passed all the toxicity tests and bioavailability tests indicating that it possesses drug-likeness. Among the studied compounds, we identified P7G of as the most promising phytocompound to combat antibiotic resistance by potentially inhibiting the β-lactamase of .Communicated by Ramaswamy H. Sarma.
PubMed: 37587843
DOI: 10.1080/07391102.2023.2248272 -
Journal of Mass Spectrometry : JMS Jun 2023We developed an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine four antibacterial drugs in human plasma for...
We developed an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to determine four antibacterial drugs in human plasma for clinical usage. Samples were prepared using protein precipitation with methanol. Chromatographic separation was accomplished in 4.5 min on a BEH C18 column (2.1 × 50 mm, 1.7 μm) using a gradient elution of methanol and water (containing 7.71 g/L concentrated ammonium acetate, adjusted to pH 6.5 with acetic acid) at a flow rate of 0.4 mL/min. Positive electrospray was used for ionization. The method was linear in the concentration range 1-100 μg/mL for vancomycin, norvoncomycin, and meropenem; and 0.5-50 μg/mL for R-isomer of moxalactam and S-isomer of moxalactam. For all analytes, the intra- and inter-day accuracies and precisions were -8.47%-10.13% and less than 12%, respectively. The internal standard normalized recoveries and matrix effect were 62.72%-105.78% and 96.67%-114.20%, respectively. All analytes were stable at six storage conditions, with variations of less than 15.0%. The method was applied in three patients with central nervous system infection. The validated method might be useful for routine therapeutic drug monitoring and pharmacokinetic study.
Topics: Humans; Chromatography, High Pressure Liquid; Tandem Mass Spectrometry; Vancomycin; Meropenem; Moxalactam; Methanol
PubMed: 37194366
DOI: 10.1002/jms.4925 -
The Journal of Veterinary Medical... Jun 2023The susceptibility of 218 extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae isolates from companion animals to three cephamycins (cefmetazole, flomoxef,...
In vitro efficacy of cephamycins against multiple extended-spectrum β-lactamase-producing Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae isolates from dogs and cats.
The susceptibility of 218 extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae isolates from companion animals to three cephamycins (cefmetazole, flomoxef, and latamoxef) was investigated. Phenotypic testing found 8 of 120 Klebsiella pneumoniae (KP) and 15 of 69 Enterobacter cloacae (EC) isolates were ESBL and AmpC β-lactamase (ABL) co-producers. Isolates of KP, Proteus mirabilis, and EC that only produced ESBL exhibited susceptibility rates to cefmetazole (95.5%, 82.7%, and 9.3%), flomoxef (99.1%, 96.6%, and 74.0%), and latamoxef (99.1%, 100%, and 100%), respectively. Notably, isolates of KP and EC co-producing ESBL and ABL had significantly lower susceptibility rates to the studied drugs when compared with only ESBL producers. This implies that the in vitro activity of cephamycins against ESBL-producing bacteria can differ depending on ABL production and bacterial species.
Topics: Cats; Dogs; Animals; Klebsiella pneumoniae; Proteus mirabilis; Anti-Bacterial Agents; Enterobacter cloacae; Cefmetazole; Cephamycins; Moxalactam; Cat Diseases; Dog Diseases; Enterobacteriaceae; beta-Lactamases; Microbial Sensitivity Tests
PubMed: 37150609
DOI: 10.1292/jvms.23-0052 -
Antimicrobial Agents and Chemotherapy Mar 2023In this study, we aimed to clarify the evolutionary trajectory of a Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) population during...
