-
Antimicrobial Agents and Chemotherapy Aug 2016Since the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus...
Since the 1950s, vancomycin has remained a reference treatment for severe infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus Vancomycin is a nephrotoxic and ototoxic drug mainly eliminated through the kidneys. It has a large interindividual pharmacokinetic variability, which justifies monitoring its plasma concentrations in patients. This is especially important in patients aged over 80 years, who frequently have renal impairment. However, the pharmacokinetics of vancomycin in this population is very poorly described in the literature. The objective of this work was to propose a model able to predict the pharmacokinetics of vancomycin in very elderly people. First, a population pharmacokinetic model was carried out using the algorithm NPAG (nonparametric adaptive grid) on a database of 70 hospitalized patients aged over 80 years and treated with vancomycin. An external validation then was performed on 41 patients, and the predictive capabilities of the model were assessed. The model had two compartments and six parameters. Body weight and creatinine clearance significantly influenced vancomycin volume of distribution and body clearance, respectively. The means (± standard deviations) of vancomycin volume of distribution and clearance were 36.3 ± 15.2 liter and 2.0 ± 0.9 liter/h, respectively. In the validation group, the bias and precision were -0.75 mg/liter and 8.76 mg/liter for population predictions and -0.39 mg/liter and 2.68 mg/liter for individual predictions. In conclusion, a pharmacokinetic model of vancomycin in a very elderly population has been created and validated for predicting plasma concentrations of vancomycin.
Topics: Aged, 80 and over; Anti-Bacterial Agents; Body Weight; Female; Humans; Male; Staphylococcus aureus; Vancomycin
PubMed: 27185796
DOI: 10.1128/AAC.00303-16 -
Scientific Reports Aug 2023Multidrug-resistant coagulase-negative staphylococci represent a real therapeutic challenge. The aim of the study was to emphasize the importance of heteroresistance to...
Multidrug-resistant coagulase-negative staphylococci represent a real therapeutic challenge. The aim of the study was to emphasize the importance of heteroresistance to vancomycin presence in methicillin-resistant strains of S. epidermidis. The research comprised 65 strains of S. epidermidis. Heteroresistance to vancomycin was detected with the use of the agar screening method with Brain Heart Infusion and a population profile analysis (PAP test). In addition, types of cassettes and genes responsible for resistance to antibiotics for 22 multidrug resistant strains were determined. Our investigations showed that 56 of 65 S. epidermidis strains were phenotypically resistant to methicillin. The tested strains were mostly resistant to erythromycin, gentamicin, clindamycin, and ciprofloxacin. Six strains showed decreased susceptibility to vancomycin and their heterogeneous resistance profiles were confirmed with the PAP test. All tested multi-resistant strains exhibited the mecA gene. More than half of them possessed type IV cassettes. ant(4')-Ia and aac(6')/aph(2''), ermC and tetK genes were most commonly found. The described phenomenon of heteroresistance to vancomycin in multidrug resistant bacteria of the Staphylococcus genus effectively inhibits a therapeutic effect of treatment with this antibiotic. That is why it is so important to search for markers that will enable to identify heteroresistance to vancomycin strains under laboratory conditions.
