Vancomycin Dosing Research Articles

1112. Vancomycin Nephrotoxicity Relative to Alternative Antibiotic Treatments: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

BackgroundVancomycin is one of the most frequently prescribed antibiotics. Existing clinical evidence on vancomycin nephrotoxicity is limited to observational studies which are prone to confounding and bias. The purpose of this systematic review and meta-analysis is to compare acute kidney injury between vancomycin and comparator anti-methicillin resistant Staphylococcus aureus (MRSA) antibiotics using randomized controlled trial (RCT) data.MethodsPubMed and Embase were searched for RCTs comparing intravenous vancomycin to other anti-MRSA antibiotics in adult patients, published from 1990 to January 2021. Studies were included if they reported comparative data on renal outcomes. The primary outcome was change in renal function, referred to as ‘nephrotoxicity’ in this study. Studies where another known nephrotoxic medication was part of study therapy in any treatment group were excluded. Eighteen studies met the inclusion criteria, and two independent reviewers assessed the risk of bias. Data on nephrotoxicity definition, comparator drug, infection type, vancomycin dosing strategy, duration of treatment, and concurrent gram-negative coverage were extracted. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Figure 1. Flow chart of article selection.ResultsOf 1,426 studies identified, 18 encompassing 8,966 patients were included. Treatment with vancomycin was associated with significantly increased odds of nephrotoxicity (OR, 2.41; 95% CI, 1.71 to 3.40; P< 0.00001) relative to its alternatives. A subgroup analysis grouping studies by reported vancomycin dosing approach revealed a stronger association between vancomycin and nephrotoxicity in studies with fixed-dose vancomycin regimens (OR 5.31; 95% CI 1.93 to 14.56; P=0.001) relative to studies with vancomycin therapeutic drug monitoring (TDM) (OR 2.17; 95% CI 1.51 to 3.13; P< 0.0001). Figure 2. Forest plot indicating the risk of nephrotoxicity associated with vancomycin vs. comparators. Odds ratios (ORs) and 95% confidence intervals (95% CIs) are shown for each study and the pooled analysis using a random effects model and the Mantel-Haenszel method. OR>1 means that the risk of kidney injury in the vancomycin group is greater than that in the comparator group.Figure 3. Forest plot indicating a strong association between vancomycin and nephrotoxicity in studies with fixed-dose vancomycin regimens relative to studies with vancomycin therapeutic drug monitoring (TDM). Odds ratios (ORs) and 95% confidence intervals (95% CIs) are shown for each study and the pooled analysis using a random effects model and the Mantel-Haenszel method. OR>1 means that the risk of kidney injury in the vancomycin group is greater than that in the comparator group.Table 1. Summary of included studies. ConclusionThis analysis shows that intravenous vancomycin is associated with greater odds of renal toxicity relative to alternative antibiotics. This effect was not as pronounced in studies where vancomycin TDM was used potentially indicating benefit of TDM although further study is required to confirm this.Disclosures All Authors: No reported disclosures

602. Intravenous Push Versus Intravenous Piggyback Administration of Cephalosporin Antibiotics: Impact on Safety, Workflow, and Cost

BackgroundIV piggyback (IVPB) infusion has been the standard method of administration of IV antibiotics since the 1970s. Literature has demonstrated that the IV push (IVP) method has similar pharmacokinetic exposures and risk for complications as short infusion IVPB, and may have potential benefits. The primary objective is to evaluate the incidence of infusion-related complications in patients receiving cefazolin, ceftriaxone, and cefepime administered via IVP versus short infusion IVPB at the Veteran Affairs Long Beach Healthcare System. The secondary objectives include evaluating the time-to-onset of complications, time-to-first-dose combination vancomycin in the emergency department (ED), cost, and nursing and pharmacy staff preference between IVP and IVPB.MethodsThis is a retrospective, single-center cohort study. Patients who received ceftriaxone, cefepime, or cefazolin between April 1st, 2019 – December 31st, 2019, and April 1st, 2020 – December 31st, 2020 were included. Patients who received the study antibiotics via IVPB during the IVP period were excluded. Statistical analyses were performed using the chi-square, fisher’s exact, Mann-Whitney U, and unpaired t-tests where appropriate. Complications associated with IVP or IVPB administration were assessed via chart review of electronic health records. Surveys to nursing and pharmacy staff were distributed using Microsoft Forms.Results366 treatment episodes were evaluated for 355 unique patients. Complications occurred in 13 out of 183 (7.1%) treatment episodes in the IVP group compared to 18 out of 183 (9.8%) treatment episodes in the IVPB group (P = 0.35). The median time to complications was 2 days for both groups. IVP cefepime and ceftriaxone reduced the median time-to-first-dose vancomycin in the ED by 25 minutes. The use of cefazolin, ceftriaxone, and cefepime as IVP yielded a quarterly cost savings of &38,890.04. 55% of nursing staff and 85% of pharmacy staff prefer IVP administration for cefazolin, ceftriaxone, and cefepime.ConclusionCefazolin, ceftriaxone, and cefepime given as IVP were observed to be as safe as IVPB while reducing time-to-first dose vancomycin in the ED and cost, and is the preferred method of administration among nursing and pharmacy staff.Disclosures All Authors: No reported disclosures

