Efficacy and Safety of Vancomycin Therapy After the Transition to AUC/MIC Monitoring in a Primary Facility

Abstract

Background:

New guidance recommends area under the curve/minimum inhibitory concentration (AUC/MIC) instead of trough-based monitoring for vancomycin therapy. While this transition has demonstrated improved safety and efficacy in large, tertiary centers, this has not been assessed in the primary hospital setting.

Objective:

The primary objectives were to evaluate the efficacy and safety of AUC/MIC monitoring in inpatient veterans treated with intravenous vancomycin for ≥72 hours compared to a historical cohort of trough-based monitoring.

Methods:

This was a retrospective, quasi-experimental study over 2 five-month study periods. Efficacy was evaluated by comparing clinical failure rates as defined by a persistent fever, clinical deterioration, or escalation of gram-positive therapy. Safety was determined by the incidence of acute kidney injury (AKI) defined by an acute increase in serum creatinine ≥0.3 mg/dL over 48 hours.

Results:

25 patients met the criteria in the before group and 19 in the after group. Efficacy was equivalent between groups; no patients exhibited clinical failure of vancomycin therapy. In the before group, 2 patients (8%) met defined criteria for AKI, while none in the after group experienced AKI (P = 0.21). Total vancomycin exposure was similar between groups (P = 0.56).

Conclusion:

AUC-based monitoring was equally efficacious as trough-based monitoring with similarly low rates of AKI.

Keywords

vancomycin therapeutic drug monitoring acute kidney injury AUC pharmacokinetics

Introduction

Vancomycin intravenous (IV) therapy is common in methicillin-resistant Staphylococcus aureus (MRSA) infections and is often used to treat other infections caused by susceptible gram-positive organisms. Vancomycin treatment with weight and renal function-based dosing and trough-based monitoring has been in clinical practice for more than a decade. In 2009, the American Society of Health-System Pharmacists (ASHP), the Infectious Diseases Society of America (IDSA), and the Society of Infectious Diseases Pharmacists (SIDP) published guidelines for monitoring vancomycin therapy and recommended abandoning routine serum peak concentrations, as peak concentrations had no data correlating to efficacy or nephrotoxicity. They instead emphasized utilizing the ratio of area under the curve over 24 hours (AUC₂₄) to minimum inhibitory concentration (MIC) >400 as the primary predictor of vancomycin pharmacodynamic activity.^1,2 Although it was well established that the AUC/MIC ratio is the best predictor of clinical efficacy, supported by in vitro data, animal models, and clinical studies that have related the value to successful outcomes, obtaining this in practice was not considered pragmatic at that time.³

The 2009 guidelines recommended maintaining a vancomycin trough of >10 mg/L to avoid the development of resistance and recommended targeting a trough of 15-20 mg/L as a surrogate marker for AUC/MIC >400, if MIC <1 mg/L in patients with adequate renal function, despite little data to back the recommendation.^1,4 Since then, studies have shown trough concentrations poorly estimate AUC₂₄ and overall vancomycin exposure. Trough concentrations can relate to a wide range of AUC₂₄ values as they show the accumulation of exposure at one point in time, while the AUC₂₄ is the integrated quantity of cumulative drug exposure over time.⁵ Additionally, recent pharmacokinetic data suggests that more than half of patients can achieve AUC₂₄ values of >400 with trough concentrations <15 mg/L.⁶ The results of one study showed no difference in the ability to reach an AUC/MIC ≥400 in patients with troughs of 10 to 14.9 mg/L and >20 mg/L when compared to patients with troughs of 15 to 20 mg/L. Additionally, they demonstrated the vancomycin trough was higher in patients developing nephrotoxicity compared to those who did not (19.5 vs 14.5 mg/L, P < 0.001).⁷ Other studies suggest the true AUC₂₄ may be underestimated by approximately 25% in trough-based monitoring and have shown wide AUC₂₄ variability between patients using these values as surrogate markers.⁸ This may explain why many studies demonstrate AUC₂₄ thresholds are associated with better outcomes and lower rates of nephrotoxicity.

