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Clinical Infectious Diseases : An... Jun 2024Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective... (Randomized Controlled Trial)
Randomized Controlled Trial
A Randomized, Double-Blind, Phase 3 Safety and Efficacy Study of Ridinilazole Versus Vancomycin for Treatment of Clostridioides difficile Infection: Clinical Outcomes With Microbiome and Metabolome Correlates of Response.
BACKGROUND
Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI.
METHODS
In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs.
RESULTS
Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome.
CONCLUSIONS
Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566.
Topics: Humans; Vancomycin; Clostridium Infections; Male; Female; Middle Aged; Double-Blind Method; Anti-Bacterial Agents; Aged; Clostridioides difficile; Gastrointestinal Microbiome; Adult; Treatment Outcome; Metabolome; Oxadiazoles; Dysbiosis; Benzimidazoles; Pyridines
PubMed: 38305378
DOI: 10.1093/cid/ciad792 -
Antimicrobial Agents and Chemotherapy Aug 2021The rate of eradication of periprosthetic joint infection (PJI) caused by methicillin-resistant Staphylococcus aureus (MRSA) is still not satisfactory with systemic...
The rate of eradication of periprosthetic joint infection (PJI) caused by methicillin-resistant Staphylococcus aureus (MRSA) is still not satisfactory with systemic vancomycin administration after one-stage revision arthroplasty. This study aimed to explore the effectiveness and safety of intraarticular (IA) injection of vancomycin in the control of MRSA PJI after one-stage revision surgery in a rat model. Two weeks of intraperitoneal (IP) and/or IA injection of vancomycin was used to control the infection after one-stage revision surgery. The MRSA PJI rats treated with IA injection of vancomycin showed better outcomes in skin temperature, bacterial counts, biofilm on the prosthesis, serum α-acid glycoprotein levels, residual bone volume, and inflammatory reaction in the joint tissue, compared with those treated with IP vancomycin, while the rats treated with IP and IA administration showed the best outcomes. However, only the IP and IA administration of vancomycin could eradicate MRSA. Minimal changes in renal pathology were observed in the IP and IP plus IA groups but not in the IA group, while no obvious changes were observed in the liver or in levels of serum markers, including creatinine, alanine aminotransferase, and aspartate aminotransferase. Therefore, IA use of vancomycin is effective and safe in the MRSA PJI rat model and is better than systemic administration, while IA and systemic vancomycin treatment could eradicate the infection with a 2-week treatment course.
Topics: Animals; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Prostheses and Implants; Prosthesis-Related Infections; Rats; Retrospective Studies; Staphylococcal Infections; Vancomycin
PubMed: 34181479
DOI: 10.1128/AAC.00303-21 -
Therapeutic Drug Monitoring Aug 2023Conventionally, vancomycin trough levels have been used for therapeutic drug monitoring (TDM). Owing to the increasing evidence of trough levels being poor surrogates of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Conventionally, vancomycin trough levels have been used for therapeutic drug monitoring (TDM). Owing to the increasing evidence of trough levels being poor surrogates of area under the curve (AUC) and the advent of advanced pharmacokinetics software, a paradigm shift has been made toward AUC-guided dosing. This study aims to evaluate the impact of AUC-guided versus trough-guided TDM on vancomycin-associated nephrotoxicity.
METHODS
A systematic review was conducted using PubMed, Embase, Web of Science, Cumulative Index to Nursing and Allied Health Literature, Google scholar, and Cochrane library databases; articles published from January 01, 2009, to January 01, 2021, were retrieved and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Studies that evaluated trough-guided or AUC-guided vancomycin TDM and vancomycin-associated nephrotoxicity were included. Random-effects models were used to compare the differences in nephrotoxicity.
RESULTS
Of the 1191 retrieved studies, 57 were included. Most studies included adults and older adults (n = 47, 82.45%). The pooled prevalence of nephrotoxicity was lower in AUC-guided TDM [6.2%; 95% confidence interval (CI): 2.9%-9.5%] than in trough-guided TDM (17.0%; 95% CI: 14.7%-19.2%). Compared with the trough-guided approach, the AUC-guided approach had a lower risk of nephrotoxicity (odds ratio: 0.53; 95% CI: 0.32-0.89). The risk of nephrotoxicity was unaffected by the AUC derivation method. AUC thresholds correlated with nephrotoxicity only within the first 96 hours of therapy.
