-
Protein Science : a Publication of the... Mar 2020Vancomycin and related glycopeptides are drugs of last resort for the treatment of severe infections caused by Gram-positive bacteria such as Enterococcus species,... (Review)
Review
Vancomycin and related glycopeptides are drugs of last resort for the treatment of severe infections caused by Gram-positive bacteria such as Enterococcus species, Staphylococcus aureus, and Clostridium difficile. Vancomycin was long considered immune to resistance due to its bactericidal activity based on binding to the bacterial cell envelope rather than to a protein target as is the case for most antibiotics. However, two types of complex resistance mechanisms, each comprised of a multi-enzyme pathway, emerged and are now widely disseminated in pathogenic species, thus threatening the clinical efficiency of vancomycin. Vancomycin forms an intricate network of hydrogen bonds with the d-Ala-d-Ala region of Lipid II, interfering with the peptidoglycan layer maturation process. Resistance to vancomycin involves degradation of this natural precursor and its replacement with d-Ala-d-lac or d-Ala-d-Ser alternatives to which vancomycin has low affinity. Through extensive research over 30 years after the initial discovery of vancomycin resistance, remarkable progress has been made in molecular understanding of the enzymatic cascades responsible. Progress has been driven by structural studies of the key components of the resistance mechanisms which provided important molecular understanding such as, for example, the ability of this cascade to discriminate between vancomycin sensitive and resistant peptidoglycan precursors. Important structural insights have been also made into the molecular evolution of vancomycin resistance enzymes. Altogether this molecular data can accelerate inhibitor discovery and optimization efforts to reverse vancomycin resistance. Here, we overview our current understanding of this complex resistance mechanism with a focus on the structural and molecular aspects.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Clostridioides difficile; Enterococcus; Microbial Sensitivity Tests; Staphylococcus aureus; Vancomycin; Vancomycin Resistance
PubMed: 31899563
DOI: 10.1002/pro.3819 -
Clinical Microbiology Reviews Jun 2023Vancomycin-resistant enterococci (VRE) are common causes of bloodstream infections (BSIs) with high morbidity and mortality rates. They are pathogens of global concern... (Review)
Review
Vancomycin-resistant enterococci (VRE) are common causes of bloodstream infections (BSIs) with high morbidity and mortality rates. They are pathogens of global concern with a limited treatment pipeline. Significant challenges exist in the management of VRE BSI, including drug dosing, the emergence of resistance, and the optimal treatment for persistent bacteremia and infective endocarditis. Therapeutic drug monitoring (TDM) for antimicrobial therapy is evolving for VRE-active agents; however, there are significant gaps in the literature for predicting antimicrobial efficacy for VRE BSIs. To date, TDM has the greatest evidence for predicting drug toxicity for the three main VRE-active antimicrobial agents daptomycin, linezolid, and teicoplanin. This article presents an overview of the treatment options for VRE BSIs, the role of antimicrobial dose optimization through TDM in supporting clinical infection management, and challenges and perspectives for the future.
Topics: Humans; Anti-Bacterial Agents; Vancomycin; Linezolid; Bacteremia; Vancomycin-Resistant Enterococci; Anti-Infective Agents; Sepsis; Gram-Positive Bacterial Infections
PubMed: 37067406
DOI: 10.1128/cmr.00059-22 -
Canadian Journal of Microbiology Jan 2020The emergence of multidrug-resistant bacteria demands innovations in the development of new antibiotics. For decades, the glycopeptide antibiotic vancomycin has been... (Review)
Review
The emergence of multidrug-resistant bacteria demands innovations in the development of new antibiotics. For decades, the glycopeptide antibiotic vancomycin has been considered as the "last resort" treatment of severe infections caused by Gram-positive bacteria. Since the discovery of the first vancomycin-resistant enterococci strains in the late 1980s, the number of resistances has been steadily rising, with often life-threatening consequences. As an alternative to the generation of completely new substances, novel approaches focus on structural modifications of established antibiotics such as vancomycin to overcome these resistances. Here, we provide an overview of several promising modifications of vancomycin to restore its efficacy against vancomycin-resistant enterococci.
Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans; Structure-Activity Relationship; Vancomycin; Vancomycin Resistance
PubMed: 31545906
DOI: 10.1139/cjm-2019-0309 -
International Journal of Molecular... Feb 2022Vancomycin is the most frequently used antibiotic, accounting for up to 35% of hospitalized patients with infection, because of its optimal bactericidal effectiveness... (Review)
Review
Vancomycin is the most frequently used antibiotic, accounting for up to 35% of hospitalized patients with infection, because of its optimal bactericidal effectiveness and relatively low price. Vancomycin-associated AKI (VA-AKI) is a clinically relevant but not yet clearly understood entity in critically ill patients. The current review comprehensively summarizes the pathophysiological mechanisms of, biomarkers for, preventive strategies for, and some crucial issues with VA-AKI. The pathological manifestations of VA-AKI include acute tubular necrosis, acute tubulointerstitial nephritis (ATIN), and intratubular crystal obstruction. The proposed pathological mechanisms of VA-AKI include oxidative stress and allergic reactions induced by vancomycin and vancomycin-associated tubular casts. Concomitant administration with other nephrotoxic antibiotics, such as piperacillin-tazobactam, high vancomycin doses, and intermittent infusion strategies compared to the continuous infusion are associated with a higher risk of VA-AKI. Several biomarkers could be applied to predict and diagnose VA-AKI. To date, no promising therapy is available. Oral steroids could be considered for patients with ATIN, whereas hemodialysis might be applied to remove vancomycin from the patient. In the future, disclosing more promising biomarkers that could precisely identify populations susceptible to VA-AKI and detect VA-AKI occurrence early on, and developing pharmacological agents that could prevent or treat VA-AKI, are the keys to improve the prognoses of patients with severe infection who probably need vancomycin therapy.
Topics: Acute Kidney Injury; Animals; Anti-Bacterial Agents; Biomarkers; Humans; Vancomycin
PubMed: 35216167
DOI: 10.3390/ijms23042052 -
The Journal of Antimicrobial... Dec 2022Clostridioides difficile infection (CDI) remains a significant clinical challenge both in the management of severe and severe-complicated disease and the prevention of... (Review)
Review
Clostridioides difficile infection (CDI) remains a significant clinical challenge both in the management of severe and severe-complicated disease and the prevention of recurrence. Guidelines released by the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America (IDSA/SHEA) and ESCMID had some consensus as well as some discrepancies in disease severity classification and treatment recommendations. We review and compare the key clinical strategies from updated IDSA/SHEA, ESCMID and current Australasian guidelines for CDI management in adults and discuss relevant issues for clinicians, particularly in the management of severe-complicated infection. Updated IDSA/SHEA and ESCMID guidelines now reflect the increased efficacy of fidaxomicin in preventing recurrence and have both promoted fidaxomicin to first-line therapy with an initial CDI episode in both non-severe and severe disease and endorsed the role of bezlotoxumab in the prevention of recurrent infection. Vancomycin remains acceptable therapy and metronidazole is not preferred. For severe-complicated infection the IDSA/SHEA recommends high-dose oral ± rectal vancomycin and IV metronidazole, whilst in an important development, ESCMID has endorsed fidaxomicin and tigecycline as part of combination anti-CDI therapy, for the first time. The role of faecal microbiota transplantation (FMT) in second CDI recurrence is now clearer, but timing and mode of FMT in severe-complicated refractory disease still requires further study.
Topics: Adult; Humans; Vancomycin; Fidaxomicin; Metronidazole; Clostridioides difficile; Clostridium Infections; Anti-Bacterial Agents
PubMed: 36441203
DOI: 10.1093/jac/dkac404 -
MSphere Jan 2021infection (CDI) is most commonly diagnosed using nucleic acid amplification tests (NAAT); the low positive predictive value of these assays results in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
infection (CDI) is most commonly diagnosed using nucleic acid amplification tests (NAAT); the low positive predictive value of these assays results in patients colonized with unnecessarily receiving CDI treatment antibiotics. The risks and benefits of antibiotic treatment in individuals with such cases are unknown. Fecal samples of NAAT-positive, toxin enzyme immunoassay (EIA)-negative patients were collected before, during, and after randomization to vancomycin ( = 8) or placebo ( = 7). and antibiotic-resistant organisms (AROs) were selectively cultured from fecal and environmental samples. Shotgun metagenomics and comparative isolate genomics were used to understand the impact of oral vancomycin on the microbiome and environmental contamination. Overall, 80% of placebo patients and 71% of vancomycin patients were colonized with posttreatment. One person randomized to placebo subsequently received treatment for CDI. In the vancomycin-treated group, beta-diversity (0.0059) and macrolide-lincosamide-streptogramin (MLS) resistance genes (0.037) increased after treatment; and vancomycin-resistant enterococci (VRE) environmental contamination was found in 53% of patients and 26% of patients, respectively. We found that vancomycin alters the gut microbiota, does not permanently clear , and is associated with VRE colonization/environmental contamination. (This study has been registered at ClinicalTrials.gov under registration no. NCT03388268.) A gold standard diagnostic for infection (CDI) does not exist. An area of controversy is how to manage patients whose stool tests positive by nucleic acid amplification tests but negative by toxin enzyme immunoassay. Existing data suggest most of these patients do not have CDI, but most are treated with oral vancomycin. Potential benefits to treatment include a decreased risk for adverse outcomes if the patient does have CDI and the potential to decrease shedding/transmission. However, oral vancomycin perturbs the intestinal microbiota and promotes antibiotic-resistant organism colonization/transmission. We conducted a double-blinded randomized controlled trial to assess the risk-benefit of oral vancomycin treatment in this population. Oral vancomycin did not result in long-term clearance of , perturbed the microbiota, and was associated with colonization/shedding of vancomycin-resistant enterococci. This work underscores the need to better understand this population of patients in the context of /ARO-related outcomes and transmission.
Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Clostridioides difficile; Clostridium Infections; Feces; Female; Gastrointestinal Microbiome; Humans; Male; Metagenomics; Middle Aged; Vancomycin; Vancomycin-Resistant Enterococci
PubMed: 33441409
DOI: 10.1128/mSphere.00936-20 -
Pharmacotherapy Apr 2020Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and...
Executive Summary: Therapeutic Monitoring of Vancomycin for Serious Methicillin-Resistant Staphylococcus aureus Infections: A Revised Consensus Guideline and Review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, the Pediatric Infectious Diseases...
BACKGROUND
Recent vancomycin PK/PD and toxicodynamic studies enable a reassessment of the current dosing and monitoring guideline in an attempt to further optimize the efficacy and safety of vancomycin therapy. The area-under-the-curve to minimum inhibitory concentration (AUC/MIC) has been identified as the most appropriate pharmacokinetic/pharmacodynamic (PK/PD) target for vancomycin. The 2009 vancomycin consenus guidelines recommended specific trough concentrations as a surrogate marker for AUC/MIC. However, more recent toxicodynamic studies have reported an increase in nephrotoxicity associated with trough monitoring.
METHODS AND RESULTS
This is the executive summary of the new vancomycin consensus guidelines for dosing and monitoring vancomycin therapy and was developed by the American Society of Health-Systems Pharmacists, Infectious Diseases Society of America, Pediatric Infectious Diseases Society and the Society of Infectious Diseases Pharmacists vancomycin consensus guidelines committee.
CONCLUSIONS
The recommendations provided in this document are intended to assist the clinician in optimizing vancomycin for the treatment of invasive MRSA infections in adult and pediatric patients. An AUC/MIC by broth microdilution (BMD) ratio of 400 to 600 (assuming MICBMD of 1 mg/L) should be advocated as the target to achieve clinical efficacy while improving patient safety for patients with serious MRSA infections. In such cases, AUC-guided dosing and monitoring is the most accurate and optimal way to manage vancomycin therapy.
Topics: Anti-Bacterial Agents; Drug Monitoring; Humans; Methicillin-Resistant Staphylococcus aureus; Practice Guidelines as Topic; Societies, Medical; Societies, Pharmaceutical; Staphylococcal Infections; United States; Vancomycin
PubMed: 32227354
DOI: 10.1002/phar.2376 -
BMC Infectious Diseases Feb 2021This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety. (Meta-Analysis)
Meta-Analysis
BACKGROUND
This systematic review and meta-analysis explored the relationship between vancomycin (VCM) monitoring strategies and VCM effectiveness and safety.
METHODS
We conducted our analysis using the MEDLINE, Web of Sciences, and Cochrane Register of Controlled Trials electronic databases searched on August 9, 2020. We calculated odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS
Adult patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia with VCM trough concentrations ≥15 μg/mL had significantly lower treatment failure rates (OR 0.63, 95% CI 0.47-0.85). The incidence of acute kidney injury (AKI) increased with increased trough concentrations and was significantly higher for trough concentrations ≥20 μg/mL compared to those at 15-20 μg/mL (OR 2.39, 95% CI 1.78-3.20). Analysis of the target area under the curve/minimum inhibitory concentration ratios (AUC/MIC) showed significantly lower treatment failure rates for high AUC/MIC (cut-off 400 ± 15%) (OR 0.28, 95% CI 0.18-0.45). The safety analysis revealed that high AUC value (cut-off 600 ± 15%) significantly increased the risk of AKI (OR 2.10, 95% CI 1.13-3.89). Our meta-analysis of differences in monitoring strategies included four studies. The incidence of AKI tended to be lower in AUC-guided monitoring than in trough-guided monitoring (OR 0.54, 95% CI 0.28-1.01); however, it was not significant in the analysis of mortality.
CONCLUSIONS
We identified VCM trough concentrations and AUC values that correlated with effectiveness and safety. Furthermore, compared to trough-guided monitoring, AUC-guided monitoring showed potential for decreasing nephrotoxicity.
