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BMJ Open Sep 2023infection (CDI) is the most prevalent cause of nosocomial bacterial diarrhoea and it is strongly associated with antibiotic use. The recurrence of CDI is a growing... (Randomized Controlled Trial)
Randomized Controlled Trial
Evaluation of the effectiveness and safety of oral vancomycin versus placebo in the prevention of recurrence of infection in patients under systemic antibiotic therapy: a phase III, randomised, double-blind clinical trial.
INTRODUCTION
infection (CDI) is the most prevalent cause of nosocomial bacterial diarrhoea and it is strongly associated with antibiotic use. The recurrence of CDI is a growing medical problem. Data from real-life studies and one open label randomised clinical trial (RCT) suggest that secondary prophylaxis with oral vancomycin (SPV) during subsequent courses of systemic antibiotics is a promising approach for reducing the risk of CDI recurrence. Our aim is to confirm the role of SPV through a double-blind RCT.
METHODS AND ANALYSIS
We will perform a phase III, multicentre, placebo-controlled RCT (PREVAN trial) in a 2:1 ratio in favour of SPV (experimental treatment), in four tertiary care hospitals in Spain. Adult patients (≥18 years) with a previous history of CDI in the previous 180 days and with requirement for hospitalisation and systemic antibiotic therapy will be randomly allocated to receive either 125 mg of oral vancomycin or placebo every 6 hours for 10 days. Patients will be followed for 60 days after the end of treatment to verify a reduction in the rate of CDI recurrence in the experimental group. We assume a recurrence rate of 5% in the experimental group versus 25% in the placebo group. Accepting an alpha risk of 0.05 and a beta risk of 0.2 in a two-sided test, 104 subjects will be required in total (68 assigned to the SPV group and 34 to the placebo group).
ETHICS AND DISSEMINATION
Ethical approval has been obtained from the Ethic Committee for Research with medicinal products of the University Hospital '12 de Octubre' (AC069/18) and from the Spanish Medicines and Healthcare Product Regulatory Agency (AEMPS, AC069/18), which is valid for all participating centres under existing Spanish legislation. The results will be presented at international meetings and will be made available to patients and funders.
TRIAL REGISTRATION NUMBER
NCT05320068.
Topics: Adult; Humans; Vancomycin; Anti-Bacterial Agents; Clostridium Infections; Secondary Prevention; Hospitals, University
PubMed: 37709311
DOI: 10.1136/bmjopen-2023-072121 -
The Canadian Journal of Hospital... 2023Little is known about the current landscape of vancomycin therapeutic drug monitoring (TDM) in Canadian hospitals, which operate within publicly funded health care...
BACKGROUND
Little is known about the current landscape of vancomycin therapeutic drug monitoring (TDM) in Canadian hospitals, which operate within publicly funded health care systems.
OBJECTIVES
To determine current TDM practices for vancomycin and associated challenges and to gather perceptions about TDM based on area under the concentration-time curve (AUC) in Canadian hospitals.
METHODS
An electronic survey was distributed to hospital pharmacists in spring 2021 through multiple national and provincial antimicrobial stewardship, public health, and pharmacy organizations. The survey gathered data about hospital characteristics, TDM methods, inclusion criteria for patient selection, pharmacokinetic and pharmacodynamic targets, vancomycin susceptibility testing and reporting, and perceived barriers and challenges.
RESULTS
In total, 120 pharmacists from 10 of the 13 provincial and territorial jurisdictions in Canada, representing 12.5% of Canadian acute care hospitals ( = 962), completed at least 90% of survey questions. The predominant TDM method was trough-based (107/119, 89.9%); another 10.1% of respondents (12/119) reported performing AUC-based TDM (with or without trough-based TDM), and 17.9% (19/106) of those not already using AUC-based TDM were considering implementing it within 1 to 2 years. Among hospitals performing trough-based TDM, 60.5% (66/109) targeted trough levels between 15 and 20 mg/L for serious infections with methicillin-resistant . One-quarter of the respondents using this method (27/109, 24.8%) agreed that trough-based TDM was of uncertain benefit, and about one-third (33/109, 30.3%) were neutral on this question. Multiple challenges were identified for trough-based TDM, including sub- or supra-therapeutic concentrations and collection of specimens at inappropriate times. Overall, 40.5% (47/116) of respondents agreed that AUC-based TDM was likely safer than trough-based TDM, whereas 23.3% (27/116) agreed that AUC-based TDM was likely more effective.