1108. Evaluation of Vancomycin Dosing in Adolescents

BackgroundPediatric vancomycin dosing varies based on age and renal function. Recent literature suggests previously recommended doses of 45-60 mg/kg/day may be insufficient to achieve an AUC:MIC ratio of 400-600 mg-hr/L and higher doses of at least 60 mg/kg/day may be required. However, data to guide dosing in adolescents is limited. MethodsA single-center, retrospective chart review of patients aged 12 to 18 years who received vancomycin and had therapeutic drug monitoring (TDM) performed between July 2017 to June 2020 were included. The primary endpoint was the median total daily dose (TDD) of vancomycin required to achieve therapeutic serum concentrations. Secondary endpoints were to characterize how factors such as age, weight, trough versus AUC monitoring, malignancy, and trauma may influence dosing. The safety endpoint was the development of acute kidney injury (AKI).Results130 vancomycin courses in 86 patients were included. Baseline characteristics are presented in Table 1. Of the 130 vancomycin courses, 50 courses (38%) achieved therapeutic serum concentrations at a median TDD of 49.8 mg/kg/day (IQR 42 – 59.4). This was not statistically different from the sub- or supra-therapeutic groups (p=0.22). Based on age, the median TDD for 12-14 year olds was higher at 60 mg/kg/day (IQR 45-78.8; n=14) than for 15-16 and 17-18 year olds [45.3 mg/kg/day (IQR 41.1-51; n=15), 48 mg/kg/day (IQR 42-52; n=21), respectively]. Obese patients needed a median TDD of 43.5 mg/kg/day vs at least 51 mg/kg/day in healthy and overweight patients. Finally, AUC guided dosing resulted in a slightly lower overall median TDD vs trough guided dosing (45.8 mg/kg/day vs 50.5 mg/kg/day). Additional dose requirements based on age, weight, TDM and other characteristics are presented in Table 2. Of the 15 patients who developed AKI per pRIFILE criteria, 2 were classified as injury and 3 as failure.Table 2. Total Daily Dose Course Analysis ConclusionTo achieve therapeutic levels, adolescents 12 to14 years old need higher empiric doses of 60 mg/kg/day compared to 45 mg/kg/day in 15 to 18 year olds. Obese patients, however, may require lower TDD than underweight, healthy, and overweight patients. Patients that receive AUC versus trough monitoring may also require lower TDD to achieve therapeutic concentrations. More data is needed to further evaluate our findings.Disclosures All Authors: No reported disclosures

64. Novel Biomarkers Improve Estimation of Vancomycin Clearance in Critically Ill Children

BackgroundThere are a paucity of robust population PK (popPK) models to inform vancomycin (VAN) dosing in critically ill children. The majority of published models incorporate peak/trough data and rely on flawed estimates of renal function. We sought to develop a popPK model for IV VAN in critically ill children utilizing novel plasma and urinary biomarkers.MethodsWe conducted a prospective observational study of critically ill children prescribed VAN for a suspected infection in the CHOP pediatric ICU. Children < 1 year of age and those receiving ECMO or CRRT were excluded. Five VAN samples were collected from a single dosing interval for each subject. Plasma biomarkers (creatinine [Cr], cystatin C [CysC], NGAL) and urinary biomarkers (CysC, NGAL, KIM-1, osteopontin) were collected the morning of PK sampling; urinary biomarkers were corrected for urine creatinine. Nonparametric popPK modeling was performed using Pmetrics. The impact of renal function (GFR) on VAN clearance (CL) was estimated first, comparing model performance with each biomarker (Cr and plasma CysC). The influence of age, sex, additional biomarkers, PIM3 score, and receipt of vasopressors as covariates was then assessed for relevant PK parameters.Results30 subjects completed the study. Median age was 10 years (range 1-17); 76% were male. The majority (90%) of children received VAN for suspected sepsis. PK sampling occurred at a median of 37.7 hours (range 24.6-94.8) into VAN treatment; 136 VAN samples were included. A 2-compartment model with fixed allometric scaling of 0.75 on clearances and 1 on volumes best described the data. CysC-based GFR as a covariate on VAN CL using the HOEK formula (GFR = -4.32 + (80.35/CysC)) resulted in the best model fit. Age and plasma NGAL were also informative on VAN CL in the final model (Figure 1). During model building, urinary NGAL was also associated with VAN CL (comparable to plasma NGAL) and outperformed Cr, although it was not retained in the final model.Figure 1. Final population PK model and parameter estimates. ConclusionPlasma CysC is a better renal function estimate than Cr to inform VAN clearance in critically ill children. Urinary and plasma NGAL also improved estimation of VAN CL during popPK modeling. Novel biomarkers can better describe VAN exposures in critically ill children than reliance on Cr alone.Disclosures Kevin J. Downes, MD, Merck (Individual(s) Involved: Self): Grant/Research Support Stuart L. Goldstein, MD, Bioporto (Consultant, Grant/Research Support)

1091. Validation of an Allometrically Scaled Body Weight Equation to Predict Vancomycin Clearance and Guide 24-Hour Vancomycin AUC Dosing in Obese Patients

