What Is the Best Vancomycin Therapeutic Drug Monitoring Parameter to Assess Efficacy? A Critical Review of Experimental Data and Assessment of the Need for Individual Patient Minimum Inhibitory Concentration Value.

Therapeutic drug monitoring is recommended for the use of vancomycin, but a recent widely publicized US medical society consensus statement has changed the suggested optimal method(s) of dose adjustment. Specifically, 24 h area under the curve (AUC24)-based monitoring is has been recommended for vancomycin in preference to monitoring of trough concentrations. One reason cited for this change is the claim that AUC24 is a superior correlate to efficacy than trough (Cmin). Evidence from a number of retrospective analyses have been critically reviewed and determined to have weaknesses. This narrative review focuses on the experimental studies performed in vivo in animal models of infection and in vitro to determine the extent to which these data may provide a compelling distinction between pharmacokinetic/pharmacodynamics (PKPD) parameters that may translate to clinical use in therapeutic drug monitoring. Animal in vivo studies have been presented at conferences, but no original peer reviewed studies could be found that compare various PKPD parameters. These conference proceeding findings were supportive but unconvincing, even though they were favorably presented subsequently in review articles and clinical practice guidelines. In vitro data are somewhat conflicting, but the range of concentrations may play a role in the discrepancies found. It has been suggested that MIC may be assumed to have a value of 1 mg/L; however, it can be demonstrated that this assumption may lead to considerable discrepancy from results with an actual MIC value. The AUC24 parameter has been weighed against the percentage of time above the MIC (%T > MIC) as a comparative PKPD parameter, yet this may be an inappropriate comparison for vancomycin since all clinically useful dosing provides 100% T > MIC. Regardless, there is a distinction between clinical TDM parameters and PKPD parameters, so, in practice, the change to AUC24:MIC based on animal experiments and in vitro evidence for vancomycin may be premature.

AUCs and 123s: a critical appraisal of vancomycin therapeutic drug monitoring in paediatrics.

The revised vancomycin guidelines recommend implementing AUC24-based therapeutic drug monitoring (TDM) using Bayesian methods in both adults and paediatrics. The motivation for this change was accumulating evidence showing aggressive dosing to achieve high troughs, as recommended in the first guidelines for adults and extrapolated to paediatrics, is associated with increased nephrotoxicity without improving clinical outcomes. AUC24-based TDM requires substantial resources that may need to be diverted from other valuable interventions. It can therefore be justified only after certain assumptions are shown to be true: (i) there is a clear relationship between vancomycin efficacy and/or toxicity and the proposed therapeutic range; and (ii) maintaining exposure within the target range with AUC24-based TDM improves clinical outcomes and/or decreases toxicity. In this review, we critically appraise the scientific basis for these assumptions. We find studies evaluating the relationship between vancomycin AUC24/MIC and efficacy in adults and children do not offer strong support for the recommended lower limit of the proposed therapeutic range (i.e. AUC24/MIC ≥400). Nephrotoxicity in children increases in a stepwise manner along the vancomycin exposure continuum but it is unclear if one parameter (AUC24 versus trough) is a superior predictor. Overall, evidence in children suggests good-to-excellent correlation between AUC24 and trough. Most importantly, there is no convincing evidence that the method of vancomycin TDM has a causal role in improving efficacy or reducing toxicity. These findings question the need to transition to resource-intensive AUC24-based TDM over retaining trough-based TDM with lower targets to minimize nephrotoxicity in paediatrics.

The case for 'conservative pharmacotherapy'.

In the modern era of rapid advances in the field of antimicrobial 'precision dosing' through therapeutic drug monitoring (TDM), there is growing pressure to adopt new technologies and expand the number of antimicrobials managed with TDM and/or the complexity of TDM methods. For many clinicians, it may seem inevitable that TDM must improve patient outcomes. However, based on the evidence to date, this concept remains largely a hypothesis. Conversely, it is plausible that focusing on TDM may distract from careful clinical monitoring of the patient for efficacy and drug-related toxicities and shift finite resources from other valuable interventions. In this article we make the case for embracing critical appraisal of precision dosing, remaining skeptical until persuaded by compelling evidence, and adopting new technologies only when they have proven their value over competing priorities; that is, we make the case for using 'conservative pharmacotherapy'.

Antimicrobial use over a four-year period using days of therapy measurement at a Canadian pediatric acute care hospital.