CONCLUSIONS
This survey represents a first step in developing evidence-based, standardized best practices for vancomycin TDM that are uniquely suited to the Canadian health care system.
PubMed: 37409147
DOI: 10.4212/cjhp.3337 -
BMC Nephrology Sep 2023Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and...
BACKGROUND
Few drug dosing recommendations for patients receiving home hemodialysis (HHD) have been published which has hindered the adoption of HHD. HHD regimens vary widely and differ considerably from conventional, thrice weekly, in-center hemodialysis in terms of treatment frequency, duration and blood and dialysate flow rates. Consequently, vancomycin and daptomycin clearances in HHD are also likely to be different, consequently HHD dosing regimens must be developed to ensure efficacy and minimize toxicity when these antibiotics are used. Many HHD regimens are used clinically, this study modeled ten common HHD regimens and determined optimal vancomycin and daptomycin dosing for each HHD regimen.
METHODS
Monte Carlo simulations using pharmacokinetic data derived from the literature and demographic data from a large HHD program treating patients with end stage kidney disease were incorporated into a one-compartment pharmacokinetic model. Virtual vancomycin and daptomycin doses were administered post-HHD and drug exposures were determined in 5,000 virtual patients receiving ten different HHD regimens. Serum concentration monitoring with subsequent dose changes was incorporated into the vancomycin models. Pharmacodynamic target attainment rates were determined for each studied dose. The lowest possible doses that met predefined targets in virtual patients were chosen as optimal doses.
RESULTS
HHD frequency, total dialysate volumes and HHD durations influenced drug exposure and led to different dosing regimens to meet targets. Antibiotic dosing regimens were identified that could meet targets for 3- and 7-h HHD regimens occurring every other day or 4-5 days/week. HHD regimens with 3-day interdialytic periods required higher doses prior to the 3-day period. The addition of vancomycin serum concentration monitoring allowed for calculation of necessary dosing changes which increased the number of virtual subjects meeting pharmacodynamic targets.
CONCLUSIONS
Doses of vancomycin and daptomycin that will meet desired pharmacodynamic targets in HHD are dependent on patient and HHD-specific factors. Doses used in conventional thrice weekly hemodialysis are unlikely to meet treatment goals. The antibiotic regimens paired with the HHD parameters studied in this analysis are likely to meet goals but require clinical validation.
Topics: Humans; Vancomycin; Daptomycin; Hemodialysis, Home; Monte Carlo Method; Anti-Bacterial Agents; Dialysis Solutions
PubMed: 37710245
DOI: 10.1186/s12882-023-03314-y -
Journal of Korean Neurosurgical Society Sep 2023Surgical site infection is the most detrimental complication following cranioplasty. In other surgical fields, intrawound vancomycin powder application has been...
OBJECTIVE
Surgical site infection is the most detrimental complication following cranioplasty. In other surgical fields, intrawound vancomycin powder application has been introduced to prevent surgical site infection and is widely used based on results in multiple studies. This study evaluated the effect of intrawound vancomycin powder in cranioplasty compared with the conventional method without topical antibiotics.
METHODS
This retrospective study included 580 patients with skull defects who underwent cranioplasty between August 1, 1998 and December 31, 2021. The conventional method was used in 475 (81.9%; conventional group) and vancomycin powder (1 g) was applied on the dura mater and bone flap in 105 patients (18.1%; vancomycin powder group). Surgical site infection was defined as infection of the incision, organ, or space that occurred after cranioplasty. Surgical site infection within 1-year surveillance period was compared between the conventional and vancomycin powder groups with logistic regression analysis. Penalized likelihood estimation method was used in logistic regression to deal with zero events. All local and systemic adverse events associated with topical vancomycin application were also evaluated.
RESULTS
Surgical site infection occurred in 31 patients (5.3%) and all were observed in the conventional group. The median time between cranioplasty and detection of surgical site infection was 13 days (range, 4-333). Staphylococci were the most common organisms and identified in 25 (80.6%) of 31 cases with surgical site infections. The surgical site infection rate in the vancomycin powder group (0/105, 0.0%) was significantly lower than that in the conventional group (31/475, 6.5%; crude odds ratio [OR], 0.067; 95% confidence interval [CI], 0.006-0.762; adjusted OR, 0.068; 95% CI, 0.006-0.731; p=0.026). No adverse events associated with intrawound vancomycin powder were observed during the follow-up.
