Lilley, L et al. Paediatric Injectable Guidelines. Flemington, Victoria. Embed your HTML code. Patient age. Dosing regimen. Continuous infusion recommended. Continuous infusion dose. Dosing frequency. Timing of initial vancomycin trough levels. Before the 5th dose. Before the 4th dose.
Before the 3rd dose. Before the 2nd dose. As outlined in Figure 1 , we evaluated all vancomycin level determinations performed during the month study period of April 1, , to April 30, , that met inclusion criteria. The first criterion required that levels have a documented collection time. Second, we only included levels for patients receiving vancomycin every 12 hours Q12H , the most common dosing interval at our institution.
Vancomycin levels included in analysis. The process of selecting vancomycin levels to include in the study is shown. Our institution has an internally developed laboratory information system LIS that we accessed to obtain a record of all vancomycin measurements performed by the BWH clinical chemistry laboratory during the study period. The time the employee badge is scanned is recorded as the drug administration time, which we used to assess level timing as described subsequently.
In most cases, we considered the last dose to be the dose given before sample collection. We compared the plasma vancomycin concentrations and subsequent clinician actions in the 2 groups drawn too early vs correctly timed to investigate the possible adverse effects of drawing a sample too early.
We also determined whether the 2 groups had similar baseline characteristics age, sex, most recent creatinine level, estimated glomerular filtration rate, and previous vancomycin test result to verify that these characteristics were not contributing to any differences in the 2 populations. For calculation purposes, all test results below the lower limit of detection of the assay 0.
Clinical actions taken in response to levels were grouped into 3 types: 1 dose held, decreased, or discontinued; 2 dose increased; and 3 repeat vancomycin level. Only clinical actions performed within 12 hours of reporting the vancomycin level, but before another level was reported, were included in the study. For cases in which no dosing adjustment was found, we determined whether a repeat vancomycin level, ie, an additional test reported within 24 hours of the original, had been performed.
A P value less than. Of 10, plasma vancomycin concentrations measured in the study period, we excluded 2, Of the In total, 2, Data for a total of 1, different patients were included in the study, of whom patients had multiple vancomycin levels included and had occasion to fall into both the correctly and incorrectly timed groups. There was no significant difference in age, sex, renal function, or previous vancomycin level between the 2 groups Table 1. Of the evaluated levels, The median sampling time relative to the last dose was 7.
Figure 3 shows the average vancomycin concentration for samples drawn at each hour after the last dose. The average concentration peaked at 2 to 3 hours at Levels drawn too early were twice as likely as correctly timed levels to be supratherapeutic Early levels accounted for Clinicians also more frequently obtained a repeat vancomycin level, as opposed to adjusting the dose when a level drawn too early was reported The absolute number of vancomycin levels and the percentage of total are shown for each hour.
Effect of sample timing on plasma vancomycin concentration. The average plasma vancomycin concentration is shown for samples obtained at each hour since the last vancomycin dose. We found that the samples for about 4 in 10 vancomycin levels intended to predict vancomycin efficacy in patients receiving Q12H dosing were collected too early and, thus, did not represent true trough levels. When compared with correctly timed levels, samples drawn too early had significantly higher plasma vancomycin concentrations and were twice as likely to be supratherapeutic.
In some cases, clinicians may have realized that levels were not drawn at the appropriate time, as suggested by a high number of repeat levels obtained, particularly for collections drawn 2 to 6 hours after the last dose.
However, in many cases, it seems that clinicians may have not have realized that elevated concentrations were due to inaccurate timing. In these cases, the inappropriate use of levels drawn too early to predict efficacy could have led to underdosing and therapeutic failure. Once the root cause of inaccurate sample timing is established, a more robust infrastructure is required to increase the accuracy of collections for vancomycin levels.
Clinicians often adjusted dosing after obtaining an incorrectly timed level Table 2 and Figure 4 , even though these levels did not represent true trough levels and, therefore, should not be used as a basis for clinical decisions. Moreover, clinicians held, decreased, and discontinued vancomycin at a higher frequency when responding to early levels, particularly when levels were drawn at 8 to 10 hours after the last dose Figure 4A.
These levels, comprising While only a couple of hours off, these samples were still 1. Effect of sample timing on clinical actions. The percentage of vancomycin levels followed by a clinical decision to hold, decrease, or discontinue vancomycin dosing A , increase vancomycin dosing B , or not adjust dosing but obtain a repeat level C is shown for levels obtained at each hour since the last dose.
In comparison, levels drawn less than 8 hours after the last dose, which were typically higher Figure 3 , were not as likely to be followed by dosing adjustments and more likely to be repeated Figure 4 , suggesting that clinicians sometimes questioned the accuracy of these results.
The pharmacists at our institution often intervene when levels are high, and they carefully consider pharmacokinetics, which may have contributed to awareness that these levels did not represent true troughs and which may explain the higher rate of repeats.
At institutions with less active clinical pharmacy programs, such recoveries would be expected to be less frequent. However, even if clinicians are realizing the levels are inaccurately timed and thus refraining from inappropriate use of the levels, repeating laboratory tests contributes to delays in patient management and waste in the system.
We observed a low percentage of levels within the therapeutic range and a higher than expected percentage below the therapeutic range, even within the group of early levels Table 2 , which may explain the relatively high rates of dosing increases in both groups Figure 4B. These findings are consistent with previous findings at our institution, and a quality improvement project is currently underway in the pharmacy department to improve vancomycin dosing.
The root cause for the high percentage of inappropriately timed levels is currently under investigation, but we suspect the cause is multifactorial. While clinicians are prompted at the time of placing an electronic order for a vancomycin level with ordering instructions and recommendations, the menu option does not default to a trough level. After a clinician places an order, the nurse must schedule for the level to be drawn, sometimes requiring coordination with the phlebotomy team, which may further complicate the process of getting a correctly timed sample.
