Vancomycin Treatment Research Articles

Evaluating the Effectiveness of a Vancomycin Stewardship Program in a Level IV NICU.

Despite recommendations to limit the use of vancomycin for known resistant infections, it remains one of the most commonly prescribed antibiotics in neonatal intensive care units (NICUs). One of the most effective approaches to reducing unnecessary antibiotic exposure is through the implementation of antibiotic stewardship programs (ASPs). The objective of this study was to evaluate the effectiveness of ASPs in reducing the use of vancomycin in neonates hospitalized in our NICU. This study was a quasi-experimental single-centre study for a quality improvement (QI) initiative. Interventions were implemented to limit the use of vancomycin, including education of the neonatal intensive care team, standardization of vancomycin therapy, and prospective audit and feedback. The pre-intervention period was compared with the post-intervention period. The initiation of vancomycin decreased from 166 times in the pre-intervention period to 71 times after stewardship implementations, representing a 57.2% reduction. Total vancomycin DOT per 1000 PD gradually declined from 113 to 45 (60.2%) (p<0.001) during the study period. There was an increase in the Gram (+) growth in the culture of patients who were started on vancomycin (p= 0.04). The number of patients receiving two or more courses of vancomycin treatment decreased by 85.7% (p= 0.03). This study has demonstrated that implementing effective multidisciplinary strategies can significantly reduce vancomycin exposure in the NICU. The application of ASP practices and management in the NICU is essential and achievable, without any increase in the duration of hospitalization or mortality rates.

P-312. Elimination of barrier contact precautions for Vancomycin-Resistant Enterococcus (VRE)-colonized patients was not associated with the acquisition of VRE in a tertiary care center

Abstract Background In April 2020, the University of Michigan discontinued barrier contact precautions for Vancomycin-Resistant Enterococcus (VRE) colonized patients while maintaining VRE surveillance. We conducted a retrospective cohort study to assess the impact of this policy change on the risk of VRE acquisition Inclusion and Exclusion Criteria of the Cohort Methods We analyzed patients admitted between 1/2018 and 3/2021 who underwent weekly surveillance. The primary outcome was VRE-free survival; the main exposure was admission before or after the contact precaution policy. Demographics, Elixhauser comorbidity index, antibiotic and PPI exposure, and colonization pressure were incorporated as covariates in an extended Cox proportional hazard model of VRE-free survival. Time-varying covariates were accounted for and modeled using log-transformed time. Patients were censored at discharge or death. VRE-free survival before and after change in contact precautions policy Change in contact precaution policy was not associated with an increased hazard of VRE-acquisition in single variable analysis Results We identified 2,221 patients admitted before the policy change and 1,830 after, with 225 cases of VRE acquisition before and 196 cases after. No significant differences in age, demographics, antibiotic use, or PPI exposure were observed among VRE patients admitted before and after the policy change. However, VRE patients admitted before the policy change had more medical comorbidities (mean Elixhauser: 23.64 before, 20.77 after; p=0.008) and lower exposure to colonization pressure (mean VRE patient days: 13.4 before, 29.9 after; p=0.019). In a multivariable extended Cox proportional hazard model, admission before or after the change in contact precaution policy showed no significant association with VRE-free survival (HR 0.81-1.1), or infection with VRE (HR 1.01, 95% CI 0.92-1.21). The most significant risk factors for VRE acquisition were vancomycin treatment (HR 1.60, 95% CI 1.25-2.03, p&amp;lt; 0.001) and PPI treatment (HR 1.43, 95% CI 1.15-1.77, p=0.001). Multivariable cox-regression model of risk factors for VRE acquisition There was no association between the change in contact precautions policy and risk of VRE acquisition Conclusion The policy change to eliminate isolation and barrier precaution requirements for VRE patients was associated with no detectible increase in the hazard of VRE acquisition. The most significant risk factors for VRE acquisition were vancomycin and PPI treatment. Our results suggest that appropriate use of PPI and antimicrobial stewardship may have a greater impact on preventing the spread and acquisition of VRE than barrier precautions. Disclosures Laraine Washer, MD, Ferring Pharmaceuticals: Advisor/Consultant

P-1463. Ceftaroline Versus Vancomycin for the Treatment of Complicated Skin and Soft Tissue Infections (cSSTIs): A Retrospective Cohort Study