BackgroundAccurately determining empiric vancomycin (VAN) doses in obese patients represents a clinical challenge. A recent population pharmacokinetic (PK) study provided an equation to estimate vancomycin clearance (CL) based on age, sex, serum creatinine (Scr), and allometrically scaled body weight. The purpose of this study was to validate this equation in a population of obese adults treated with vancomycin at eight community-based hospitals and use the CL estimate to guide empiric VAN dosing. MethodsThe study period was November 1, 2020 and March 30, 2021. Patients were included if they were ≥ 18-year-old with a body mass index (BMI) ≥ 30 kg/m2, had an empiric dose targeting an AUC24 determined using the above referenced equation, and had a calculated AUC24. Only the first vancomycin course and AUC calculation for each patient were included. Patients with a creatinine clearance < 30ml/min and pregnant women were excluded. AUC24 and other PK parameters were calculated using two levels and noncompartmental analysis. Observed versus predicted CL and AUC24 were plotted to determine correlation. ResultsSixty patients were included, of which 60% were male and 33% had a confirmed methicillin-resistant Staphylococcus aureus infection. The mean age, BMI, and baseline Scr were 61.8 years, 37.8 kg/m2, and 0.99 mg/dL, respectively. Fifty-three (88%) patients received a loading dose, with a mean dose of 20.3mg/kg. The mean initial total daily maintenance dose was 2397.9mg. The mean predicted AUC24 was 476.4mg*h/L while the mean observed AUC24 was 556.3mg*h/L. For CL, the correlation between observed and predicted values was R2=0.38 (Figure 1). The correlation between predicted and observed AUC24 values was R2=0.08 (Figure 2). The percent of patients with observed AUC24 values of < 400mg*h/L, 400-600mg*h/L, and >600mg*h/L were 23%, 40%, and 37%, respectively. The relationship between calculated minimum concentrations (Cmin) and AUC24 is shown in Figure 3. 65% of patients with a therapeutic AUC achieved it with a Cmin < 15mg/L while 4.5% of patients with a supratherapeutic AUC had a Cmin < 15mg/L. Figure 1. Observed versus Predicted Clearance (CL) of Vancomycin Figure 2. Observered versus Predicted 24 hour Vancomycin Area Under the Curve (AUC24) Figure 3. Calculated 24 hour Vancomycin Area Under the Curve (AUC24) versus Calculated minimal concentration (Cmin) ConclusionThe correlation between observed and predicted CL was 0.38. Using these CL estimates to guide empiric VAN dosing resulted in only 40% of patients achieving a therapeutic AUC24. Disclosures All Authors: No reported disclosures

125. Dynamic PET facilitated Pharmacokinetic Modeling and High-dose Rifampin Regimens for Staphylococcus aureus Orthopedic Implant Associated Infections: Bench to Bedside

125. Dynamic PET facilitated Pharmacokinetic Modeling and High-dose Rifampin Regimens for <i>Staphylococcus aureus</i> Orthopedic Implant Associated Infections: Bench to Bedside

621. Identifying Quality-Improvement Interventions to Improve Inpatient Intravenous Vancomycin Safety at an Academic Medical Center

BackgroundThe reported incidence of intravenous (IV) vancomycin-associated acute kidney injury (AKI) is highly variable. The primary purpose of this study was to determine the baseline rate of IV vancomycin-associated AKI at the University of Utah Hospital (UUH) and Huntsman Cancer Institute (HCI) with the goal of identifying areas of focus for future quality improvement (QI) initiatives.MethodsThis was a retrospective descriptive study of patients ≥ 18 years old, hospitalized at UUH or HCI, who received at least daily scheduled doses of IV vancomycin for ≥ 72 hours between November 1, 2018 and October 31, 2019. AKI was defined using the serum creatinine (SCr) aspect of the AKIN criteria. Variables assessed for association with AKI included demographic characteristics, hospital and unit where vancomycin was initiated, duration of therapy, administration method, and concomitant nephrotoxic medications. Multivariable logistic regression was used to identify variables independently associated with AKI as potential QI interventions.ResultsOne thousand eighty-six patients were included. Baseline patient characteristics are listed in Table 1. Throughout our system, 19.7% of patients experienced an AKI while receiving vancomycin. Univariate comparisons are listed in Table 1. Variables independently associated with AKI on multivariable analysis included total body weight (HR 1.02, 95% CI [1.01-1.03]), concomitant administration of calcineurin inhibitors or vasopressors (HR 1.97, 95% CI [1.18-3.29] and HR 1.68, 85% CI [1.07-2.64] respectively), duration of vancomycin therapy (HR, 1.04, 95% CI [1.02-1.06]), and administration in specific units (see Table 1). Administration of vancomycin by continuous infusion showed a protective effect (HR 0.13, 95% CI [0.02-1.12]) as did baseline SCr and total daily dose of vancomycin (HR 0.76, 95% CI [0.61-0.94] and HR 0.63, 95% CI [0.51-0.78] respectively); the latter two are likely a reflection of the study design. The median hospital length of stay in days was longer in individuals experiencing an AKI (19 vs 10, p < 0.0001).Table 1. Univariate and Multivariate Associations with Vancomycin-Associated Acute Kidney Injury aFor continuous variables, the HR reported is for each unit increaseTable 1. (Continued) Univariate and Multivariate Associations with Vancomycin-Associated Acute Kidney Injury aFor continuous variables, the HR reported is for each unit increaseConclusionSeveral variables associated with vancomycin-associated AKI within our health system were identified. Future QI interventions to improve vancomycin safety will be pursued.Disclosures Russell J. Benefield, PharmD, Paratek Pharmaceuticals (Grant/Research Support)