Wider AUC₂₄ variability, including AUC₂₄ >600, and higher vancomycin trough levels are associated with increased risk of nephrotoxicity.⁹ Both the Acute Dialysis Quality Initiative (ADQI) and the Acute Kidney Injury Network (AKIN) have published diagnostic criteria for acute kidney injury (AKI). The ADQI definition is based on the Risk-Injury-Failure-Loss-End-stage renal disease (RIFLE) classification, where each component is a separate class relating to renal dysfunction. In this criteria, “Risk” is defined as a 50% increase in baseline serum creatinine (SCr) or a reduction in urine output to <0.5 mL/hr/kg of body weight for 6 hours. Each of the following components describes progressively worsening renal function, where the last class, “End-stage,” is defined as loss of renal function for more than 3 months. Worsening RIFLE class equates to a higher mortality rate, longer ICU and hospital stay, and lower renal recovery rate.¹⁰ AKIN has proposed more sensitive diagnostic criteria than the RIFLE classification, separating renal dysfunction into 3 stages which correspond with the “Risk,” “Injury,” and “Failure” classes of the RIFLE criteria, while stages correlating with the “Loss” and “ESRD” classes were omitted. Stage 1, corresponding to the “Risk” class, was broadened to include a reduction in kidney function based on an absolute increase in SCr ≥0.3 mg/dL within 48 hours, an increase in SCr ≥50%, or a reduction in urine output <0.5 mL/hr/kg of body weight for 6 hours. The AKIN definition may be beneficial in vancomycin-induced AKI due to its higher sensitivity which may allow for earlier identification and intervention before the potential development of renal failure.¹¹

In 2020, ASHP, IDSA, SIPD, and the Pediatric Infectious Diseases Society (PIDS) published the updated vancomycin monitoring consensus guidelines and no longer recommend trough-based monitoring. Instead, they recommend implementing AUC-based monitoring targeting a goal range of 400-600 for improved efficacy and safety.¹² These guidelines offer 2 primary options for calculating AUC₂₄. One by collecting 2 samples, a peak obtained at steady-state and a trough concentration, and utilizing first-order pharmacokinetic (PK) equations to estimate the AUC₂₄, the other by employing Bayesian software to estimate the AUC₂₄. Bayesian software programs offer several advantages, such as adaptive predictions and ability to use one level to estimate the AUC₂₄, however, these programs may not be cost-effective in smaller facilities. While the transition to AUC₂₄ monitoring, sparked by the recently updated guideline recommendations, has demonstrated improved safety and efficacy in large, tertiary centers, this has not been reported from primary hospitals. The purpose of this study was to evaluate these endpoints in a small, rural medical facility.

Methods

Study Design and Setting

This was a retrospective, quasi-experimental study at the Veterans Health Care System of the Ozarks (VHSO) in Fayetteville, Arkansas, a 52-bed primary hospital. The licensed bed total includes 7 ICU beds and 28 general medical/surgical ward beds. The pharmacy and laboratory are staffed 24 hours a day. There are 5 hospitalists (not including nocturnists) and 1 clinical pharmacy specialist who covers all ICU and general ward beds Monday through Friday from 07:30 to 16:00. Vancomycin management is conducted through a consult-based collaborative agreement with pharmacy monitoring all cases.

The facility transitioned from trough-based to AUC-based monitoring in April 2019, and before and after groups were used to compare the monitoring methods over 2 five-month study periods. The pre-implementation comparison group consisted of patients in whom vancomycin was initiated using a trough-based dosing strategy between April and August 2018. The post-implementation group included patients in whom vancomycin was initiated under an AUC-based dosing strategy between April and August 2019.

A computerized pharmacy list was generated to identify study patients. All adult patients who were admitted and received IV vancomycin for ≥72 hours during the 2 study periods were considered for inclusion. Exclusion criteria included patients transferred from outside facilities on vancomycin, patients with acute renal failure prior to therapy (defined by increase in SCr >0.5 mg/dL or >50% increase within 72 hours preceding vancomycin therapy), baseline serum creatinine ≥2.5 mg/dL, and patients on renal replacement therapy at baseline. Indications of skin and soft tissue infections and urinary tract infections were also excluded as AUC₂₄ monitoring is generally not performed in these infections.

Outcome Analysis

The primary outcomes were to evaluate the efficacy and safety of AUC/MIC monitoring compared to a historical cohort. Efficacy was evaluated by comparing clinical failure rates as defined by persistent fever (≥38°C) after 48 hours of therapy, deterioration of patient’s condition as assessed by attending physician, or change in the prescribed antibiotic regimen (escalation of gram-positive therapy). Safety was evaluated by the incidence of AKI as defined by an acute increase in serum creatinine ≥0.3 mg/dL over 48 hours and RIFLE criteria.¹³ The secondary outcome was to compare the 2 monitoring methods. The overall vancomycin exposure was evaluated by comparing the average vancomycin daily doses and the serum trough levels between cohorts. As trough values have been shown to poorly estimate AUC₂₄, the trough and AUC₂₄ values from the AUC-based monitoring cohort were collected to compare the values falling within the goal range, a trough of 15-20 mg/L and AUC₂₄ of 400-600. The number of dose adjustments for each group and for each individual patient were also recorded to compare the monitoring methods.