Topics: Anti-Bacterial Agents; Vancomycin; Staphylococcus epidermidis; Clindamycin; Staphylococcus; Hospitals
PubMed: 37604965
DOI: 10.1038/s41598-023-40866-3 -
Antimicrobial Agents and Chemotherapy Mar 2015Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem.... (Comparative Study)
Comparative Study Randomized Controlled Trial
Clostridium difficile infection causes serious diarrheal disease. Although several drugs are available for treatment, including vancomycin, recurrences remain a problem. LFF571 is a semisynthetic thiopeptide with potency against C. difficile in vitro. In this phase 2 exploratory study, we compared the safety and efficacy (based on a noninferiority analysis) of LFF571 to those of vancomycin used in adults with primary episodes or first recurrences of moderate C. difficile infection. Patients were randomized to receive 200 mg of LFF571 or 125 mg of vancomycin four times daily for 10 days. The primary endpoint was the proportion of clinical cures at the end of therapy in the per-protocol population. Secondary endpoints included clinical cures at the end of therapy in the modified intent-to-treat (mITT) population, the time to diarrhea resolution, and the recurrence rate. Seventy-two patients were randomized, with 46 assigned to receive LFF571. Based on the protocol-specified definition, the rate of clinical cure for LFF571 (90.6%) was noninferior to that of vancomycin (78.3%). The 30-day sustained cure rates for LFF571 and vancomycin were 56.7% and 65.0%, respectively, in the per-protocol population and 58.7% and 60.0%, respectively, in the modified intent-to-treat population. Using toxin-confirmed cases only, the recurrence rates were lower for LFF571 (19% versus 25% for vancomycin in the per-protocol population). LFF571 was generally safe and well tolerated. The incidence of adverse events (AEs) was higher for LFF571 (76.1% versus 69.2% for vancomycin), although more AEs in the vancomycin group were suspected to be related to the study drug (38.5% versus 32.6% for LFF571). One patient receiving LFF571 discontinued the study due to an AE. (This study has been registered at ClinicalTrials.gov under registration no. NCT01232595.).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Female; Humans; Male; Middle Aged; Thiazoles; Vancomycin
PubMed: 25534727
DOI: 10.1128/AAC.04251-14 -
Antimicrobial Agents and Chemotherapy Jan 2011The prevalence of heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) is 1.3% in published studies. Clinical associations include high-inoculum... (Meta-Analysis)
Meta-Analysis Review
The prevalence of heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) is 1.3% in published studies. Clinical associations include high-inoculum infections and glycopeptide failure, with hVISA infections associated with a 2.37-times-greater failure rate (95% confidence interval [CI], 1.53 to 3.67) compared to vancomycin-sensitive Staphylococcus aureus (VSSA) infections. Despite this, 30-day mortality rates were similar to those for VSSA infections (odds ratio [OR], 1.18; 95% CI, 0.81 to 1.74). The optimal therapy for hVISA requires further study.
Topics: Anti-Bacterial Agents; Humans; Staphylococcal Infections; Staphylococcus aureus; Vancomycin; Vancomycin Resistance
PubMed: 21078939
DOI: 10.1128/AAC.01133-10 -
Clinical Microbiology and Infection :... May 2023The pharmacokinetics (PK)/pharmacodynamics (PD; PK/PD) characteristics of fidaxomicin (FDX) and vancomycin (VCM) against Clostridioides difficile infection (CDI) are yet...
Fecal pharmacokinetics/pharmacodynamics characteristics of fidaxomicin and vancomycin against Clostridioides difficile infection elucidated by in vivo feces-based infectious evaluation models.
OBJECTIVES
The pharmacokinetics (PK)/pharmacodynamics (PD; PK/PD) characteristics of fidaxomicin (FDX) and vancomycin (VCM) against Clostridioides difficile infection (CDI) are yet to be elucidated because of the lack of an established PK/PD analysis method for intestinal infections and unabsorbed oral drugs. Here, we developed a feces-based PK/PD analysis method and determined the fecal PK/PD index, with target values of FDX and VCM against CDI.
METHODS
The antimicrobial susceptibility, time-kill curves, and post-antibiotic effects (PAEs) of FDX and VCM against C. difficile were determined in vitro. The optimal fecal PK/PD indices, with target values, were determined from the results of PK and PD studies involving 5-week-old female C57BL/6J mice infected with C. difficile ATCC® 43255. The minimum inhibitory concentration (MIC) breakpoints for C. difficile were estimated based on clinical data concerning fecal antibiotic concentrations in patients with CDI.