In this study, we aimed to clarify the evolutionary trajectory of a Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae (KPC-Kp) population during β-lactam antibiotic therapy. Five KPC-Kp isolates were collected from a single patient. Whole-genome sequencing and a comparative genomics analysis were performed on the isolates and all -containing plasmids to predict the population evolution process. Growth competition and experimental evolution assays were conducted to reconstruct the evolutionary trajectory of the KPC-Kp population . Five KPC-Kp isolates (KPJCL-1 to KPJCL-5) were highly homologous, and all harbor an IncFII -containing plasmid (pJCL-1 to pJCL-5). Although the genetic structures of these plasmids were almost identical, distinct copy numbers of the gene were detected. A single copy of was presented in pJCL-1, pJCL-2, and pJCL-5, two copies of ( and ) were presented in pJCL-3, and three copies of were presented in pJCL-4. The -harboring KPJCL-3 isolate presented resistance to ceftazidime-avibactam and cefiderocol. The multicopy strain KPJCL-4 had an elevated ceftazidime-avibactam MIC. The patient had been exposed to ceftazidime, meropenem, and moxalactam, after which KPJCL-3 and KPJCL-4 were isolated, which both showed a significant competitive advantage under antimicrobial pressure . Experimental evolution assays revealed that multicopy-containing cells were increased in the original single-copy -harboring KPJCL-2 population under selection with ceftazidime, meropenem, or moxalactam, generating a low-level ceftazidime-avibactam resistance phenotype. Moreover, mutants with a G532T substitution, G820 to C825 duplication, G532A substitution, G721 to G726 deletion, and A802 to C816 duplication increased in the multicopy-containing KPJCL-4 population, generating high-level ceftazidime-avibactam resistance and reduced cefiderocol susceptibility. Ceftazidime-avibactam and cefiderocol resistance can be selected by β-lactam antibiotics other than ceftazidime-avibactam. Notably, gene amplification and mutation are important in KPC-Kp evolution under antibiotic selection.
Topics: Humans; Ceftazidime; Klebsiella pneumoniae; Meropenem; Klebsiella; Moxalactam; Klebsiella Infections; Anti-Bacterial Agents; Azabicyclo Compounds; beta-Lactamases; Bacterial Proteins; Drug Combinations; Microbial Sensitivity Tests; Cefiderocol
PubMed: 36794957
DOI: 10.1128/aac.01279-22 -
Journal of Biomolecular Structure &... Nov 2023Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of...
Human lactate dehydrogenase A (LDHA) is an anaerobic glycolytic enzyme involved in the inter-conversion of pyruvate to lactate. The level of LDHA in various types of cancer cells is found to be elevated and the dependence of cancer cells on anaerobic glycolysis is viewed as the reason for this elevation. Moreover, inhibition of LDHA activity has been shown to be effective in impairing the growth of tumors, making the LDHA as a potential target for cancer therapy. In this computational study, we have performed a pharmacophore based screening of approved drugs followed by a molecular docking based screening to find a few potential LDHA inhibitors. Molecular dynamics simulations have also been performed to examine the stability of the LDHA-drug complexes as obtained from the docking study. The result of the study showed that darunavir, moxalactam and eprosartan can bind to the active site of LDHA with high affinity in comparison to two known synthetic inhibitors of LDHA. The results of the molecular dynamics simulation showed that these drugs can bind stably with the enzyme through hydrogen bond and hydrophobic interactions. Hence, it is concluded that darunavir, moxalactam and eprosartan may be considered as potential inhibitors of LDHA and can be used for cancer therapy after proper validation of their effectiveness through in vitro, in vivo and clinical trials.Communicated by Ramaswamy H. Sarma.
Topics: Humans; Lactate Dehydrogenase 5; Molecular Docking Simulation; Drug Repositioning; Darunavir; Moxalactam; L-Lactate Dehydrogenase; Cell Line, Tumor; Neoplasms
PubMed: 36576127
DOI: 10.1080/07391102.2022.2158134 -
Nature Communications Nov 2022Serial x-ray crystallography can uncover binding events, and subsequent chemical conversions occurring during enzymatic reaction. Here, we reveal the structure, binding...