38. Impact of Antimicrobial Stewardship Interventions on Adherence to Clostridioides difficile Treatment Guidelines

Abstract Background Facility-specific treatment guidelines are a priority intervention recommended in the CDC Core Elements of Hospital Antimicrobial Stewardship Programs (ASPs). Our ASP sought to improve adherence to the facility C. difficile infection (CDI) treatment guideline by implementing prospective audit and feedback of CDI cases, changing fidaxomicin from being restricted to Infectious Diseases consult use, to only requiring prospective audit and feedback, and allowing fidaxomicin and oral vancomycin orders only through the order set. This study reviews the impact of these interventions. Methods This single-center retrospective quasi-experimental study evaluated inpatient CDI lab events 3 months pre-intervention (10/1/2019-12/31/2019) and post-intervention (10/14/2020-1/14/2021). Patient and treatment data was evaluated via chart review. The primary outcome was adherence to CDI treatment guideline. ASP intervention types were categorized. Statistical analyses were performed using Chi-squared or Fischer’s exact, where appropriate. Results Baseline characteristics were well matched between the 58 and 70 patients pre and post intervention respectively (Table 1). ASP interventions resulting from the prospective audit and feedback are described in Table 2 and overall acceptance rates were high (88%). Guideline adherence improved significantly from 71% pre to 90% post-intervention (p=0.005). Reasons for non-adherence included vancomycin dose incorrect for the severity of illness (9 pre vs 2 post), inappropriate duration (4 pre vs 0 post), use of combination therapy in non-fulminant disease (5 pre vs 3 post), and not using fidaxomicin for recurrent disease (3 pre vs 2 post). Clinical outcomes pre and post intervention were not different in this small sample size: colectomy 1 (2%) vs 1 (1%) p=1, 60 day all- cause mortality 15 (26%) vs 14 (20%) p=0.43, and CDI recurrence at day 60 9/43 (21%) vs 5/56 (9%) p=0.131. Conclusion A bundle of ASP interventions including prospective audit and feedback of CDI cases improved adherence to facility-specific CDI treatment guidelines. Disclosures Tamara Krekel, PharmD, BCPS, BCIDP, Merck (Speaker’s Bureau) Erik R. Dubberke, MD, MSPH, Ferring (Grant/Research Support)Merck (Consultant)Pfizer (Consultant, Grant/Research Support)Seres (Consultant)Summit (Consultant)

1102. Evaluation of Vancomycin Accumulation in Patients with Obesity

BackgroundCurrent vancomycin guidelines recommend using actual body weight for dosing. However, in patients with obesity, this may result in lower initial vancomycin concentrations that can accumulate with continued doses due to differences in volume of distribution. The objective of this study is to evaluate the incidence of vancomycin accumulation in patients with obesity and identify potential factors associated with accumulation.MethodsThis is a single-center, retrospective, observational study at a tertiary academic medical center. Adult patients with a BMI ≥ 30 kg/m2 and with ≥ 2 vancomycin serum trough concentrations within the same encounter in 2019 were screened. Patients were excluded if they were pregnant, had unstable renal function or severe renal impairment, received < 3 doses before a concentration was drawn, or had inconsistent dosing prior to a concentration draw. Linear kinetics were used to correct for differences in timing of concentration or dose changes. The major endpoint was the incidence of vancomycin accumulation, defined as a 20% increase in trough concentration between the first and any subsequent trough concentrations within the first 10 days of therapy. Minor endpoints included the percentage of supratherapeutic concentrations and the incidence of acute kidney injury (AKI). Descriptive statistics were used to evaluate endpoints and multivariable logistic regression was used to evaluate factors associated with accumulation.ResultsWe screened 543 patients, and 162 were included in our analysis. The median age was 56.5 years (interquartile range [IQR] 43 - 65.3), and 62.3% were male. The median weight was 112.7 kg (IQR 99.8 - 122.6) and the median BMI was 36.8 kg/m2 (IQR 33.1 - 41). The median total daily vancomycin dose at initiation was 28.7 mg/kg/day (IQR 25.4 - 31.2). Vancomycin accumulation occurred in 99 patients (61.1%) within the first 10 days of therapy and AKI occurred in 21 patients (14.9%). No factors studied, including age, gender, obesity class, initial dose, SCr, or frequency were associated with accumulation.ConclusionMost patients with obesity experienced vancomycin accumulation within the first 10 days of therapy. Providers should be cautious when assessing a vancomycin concentration early in the treatment course.Disclosures All Authors: No reported disclosures