Calculations and Definitions

In the historical, trough-based cohort, 25-30 mg/kg loading doses with a maximum loading dose of 2 grams were recommended for most patients and elimination rate constants were estimated with the Matzke equation. Guidance for maintenance dosing was 15-20 mg/kg with dosing interval determined by creatinine clearance. Maintenance doses were adjusted using trough levels at steady state, typically before the 4th dose, with a goal of 15-20 mg/L and renal function to determine the interval.

Facility dosing guidance for the AUC-based cohort included a recommended 25-30 mg/kg loading dose for most patients with a maximum loading dose of 2 grams. Maintenance dosing was guided by either the Matzke or Crass equations (for BMI >30) to determine elimination constant and initial dose, with the frequency determined by the patient’s renal function.^14,15 All levels were drawn at estimated steady-state; peaks drawn 1 to 2 hours after the end of infusion and troughs drawn 30 to 60 minutes before the next dose. Doses were then adjusted using AUC₂₄ values calculated by the logarithmic trapezoidal rule, which is highly correlated with the Bayesian AUC estimation method, using 2 serum levels drawn during the same dosing interval.¹⁶

Data Collection and Statistics

Patient demographics, co-morbidities, laboratory and physiological parameters, and other clinical data were recorded to compare groups. Severity of illness was measured by the Acute Physiology and Chronic Health Evaluation (APACHE) II score calculated using the worst physiological parameters within 24 hours of vancomycin initiation.¹⁷ Additionally the Elixhauser Comorbidity Index was collected to compare pre-existing comorbidities.¹⁸ The concomitant use of other potentially nephrotoxic medications, including IV contrast dye, aminoglycosides, piperacillin/tazobactam, furosemide, vasopressors, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and non-steroidal anti-inflammatory drugs (NSAID) were identified through medication administration records and recorded.

The analysis consisted of descriptive statistics including mean with standard deviation (SD) and median with interquartile range (IQR), where appropriate. Categorical variables were compared with a Chi Square test or Fisher’s Exact where appropriate. Continuous variables were compared with a Student’s T test for normally distributed data or Mann Whitney U for non-normally distributed and ordinal data. A p-value < 0.05 was considered statistically significant. Analyses were performed in R Foundation for Statistical Computing version 3.6.3 (Vienna, Austria). These methods were approved by both the facility Research and Development committee and the Institutional Review Board.

Results

In total, 268 patients were identified as receiving IV vancomycin during the 2 study periods. The most common reason for exclusion was treatment for <72 hours (see Figure 1). Overall, 44 patients were included: 25 in the trough-based group and 19 in the AUC-based group. All of the patients were male with a mean age of 68 years (±10.3 years). Patients presenting with fever at the time of vancomycin initiation were similar between groups (p = 0.62). White blood cell (WBC) counts on the initiation of vancomycin were also similar between groups (11.6 vs 13.7 K/cmm; p = 0.36). APACHE II scores indicated a higher severity of illness in the AUC-based monitoring cohort (p = 0.047). Indications for vancomycin included sepsis (25%), pneumonia (27%), osteomyelitis (34%), and abscess (14%). Baseline demographics, dosing information, and vancomycin indications for each group are shown in Table 1.

Figure 1.

Patients meeting inclusion/exclusion criteria.

Table 1.

Baseline Demographics and Clinical Characteristics.

Variable	Trough method (n = 25)	AUC method (n = 19)	P-value
Age, year, mean (SD)	65 (11)	70 (9.2)	0.35
Male, n (%)	25 (100)	19 (100)	-
Weight, kg, mean (SD)	97.35 (25.96)	97.44 (18.83)	0.69
Fever present at initiation of Vancomycin, n (%)	5 (20)	5 (26)	0.62
WBC count at initiation of Vancomycin, K/cmm, median (IQR)	11.6 (8.6-16.1)	13.7 (8.7-18.7)	0.36
APACHE II, median (IQR)	8 (6-13)	12 (9.5-14)	0.047
ECI, median (IQR)	3 (1-8)	0 (-1-3.5)	0.22
Indication for Vancomycin
Sepsis, n (%)	4 (16)	7 (37)	0.11
Pneumonia, n (%)	7 (28)	5 (26)	0.80
Osteomyelitis, n (%)	9 (36)	6 (32)	0.76
Abscess, n (%)	5 (20)	1 (5)	0.16

Abbreviations: SD, standard deviation; WBC, white blood cell; IQR, interquartile range; APACHE II, Acute Physiology and Chronic Health Evaluation; ECI, Elixhauser Comorbidity Index.