Serial x-ray crystallography can uncover binding events, and subsequent chemical conversions occurring during enzymatic reaction. Here, we reveal the structure, binding and cleavage of moxalactam antibiotic bound to L1 metallo-β-lactamase (MBL) from Stenotrophomonas maltophilia. Using time-resolved serial synchrotron crystallography, we show the time course of β-lactam hydrolysis and determine ten snapshots (20, 40, 60, 80, 100, 150, 300, 500, 2000 and 4000 ms) at 2.20 Å resolution. The reaction is initiated by laser pulse releasing Zn ions from a UV-labile photocage. Two metal ions bind to the active site, followed by binding of moxalactam and the intact β-lactam ring is observed for 100 ms after photolysis. Cleavage of β-lactam is detected at 150 ms and the ligand is significantly displaced. The reaction product adjusts its conformation reaching steady state at 2000 ms corresponding to the relaxed state of the enzyme. Only small changes are observed in the positions of Zn ions and the active site residues. Mechanistic details captured here can be generalized to other MBLs.
Topics: beta-Lactams; Moxalactam; beta-Lactamases; Crystallography, X-Ray
PubMed: 36450742
DOI: 10.1038/s41467-022-35029-3 -
Journal of Clinical Pharmacy and... Oct 2021To observe the effect of latamoxef on coagulation function and to analyse its risk factors.
WHAT IS KNOWN AND OBJECTIVE
To observe the effect of latamoxef on coagulation function and to analyse its risk factors.
METHODS
A retrospective cohort study was performed to compare patients receiving latamoxef versus those treated with ceftazidime. Baseline characteristics and coagulation parameters were recorded and analysed to explore whether treatment with latamoxef increased the risks of coagulation disorders and bleeding.
RESULTS AND DISCUSSION
A total number of 162 patients receiving latamoxef and 93 patients receiving ceftazidime were included. Haemorrhagic events were similar between groups, but patients receiving latamoxef had a higher risk of coagulation disorders compared to those receiving ceftazidime. Multivariate analysis revealed that the exposure of antibiotics, especially the cumulative defined daily doses (DDDs), and the nutrition risk may be the predictors of coagulation disorders.
WHAT IS NEW AND CONCLUSION
Latamoxef might induce coagulation disorders. Cumulative DDDs and the nutrition risk were linked with coagulation disorders.
Topics: Adult; Age Factors; Aged; Anti-Bacterial Agents; Blood Coagulation; Blood Coagulation Disorders; Ceftazidime; Comorbidity; Female; Hemorrhage; Humans; Incidence; Male; Middle Aged; Moxalactam; Retrospective Studies; Risk Factors; Sex Factors
PubMed: 34114239
DOI: 10.1111/jcpt.13435 -
Food Science and Technology... Jan 2022The aims of this study were to evaluate the occurrence of lostridium in commercial raw meat and meat products commercialized in Brazil, and to determine the pathogenic...
The aims of this study were to evaluate the occurrence of lostridium in commercial raw meat and meat products commercialized in Brazil, and to determine the pathogenic potential and antimicrobial susceptibility of the isolates. After selective enrichment, the isolation of involved plating with and without an alcohol shock treatment onto moxalactam agar (CDMNA). The toxigenic profile was determined through PCR for detection of and genes and an enzyme-linked immunosorbent assay for toxin A/B. was isolated from 8.9% (17 out of 192) of analyzed samples. Plating without alcohol treatment (sensitivity of 88.23%) was more efficient than with alcohol treatment (sensitivity of 29.41%) in isolation. The profile A + B+CDT- was observed in 35.0% (28/80) of the isolates. The A/B toxin was tested in 44 isolates and 15.9% of them were positive. Resistance to clindamycin, ceftizoxime tetracycline, metronidazole, vancomycin, and ceftriaxone were observed among isolates. Multi-drug resistance was detected in 36.4% (8/22) of the isolates evaluated.
Topics: Bacterial Toxins; Brazil; Clostridioides difficile; Meat; Meat Products; Microbial Sensitivity Tests
PubMed: 33573407
DOI: 10.1177/1082013221992665