CONCLUSIONS
The AUC-guided approach had a lower risk of nephrotoxicity, supporting the updated American Society of Health-System Pharmacists guidelines. Further studies are needed to evaluate the optimal AUC-derivation methods and clinical utility of repeated measurements of the AUC and trough levels of vancomycin.
Topics: Humans; Aged; Vancomycin; Anti-Bacterial Agents; Area Under Curve; Drug Monitoring; Retrospective Studies; Microbial Sensitivity Tests
PubMed: 36728329
DOI: 10.1097/FTD.0000000000001075 -
Communications Biology Jan 2021The development and dissemination of antibiotic-resistant bacterial pathogens is a growing global threat to public health. Novel compounds and/or therapeutic strategies...
The development and dissemination of antibiotic-resistant bacterial pathogens is a growing global threat to public health. Novel compounds and/or therapeutic strategies are required to face the challenge posed, in particular, by Gram-negative bacteria. Here we assess the combined effect of potent cell-wall synthesis inhibitors with either natural or synthetic peptides that can act on the outer-membrane. Thus, several linear peptides, either alone or combined with vancomycin or nisin, were tested against selected Gram-negative pathogens, and the best one was improved by further engineering. Finally, peptide D-11 and vancomycin displayed a potent antimicrobial activity at low μM concentrations against a panel of relevant Gram-negative pathogens. This combination was highly active in biological fluids like blood, but was non-hemolytic and non-toxic against cell lines. We conclude that vancomycin and D-11 are safe at >50-fold their MICs. Based on the results obtained, and as a proof of concept for the newly observed synergy, a Pseudomonas aeruginosa mouse infection model experiment was also performed, showing a 4 log reduction of the pathogen after treatment with the combination. This approach offers a potent alternative strategy to fight (drug-resistant) Gram-negative pathogens in humans and mammals.
Topics: Anti-Bacterial Agents; Bacterial Outer Membrane; Drug Therapy, Combination; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Microbial Sensitivity Tests; Nisin; Peptides; Uridine Diphosphate N-Acetylmuramic Acid; Vancomycin
PubMed: 33398076
DOI: 10.1038/s42003-020-01511-1 -
ACS Infectious Diseases Sep 2021Vancomycin functions by binding to lipid II, the penultimate bacterial cell wall building block used by both Gram-positive and Gram-negative species. However, vancomycin...
Vancomycin functions by binding to lipid II, the penultimate bacterial cell wall building block used by both Gram-positive and Gram-negative species. However, vancomycin is generally only able to exert its antimicrobial effect against Gram-positive strains as it cannot pass the outer membrane (OM) of Gram-negative bacteria. To address this challenge, we here describe efforts to conjugate vancomycin to the OM disrupting polymyxin E nonapeptide (PMEN) to yield the hybrid "vancomyxins". In designing these hybrid antibiotics, different spacers and conjugation sites were explored for connecting vancomycin and PMEN. The vancomyxins show improved activity against Gram-negative strains compared with the activity of vancomycin or vancomycin supplemented with PMEN separately. In addition, the vancomyxins maintain the antimicrobial effect of vancomycin against Gram-positive strains and, in some cases, show enhanced activity against vancomycin-resistant strains. The hybrid antibiotics described here have reduced nephrotoxicity when compared with clinically used polymyxin antibiotics. This study demonstrates that covalent conjugation to an OM disruptor contributes to sensitizing Gram-negative strains to vancomycin while retaining anti-Gram-positive activity.
Topics: Anti-Bacterial Agents; Gram-Negative Bacteria; Microbial Sensitivity Tests; Polymyxins; Vancomycin
PubMed: 34387988
DOI: 10.1021/acsinfecdis.1c00318 -
Microbiology Spectrum Feb 2023Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in U.S. cystic fibrosis (CF) patients and is associated with worse clinical outcomes in CF. These...
Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in U.S. cystic fibrosis (CF) patients and is associated with worse clinical outcomes in CF. These infections often become chronic despite repeated antibiotic therapy. Here, we assessed whether bacterial phenotypes, including antibiotic tolerance, can predict the clinical outcomes of MRSA infections. MRSA isolates ( = 90) collected at the incident (i.e., acute) and early infection states from 57 patients were characterized for growth rates, biofilm formation, hemolysis, pigmentation, and vancomycin tolerance. The resistance profiles were consistent with those in prior studies. Isolates from the early stage of infection were found to produce biofilms, and 70% of the isolates exhibited delta-hemolysis, an indicator of activity. Strong vancomycin tolerance was present in 24% of the isolates but was not associated with intermediate vancomycin susceptibility. There were no associations between these phenotypic measures, antibiotic tolerance, and MRSA clearance. Our research suggests that additional factors may be relevant for predicting the clearance of MRSA. Chronic MRSA infections remain challenging to treat in patients with cystic fibrosis (CF). The ability of the bacterial population to survive high concentrations of bactericidal antibiotics, including vancomycin, despite lacking resistance is considered one of the main reasons for treatment failures. The connection between antibiotic tolerance and treatment outcomes remains unexplored and can be crucial for prognosis and regimen design toward eradication. In this study, we measured the capacity of 90 MRSA isolates from CF patients to form vancomycin-tolerant persister cells and evaluated their correlation with the clinical outcomes. Additionally, various traits that could reflect the metabolism and/or virulence of those MRSA isolates were systematically phenotyped and included for their predictive power. Our research highlights that despite the importance of antibiotic tolerance, additional factors need to be considered for predicting the clearance of MRSA.
Topics: Humans; Anti-Bacterial Agents; Methicillin-Resistant Staphylococcus aureus; Vancomycin; Cystic Fibrosis; Hemolysis; Staphylococcal Infections; Treatment Outcome; Microbial Sensitivity Tests
PubMed: 36519944
DOI: 10.1128/spectrum.04061-22 -
The Journal of Infection Oct 2022To evaluate the effectiveness of an antimicrobial guideline for vancomycin prescribing deployed using electronic prescribing aid and web/phone-based app. To define...
OBJECTIVES
To evaluate the effectiveness of an antimicrobial guideline for vancomycin prescribing deployed using electronic prescribing aid and web/phone-based app. To define factors associated with guideline compliance and drug levels, and to investigate if antimicrobial dosing recommendations can be refined using routinely collected electronic healthcare record data.
METHODS
We used data from Oxford University Hospitals between 01-January-2016 and 01-June-2021 and multivariable regression models to investigate factors associated with dosing compliance, drug levels and acute kidney injury (AKI).
RESULTS
3767 patients received intravenous vancomycin for ≥24 h. Compliance with recommended loading and initial maintenance doses reached 84% and 70% respectively; 72% of subsequent maintenance doses were correctly adjusted. However, only 26% first and 32% subsequent levels reached the target range, and for patients with ongoing vancomycin treatment, 55-63% achieved target levels at 5 days. Drug levels were independently higher in older patients. Incidence of AKI was low (5.7%). Model estimates were used to propose updated age, weight and eGFR specific guidelines.
CONCLUSION
Despite good compliance with guidelines for vancomycin dosing, the proportion of drug levels achieving the target range remained suboptimal. Routinely collected electronic data can be used at scale to inform pharmacokinetic studies and could improve vancomycin dosing.
Topics: Acute Kidney Injury; Administration, Intravenous; Aged; Anti-Bacterial Agents; Drug Monitoring; Humans; Retrospective Studies; Vancomycin
PubMed: 35840011
DOI: 10.1016/j.jinf.2022.06.029 -
Microbial Genomics Jul 2023Linezolid is used as first-line treatment of infections caused by vancomycin-resistant . However, resistance to linezolid is increasingly detected. The aim of the...