BACKGROUND: Antimicrobial resistance is a concern that is challenging the ability to treat common infections. Surveillance of antimicrobial use in pediatric acute care institutions is complicated because the common metric unit, the defined daily dose, is problematic for this population. OBJECTIVE: During a four-year period in which no specific antimicrobial stewardship initiatives were conducted, pediatric antimicrobial use was quantified using days of therapy (DOT) per 100 patient days (PD) (DOT/100 PD) at the Alberta Children's Hospital (Calgary, Alberta) for benchmarking purposes. METHODS: Drug use data for systemic antimicrobials administered on wards at the Alberta Children's Hospital were collected from electronic medication administration records. DOT were calculated and rates were determined using 100 PD as the denominator. Changes over the surveillance period and subgroup proportions were represented graphically and assessed using linear regression. RESULTS: Total antimicrobial use decreased from 93.6 DOT/100 PD to 75.7 DOT/100 PD (19.1%) over the 2010/2011 through to the 2013/2014 fiscal years. During this period, a 20.0% increase in PD and an essentially stable absolute count of DOT (2.9% decrease) were observed. Overall, antimicrobial use was highest in the pediatric intensive care and oncology units. DISCUSSION: The exact changes in prescribing patterns that led to the observed reduction in DOT/100 PD with associated increased PD are unclear, but may be a topic for future investigations. CONCLUSION: Antimicrobial use data from a Canadian acute care pediatric hospital reported in DOT/100 PD were compiled for a four-year time period. These data may be useful for benchmarking purposes.

HISTORIQUE: La résistance aux antimicrobiens nuit à la capacité de traiter les infections courantes. Il est difficile de surveiller l'utilisation d'antimicrobiens dans les établissements de soins aigus en pédiatrie, parce qu'il est difficile d'établir l'unité métrique habituelle, qui est la dose quotidienne définie, au sein de cette population. OBJECTIF: Après quatre ans sans initiative de gérance des antimicrobiens précise, les chercheurs ont quantifié l'utilisation des antimicrobiens pédiatriques au moyen des jours de traitement (JdT) par 100 jours-patients (JP) (JdT/100 JP) à l'Alberta Children's Hospital de Calgary en vue d'une analyse comparative. MÉTHODOLOGIE: À partir des dossiers électroniques sur l'administration des médicaments, les chercheurs ont colligé les données sur l'utilisation des antimicrobiens systémiques administrés dans les services de l'Alberta Children's Hospital. Ils ont calculé les JdT et déterminé les taux à l'aide du dénominateur 100 JP. Ils ont représenté graphiquement les changements pendant la période de surveillance et les proportions des sous-groupes et les ont évalués à l'aide de la régression linéaire. RÉSULTATS: L'utilisation totale d'antimicrobiens a reculé de 93,6 JdT/100 JP à 75,7 JdT/100 JP (19,1 %) entre les exercices 2010­2011 et 2013­2014. Pendant cette période, les chercheurs ont observé une augmentation de 20,0 % des JP et une numération absolue de JdT pratiquement stable (diminution de 2,9 %). Dans l'ensemble, l'utilisation d'antimicrobiens était plus élevée dans les unités pédiatriques de soins intensifs et d'oncologie. EXPOSÉ: On ne sait pas exactement quels changements aux profils de prescription ont donné lieu à la réduction observée de JdT/100 JP et à l'augmentation connexe de JP, mais cette question pourrait faire l'objet de prochaines recherches. CONCLUSION: Pendant quatre ans, les chercheurs ont compilé les données sur l'utilisation d'antimicrobiens en JdT/100 JP dans un hôpital pédiatrique canadien de soins aigus. Ces données peuvent être utiles dans une analyse comparative.

Use of an electronic medication administration record (eMAR) for surveillance of medication omissions: results of a one year study of antimicrobials in the inpatient setting.