Exploring population pharmacokinetic models in patients treated with vancomycin during continuous venovenous haemodiafiltration (CVVHDF)

BackgroundTherapeutic antibiotic dose monitoring can be particularly challenging in septic patients requiring renal replacement therapy. Our aim was to conduct an exploratory population pharmacokinetic (PK) analysis on PK of vancomycin following intermittent infusion in critically ill patients receiving continuous venovenous haemodiafiltration (CVVHDF); focussing on the influence of dialysis-related covariates.MethodsThis was a retrospective single-centre tertiary level intensive care unit (ICU) study, which included patients treated concurrently with vancomycin and CVVHDF between January 2015 and July 2016. We extracted clinical, laboratory and dialysis data from the electronic healthcare record (EHR), using strict inclusion criteria. A population PK analysis was conducted with a one-compartment model using the PMetrics population PK modelling package. A base structural model was developed, with further analyses including clinical and dialysis-related data to improve model prediction through covariate inclusion. The final selected model simulated patient concentrations using probability of target attainment (PTA) plots to investigate the probability of different dosing regimens achieving target therapeutic concentrations.ResultsA total of 106 vancomycin dosing intervals (155 levels) in 24 patients were examined. An acceptable 1-compartment base model was produced (Plots of observed vs. population predicted concentrations (Obs–Pred) R2 = 0.78). No continuous covariates explored resulted in a clear improvement over the base model. Inclusion of anticoagulation modality and vasopressor use as categorical covariates resulted in similar PK parameter estimates, with a trend towards lower parameter estimate variability when using regional citrate anti-coagulation or without vasopressor use. Simulations using PTA plots suggested that a 2 g loading dose followed by 750 mg 12 hourly as maintenance dose, commencing 12 h after loading, is required to achieve adequate early target trough concentrations of at least 15 mg/L.ConclusionsPTA simulations suggest that acceptable trough vancomycin concentrations can be achieved early in treatment with a 2 g loading dose and maintenance dose of 750 mg 12 hourly for critically ill patients on CVVHDF.

Pharmacist-directed vancomycin therapeutic drug monitoring in pediatric patients: a collaborative-practice model

BackgroundTherapeutic drug monitoring (TDM) of Vancomycin (VCM) is required to prevent inappropriate dosage-associated bacterial resistance, therapeutic failure, and toxicities in pediatrics. Anecdotal experience and studies show that many healthcare institutions confront barriers while implementing TDM services, this study aimed to assess a pharmacist-directed VCM–TDM service for optimizing patient care in our institution.Materials and methodsPatients aged 1 month–18 years who received intravenous VCM were included in this quasi-experimental study. The pre-implementation phase (March–June 2018) consisted of retrospective assessment of pediatric patients, the interventional phase (July 2018 to February 2020) included educational programs and the post-implementation phase (March–June 2020) evaluated the participants based on pharmacist-directed VCM–TDM services as a collaborative-practice model including clinical and inpatient pharmacists to provide 24/7 TDM services. Outcomes of the study included the mean difference in the number of optimal (i) prescribed initial VCM doses (primary) (ii) dosage adjustments and (iii) VCM-sampling time (secondary). After ethical approval, data were collected retrospectively.ResultsA hundred patients were there in each phase. The number of cases who were correctly prescribed initial VCM doses was significantly higher in the post-implementation phase, mean difference of 0.22, [95% CI (0.142–0.0.358), p < 0.0001]. Patients who had correct dosage adjustments in the post-implementation phase also had higher statistical significance, mean difference of 0.29, [95% CI (0.152–0.423), p < 0.05]. More correct practices of VCM-levels timing were observed in the post-implementation phase, mean difference of 0.15, [95% CI (− 0.053–0.264), p = 0.079].ConclusionThis study showed the significant role of pharmacist-directed TDM services to optimize the correct prescribing of initial VCM doses and dose adjustments.

The relationship of vancomycin 24-hour AUC and trough concentration.

Prior to the 2020 release of a joint consensus guideline on monitoring of vancomycin therapy for serious methicillin-resistant Staphylococcus aureus (MRSA) infections, clinicians had escalated vancomycin doses for 2 decades while targeting trough concentrations of 15 to 20 µg/mL, leading to an increased frequency of nephrotoxicity. For MRSA infections, the 2020 guideline recommends adjusting doses to achieve a 24-hour area under the concentration-time curve (AUC) of 400 to 600 µg · h/mL; however, monitoring of trough concentrations has been entrenched for 3 decades. Calculating dose regimens based on AUC will require obtaining an increased number of vancomycin serum concentrations and, possibly, advanced software. The aim of this investigation was to determine the relationship between AUC and trough concentration and the influence of dosing regimen on goal achievement. The relationship between trough concentration and AUC was explored through derivation of an equation based on a 1-compartment model and simulations. 24-hour AUC is related to dosing interval divided by half-life in a nonlinear fashion. The target trough concentration can be individualized to achieve a desired AUC range, and limiting use of large doses (>15-20 mg/kg) can protect against excessive 24-hour AUC with trough-only monitoring. After initially determining pharmacokinetic parameters, subsequent monitoring of AUC can be accomplished using trough concentrations only. Trough concentration may be used as a surrogate for AUC, although the acceptable target trough concentration will vary depending on dosing interval and elimination rate constant. This work included development of an AUC-trough equation to establish a patient-specific target for steady-state trough concentration.