CONCLUSION
Intrawound vancomycin powder effectively prevented surgical site infections following cranioplasty without local or systemic adverse events. Our results suggest that intrawound vancomycin powder is an effective and safe strategy for patients undergoing cranioplasty.
PubMed: 37032483
DOI: 10.3340/jkns.2023.0024 -
Microorganisms Sep 2023Antibiotic resistance is a serious global health problem that poses a threat to the successful treatment of various bacterial infections, especially those caused by... (Review)
Review
Antibiotic resistance is a serious global health problem that poses a threat to the successful treatment of various bacterial infections, especially those caused by methicillin-resistant (MRSA) and vancomycin-resistant (VRE). Conventional treatment of MRSA and VRE infections is challenging and often requires alternative or combination therapies that may have limited efficacy, higher costs, and/or more adverse effects. Therefore, there is an urgent need to find new strategies to combat antibiotic-resistant bacteria. Probiotics and antimicrobial peptides (AMPs) are two promising approaches that have shown potential benefits in various diseases. Probiotics are live microorganisms that confer health benefits to the host when administered in adequate amounts. AMPs, usually produced with probiotic bacteria, are short amino acid sequences that have broad-spectrum activity against bacteria, fungi, viruses, and parasites. Both probiotics and AMPs can modulate the host immune system, inhibit the growth and adhesion of pathogens, disrupt biofilms, and enhance intestinal barrier function. In this paper, we review the current knowledge on the role of probiotics and AMPs in targeting multi-drug-resistant bacteria, with a focus on MRSA and VRE. In addition, we discuss future directions for the clinical use of probiotics.
PubMed: 37894051
DOI: 10.3390/microorganisms11102393 -
Archivos Argentinos de Pediatria Jun 2024Introduction: This study investigated the serum concentration of vancomycin during prolonged infusion in children. Population and methods: This retrospective cohort...
Introduction: This study investigated the serum concentration of vancomycin during prolonged infusion in children. Population and methods: This retrospective cohort study included pediatric patients who received vancomycin from June 2017 to June 2020 at a tertiary referral hospital. The patients were divided into two groups according to infusion strategy, the SII (standard intermittent infusion) group and the PI (prolonged infusion) group. Demographic details, infusion period, serum creatinine, duration of vancomycin therapy, trough concentration of vancomycin, and pediatric intensive care unit stay were reviewed. Differences of the concentrations were measured. Results: Sixty-eight patients were included: 31 in the SII group and 37 in the PI group. The trough concentration of vancomycin was significantly higher in the PI group than in SII group (11.2 mg/L [5.9-13.7] vs. 7 mg/L [3.5- 9.3]; p = 0.02). The target attainment rate was higher in the PI group than in the SII group (59.4% and 19.3%, respectively; p = 0.001). There were no significant differences between the SII and PI groups regarding the peak concentrations of vancomycin, final creatinine and peak creatinine. There were no differences between the SII and PI groups regarding the failure events, PICU stay and duration of vancomycin therapy. The multivariable analysis showed that PI was significantly associated with higher trough serum concentrations of vancomycin (OR = 2.27; p = 0.005). Conclusion: Compared to the SII strategy, the PI strategy may be an optimized option to children with severe infection, as it can achieve higher trough concentrations and target concentration attainment.
PubMed: 38820115
DOI: 10.5546/aap.2023-10236.eng -
Pharmaceuticals (Basel, Switzerland) Nov 2023Ceragenins (CSAs) are a new class of antimicrobial agents designed to mimic the activities of endogenous antimicrobial peptides. In this study, the antibacterial...
Ceragenins (CSAs) are a new class of antimicrobial agents designed to mimic the activities of endogenous antimicrobial peptides. In this study, the antibacterial activities of various ceragenins (CSA-13, CSA-44, CSA-90, CSA-131, CSA-138, CSA-142, and CSA-192), linezolid, and daptomycin were assessed against 50 non-repeated spp. (17 of them vancomycin-resistant Enterococcus-VRE) isolated from various clinical specimens. Among the ceragenins evaluated, the MIC and MIC values of CSA-44 and CSA-192 were the lowest (2 and 4 μg/mL, respectively), and further studies were continued with these two ceragenins. Potential interactions between CSA-44 or CSA-192 and linezolid were tested and synergistic interactions were seen with the CSA-192-linezolid combination against three spp., one of them VRE. The effects of CSA-44 and CSA-192 on the MIC values of vancomycin were also investigated, and the largest MIC change was seen in the vancomycin-CSA-192 combination. The in vivo effects of CSA-44 and CSA-192 were evaluated in a model system. Compared to no treatment, increased survival was observed with when treated with ceragenins. In conclusion, CSA-44 and CSA-192 appear to be good candidates (alone or in combination) for the treatment of enterococcal infections, including those from VRE.
