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Kidney360 Feb 2022
Topics: Fantasy; Humans; Kidney; Kidney Diseases; Vancomycin
PubMed: 35373135
DOI: 10.34067/KID.0007282021 -
Biomaterials Advances Jul 2024Surgical site infection (SSI) is a common issue post-surgery which often prolongs hospitalization and can lead to serious complications such as sternal wound infection...
Surgical site infection (SSI) is a common issue post-surgery which often prolongs hospitalization and can lead to serious complications such as sternal wound infection following cardiac surgery via median sternotomy. Controlled release of suitable antibiotics could allow maximizing drug efficacy and safety, and therefore achieving a desired therapeutic response. In this study, we have developed a vancomycin laden PEGylated fibrinogen-polyethylene glycol diacrylate (PF-PEGDA) hydrogel system that can release vancomycin at a controlled and predictable rate to be applied in SSI prevention. Two configurations were developed to study effect of the hydrogel on drug release, namely, vancomycin laden hydrogel and vancomycin solution on top of blank hydrogel. The relationship between the rigidity of the hydrogel and drug diffusion was found to comply with a universal power law, i.e., softer hydrogels result in a greater diffusion coefficient hence faster release rate. Besides, vancomycin laden hydrogels exhibited burst release, whereas the vancomycin solution on top of blank hydrogels exhibited lag release. A mathematical model was developed to simulate vancomycin permeation through the hydrogels. The permeation of vancomycin can be predicted accurately by using the mathematical model, which provided a useful tool to customize drug loading, hydrogel thickness and stiffness for personalized medication to manage SSI. To evaluate the potential of hydrogels for bone healing applications in cardiovascular medicine, we performed a proof-of-concept median sternotomy in rabbits and applied the hydrogels. The hydrogel formulations accelerated the onset of osteo-genetic processes in rabbits, demonstrating its potential to be used in human.
Topics: Vancomycin; Polyethylene Glycols; Fibrinogen; Animals; Hydrogels; Delayed-Action Preparations; Anti-Bacterial Agents; Drug Liberation; Rabbits; Surgical Wound Infection; Humans
PubMed: 38795473
DOI: 10.1016/j.bioadv.2024.213896 -
Scientific Reports Jul 2017Vancomycin is known to bind to Zn(II) and can induce a zinc starvation response in bacteria. Here we identify a novel polymerization of vancomycin dimers by structural...
Vancomycin is known to bind to Zn(II) and can induce a zinc starvation response in bacteria. Here we identify a novel polymerization of vancomycin dimers by structural analysis of vancomycin-Zn(II) crystals and fibre X-ray diffraction. Bioassays indicate that this structure is associated with an increased antibiotic activity against bacterial strains possessing high level vancomycin resistance mediated by the reprogramming of peptidoglycan biosynthesis to use precursors terminating in D-Ala-D-Lac in place of D-Ala-D-Ala. Polymerization occurs via interaction of Zn(II) with the N-terminal methylleucine group of vancomycin, and we show that the activity of other glycopeptide antibiotics with this feature can also be similarly augmented by Zn(II). Construction and analysis of a model strain predominantly using D-Ala-D-Lac precursors for peptidoglycan biosynthesis during normal growth supports the hypothesis that Zn(II) mediated vancomycin polymerization enhances the binding affinity towards these precursors.
Topics: Anti-Bacterial Agents; Bacteria; Biosynthetic Pathways; Cations, Divalent; Cell Wall; Enterococcus faecalis; Microbial Sensitivity Tests; Peptidoglycan; Polymerization; Streptomyces; Vancomycin; X-Ray Diffraction; Zinc
PubMed: 28687742
DOI: 10.1038/s41598-017-04868-2 -
PloS One 2019Vancomycin is frequently used in hemodialysis (HD) and in hemodiafiltration (HDF) patients and is usually administered in the last 30 or 60 minutes of a dialysis... (Observational Study)
Observational Study
BACKGROUND
Vancomycin is frequently used in hemodialysis (HD) and in hemodiafiltration (HDF) patients and is usually administered in the last 30 or 60 minutes of a dialysis session. Vancomycin pharmacokinetics are not well described in HDF patients. The aim of this study is to develop a population pharmacokinetic (PPK) model and dosing regimen for vancomycin in HDF patients and to evaluate its applicability in low-flux (LF-HD) patients.