Abstract Background Complicated skin and soft tissue infections (cSSTIs) caused by resistant pathogens like methicillin-resistant Staphylococcus aureus (MRSA) require effective treatment. Vancomycin is the standard-of-care for MRSA-associated cSSTIs, but its efficacy is questioned due to poor tissue penetration. Ceftaroline, an anti-MRSA cephalosporin with improved tissue penetration, may offer better outcomes. This real-world study compares the effectiveness of ceftaroline and vancomycin in treating cSSTIs. Methods A multicenter retrospective cohort study was conducted in five Memorial Health System hospitals from 2019-2023. Here we present an interim analysis of 90 patients per arm. Included were adults diagnosed with cSSTIs who received ≥48 hours of ceftaroline or vancomycin treatment and were discharged alive. Exclusions were patients with any concurrent infection at initial diagnosis, infections requiring prolonged therapy, combination therapy, pregnancy, or incarceration. The primary outcome was clinical cure rate. Secondary outcomes were hospital length of stay (LOS), 30-day readmission, 30-day recurrence, time to oral antibiotic switch, and nephrotoxicity. Multivariable logistic regression was used to assess the independent association between ceftaroline therapy and clinical cure, adjusting for confounders. Results Overall, 180 patients were included. For the ceftaroline and vancomycin groups, median (IQR) APACHE scores were 10.5 (6-13.8) and 8 (6-12) (p=0.09), and SOFA scores were 1 (0-2) and 0 (0-1) (p=0.03), respectively. Clinical cure rates were 93.3% for ceftaroline and 88.9% for vancomycin (p=0.43). Multivariate analysis showed ceftaroline is independently associated with clinical cure (p=0.04). For vancomycin and ceftaroline, median (IQR) LOS was 4 days (2-6) versus 10 days (6-14) (p&amp;lt; 0.01), and 30-day readmission rates were 7.8% and 18.9%, respectively (p=0.04). No significant differences in other outcomes were noted. Conclusion Interim analysis shows ceftaroline is associated with numerically higher clinical cure rates than vancomycin, despite higher disease severity in the ceftaroline group. Ceftaroline is an independent predictor of clinical cure. Further investigation is needed to compare the efficacy and safety of both treatments. Disclosures All Authors: No reported disclosures

P-1097. Efficacy of Rifaquizinone in a Murine Model of Prosthetic Joint Infection (PJI) with Fluoroquinolone-Sensitive and -Resistant Staphylococcus aureus

Abstract Background Rifaquizinone (RFQ, TNP-2092) is a novel multitargeting drug conjugate in development for the treatment of serious or life-threatening bacterial infections including those caused by gram-positive pathogens that have developed or acquired resistance to commonly used antibiotics and those associated with medical devices. RFQ exerts its antibacterial activity by inhibiting RNA polymerase, DNA gyrase, and topoisomerase IV. Current studies sought to evaluate the therapeutic efficacy of RFQ following intraperitoneal (IP) administration for 7- to14-day treatment in a murine model of S. aureus prosthetic joint infection (PJI). Methods K-wire was implanted in right hindlimb femurs of C57/BL6 mice followed by infection with 6.5-6.9 log10 CFU of a fluoroquinolone-sensitive (UNT005-4) or -resistant (UNT002-3) S. aureus strain. Doses of RFQ, ciprofloxacin, vancomycin, and vehicle were IP administered BID for 7 or 14 consecutive days starting 7 or 21 days after infection. Infected wires and femurs were collected and processed for CFU counts from untreated groups at the start of treatment and treated/vehicle groups within 18 hours of the final administered dose. Results In the 7 day UNT005-4 infection study, mean wire and femur counts for the infection group were 4.77 log10 CFU and 7.89 log10 CFU on Day 7 and for vehicle treatment were 5.02 log10 CFU and 6.83 log10 CFU on Day 14. Comparatively, RFQ at doses of 10, 25, and 62.5 mg/kg for 7 days treatment significantly reduced mean wire and femur counts by &amp;gt; 2.40 and &amp;gt; 1.60 log10 CFU. In the 21 day UNT005-4 infection study, compared to the infection and vehicle treatment, the same doses of RFQ administered for 14 days significantly reduced mean counts by &amp;gt;1.02 log10 CFU for wires and &amp;gt; 0.88 log10 CFU for femurs. In the 21 day UNT002-3 infection study, RFQ administered for 14 days significantly reduced mean counts by &amp;gt; 1.50 log10 CFU for wire and &amp;gt; 0.9 log10 CFU for femur. As expected, reduction in mean counts following 7 or 14 days of ciprofloxacin and vancomycin treatments were less than RFQ. Conclusion RFQ IP administered doses significantly reduced wire- and femur-associated counts for both S. aureus strains, and despite UNT002-3 resistant to ciprofloxacin treatment, the RFQ remained efficacious in the murine PJI model. Disclosures Mark E Pulse, MS, TenNor Therapeutics (Suzhou) Ltd: Investigator Phung Nguyen, BS, TenNor Therapeutics (Suzhou) Ltd: Investigator David Valtierra, Master, TenNor Therapeutics (Suzhou) Ltd: Investigator Kelly Peterson, PhD, TenNor Therapeutics (Suzhou) Ltd: Investigator Zhenkun Ma, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee Huan Wang, PhD, TenNor Therapeutics (Suzhou) Ltd: Employee William J Weiss, MS, TenNor Therapeutics (Suzhou) Ltd: Investigator