Topics: Acute Kidney Injury; Adult; Anti-Bacterial Agents; Area Under Curve; Bacteremia; Drug Monitoring; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Odds Ratio; Safety; Staphylococcal Infections; Treatment Failure; Vancomycin
PubMed: 33549035
DOI: 10.1186/s12879-021-05858-6 -
Antimicrobial Agents and Chemotherapy May 2022Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding...
Vancomycin usage is often unavoidable in pregnant patients; however, literature suggests vancomycin can cross the placental barrier and reach the fetus. Understanding the mass transit of vancomycin to the fetus is important in pregnancy. We aimed to (i) identify a relevant population pharmacokinetic (PK) model for vancomycin in pregnancy and (ii) estimate PK parameters and describe the mass transit of vancomycin from mother to pup kidneys. Pregnant Sprague-Dawley rats (i.e., trimester 1 and trimester 3) received 250 mg/kg vancomycin once daily for three days through intravenous injection via an internal jugular vein catheter. Vancomycin concentrations in maternal plasma and pup kidneys were quantified via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple compartment models were fitted and assessed using a nonparametric approach with Pmetrics. A total of 10 vancomycin-treated rats and 48 pups contributed PK data. A 3-compartment model adjusted for trimester fit the data well (maternal plasma Bayesian, observed versus predicted R = 0.978; pup kidney Bayesian, observed versus predicted R = 0.999). The mean rate constant for vancomycin mass transit to the pup kidney was 0.72 h for trimester 1 dams and 0.75 h for trimester 3 dams. Median vancomycin concentrations in pup kidneys from trimester 3 were significantly higher than those in trimester 1 (8.62 versus 0.36 μg/mL, < 0.001). Vancomycin transited to the fetus from the mother and was; kidney accumulation differed by trimester. This model may be useful for a translational understanding of vancomycin distribution in pregnancy to ensure efficacious and safe doses to both mother and fetus.
Topics: Animals; Bayes Theorem; Chromatography, Liquid; Female; Humans; Placenta; Pregnancy; Rats; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Vancomycin
PubMed: 35446134
DOI: 10.1128/aac.00056-22 -
Microbiology Spectrum Apr 2022This study aimed to evaluate whether trough level-guided monitoring can be replaced by area under the concentration-time curve (AUC) and MIC ratio-guided monitoring...
This study aimed to evaluate whether trough level-guided monitoring can be replaced by area under the concentration-time curve (AUC) and MIC ratio-guided monitoring (AUC/MIC ratio = 400) in patients infected with methicillin-resistant Staphylococcus aureus (MRSA) with a vancomycin MIC = 1 mg/L in Taiwan. In this retrospective study, patients treated with vancomycin for Methicillin-resistant Staphylococcus aureus (MRSA) infection were recruited from a teaching hospital in Taiwan from January 2016 to December 2017. Average trough concentrations were adjusted based on the average daily vancomycin dose, and the AUC/MIC ratio was calculated using the AUC/MIC conversion formula to analyze the correlation between trough or AUC/MIC ratio, nephrotoxicity, and clinical efficacy. As the primary outcome, the overall mean adjusted vancomycin average AUC/MIC ratio was 526.87 for a total of 102 patients. A total of 67% and 76% of the patients attained an AUC/MIC of ≥400 when the adjusted vancomycin trough concentrations were 10 to 15 mg/L and 15 to 20 mg/L, respectively. Additionally, 81.37% of the total study population had MRSA isolates with a vancomycin MIC of ≤1 mg/L. Moreover, in the subgroup, 92% of the patients attained an AUC/MIC of ≥400 on receiving vancomycin in the 10 to 15 mg/L trough range. An AUC/MIC of ≥400 was attained in patients infected with MRSA strains, who were treated by maintaining the vancomycin trough concentrations at 10 to 15 mg/L. Moreover, these patients demonstrated a lower incidence of nephrotoxicity. These findings support the use of the AUC/MIC ratio as a useful marker for the therapeutic monitoring of vancomycin owing to the clinical efficacy and safety of vancomycin in Taiwan. Since 2020, the Infectious Diseases Society of America (IDSA) updated vancomycin guidelines, and vancomycin AUC therapeutic drug monitor was updated to AUC/MIC in the United States. But acceptable rate of infection physicians in Taiwan was low. That is why this study evaluated in Taiwan.
Topics: Anti-Bacterial Agents; Humans; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Retrospective Studies; Staphylococcal Infections; Taiwan; Vancomycin
PubMed: 35412391
DOI: 10.1128/spectrum.01562-21