METHODS
Two-compartment PPK models were developed using data from HDF patients (n = 17), and was parameterized as follows: non-renal clearance (CLm), renal clearance as a fraction of creatinine clearance (fr), central volume of distribution (V1), intercompartmental clearance (CL12), peripheral volume of distribution (V2) and extracorporeal extraction ratio (Eec). We evaluated the final model in a cohort of LF-HD patients (n = 21). Dosing schemes were developed for a vancomycin 24-h AUC of 400 mg*h/L.
RESULTS
Model parameters (± SD) were: CLm = 0.473 (0.271) L/h, fr = 0.1 (fixed value), V1 = 0.278 (0.092) L/kgLBMc, CL12 = 9.96 L/h (fixed value), V2 = 0.686 (0.335) L/kgLBMc and Eec = 0.212 (0.069). The model reliably predicted serum levels of vancomycin in both HDF and LF-HD patients during and between dialysis sessions. The median of the prediction error (MDPE) as a measure of bias is -0.7% (95% CI: -3.4%-1.7%) and the median of the absolute values of the prediction errors (MDAPE) as a measure of precision is 7.9% (95% CI: 6.0%-9.8%). In both HDF and LF-HD, the optimal vancomycin loading dose for a typical patient weighing 70 kg is 1700 mg when administered during the last 60 minutes of the hemodialysis session. Maintenance dose is 700 mg if administered during the last 30 or 60 minutes of the hemodialysis session.
CONCLUSION
The developed PPK model for HDF is also capable of predicting serum levels of vancomycin in patients on LF-HD. A dosing regimen was developed for the use of vancomycin in HDF and LF-HD.
Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Female; Hemodiafiltration; Humans; Male; Middle Aged; Models, Biological; Retrospective Studies; Vancomycin
PubMed: 31086400
DOI: 10.1371/journal.pone.0216801 -
Frontiers in Immunology 2023Methicillin-resistant (MRSA) is a strain with resistance to beta-lactam antibiotics, making it a global human and veterinary health concern. Specifically,...
Identification of Vancomycin Resistance in Methicillin-resistant in two macaque species and decolonization and long-term prevention of recolonization in Cynomolgus Macaques ().
Methicillin-resistant (MRSA) is a strain with resistance to beta-lactam antibiotics, making it a global human and veterinary health concern. Specifically, immunosuppressed patients have a remarkably higher risk of clinical MRSA infections with significantly increased rates of prolonged clinical recovery, morbidity, and mortality. The current treatment of choice for MRSA is vancomycin. Importantly, we report the first known vancomycin-resistant (VRSA) carriers in a cohort of Mauritian cynomolgus macaques (CM) imported to the Oregon National Primate Research Center (ONPRC), with a MRSA carrier rate of 76.9% (10/13 animals). All MRSA isolates also demonstrated resistance to vancomycin with prevalence of vancomycin-intermediate (VISA) at 30% (3/10 MRSA-positive CMs) and VRSA at 70% (7/10 MRSA-positive CMs). Additionally, we identified VRSA in a rhesus macaque (RM) housed within the same room as the VRSA-positive CMs and identified a MRSA/VISA carrier rate of 18.8% in RMs (3/16 positive for both MRSA and VISA) in unexposed recently assigned animals directly from the ONPRC RM breeding colony. Considering that the MRSA and VRSA/VISA-positive CMs future study aims included significant immunosuppression, MRSA/VRSA/VISA decolonization treatment and expanded "MRSA-free" practices were employed to maintain this status. We report the first controlled study using in-depth analyses with appropriate diagnostic serial testing to definitively show an MRSA decolonization therapy (90% success rate) and expanded barrier practice techniques to successfully prevent recolonization (100%) of a cohort of CMs MRSA-free (up to 529 days with a total of 4,806 MRSA-free NHP days).
Topics: Animals; Humans; Macaca fascicularis; Methicillin-Resistant Staphylococcus aureus; Vancomycin Resistance; Macaca mulatta; Staphylococcus aureus; Vancomycin
PubMed: 37675101
DOI: 10.3389/fimmu.2023.1244637 -
Accounts of Chemical Research Nov 2020Since its discovery, vancomycin has been used in the clinic for >60 years. Because of their durability, vancomycin and related glycopeptides serve as the antibiotics of...