P-1710. Prescribing Patterns for Clostridioides difficile Treatment in Outpatient Setting Using the Collaboration to Harmonize Antimicrobial Registry Measures (CHARM)

Abstract Background Clostridioides difficile infection (CDI) is a form of infectious diarrhea associated with antibiotic use. In 2021, the IDSA released guidelines for treatment of CDI, which recommended fidaxomicin for 10 days as the first line treatment and vancomycin as an acceptable alternate. It is unclear to what extent prescribers have adopted this recommendation. This study aimed to examine patients’ antibiotic exposure before developing CDI and describe the prescribing patterns for CDI treatment in outpatient settings.Table 1:Frequency and Duration of Initial Clostridioides difficile Infection (CDI) Therapy Methods This observational study used the CHARM database, which contains outpatient encounter data extracted from the medical records of nine health systems. Patients with CDI were identified using ICD-10 codes and medications commonly used for CDI. The data period was between July 2019 and June 2023. The frequency and duration of antibiotics used for CDI treatment and the percentage of patients receiving subsequent therapy were estimated. Antibiotics prescribed within 180 days prior to a diagnosis of CDI visit were captured.Figure 1:Duration Distribution of Initial Clostridioides difficile Infection (CDI) Therapy Results A total of 551 patients with CDI were identified. Of those, 439 (80%) received vancomycin, 80 (15%) received fidaxomicin, and 52 (9%) received metronidazole. The average duration of therapy in days for vancomycin, fidaxomicin, and metronidazole was 12, 8, and 10, respectively (Table 1). The most common duration of therapy was 7-days for vancomycin (46%), fidaxomicin (41%), and metronidazole (50%) (Figure 1). After the initial treatment, 4% received a subsequent treatment within 3 weeks. Fluoroquinolone prescriptions had the highest prevalence of CDI (3.6 cases per 10,000 prescriptions). Of patients with an identified antibiotic 30 days prior to CDI, 38% had multiple courses of antibiotics. Conclusion Receiving multiple courses of antibiotics is associated with developing CDI. The majority of patients with CDI received vancomycin treatment (the alternative recommended therapy). The average duration of therapy was longer than recommended. Metronidazole use is still common. Disclosures Minji Sohn, PhD, Emergent BioSolutions, Inc.: Grant/Research Support

P-1763. Implementation of a Pharmacy-based Automated MRSA PCR Screening Intervention to Guide Discontinuation of Vancomycin for Pneumonia

Abstract Background Vancomycin is administered for suspected methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in hospital settings, but is also associated with adverse effects, emergence of resistance, and requires lab and pharmacy monitoring. MRSA nares screening has excellent negative predictive value for MRSA pneumonia and results faster than culture. We sought to decrease vancomycin overuse by identifying patients at low risk for MRSA pneumonia using rapid polymerase chain reaction (PCR) as part of an automated pharmacy-based intervention. Methods We performed a retrospective cohort study of inpatients prescribed vancomycin for pneumonia at University Hospitals Cleveland Medical Center from November to May 2022 (pre-intervention) and November 2022 to May 2023 (post-intervention). In June 2022, we implemented a rapid MRSA PCR screen that was automatically added to orders when vancomycin was ordered for pneumonia. We compared median time to vancomycin discontinuation between the two groups. We performed a desirability of outcome ranking and response adjusted for duration of antibiotic risk (DOOR-RADAR) analysis, ranking patients according to duration of therapy within clinical categories to assess the effect of the intervention on patient-centered outcomes. Results We identified 127 pre-intervention and 125 post-intervention patients (Table 1). Median vancomycin order to discontinue time was lower in post-intervention patients, though this was meaningfully different only for patients whose PCR test was collected after the automated order was placed (41.75 vs 55 hours respectively, p = 0.035) (Table 2). Most patients in the post-intervention group with vancomycin duration &amp;gt;48 hours had delayed collection or were treated for other infections (Figure 1). The DOOR ranks for median time to discontinuation within clinical outcome categories were not meaningfully different between the two groups (p &amp;gt;0.05) (Table 2 and Figure 2) which may relate to sample size. Conclusion Vancomycin treatment duration was shorter in patients after a pharmacy-based automated MRSA PCR screening intervention when implemented efficiently. This research will guide future interventions including pairing automated rapid testing with active stewardship response. Disclosures Elie Saade, MD, MPH, FIDSA, Janssen Global Services: Advisor/Consultant|Janssen Global Services: Advisor/Consultant|Janssen Research and Development: Advisor/Consultant|Janssen Research and Development: Advisor/Consultant Lisa M, Stempak, MD, Cytovale Inc.: Advisor/Consultant