PubMed: 38139770
DOI: 10.3390/ph16121643 -
ACS Infectious Diseases Jul 2023Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites of infection....
Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites of infection. Instead, screening in more physiologically relevant conditions may reveal novel activity for existing antibiotics. Here, we screened a panel of antibiotics reported to lack activity against the opportunistic Gram-negative bacterium, , under low-nutrient and low-iron conditions, and discovered that the glycopeptide vancomycin inhibited the growth of at low micromolar concentrations through its canonical mechanism of action, disruption of peptidoglycan crosslinking. Spontaneous vancomycin-resistant mutants underwent activating mutations in the sensor kinase of the two-component CpxSR system, which induced cross-resistance to almost all classes of β-lactams, including the siderophore antibiotic cefiderocol. Other mutations that conferred vancomycin resistance mapped to WapR, an α-1,3-rhamnosyltransferase involved in lipopolysaccharide core biosynthesis. A WapR P164T mutant had a modified LPS profile compared to wild type that was accompanied by increased susceptibility to select bacteriophages. We conclude that screening in nutrient-limited conditions can reveal novel activity for existing antibiotics and lead to discovery of new and impactful resistance mechanisms.
Topics: Vancomycin; Pseudomonas aeruginosa; Anti-Bacterial Agents; Glycopeptides; Nutrients
PubMed: 37279282
DOI: 10.1021/acsinfecdis.3c00167 -
Antimicrobial Agents and Chemotherapy Aug 2023Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to...
Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination. Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 h. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated with the urinary biomarkers kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to the control, rats that received vancomycin had numerically lower GFRs after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin plus piperacillin-tazobactam (vancomycin+piperacillin-tazobactam) did not exhibit worse kidney function or injury biomarkers than rats receiving vancomycin alone. The combination of vancomycin and piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.
Topics: Male; Rats; Animals; Vancomycin; Iohexol; Piperacillin; Glomerular Filtration Rate; Penicillanic Acid; Retrospective Studies; Acute Kidney Injury; Drug Therapy, Combination; Rats, Sprague-Dawley; Anti-Bacterial Agents; Piperacillin, Tazobactam Drug Combination; Biomarkers
PubMed: 37428202
DOI: 10.1128/aac.00304-23 -
International Journal of Antimicrobial... Jan 2024To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and...
OBJECTIVES
To illustrate the impact of errors in documented dose administration time on therapeutic drug monitoring (TDM)-based target attainment evaluation for vancomycin and meropenem, and to explore the influence of drug and patient characteristics, and TDM sampling strategies.
METHODS
Bedside observations of errors in documented dose administration times were collected. Population pharmacokinetic simulations were performed for vancomycin and meropenem, evaluating different one- and two-sampling strategies for populations with estimated creatinine clearance (CLcr) of 30, 80 or 130 mL/min. The impact of errors was evaluated as the proportion of individuals incorrectly considered to have reached the target.
RESULTS
Of 143 observed dose administrations, 97% of doses were given within ±30 min of the documented time. For vancomycin, a +30 min error was predicted to result in a 0.1-3.9 percentage point increase of cases incorrectly evaluated as reaching area under the concentration-time curve during a 24-hour period (AUC)/minimum inhibitory concentration (MIC) >400, with the largest increase for patients with augmented renal clearance and peak and trough sampling. For meropenem, a +30 min error resulted in a 1.3-6.4 and 0-20 percentage point increase of cases incorrectly evaluated as reaching 100% T, and 50% T, respectively. Overall, mid-dose and trough sampling was most favourable for both antibiotics.
CONCLUSIONS
For vancomycin, simulations indicate that TDM-based target attainment evaluation is robust with respect to the observed errors in dose administration time of ±30 min; however, the errors had a potentially clinically important impact in patients with augmented renal clearance. For meropenem, extra measures to promote correct documentation are warranted when using TDM, as the impact of errors was evident even in patients with normal renal function.
Topics: Humans; Vancomycin; Meropenem; Drug Monitoring; Anti-Bacterial Agents; Kidney Function Tests; Renal Insufficiency
PubMed: 37956952
DOI: 10.1016/j.ijantimicag.2023.107032