Since its discovery, vancomycin has been used in the clinic for >60 years. Because of their durability, vancomycin and related glycopeptides serve as the antibiotics of last resort for the treatment of protracted bacterial infections of resistant Gram-positive pathogens, including methicillin-resistant (MRSA) and multidrug-resistant (MDR) . After 30 years of use, vancomycin resistance was first observed and is now widespread in enterococci and more recently in . The widespread prevalence of vancomycin-resistant enterococci (VRE) and the emergence of vancomycin-resistant (VRSA) represent a call to focus on the challenge of resistance, highlight the need for new therapeutics, and provide the inspiration for the design of more durable antibiotics less prone to bacterial resistance than even vancomycin.Herein we summarize progress on efforts to overcome vancomycin resistance, first addressing recovery of its original durable mechanism of action and then introducing additional independent mechanisms of action intended to increase the potency and durability beyond that of vancomycin itself. The knowledge of the origin of vancomycin resistance and an understanding of the molecular basis of the loss of binding affinity between vancomycin and the altered target ligand d-Ala-d-Lac provided the basis for the subtle and rational redesign of the vancomycin binding pocket to remove the destabilizing lone-pair repulsion or reintroduce a lost H-bond while not impeding binding to the unaltered ligand d-Ala-d-Ala. Preparation of the modified glycopeptide core structure was conducted by total synthesis, providing binding pocket-modified vancomycin aglycons with dual d-Ala-d-Ala/d-Lac binding properties that directly address the intrinsic mechanism of resistance to vancomycin. Fully glycosylated pocket-modified vancomycin analogues were generated through a subsequent two-step enzymatic glycosylation, providing a starting point for peripheral modifications used to introduce additional mechanisms of action. A well-established vancosamine -(4-chlorobiphenyl)methyl (CBP) modification as well as newly discovered C-terminal trimethylammonium cation (C1) or guanidine modifications were introduced, providing two additional synergistic mechanisms of action independent of d-Ala-d-Ala/d-Lac binding. The CBP modification provides an additional stage for inhibition of cell wall synthesis that results from direct competitive inhibition of transglycosylase, whereas the C1/guanidine modification induces bacteria cell permeablization. The synergistic behavior of the three independent mechanisms of action combined in a single molecule provides ultrapotent antibiotics (MIC = 0.01-0.005 μg/mL against VanA VRE). Beyond the remarkable antimicrobial activity, the multiple mechanisms of action suppress the rate at which resistance may be selected, where any single mechanism of action is protected by the action of others. The results detailed herein show that rational targeting of durable vancomycin-derived antibiotics has generated compounds with a "resistance against resistance", provided new candidate antibiotics, and may serve as a generalizable strategy to combat antibacterial resistance.
Topics: Anti-Bacterial Agents; Binding Sites; Dipeptides; Drug Design; Glycopeptides; Guanidine; Half-Life; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Staphylococcus aureus; Vancomycin; Vancomycin Resistance
PubMed: 33138354
DOI: 10.1021/acs.accounts.0c00569 -
Critical Care (London, England) Aug 2016
Topics: Anti-Bacterial Agents; Critical Illness; Humans; Infections; Obesity; Vancomycin
PubMed: 27506812
DOI: 10.1186/s13054-016-1426-y -
ACS Infectious Diseases Aug 2020A series of vancomycin C-terminus guanidine modifications is disclosed that improves antimicrobial activity, enhances the durability of antimicrobial action against...
A series of vancomycin C-terminus guanidine modifications is disclosed that improves antimicrobial activity, enhances the durability of antimicrobial action against selection or induction of resistance, and introduces a synergistic mechanism of action independent of d-Ala-d-Ala binding and inhibition of cell wall biosynthesis. The added mechanism of action results in induced bacterial cell permeability, which we show may involve interaction with cell envelope teichoic acid. Significantly, the compounds examined that contain two combined peripheral modifications, a (4-chlorobiphenyl)methyl (CBP) and C-terminus guanidinium modification, offer opportunities for new treatments against not only vancomycin-sensitive but especially vancomycin-resistant bacteria where they act by two synergistic and now durable mechanisms of action independent of d-Ala-d-Ala/d-Lac binding and display superb antimicrobial potencies (MIC 0.6-0.15 μg/mL, VanA VRE). For the first time, we demonstrate that the synergistic behavior of the peripheral modifications examined requires the presence of both the CBP and guanidine modifications in a single molecule versus their combined use as an equimolar mixture of singly modified compounds. Finally, we show that a prototypical member of the series, G3-CBP-vancomycin (), exhibits no hemolytic activity, displays no mammalian cell growth inhibition, possesses improved and especially attractive pharmacokinetic (PK) properties, and displays excellent efficacy and potency against an especially challenging multidrug-resistant (MRSA) and VanA vancomycin-resistant (VRSA) bacterial strain.