P-307. Antibiotic Exposure and Community Resilience Shape Colonization Resistance to Vancomycin-Resistant Enterococci: Effects of Prior Antiboitics on Colonization Re-emergence

Abstract Background For life-threatening healthcare-associated vancomycin-resistant enterococci (VRE), gut colonization is a prerequisite for infection and is not predicted by prior Vancomycin treatment, indicating other selective forces are important. Host characteristics, strain variation and other microbial selective forces determine whether a patient's microbiome resists or permits VRE colonization. Methods Two preclinical models study VRE colonization resistance using fluorescently labeled clinical VRE strains. First, human microbiome stool communities were anaerobically cultivated in defined media, resulted in reproducible complex communities retaining 72-89% of microbial members. They are challenged with clinical VRE strains (10^3 cfu) to assess microbiome's role in resistance. Second, BL6 mice were pre-treated with PO Vancomycin, IP Cefepime+ IP Vancomycin, IP Meropenem, IP Pipercillin/Tazobactam, PO Metronidazole, or PO Clindamycin for one week. Post-treatment, they are inoculated with clinical VRE and clearance time was monitored. After a week without VRE detection in stool culture and by FACs, mice resume PO Vancomycin to observe re-emergence. Results When complex human stool cultivated microbiomes are exposed to clinical VRE strains, some prevent colonization while others facilitate it. Intriguingly, both the VRE strain and the community composition influence colonization (fig 1). In mice treated with anaerobic-active antibiotics, consistent VRE colonization occured. However, duration varied significantly (e.g. PO Vancomycin cleared in 14-22 days, IP Pipercillin/Tazobactam in 20-54 days). After VRE clearance, re-challenge with antibiotics lead to VRE re-emergence in all previously colonized animals. Conclusion Within human microbiome communities there is redundancy and variation in the members that can create a bacterial community barrier to VRE colonization. In mice, previous antibiotic use affects both how long VRE colonizes and its likelihood of returning after further disturbance. This may explain varying findings in studies on factors influencing MDRO colonization. Disclosures Ellie Margolis, MD PhD, ICLR: Stocks/Bonds (Private Company)

Impact of vancomycin area under the curve in early or later phase on efficacy and nephrotoxicity in patients with enterococcal bloodstream infections: a multicenter study

BackgroundThe optimal pharmacokinetic and pharmacodynamic (PK/PD) parameters of vancomycin that can improve outcomes in enterococcal infections remain controversial. To clarify the therapeutic target for this antibiotic, this study aimed to determine vancomycin PK/PD parameters associated with efficacy in the early (during 72 h) or later (after 72 h) phase of treatment and nephrotoxicity in enterococcal bloodstream infection patients.MethodsThis multicenter retrospective study reviewed medical records of patients with enterococcal bloodstream infections treated with intravenous vancomycin infusion for at least 72 h between January 2016 and March 2024 at Phramongkutklao Hospital or Nopparatrajathanee Hospital in Bangkok, and Rachaburi Hospital in Rachaburi Province, Thailand. Patients with data available on serum vancomycin concentration were analyzed. The primary outcomes were 30-day mortality and acute kidney injury. The estimates of the mean 24-h area under the curve in the first 72 h (AUC24) and in steady state (AUCss) were determined by Bayesian theorem.ResultsOverall, 201 vancomycin concentrations were measured within the first 72 h after vancomycin treatment, while 156 were in a steady state (> 72 h). According to Classification and Regression Tree analysis, vancomycin AUC at 420 mg·h/l was the PK/PD target for 30-day mortality. Results reveal that patients with AUC24 (early phase) and AUCss < 420 mg·h/l (later phase) had significantly higher 14-day, 30-day, and in-hospital mortality than AUC ≥ 420 mg·h/l groups. In addition, patients with AUC24 ≥ 420 mg·h/l in the early phase had significantly reduced microbiological failure (p = 0.004). Patients with AUC ≥ 700 mg·h/l in early and later phases had significantly increased acute kidney injury risk. In addition, patients receiving concomitant nephrotoxic drugs had an AUC cutoff value of 650 mg·h/l. Multivariate Cox regression analysis showed that vancomycin AUCss < 420 mg·h/l, unknown source of bacteremia, and acute kidney injury were significantly associated with 30-day mortality.ConclusionsAUC 420–650 mg·h/l in early and later phases was the target of vancomycin’s PK/PD in enterococcal bacteremia patients for efficacy and to prevent acute kidney injury. This study suggests close monitoring of vancomycin levels to ensure efficacy and safety.