Optimised versus standard dosing of vancomycin in infants with Gram-positive sepsis (NeoVanc): a multicentre, randomised, open-label, phase 2b, non-inferiority trial

Vancomycin is the most widely used antibiotic for neonatal Gram-positive sepsis, but clinical outcome data of dosing strategies are scarce. The NeoVanc programme comprised extensive preclinical studies to inform a randomised controlled trial to assess optimised vancomycin dosing. We compared the efficacy of an optimised regimen to a standard regimen in infants with late onset sepsis that was known or suspected to be caused by Gram-positive microorganisms. NeoVanc was an open-label, multicentre, phase 2b, parallel-group, randomised, non-inferiority trial comparing the efficacy and toxicity of an optimised regimen of vancomycin to a standard regimen in infants aged 90 days or younger. Infants with at least three clinical or laboratory sepsis criteria or confirmed Gram-positive sepsis with at least one clinical or laboratory criterion were enrolled from 22 neonatal intensive care units in Greece, Italy, Estonia, Spain, and the UK. Infants were randomly assigned (1:1) to either the optimised regimen (25 mg/kg loading dose, followed by 15 mg/kg every 12 h or 8 h dependent on postmenstrual age, for 5 ± 1 days) or the standard regimen (no loading dose; 15 mg/kg every 24 h, 12 h, or 8 h dependent on postmenstrual age for 10 ± 2 days). Vancomycin was administered intravenously via 60 min infusion. Group allocation was not masked to local investigators or parents. The primary endpoint was success at the test of cure visit (10 ± 1 days after the end of actual vancomycin therapy) in the per-protocol population, where success was defined as the participant being alive at the test of cure visit, having a successful outcome at the end of actual vancomycin therapy, and not having a clinically or microbiologically significant relapse or new infection requiring antistaphylococcal antibiotics for more than 24 h within 10 days of the end of actual vancomycin therapy. The non-inferiority margin was -10%. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov (NCT02790996). Between March 3, 2017, and July 29, 2019, 242 infants were randomly assigned to the standard regimen group (n=122) or the optimised regimen group (n=120). Primary outcome data in the per-protocol population were available for 90 infants in the optimised group and 92 in the standard group. 64 (71%) of 90 infants in the optimised group and 73 (79%) of 92 in the standard group had success at test of cure visit; non-inferiority was not confirmed (adjusted risk difference -7% [95% CI -15 to 2]). Incomplete resolution of clinical or laboratory signs after 5 ± 1 days of vancomycin therapy was the main factor contributing to clinical failure in the optimised group. Abnormal hearing test results were recorded in 25 (30%) of 84 infants in the optimised group and 12 (15%) of 79 in the standard group (adjusted risk ratio 1·96 [95% CI 1·07 to 3·59], p=0·030). There were six vancomycin-related adverse events in the optimised group (one serious adverse event) and four in the standard group (two serious adverse events). 11 infants in the intention-to-treat population died (six [6%] of 102 infants in the optimised group and five [5%] of 98 in the standard group). In the largest neonatal vancomycin efficacy trial yet conducted, no clear clinical impact of a shorter duration of treatment with a loading dose was demonstrated. The use of the optimised regimen cannot be recommended because a potential hearing safety signal was identified; long-term follow-up is being done. These results emphasise the importance of robust clinical safety assessments of novel antibiotic dosing regimens in infants. EU Seventh Framework Programme for research, technological development and demonstration.

Did the severe acute respiratory syndrome-coronavirus 2 pandemic cause an endemic Clostridium difficile infection?

BACKGROUND Clostridium difficile infection (CDI) has increased in prevalence during the last years. The coronavirus disease 2019 (COVID-19) pandemic has negatively influenced patient outcomes. The majority of the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)-infected patients received antibiotics during hospitalization.AIMTo analyze the factors that influenced CDI development after SARS-CoV-2 infection. METHODSBetween March 2020 to December 2020, we performed a prospective observational study including 447 patients diagnosed with CDI who were admitted to our tertiary referral university hospital. The diagnosis of CDI was based on the presence of diarrhea (≥ 3 watery stools within 24 h) associated with Clostridium difficile toxins A or B. We excluded patients with other etiology of acute diarrhea.RESULTSAmong the total 447 (12.5%) patients with CDI, most were male (54.3%) and mean age was 59.7 ± 10.8 years. Seventy-six (17.0%) had history of COVID-19, most being elderly (COVID-19: 62.6 ± 14.6 years vs non-COVID-19: 56.8 ± 17.6 years, P = 0.007), with history of alcohol consumption (43.4% vs 29.4%, P = 0.017), previous hospitalizations (81.6% vs 54.9%, P < 0.001) and antibiotic treatments (60.5% vs 35.5%, P < 0.001), requiring higher doses of vancomycin and prone to recurrent disease (25.0% vs 13.1%, P = 0.011). Age over 60 years [odds ratio (OR): 2.591, 95% confidence interval (CI): 1.452-4.624, P = 0.001], urban residence (OR: 2.330, 95%CI: 1.286-4.221, P = 0.005), previous antibiotic treatments (OR: 1.909, 95%CI: 1.083-3.365, P = 0.025), previous hospitalizations (OR: 2.509, 95%CI: 1.263-4.986, P = 0.009) and alcohol consumption (OR: 2.550, 95%CI: 1.459-4.459, P = 0.001) were risk factors of CDI in COVID-19.CONCLUSIONCDI risk is unrelated to history of SARS-CoV-2 infection. However, previous COVID-19 may necessitate higher doses of vancomycin for CDI.