Linezolid is used as first-line treatment of infections caused by vancomycin-resistant . However, resistance to linezolid is increasingly detected. The aim of the present study was to elucidate the causes and mechanisms for the increase in linezolid-resistant at Copenhagen University Hospital - Rigshospitalet. We therefore combined patient information on linezolid treatment with whole-genome sequencing data for vancomycin- or linezolid-resistant isolates that had been systematically collected since 2014 (=458). Whole-genome sequencing was performed for multilocus sequence typing (MLST), identification of linezolid resistance-conferring genes/mutations and determination of phylogenetically closely related strains. The collection of isolates belonged to prevalent vancomycin-resistant MLST types. Among these, we identified clusters of closely related linezolid-resistant strains compatible with nosocomial transmission. We also identified linezolid-resistant enterococcus isolates not genetically closely related to other isolates compatible with generation of linezolid resistance. Patients with the latter isolates were significantly more frequently exposed to linezolid treatment than patients with related linezolid-resistant enterococcus isolates. We also identified six patients who initially carried a vancomycin-resistant, linezolid-sensitive enterococcus, but from whom vancomycin-resistant, linezolid-resistant enterococci (LVRE) closely related to their initial isolate were recovered after linezolid treatment. Our data illustrate that linezolid resistance may develop in the individual patient subsequent to linezolid exposure and can be transmitted between patients in a hospital setting.
Topics: Humans; Linezolid; Anti-Bacterial Agents; Enterococcus faecium; Vancomycin; Tertiary Care Centers; Multilocus Sequence Typing; Vancomycin-Resistant Enterococci
PubMed: 37410656
DOI: 10.1099/mgen.0.001055 -
Medicina (Kaunas, Lithuania) Jun 2021The long-term administration of vancomycin has increased; however, the pulmonary adverse reactions of long-term vancomycin treatment remain under-studied. A 75-year-old... (Review)
Review
The long-term administration of vancomycin has increased; however, the pulmonary adverse reactions of long-term vancomycin treatment remain under-studied. A 75-year-old male patient with vertebral osteomyelitis receiving long-term vancomycin therapy developed a fever. High resolution computed tomography showed irregular ground glass opacity and consolidation in the right upper lung. The patient developed organizing pneumonia. This occurred without peripheral eosinophilia or adverse reactions in the skin and liver. The administration of vancomycin was discontinued. He recovered from organizing pneumonia after four weeks of steroid therapy. Solitary organizing pneumonia can develop during treatment with vancomycin. When pulmonary inflammation occurs and other causes of pneumonia are excluded, vancomycin therapy should be discontinued.
Topics: Aged; Eosinophilia; Humans; Lung; Lung Diseases; Male; Pneumonia; Vancomycin
PubMed: 34208316
DOI: 10.3390/medicina57060610 -
European Journal of Clinical... Apr 2024To investigate the occurrence of vancomycin-variable enterococci (VVE) in a hospital in central Italy.
PURPOSE
To investigate the occurrence of vancomycin-variable enterococci (VVE) in a hospital in central Italy.
METHODS
vanA positive but vancomycin-susceptible Enterococcus faecium isolates (VVE-S) were characterized by antibiotic susceptibility tests, molecular typing (PFGE and MLST), and WGS approach. The reversion of VVE-S to a resistant phenotype was assessed by exposure to increasing vancomycin concentrations, and the revertant isolates were used in filter mating experiments. qPCR was used to analyze the plasmid copy number.
RESULTS
Eleven putative VVE-S were selected. WGS revealed two categories of vanA cluster plasmid located: the first type showed the lack of vanR, the deletion of vanS, and an intact vanH/vanA/vanX cluster; the second type was devoid of both vanR and vanS and showed a deletion of 544-bp at the 5'-end of the vanH. Strains (n = 7) carrying the first type of vanA cluster were considered VVE-S and were able to regain a resistance phenotype (VVE-R) in the presence of vancomycin, due to a 44-bp deletion in the promoter region of vanH/vanA/vanX, causing its constitutive expression. VVE-R strains were not able to transfer resistance by conjugation, and the resistance phenotype was unstable: after 11 days of growth without selective pressure, the revertants were still resistant but showed a lower vancomycin MIC. A higher plasmid copy number in the revertant strains was probably related to the resistance phenotype.
CONCLUSION
We highlight the importance of VVE transition to VRE under vancomycin therapy resulting in a potential failure treatment. We also report the first-time identification of VVE-S isolates pstS-null belonging to ST1478.
Topics: Humans; Vancomycin; Enterococcus faecium; Anti-Bacterial Agents; Multilocus Sequence Typing; Vancomycin Resistance; Microbial Sensitivity Tests; Enterococcus; Bacterial Proteins; Gram-Positive Bacterial Infections
PubMed: 38296911
DOI: 10.1007/s10096-024-04768-0