Borrelia burgdorferi tolerates alteration to P66 porin function in a murine infectivity model.

Borrelia burgdorferi exists in a complex enzootic life cycle requiring differential gene regulation. P66, a porin and adhesin, is upregulated and essential during mammalian infection, but is not produced or required within the tick vector. We sought to determine whether the porin function of P66 is essential for infection. Vancomycin treatment of B. burgdorferi cultures was used to screen for P66 porin function and found to generate spontaneous mutations in p66 (bb0603). Three novel, spontaneous, missense P66 mutants (G175V, T176M, and G584R) were re-created by site-directed mutagenesis in an infectious strain background and tested for infectivity in mice by ID50 experiments. Two of the three mutants retained infectivity comparable to the isogenic control, suggesting that B. burgdorferi can tolerate alteration to P66 porin function during infection. The third mutant exhibited highly attenuated infectivity and produced low levels of P66 protein. Interestingly, four isolates that were recovered for p66 sequencing from mouse tissues revealed novel secondary point mutations in genomic p66. However, these secondary mutations did not rescue P66 porin function. New structural modeling of P66 is presented and consistent with these experimental results. This is the first work to assess the contribution of P66 porin function to B. burgdorferi pathogenesis.

Oral vancomycin treatment alters levels of indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes during EAE.

Astrocytes play important roles in the central nervous system (CNS) during health and disease. Prior studies have shown that gut commensals derived indole derivatives as well as secondary bile acids modulate astrocyte function during the late stage of EAE (recovery phase). Here we show that administering vancomycin to mice starting during the early stage of EAE improved disease recovery, an effect that is mediated by the gut microbiota. We observed that 6 taxa within the Clostridia vadin BB60 group were enriched in vancomycin treated mice compared to untreated EAE mice. Vancomycin-treated EAE mice also had elevated serum levels of the anti-inflammatory tryptophan derived metabolite, indole-3-lactic acid and decreased levels of deoxycholic acid, a pro-inflammatory secondary bile acid. RNA sequencing revealed altered expression of several genes belonging to the mammalian target of rapamycin (mTOR) pathway in astrocytes obtained during the late stage of EAE from vancomycin treated EAE mice. Furthermore, we observed a link between serum levels of indole derivatives and bile acids and expression of several genes belonging to the mTOR pathway. Interestingly, the mTOR signaling cascades have been implicated in several key biological processes including innate (e.g., astrocyte) immune responses as well as neuronal toxicity/degeneration. In addition, rapamycin, a specific inhibitor of mTOR, has been shown to inhibit the induction and progression of established EAE. Collectively, our findings suggest that the neuroprotective effect of vancomycin is at least partially mediated by indole derivatives and secondary bile acids modulating the expression of mTOR pathway genes in astrocytes.

Sesamin targets ClpP which attenuates virulence of S. aureus and protects mice from fatal pneumonia induced by MRSA.

The aim of this study was to identify sesamin as a Casein hydrolase P (ClpP) inhibitor and to determine whether it could attenuate the virulence of methicillin-resistant Staphylococcus aureus (MRSA). Through fluorescence resonance energy transfer (FRET) screening, a natural compound sesamin demonstrated a significant inhibitory effect on ClpP enzyme activity with an IC50 of 20.62μg/mL. Sesamin suppressed the expression of virulence factors of MRSA such as α-hemolysin (Hla) and Panton-Valentine leucocidin (PVL) by protein immunoblotting. Thermal shift assay (TSA) and cellular thermal shift assay (CETSA) showed that sesamin could bind to ClpP and enhance the thermal stability of ClpP. Furthermore, the binding affinity between sesamin and ClpP was determined by surface plasmon resonance (SPR) with a KD value of 7.18×10-6M. Molecular docking, dynamics simulations and point mutation analysis confirmed the stability of the sesamin-ClpP complex with a -10.184kcal/mol total binding energy and identified PHE-174 in ClpP as a key binding site. In mice pneumonia model, sesamin combined vancomycin treatment markedly reduced the pathogenicity of MRSA-infected mice, offering protection against fatal lung infections. Overall, these findings validate sesamin as a promising compound that targets ClpP, reducing virulence factor expression, that holds potential as a hit compound against MRSA infections.