Index for the appropriate vancomycin dosing in premature neonates and infants.

BackgroundIn neonates, vancomycin (VCM) is used to treat Gram‐positive bacterial infections. However, VCM blood concentrations are affected by gestational age, bodyweight (BW), and renal function. The initial VCM dose adjustment can therefore be difficult, and few reports have evaluated this issue. In this study, we investigated the factors determining the appropriate VCM dosing schedule in neonates, especially premature infants.MethodsThe VCM dosage and trough concentrations were retrospectively investigated from the initial treatment to maintenance therapy in neonatal intensive care unit patients who underwent therapeutic drug monitoring. We examined the average single‐administration VCM dosage during maintenance therapy. We then compared the actual VCM dose with that calculated using an index comprising six items that influence the VCM daily dose (postnatal age, gestational age, BW, serum creatinine level, urine output, and lactate level).ResultsTwenty premature infants were included. The average BW of patients at the initial VCM administration was 975 g. During maintenance therapy, the average VCM dose was 8.4 mg/kg, and the median trough concentration was 12.4 μg/mL. When we applied the six‐item index, 18 of 20 patients (90%) had concordant results between the actual VCM dosing schedule and the VCM calculated using the index.ConclusionsThe average VCM dose and six‐item index can facilitate the transition from the initial VCM dose to an appropriate dose in many cases and contribute to early treatment in low‐birthweight infants with more variable BW, distribution volumes, and renal function. In conclusion, our six‐item index may help standardize VCM administration in premature infants.

Dosage, Efficacy, and Safety of Intra-articular Vancomycin for Prophylaxis of Periprosthetic Joint Infection Caused by Methicillin-Resistant Staphylococcus aureus after Total Knee Arthroplasty in a Rat Model.

Although intra-articular vancomycin powder (VP) is sometimes applied before the closure of the incision to prevent periprosthetic joint infection (PJI) after joint replacement, the dosage, efficacy, and safety remain controversial. This study aimed to explore the dosage, efficacy, and safety of intra-articular VP in the prophylaxis of infection after total knee arthroplasty (TKA) in a rat model. Sixty male rats were randomly divided into five groups after receiving TKA: control (no antibiotics); systemic vancomycin (SV) (intraperitoneal injection, 88 mg/kg of body weight, equal to 1 g in a patient weighing 70 kg); and VP0.5, VP1.0, and VP2.0 (44 mg/kg, 88 mg/kg and 176 mg/kg, respectively; intra-articular). All animals were inoculated in the knee with methicillin-resistant S. aureus (MRSA). General status, serum biomarkers, radiology, microbiological assay, and histopathological tests were assessed within 14 days postoperation. Compared with the control and SV groups, bacterial counts, knee width, tissue inflammation, and osteolysis were reduced in the VP0.5, VP1.0, and VP2.0 groups, without notable body weight loss and incision complications. Among all the VP groups, VP1.0 and VP2.0 groups presented superior outcomes with regard to knee width and tissue inflammation than the VP0.5 group. Microbial culture indicated that no MRSA survived in the knee of VP1.0 and VP2.0 groups, while bacteria growth was observed in the VP0.5 group. No obvious changes in the structure and functional biomarkers of liver and kidney were observed in either the SV or VP groups. Therefore, intra-articular vancomycin powder at a dosage from 88 mg/kg to 176 mg/kg may be effective and safe in preventing PJI induced by methicillin-resistant S. aureus in the rat TKA model.

Dose Optimization of Vancomycin for Critically Ill Patients Undergoing CVVH: A Prospective Population PK/PD Analysis

The optimal dose of vancomycin in critically ill patients receiving continuous venovenous hemofiltration (CVVH) remains unclear. The objective of this study was to identify factors that significantly affect pharmacokinetic profiles and to further investigate the optimal dosage regimens for critically ill patients undergoing CVVH based on population pharmacokinetics and pharmacodynamic analysis. A prospective population pharmacokinetic analysis was performed at the surgical intensive care unit in a level A tertiary hospital. We included 11 critically ill patients undergoing CVVH and receiving intravenous vancomycin. Serial blood samples were collected from each patient, with a total of 131 vancomycin concentrations analyzed. Nonlinear mixed effects models were developed using NONMEM software. Monte Carlo Simulation was used to optimize vancomycin dosage regimens. A two-compartment model with first-order elimination was sufficient to characterize vancomycin pharmacokinetics for CVVH patients. The population typical vancomycin clearance (CL) was 1.15 L/h and the central volume of distribution was 16.9 L. CL was significantly correlated with ultrafiltration rate (UFR) and albumin level. For patients with normal albumin and UFR between 20 and 35 mL/kg/h, the recommended dosage regimen was 10 mg/kg qd. When UFR was between 35 and 40 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. For patients with hypoalbuminemia and UFR between 20 and 25 mL/kg/h, the recommended dosage regimen was 5 mg/kg q8h. When UFR was between 25 and 40 mL/kg/h, the recommended dosage regimen was 10 mg/kg q12h. We recommend clinicians choosing the optimal initial vancomycin dosage regimens for critically ill patients undergoing CVVH based on these two covariates.