INTRODUCTION: Medication administration omissions (MAO) are usually considered medication errors but not all MAO are clinically relevant. We determined the frequency of clinically relevant MAO of antimicrobial drugs in adult hospitals in Calgary, Alberta, Canada based on electronic medication administration record (eMAR). METHODS: We examined 2011 data from eMAR records on medical wards and developed a reproducible assessment scheme to categorize and determine clinical relevance of MAO. We applied this scheme to records from 2012 in a retrospective cohort study to quantify clinically relevant MAO. Significant predictors of clinically relevant MAO were identified. RESULTS: A total of 294,718 dose records were assessed of which 10,282 (3.49%) were for doses not administered. Among these 4903 (1.66% of total); 47.68% of MAO were considered clinically relevant. Significant positive predictors of clinically relevant MAO included inhaled (OR 4.90, 95% CI 3.54-6.94) and liquid oral (OR 1.32, 95% CI 1.18-1.47) route of medication compared to solid oral and irregular dose schedules. Evening nursing shift compared to night shift (OR 0.77 95% CI 0.70-0.85) and parenteral (OR 0.50, 95% CI 0.46-0.54) were negative predictors, The commonest reasons for relevant MAO were patient preference, unspecified reason, administration access issues, drug not available or patient condition. CONCLUSION: Assessment of MAO by review of computer records provides a greater scope and sample size than directly observed medication administration assessments without "observer" effect. We found that MAO of antimicrobials in inpatients were uncommon but were seen more frequently with orally administered antimicrobials which may have significance to antimicrobial stewardship initiatives.

Assessment of antimicrobial utilization metrics: days of therapy versus defined daily doses and pharmacy dispensing records versus nursing administration data.

OBJECTIVE: To compare antimicrobial utilization data derived from pharmacy dispensing records and nursing administration record data by 2 commonly used units of measure. DESIGN, PARTICIPANTS, AND METHODS: Data from nursing administration records and pharmacy dispensing records were obtained for 32 medical wards. From nursing and pharmacy data, defined daily doses (DDD) were calculated, and from the nursing data, days of therapy were derived. Direct comparison of total antimicrobial use was performed by graphical analysis and linear regression. Slope of trend line was used to quantify the difference between pairs of measures. Bland-Altman plots were constructed to determine constant and proportional bias. At the level of individual agents, difference between pairs of measures was calculated and presented graphically and the average (95% CI) for the difference between measures was determined. RESULTS: Nursing administration record-derived DDD were on average 23% lower than corresponding rates of pharmacy dispensing record-derived DDD. The difference between rates of utilization by days of therapy vs DDD from the same source (nursing) was relatively small. Results from analysis of different individual agents were highly variable with wide 95% CIs. CONCLUSIONS: In our setting, we found clinically relevant differences in antimicrobial utilization associated with data from different sources. This outweighed the importance of the metric (DDD or days of therapy). However, measurement of use of individual agents was highly variable and sensitive to both metric unit and data sources.

Concomitant ceftriaxone and high-concentration intravenous calcium therapy in adult critical care patients: a matched cohort study.

BACKGROUND: Based on case reports in infants, the safety of concomitant use of ceftriaxone and intravenous calcium in all ages has recently come under challenge. Systematic population-based data to guide clinicians with respect to this risk are, however, lacking. OBJECTIVE: To determine whether concomitant administration of ceftriaxone and intravenous calcium was associated with the occurrence of severe cardiorespiratory events or death in critically ill adults. METHODS: We performed a matched-cohort study from retrospective data of adults admitted to intensive care units (ICUs) in Calgary, Canada, who were provided continuous high-dose intravenous calcium. Those who received ceftriaxone while on continuous renal replacement therapy were considered exposed. Up to 3 unexposed patients were selected by matching on a number of prognostic factors from the remaining subjects not concurrently exposed to ceftriaxone and calcium. Univariate methods and multivariate conditional logistic regression were used for statistical analysis. RESULTS: We identified 142 patients exposed to the implicated combination who could be matched to at least one unexposed patient. Hospital mortality was 66% in the exposed versus 63% in unexposed patients (p = 0.442). ICU length of stay, ICU mortality, hospital length of stay, and the frequency of acute oxygenation events were all similar by univariate analysis. Multivariate conditional logistic regression modeling failed to find a significant association between exposure and hospital mortality (adjusted OR 1.15, 95% CI 0.65 to 2.04) or other relevant outcomes. CONCLUSIONS: In this high-risk group, administration of high concentrations of calcium and concurrent ceftriaxone was not significantly associated with greater mortality or adverse outcomes compared to matched unexposed patients. Although this was an underpowered study and rare adverse effects from the interaction of these 2 compounds cannot be completely excluded, these data provide overall reassurance of the safety of this combination in the majority of critically ill adults.