Finally, neither the sample collection time nor any dosing information is displayed with the vancomycin result in our LIS, making it difficult for clinicians to be cognizant of sample timing relative to dose administration and providing 1 explanation why inappropriate clinical actions were observed for early levels. The increased adoption of clinical information systems presents new opportunities to address the issue of correct timing of monitoring for vancomycin and other therapeutic drugs through real-time display of dose administration, specimen collection, and test result data, as well as automated guidance to help clinicians time samples correctly.
Of note, the method we used to gather data and evaluate the timing of specimen collection was automated and used data recorded by our LIS and eMAR. Our ongoing efforts are aimed at linking the LIS, positive patient identification system, and eMAR such that we can display the time relative to last administration along with each drug level.
It is possible that some of the levels we evaluated were intended as peaks or random levels, although peaks are rarely clinically indicated, and we carefully designed criteria to exclude random levels. This variability was due to varying baseline levels among the study population, length of vancomycin therapy, receipt of other nephrotoxic agents, and renal function creatinine clearance. From the 19 studies in this analysis, the study in patients with any type of nosocomial MRSA infection had the lowest nephrotoxicity rate [ 30 ] while the study in patients with MRSA HCAP had the highest nephrotoxicity rate in both trough level groups [ 31 ].
Patients in the study with the highest rate of nephrotoxicity had higher APACHE II scores and received more concomitant nephrotoxic agents than patients in all other studies. These results support the finding of some other studies that concomitant nephrotoxic agents were a risk factor for renal function impairment during vancomycin therapy [ 30 — 32 ].
Nephrotoxicity ranges in the van Hal, et al. Clinical success was extremely variable across the studies in this analysis with most differences between high and low trough levels being statistically non-significant. This variability was due to baseline clinical status of study population and sites of MRSA infections.
No statistically significant differences were observed between high and low trough groups. Patients who had either MRSA bacteremia or who required intensive care had higher mortality rates.
The results of this meta-analysis support the results of previous studies [ 15 , 39 ], all finding that there is no evidence supporting association between higher vancomycin trough levels and improved outcome in patients with MRSA. Although we had originally planned to conduct analysis using a meta-regression model to investigate possible sources of heterogeneity of clinical success among the studies, sufficient data were not available to conduct this analysis.
Based on our review of the literature, this study is the first meta-analysis to compare the safety and efficacy of high vs. The results of this analysis also confirm the results of previous studies that were not included in this meta-analysis, which showed that higher vancomycin trough levels or higher vancomycin doses were associated with increase risk of nephrotoxicity [ 8 , 30 , 40 — 46 ]. Considerable controversy exists concerning the relationship between vancomycin MICs and clinical outcomes.
Several studies have reported association between higher vancomycin MIC and increased risk of treatment failure or mortality [ 30 , 47 — 54 ], with others finding no significant association with poor outcomes [ 37 , 55 — 59 ]. However, recent meta-analysis study in high vancomycin MIC and clinical outcomes in adults with MRSA infections by Jacob and DiazGranados [ 60 ] found that high vancomycin MIC was associated with increased mortality and treatment failure.
In this study, the random effects model was used to combine the odds ratios for the outcomes of interest, even though there was no evidence of heterogeneity.
The decision to use the random effects model was made a priori, depending upon the nature of the eligible studies and our goals for the following reasons: individual eligible studies were collected from several independent studies; included studies were heterogeneous for study design; and, inferences based on the random effects model can be generalized beyond the studies included in the meta-analysis.
This study has several notable strengths. First, studies that were included in this meta-analysis were independent studies that were conducted during different periods of observation.
The results, both individually and collectively, strongly support the fact that there is evidence that higher trough levels are more harmful than low trough levels in terms of nephrotoxicity.
Secondly, the results of influence analysis on all outcomes in which each study was removed from the analysis one by one to determine the magnitude of influence on overall effect size, showed that overall effect size was relatively independent of any one particular study. Third, adjusting for asymmetric funnel plots using the trim and fill method did not significantly change the results of this meta-analysis for nephrotoxicity and mortality, indicating that the missing studies were unlikely to have changed the conclusions relating to these outcomes.
However, the results of trim and fill analysis showed substantial impact of publication bias on the conclusion for clinical success. Specifically, after trim and fill, the association between high trough level and clinical success was no longer non-significant.
This study also has some mentionable limitations. Second, this meta-analysis included a combination of different study designs, including: nine retrospective cohort studies, four prospective cohort studies, two retrospective studies, one non-randomized comparative study, one retrospective quasi-experimental study, one prospective surveillance study, and one multicenter prospective study.
Third, only one study met the criteria for combining adjusted OR from different studies for the outcomes of clinical success and mortality; thus, these analyses were not performed.
Finally, we did not evaluate the other factors that might associate with high vancomycin trough levels due to lack of information.
The research cited in published reviews demonstrates that studies published in journals have a tendency to report larger effect sizes than studies published in grey literature [ 63 , 64 ]. Based on pooled adjusted OR, high vancomycin trough level is the variable that was identified as the independent factor associated with risk of nephrotoxicity in MRSA infections. However, we need to acknowledge that this conclusion does not take into account vancomycin MIC data, which were not available for analysis in this study.
Since adjustment of funnel plot asymmetry using the trim and fill method yielded significant change in pooled OR for clinical success, association between high vancomycin trough levels and both risk for adverse events and improvement in clinical outcomes in patients with MRSA infection requires further study. Clinical failure of vancomycin treatment of Staphylococcus aureus infection in a tertiary care hospital in southern Brazil.
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