Phage-Encoded Virulence Factor, Gp05, Alters Membrane Phospholipids and Reduces Antimicrobial Susceptibility in Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading pathogen causing severe endovascular infections. The prophage-encoded protein Gp05 has been identified as a critical virulence factor that contributes to MRSA persistence during vancomycin (VAN) treatment in an experimental endocarditis model. However, the underlining mechanisms driving this persistence phenotype remain poorly understood. The current study aimed to elucidate the genetic factors contributing to Gp05-associated MRSA persistence by utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate (PB 300-169), its isogenic chromosomal gp05 deletion mutant, and gp05-complemented strains. RNA-seq analysis revealed significantly downregulation of the graSR-vraFG regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. Notably, this downregulation led to a substantial shift in cell membrane composition, with a marked increase in negatively charged phosphatidylglycerol (PG) and a concomitant decrease in positively charged lysyl-PG (LPG). These changes in membrane lipid composition resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, polymorphonuclear neutrophil (PMN) and VAN. Similar findings were observed in an isogenic gp05 overexpression strain set with different genetic background (MRSA USA300 JE2). These findings suggest that Gp05 plays a pivotal role in MRSA persistence by modulating cell surface components and surface charge. This study provides new insights into the molecular mechanisms underlying Gp05-mediated persistence in MRSA endovascular infections and highlights potential therapeutic targets to combat persistent MRSA infections.

Efficacy of Cefiderocol Against Endophthalmitis Isolates.

Background/Objectives: Endophthalmitis is an intraocular microbial infection that can lead to permanent blindness, even with prompt anti-microbial therapy. Multi-drug-resistant organisms are on the rise, potentially limiting the efficacy of current empiric antibiotic therapies of intravitreal ceftazidime and vancomycin. Cefiderocol is a recent FDA- and EMA-approved antibiotic for multi-drug-resistant Gram-negative bacteria. Methods: To better understand its potential utility in the treatment of ocular infections, the MIC of cefiderocol was compared to ceftazidime and amikacin in endophthalmitis bacterial isolates using Epsilometer testing. Because vancomycin is commonly given concomitantly as part of empiric endophthalmitis treatment, possible synergistic and antagonistic effects of concomitant vancomycin and cefiderocol were also evaluated. Results: Cefiderocol was found to have lower MIC values compared to ceftazidime for Pseudomonadales or Enterobacterales species. When comparing the MICs of cefiderocol and vancomycin, there appeared to be no antagonism between the two antibiotics. Conclusions: This is the first report exploring the use of cefiderocol in endophthalmitis strains. The results of this study show this is a promising antibiotic for multi-drug-resistant Gram-negative organisms but further research is needed to investigate its intraocular safety profile.

Use of vancomycin and acute kidney injury in critically ill patients with sepsis or septic shock: A retrospective observational cohort study.

The independent association of vancomycin with Acute Kidney Injury (AKI) in the critically ill patient with sepsis or septic Shock is controversial. The aim of this study was to evaluate the incidence of AKI in a cohort of patients with sepsis or septic Shock with an adequate and strict monitoring of vancomycin, guided by the area under the concentration-time curve in relation to the minimum inhibitory concentration (AUC/MIC ratio). Retrospective cohort study on 106 patients admitted to the ICU with a diagnosis of sepsis or septic shock with vancomycin treatment, consecutively from January 2017 to December 2019. AKI was defined according to Kidney Disease Improving Global Outcomes criteria. Risk factors associated with AKI were determined by multivariable logistic regression analysis. In our cohort, 28 patients out of 106 (26%) developed AKI. ICU and 30-day mortality were 18% and 22%, respectively. After multivariable logistic regression adjusted analysis, chronic liver disease was associated with AKI. In our retrospective cohort study on critical patients with sepsis and septic shock, treated with vancomycin adjusting the dose guided by a pharmacokinetic/pharmacodynamic monitoring to achieve the target AUC0-24/CMI ratio, the incidence of AKI was 26%.

Treatment of Periprosthetic Joint Infection with Intravenous Vancomycin: Do We Hit the Target?