Variation in vancomycin dosing and therapeutic drug monitoring practices in neonatal intensive care units.

Background Vancomycin is a frequently used antibiotic in neonates. However, there is no consensus guideline on the optimal dosing regimen and therapeutic drug monitoring (TDM) practices in this patient population. Objective To document the variability in the current dosing and TDM practices in neonatal intensive care units (NICU). Setting Belgian and Dutch NICUs. Method An online questionnaire was disseminated by e-mail to potential respondents. Main outcome measure Differences in vancomycin dosing and TDM practices in comparison with a reference source, the Dutch Paediatric Formulary. Results Eighteen NICUs (response rate 62%) participated. Eleven different dosing regimens are applied, with 83% using intermittent dosing regimens. Stratifying covariates used to determine the (initial) dosage include gestational age, postnatal age, serum creatinine, concurrent use of non-steroidal anti-inflammatory drugs, birth weight and current weight. Large variability is observed with regard to TDM practice as well, both for the concentration target range and the times of (re)sampling. Dosing calculators are more commonly used in the Netherlands than Belgium. Conclusion Significant inter-centre variability in dosing and TDM practices was found. The development of international consensus guidelines is required to optimize therapy. Dosing calculators to guide dosing are not yet considered as part of standard-of-care.

A Multicenter Retrospective Study of Vancomycin Dosing by Weight Measures in Children.

Vancomycin carries risks of treatment failure and emergent resistance with underexposure and renal toxicity with overexposure. Children with overweight or obesity may have altered pharmacokinetics. We aimed to examine how body weight metrics influence vancomycin serum concentrations and to evaluate alternative dosing strategies. This was a multicenter retrospective cohort study across 3 large, academic hospitals. Patients aged 2 to 18 years old who received ≥3 doses of intravenous vancomycin were included. Weight metrics included total body weight, adjusted body weight, ideal body weight, body surface area, and allometric weight. Outcomes included vancomycin concentration and ratios of area under the curve (AUC) to minimum inhibitory concentration (MIC). Regression analyses were used to examine which body-weight identifier predicted outcomes. Of the 1099 children, 45% were girls, mean age was 9.0 (SD = 5.4) years, 14% had overweight, and 17% had obesity. Seventy-five percent of children had vancomycin concentrations in the subtherapeutic range by trough <10 µg/mL, and 63% had a ratio of AUC to MIC <400 μg-hr/mL. Three percent had a supratherapeutic initial trough >20 µg/mL or ratio of AUC to MIC >600 μg-hr/mL. Serum vancomycin concentrations were higher in children with overweight or obesity compared with children who were at a normal weight or underweight; the mean ratio of AUC to MIC also trended higher in the groups with overweight or obesity. Most children received vancomycin regimens that produced suboptimal trough levels. Children with overweight or obesity experienced higher vancomycin trough levels than children of normal weight despite receiving lower total body weight dosing. Using the ratio of AUC to MIC was a better measure of drug exposure.

Evaluation of intraperitoneal vancomycin in peritoneal dialysis-associated peritonitis.

Intraperitoneal (IP) vancomycin is recommended as one of the treatment options for gram-positive coverage in the management of peritoneal dialysis (PD)-associated peritonitis. There is a lack of literature supporting the optimal dose and approach to vancomycin therapeutic drug-level monitoring. A retrospective chart review was conducted using the BC Renal Agency PROMIS Database and our hospital records from 1 June 2011 to 1 July 2019. Adult patients with PD-associated peritonitis who received IP vancomycin and had at least one serum vancomycin level drawn were included. All patients received a loading dose of 30 mg/kg, which was repeated every 3-5 days depending on PD modality. Serum vancomycin levels were drawn prior to the second vancomycin dose, then at the discretion of the prescriber. The primary end point was the rate of therapeutic serum vancomycin levels ≥15 mg/L. Twenty-three episodes of PD-associated peritonitis in 20 patients met the eligibility criteria. Only 15/23 serum vancomycin levels were drawn appropriately after the first dose. Sixty per cent of these levels were subtherapeutic at <15 mg/L. All subsequent serum vancomycin levels were above the therapeutic target. Most peritonitis episodes (78%) achieved resolution of infection. Residual kidney function was not significantly correlated with serum vancomycin levels (p = 0.19). An IP vancomycin regimen of 30 mg/kg every 3-5 days resulted in subtherapeutic serum vancomycin levels in most patients following the loading dose but therapeutic levels thereafter. A large percentage of vancomycin levels were drawn inappropriately due to misalignment of outpatient follow-up visits and timing of blood work.