Topics: Anti-Bacterial Agents; Cell Wall; Guanidine; Vancomycin; Vancomycin Resistance
PubMed: 32598127
DOI: 10.1021/acsinfecdis.0c00258 -
BMC Pediatrics Oct 2023It is usually difficult for the trough concentration of vancomycin to reach the recommended lower limit of 10 mg/L per the label dose in the paediatric population....
Age-associated augmented renal clearance and low BMI trigger suboptimal vancomycin trough concentrations in children with haematologic diseases: data of 1453 paediatric patients from 2017 to 2022.
BACKGROUND
It is usually difficult for the trough concentration of vancomycin to reach the recommended lower limit of 10 mg/L per the label dose in the paediatric population. Moreover, children with haematologic diseases who suffer from neutropenia are more likely to have lower exposure of vancomycin, and the risk factors have been poorly explored.
METHOD
We reviewed and analysed the initial trough concentration of vancomycin and synchronous cytometry and biochemical parameters in the blood of 1453 paediatric patients with haematologic diseases over a 6 year period, from 2017 to 2022.
RESULTS
Forty-five percent of the enrolled children had vancomycin trough concentrations below 5 mg/L after receiving a dose of 40 mg/kg/day, and the multiple regression showed that age (OR = 0.881, 95% CI 0.855 to 0.909, P < 0.001), BMI (OR = 0.941, 95% CI 0.904 to 0.980, P = 0.003) and the glomerular filtration rate (OR = 1.006, 95% CI 1.004 to 1.008, P < 0.001) were independent risk factors. A total of 79.7% of the children experienced augmented renal clearance, which was closely correlated to age-associated levels of serum creatinine. The vancomycin trough concentration was higher in children with aplastic anaemia than in those with other haematologic diseases due to a higher BMI and a lower glomerular filtration rate.
CONCLUSION
Age-associated augmented renal clearance and low BMI values contributed to suboptimal trough concentrations of vancomycin in children with haematologic diseases, and the effects of long-term use of cyclosporine and glucocorticoids need to be taken into account.
Topics: Child; Humans; Anti-Bacterial Agents; Body Mass Index; Hematologic Diseases; Vancomycin
PubMed: 37880633
DOI: 10.1186/s12887-023-04288-4 -
FEMS Microbiology Reviews Jan 2003Oritavancin (LY333328) is a semisynthetic glycopeptide antibiotic having excellent bactericidal activity against glycopeptide-susceptible and -resistant Gram-positive... (Review)
Review
Oritavancin (LY333328) is a semisynthetic glycopeptide antibiotic having excellent bactericidal activity against glycopeptide-susceptible and -resistant Gram-positive bacteria. Oritavancin is the N-alkyl-p-chlorophenylbenzyl derivative of chloroeremomycin (LY264826) and is currently in phase III clinical trials for use in Gram-positive infections. Studies show that oritavancin and related alkyl glycopeptides inhibit bacterial cell wall formation by blocking the transglycosylation step in peptidoglycan biosynthesis in a substrate-dependent manner. As with other glycopeptide antibiotics, including vancomycin, the effects of oritavancin on cell wall synthesis are attributable to interactions with dipeptidyl residues of peptidoglycan precursors. Unlike vancomycin, however, oritavancin is strongly dimerized and can anchor to the cytoplasmic membrane, the latter facilitated by its alkyl side chain. Cooperative interactions derived from dimerization and membrane anchoring in situ can be of sufficient strength to enable binding to either dipeptidyl or didepsipeptidyl peptidoglycan residues of vancomycin-susceptible and -resistant enterococci, respectively. This review describes the antibacterial activity of oritavancin, and examines the evidence supporting the proposed mechanism of action for this agent and related analogs.
Topics: Anti-Bacterial Agents; Drug Resistance, Microbial; Glycopeptides; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Lipoglycopeptides; Models, Molecular; Peptidoglycan; Vancomycin; Vancomycin Resistance
PubMed: 12586393
DOI: 10.1111/j.1574-6976.2003.tb00628.x