Background/objectives: Vancomycin is commonly used in the treatment of periprosthetic joint infection (PJI), and trough concentrations are measured to ascertain that they are within the therapeutic range. It has not been investigated what proportion of vancomycin concentrations during treatment of PJI patients is accurately within this range, how many dose adjustments are commonly needed, and which patient factors predispose towards aberrations from the desired range. Method: In this single-center cohort study, we investigated vancomycin trough concentrations in 108 patients with surgically treated PJI who received IV administered vancomycin treatment post-operatively. Patients were identified in our local arthroplasty register, and data beyond what was available in the register were collected from electronic medical charts. Results: Of the final study cohort, 41% were women, and the median age was 71 (IQR 63–79) years. Most patients had PJI of the hip (73%), the majority (54%) underwent a debridement, antibiotics and implant retention (DAIR) procedure prior to vancomycin treatment, and 39% received vancomycin-loaded bone cement during the preceding revision procedure. Of 791 vancomycin trough measurements, only 58.2% were within the target range of 15–20 mg/L, 18.5% were below, and 23.4% were above. A total of 71% of all patients required at least one dose adjustment, and the median length of vancomycin treatment was 8 days. We observed positive correlations of vancomycin trough concentrations with both age (Spearman’s rho = 0.35, p &lt; 0.001) and pre-treatment creatinine concentrations (Spearman’s rho = 0.34, p &lt; 0.001), but no statistically significant difference between patients who had received vancomycin-loaded bone cement and those who had not. Conclusions: In our PJI patients, a high proportion of vancomycin trough concentrations were outside the therapeutic range, despite adherence to local and national guidelines. We can also confirm that caution needs to be exerted in patients of advanced age and those with compromised kidney function. Alternative broad-spectrum antibiotics that do not require as extensive therapeutic drug monitoring should be further explored.

Clostridium Scindens Protects Against Vancomycin-Induced Cholestasis and Liver Fibrosis by Activating Intestinal FXR-FGF15/19 Signaling.

Primary sclerosing cholangitis (PSC) is characterized by abnormal bile acid metabolites and altered gut microbiota, with no effective treatments available. Vancomycin, a glycopeptide antibiotic, has emerged as a promising candidate. However, the mechanism by which vancomycin impacts the progression of PSC remains unknown. Mice treated with vancomycin exhibit increased hepatic collagen deposition and injury, due to the inhibition of intestinal FXR-FGF15/19 axis and the elevation of bile acid levels. These effects are associated with the reduction in Clostridia XIVa, especially Clostridium scindens (C. scindens). Gavage of C. scindens alleviates vancomycin-induced bile acid accumulation and liver fibrosis via activating intestinal FXR-FGF15/19 signaling. Similar effects are observed in mice treated with engineered Escherichia coli Nissle 1917 that are capable of expressing bile acid 7α-dehydratas (BaiE) from C. scindens (EcN-BaiE). Activating intestinal FXR-FGF15/19 signaling by fexaramine (Fex) or recombinant protein FGF19 reverse vancomycin-induced liver injury and fibrosis. These results demonstrate that long-term oral vancomycin exacerbates cholestatic liver injury, while C. scindens mitigates this effect by activating the intestinal FXR-FGF15/19 signaling pathway. This underscores the importance of monitoring bile acid levels in PSC patients receiving vancomycin treatment and suggests that C. scindens may serve as a potential therapeutic approach for PSC patients.

Open label vancomycin in primary sclerosing cholangitis-inflammatory bowel disease: improved colonic disease activity and associations with changes in host-microbiome-metabolomic signatures.

We conducted a single-arm interventional study, to explore mucosal changes associated with clinical remission under oral vancomycin (OV) treatment, in primary sclerosing cholangitis associated inflammatory bowel disease (PSC-IBD); NCT05376228. Fifteen patients with PSC and active colitis (median faecal calprotectin 459µg/g; median total Mayo score 5) were treated with OV (125mg QID) for 4 weeks and followed-up for a further 4 weeks of treatment withdrawal (8 weeks, end-of-study). Colonic biopsies were obtained at baseline and week 4. Clinical assessments, and serum and stool samples (metagenomics, metatranscriptomics and metabolomics) were collected at weeks 0, 2, 4 and 8. The primary efficacy outcome measure was induction of clinical remission. OV resulted in clinical remission in 12/15 patients and significant reductions in faecal calprotectin. OV was associated with reduced abundances of Lachnospiraceae, genera Blautia and Bacteroides; and enrichment of Enterobacteriaceae, and genera Veillonella, Akkermansia and Escherichia. OV treatment was associated with downregulation of multiple metatranscriptomic pathways (including short chain fatty acid [SCFA] metabolism and bile acid [BA] biotransformation), along with host genes and multiple pathways involved in inflammatory responses and antimicrobial defence; and an upregulation of genes associated with extracellular matrix repair. OV use resulted in loss of specific faecal SCFAs and secondary BAs, including lithocholic acid derivatives. Colitis activity relapsed following OV withdrawal, with host mucosal and microbial changes trending towards baseline. Four weeks of OV induces remission in PSC-IBD activity, associated with a reduction in gut bacterial diversity and compositional changes relating to BA and SCFA homeostasis.

Utilizing deep learning-based causal inference to explore vancomycin's impact on continuous kidney replacement therapy necessity in blood culture-positive intensive care unit patients.