RESULTS
FDX and VCM inhibited C. difficile growth via time-dependent antibacterial activity and exerted PAEs. In the CDI mouse model experiments, the changes in C. difficile load and clinical cures (72-hour survival rates and clinical sickness score grading) were most highly correlated with the ratio of area under the fecal drug concentration-time curve to MIC (AUC/MIC). The target AUC/MIC values of FDX and VCM for 3 log reduction in C. difficile load was 13,173 and 8,308, respectively. The MIC breakpoints of FDX and VCM for C. difficile was estimated to be 1.0 and 2.0 μg/mL, respectively.
CONCLUSIONS
The developed in vivo feces-based PK/PD analysis method elucidated the optimal fecal PK/PD index, with target values of FDX and VCM against CDI.
Topics: Animals; Mice; Female; Vancomycin; Fidaxomicin; Clostridioides difficile; Mice, Inbred C57BL; Anti-Bacterial Agents; Clostridium Infections; Communicable Diseases; Feces
PubMed: 36574949
DOI: 10.1016/j.cmi.2022.12.015 -
Clinical Microbiology and Infection :... Jul 2015Recent Infectious Diseases Society of America guidelines for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend maintaining... (Meta-Analysis)
Meta-Analysis Review
Recent Infectious Diseases Society of America guidelines for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections recommend maintaining vancomycin trough concentrations of 15-20 mg/L for serious infections. We conducted a systematic review and meta-analysis of all studies assessing the impact of low (<15 mg/L) vs. high (≥ 15 mg/L) vancomycin trough level on the efficacy of MRSA infections treatment. Four prospective and 12 retrospective studies were included (2003 participants). No significant difference was demonstrated between low and high vancomycin trough level for the outcome of all-cause mortality (odds ratio (OR) 1.07, 95% confidence interval (CI) 0.78-1.46, I(2) = 28%). In studies evaluating mainly MRSA pneumonia, there was significantly higher mortality with low vancomycin level (OR 1.78, 95% CI 1.11-2.84). No significant difference was demonstrated in treatment failure rates (OR 1.25, 95% CI 0.88-1.78, I(2) = 51%). However, excluding one outlier study from the analysis, treatment failure became significantly higher in patients with low vancomycin trough level (OR 1.46, 95% CI 1.12-1.91, I(2) = 16%). Microbiologic failure rates were significantly higher in patients with low vancomycin levels (OR 1.56, 95% CI 1.08-2.26, I(2) = 0%). Nephrotoxicity was significantly higher with vancomycin levels of ≥ 15 mg/L. However, no cases of irreversible renal damage were reported. Current data on the effectiveness of higher vancomycin trough levels in the treatment of MRSA infections are limited to few prospective and mainly retrospective studies. Our findings support the current recommendations for maintaining vancomycin trough levels of ≥ 15 mg/L in the treatment of severe MRSA infections, although no difference in all-cause mortality was observed.
Topics: Anti-Bacterial Agents; Humans; Methicillin-Resistant Staphylococcus aureus; Renal Insufficiency; Serum; Staphylococcal Infections; Treatment Outcome; Vancomycin
PubMed: 25887712
DOI: 10.1016/j.cmi.2015.04.003 -
Vancomycin use and cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation.Blood Advances Jun 2020Vancomycin exposure in the pre-engraftment period was associated with an increased risk for CMV reactivation after allogeneic HCT. Some gram-positive bacteria may...
Vancomycin exposure in the pre-engraftment period was associated with an increased risk for CMV reactivation after allogeneic HCT. Some gram-positive bacteria may protect against CMV reactivation.
Topics: Cytomegalovirus; Hematopoietic Stem Cell Transplantation; Transplantation Conditioning; Vancomycin
PubMed: 32556279
DOI: 10.1182/bloodadvances.2020001984 -
Proceedings of the National Academy of... Feb 2022Dynamic biomaterials excel at recapitulating the reversible interlocking and remoldable structure of the extracellular matrix (ECM), particularly in manipulating cell...
Dynamic biomaterials excel at recapitulating the reversible interlocking and remoldable structure of the extracellular matrix (ECM), particularly in manipulating cell behaviors and adapting to tissue morphogenesis. While strategies based on dynamic chemistries have been extensively studied for ECM-mimicking dynamic biomaterials, biocompatible molecular means with biogenicity are still rare. Here, we report a nature-derived strategy for fabrication of dynamic biointerface as well as a three-dimensional (3D) hydrogel structure based on reversible receptor-ligand interaction between the glycopeptide antibiotic vancomycin and dipeptide d-Ala-d-Ala. We demonstrate the reversible regulation of multiple cell types with the dynamic biointerface and successfully implement the dynamic hydrogel as a functional antibacterial 3D scaffold to treat tissue repair. In view of the biogenicity and high applicability, this nature-derived reversible molecular strategy will bring opportunities for malleable biomaterial design with great potential in biomedicine.
Topics: Alanine; Biocompatible Materials; Biomimetics; Dipeptides; Extracellular Matrix; Humans; Hydrogels; Ligands; Protein Engineering; Vancomycin
PubMed: 35181608
DOI: 10.1073/pnas.2117221119 -
Journal of the American Chemical Society Mar 2015Full details of studies are disclosed on the total syntheses of binding pocket analogues of vancomycin bearing the peripheral L-vancosaminyl-1,2-D-glucosyl disaccharide...
Total syntheses and initial evaluation of [Ψ[C(═S)NH]Tpg⁴]vancomycin, [Ψ[C(═NH)NH]Tpg⁴]vancomycin, [Ψ[CH₂NH]Tpg⁴]vancomycin, and their (4-chlorobiphenyl)methyl derivatives: synergistic binding pocket and peripheral modifications for the glycopeptide antibiotics.
Full details of studies are disclosed on the total syntheses of binding pocket analogues of vancomycin bearing the peripheral L-vancosaminyl-1,2-D-glucosyl disaccharide that contain changes to a key single atom in the residue-4 amide (residue-4 carbonyl O → S, NH, H2) designed to directly address the underlying molecular basis of resistance to vancomycin. Also disclosed are studies piloting the late-stage transformations conducted on the synthetically more accessible C-terminus hydroxymethyl aglycon derivatives and full details of the peripheral chlorobiphenyl functionalization of all of the binding-pocket-modified vancomycin analogues designed for dual D-Ala-D-Ala/D-Ala-D-Lac binding. Their collective assessment indicates that combined binding pocket and chlorobiphenyl peripherally modified analogues exhibit a remarkable spectrum of antimicrobial activity (VSSA, MRSA, and VanA and VanB VRE) and impressive potencies against both vancomycin-sensitive and vancomycin-resistant bacteria (MICs = 0.06-0.005 and 0.5-0.06 μg/mL for the amidine and methylene analogues, respectively) and likely benefit from two independent and synergistic mechanisms of action, only one of which is dependent on D-Ala-D-Ala/D-Ala-D-Lac binding. Such analogues are likely to display especially durable antibiotic activity that is not prone to rapidly acquired clinical resistance.
Topics: Anti-Bacterial Agents; Bacteria; Binding Sites; Biphenyl Compounds; Chemistry Techniques, Synthetic; Drug Resistance, Bacterial; Microbial Sensitivity Tests; Structure-Activity Relationship; Vancomycin
PubMed: 25750995
DOI: 10.1021/jacs.5b01008 -
Antimicrobial Agents and Chemotherapy Sep 2008There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end...
There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia >or=10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was >or=1.5 mg/liter. The 66 patients with vancomycin MICs of >or=1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of
vancomycin MIC of >or=1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of >or=1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients. Topics: Adult; Aged; Anti-Bacterial Agents; Bacteremia; Female; Humans; Male; Methicillin Resistance; Microbial Sensitivity Tests; Middle Aged; Staphylococcal Infections; Staphylococcus aureus; Treatment Failure; Vancomycin
PubMed: 18591266
DOI: 10.1128/AAC.00113-08