Patients with positive blood cultures in the intensive care unit (ICU) are at high risk for septic acute kidney injury requiring continuous kidney replacement therapy (CKRT), especially when treated with vancomycin. This study developed a machine learning model to predict CKRT and examined vancomycin's impact using deep learning-based causal inference. We analyzed ICU patients with positive blood cultures, utilizing the Medical Information Mart for Intensive Care III data set. The primary outcome was defined as the initiation of CKRT during the ICU stay. The machine learning models were developed to predict the outcome. The deep learning-based causal inference model was utilized to quantitatively demonstrate the impact of vancomycin on the probability of CKRT initiation. Logistic regression was performed to analyze the relationship between the variables and the susceptibility of vancomycin. A total of 1,318 patients were included in the analysis, with 41 requiring CKRT. The Random Forest and Light Gradient Boosting Machine exhibited the best performance, with Area Under Curve of Receiver Operating Characteristic Curve values of 0.905 and 0.886, respectively. The deep learning-based causal inference model demonstrated an average 7.7% increase in the probability of CKRT occurrence when administrating vancomycin in total data set. Additionally, that younger age, lower diastolic blood pressure, higher heart rate, higher baseline creatinine, and lower bicarbonate levels sensitized the probability of CKRT application in response to vancomycin treatment. Deep learning-based causal inference models showed that vancomycin administration increases CKRT risk, identifying specific patient characteristics associated with higher susceptibility.IMPORTANCEThis study assesses the impact of vancomycin on the risk of continuous kidney replacement therapy (CKRT) in intensive care unit (ICU) patients with blood culture-positive infections. Utilizing deep learning-based causal inference and machine learning models, the research quantifies how vancomycin administration increases CKRT risk by an average of 7.7%. Key variables influencing susceptibility include baseline creatinine, diastolic blood pressure, heart rate, and bicarbonate levels. These findings offer insights into managing vancomycin-induced kidney risk and may inform patient-specific treatment strategies in ICU settings.

Methicillin-Resistant Staphylococcus aureus Nasal Screening With Polymerase Chain Reaction for Early De-escalation of Empiric Vancomycin in the Treatment of Suspected/Confirmed Respiratory Infection in Critically Ill Patients.

Vancomycin empirically for methicillin-resistant Staphylococcus aureus (MRSA) pneumonia coverage often is prolonged. With high negative predictive value for MRSA pneumonia, we evaluated the efficacy of MRSA nasal screening with polymerase chain reaction for early de-escalation of empiric vancomycin for treatment of respiratory infections in patients admitted to the intensive care units. The impact of MRSA nasal screening on early de-escalation of vancomycin for respiratory infections. A retrospective, single-center cohort study was conducted to evaluate the outcomes of vancomycin therapy in patients admitted to the intensive care units with diagnosis of pneumonia before (control group) and after (study group) implementation of MRSA nasal screening. The primary end point was the difference in duration of vancomycin drug therapy in patients with suspected/confirmed pneumonia between the control and study groups. Secondary end points included the number of vancomycin trough levels obtained, discordance between polymerase chain reaction and sputum culture results, and clinical outcomes. In total, 123 patients (control: n = 76; study: n = 47) were included. The median vancomycin duration in the control group and the study group was 73.3 hours (54.3-110.6) and 30.2 hours (20.3-39.7), respectively, P < 0.0001. The control group had 2.73 times (95% CI: 2.15-3.45, P < 0.0001) longer vancomycin duration than the study group. There was a significant difference in the number of trough levels obtained between the 2 groups. The median in the control and study groups were 1 (1-3) and 1 (0-1), respectively, P < 0.0001. There was no difference between groups for length of stay, 30-day readmission for MRSA infection, reinitiation of anti-MRSA therapy for infection, vancomycin-resistant enterococci infection within 30 days, acute kidney injury, and in-hospital all-cause mortality. The implementation of a MRSA nasal screening for critically ill patients treated with vancomycin for pneumonia resulted in a significantly shorter duration of vancomycin treatment without negatively affecting patient outcomes.

Clostridium difficile Bacteremia in an Elderly Patient with Multiple Comorbidities: A Case Report.

Clostridium difficile (C. difficile) stands as a primary cause of health-care-associated colitis in adults; however, extraintestinal manifestations of C. difficile, particularly bacteremia, are exceptionally rare. In this report, we document a case of an elderly male with multiple comorbidities who presented with an acute onset of fever. Diagnostic testing revealed the presence of concurrent bacteremia involving C. difficile and Klebsiella pneumonia. The multilocus sequence typing analysis identified this C. difficile strain as ST81. After receiving a combination treatment of vancomycin and biapenem, the patient successfully recovered and was subsequently discharged. This case report elucidates the clinical presentation and treatment strategies for C. difficile ST81 bacteremia, underscoring the critical need for heightened monitoring of extraintestinal infections in high-risk patients.