Efficacy was equivalent between groups; none of the 44 patients met the study criteria for clinical failure with vancomycin therapy. The median duration of therapy was similar in the trough-based and the AUC-based groups, 5 versus 6 days, respectively (p = 0.72). There was no statistical difference in vancomycin daily doses between groups, averaging 1919 mg (±669) per day in the trough-based group and 1803 mg (±619) per day in the AUC-based group (p = 0.56). However, the mean vancomycin trough concentrations were lower in the AUC-based group; 14.6 mg/L versus 11.9 mg/L (p = 0.001). A trend toward fewer patients requiring dose adjustments after initiation of vancomycin in the AUC-based group was noted (80% vs 53%; p = 0.05). Patients in the AUC-based group required fewer dose adjustments during therapy, averaging 0.74 adjustments per patient versus 1.32 in the trough based group (p = 0.04). Details of results are included in Table 2.

Table 2.

Comparative Clinical Outcomes.

Variable	Trough method (n = 25)	AUC method (n = 19)	P-value
Vancomycin exposure as average TDD, mg (SD)	1919 (669)	1803 (619)	0.56
Vancomycin trough concentration, mean (SD)	14.6 (5.1)	11.9 (4.5)	0.001
Duration of therapy, median (IQR)	5 (4-9.5)	6 (4-8)	0.72
Number of patients requiring dose adjustments, n (%)	20 (80)	10 (53)	0.05
Number of dose adjustments per patient, mean (SD)	1.32 (1.03)	0.74 (0.73)	0.04
AKI, n (%)	2 (8)	0 (0)	0.21
Treatment failure, n (%)	0 (0)	0 (0)	-
Values within therapeutic range, n (%)	18 (38.3)	17 (65.4)	0.03
Patients with concomitant nephrotoxins, n (%)	21 (84)	13 (68)	0.22

Abbreviations: TDD, total daily dose; SD, standard deviation; IQR, interquartile range.

There were 47 total trough levels drawn in the trough-based cohort. Troughs fell within the desired range of 15-20 mg/L in 38.3% of cases (n = 14 supratherapeutic, n = 15 subtherapeutic). There were 26 peak/trough couplets for AUC monitoring in the AUC-based group. AUC₂₄ fell with the desired range of 400-600 in 65.4% of cases (n = 4 supratherapeutic, n = 5 subtherapeutic). Therapeutic discordance between the trough and AUC₂₄ values were observed in the AUC-based group. Ten of the AUC₂₄ values within the target range of 400-600 had a trough value of less than 15 mg/L. Three cases had a calculated AUC₂₄ >600 though within the goal trough range of 15-20 mg/L. These variances in AUC₂₄ and trough values are shown in Figure 2.

Figure 2.

AUC24 versus trough concentrations in the AUC-based monitoring (post-implementation) cohort.

In the trough-based group, 2 patients (8%) met defined criteria for AKI, while no patients in the AUC-based group experienced AKI (p = 0.21). Of the 2 patients, one fell into the “Risk” class of the RIFLE classification, experiencing a 1.5 times increase in serum creatinine. The other patient did not meet the criteria to be placed into a RIFLE class. Each group had similar exposure to concomitant nephrotoxins (84% vs 68%; p = 0.22), with ACE inhibitors or ARBs, piperacillin/tazobactam, and loop diuretics as the main contributors. Each of the 2 patients who met the criteria for AKI were also on concomitant nephrotoxins, one receiving piperacillin/tazobactam, losartan, and furosemide, the other norepinephrine. The vancomycin troughs for these patients were of 21.6 mg/dL and 22.5 mg/dL at the time of AKI.

Discussion

To the authors’ knowledge, this is the first report comparing the effects of vancomycin monitoring method changes in a small, primary facility. This report is timely in light of a recent survey of medical facilities that indicated the majority (88.3%) of responders did not have plans to transition to AUC monitoring within the next year.¹⁹ Historically, smaller hospitals in rural settings have struggled with guideline implementation compared to their more urban counterparts due to limited personnel and resources.²⁰

In one of the largest cohorts to date, Finch et al. (2017) were able to demonstrate lower nephrotoxicity rates via logistic regression model after transitioning to AUC-guided dosing at a large, academic medical center.⁶ After accounting for the severity of illness and the presence of nephrotoxins, AUC-guided dosing was associated with less nephrotoxicity compared to trough-guided dosing with an odds ratio of 0.514 (95% CI 0.332 – 0.794, p = 0.003). Vancomycin exposure was lower in the AUC-guided group with lower daily doses and lower serum trough levels (15.0 mg/L vs 12.0 mg/L, p = 0.001). This is similar to the reported findings herein. While the present study was unable to demonstrate lower rates of nephrotoxicity, this is likely due to the limited patient enrollment capacity of the small facility. Of note, there was a trend towards lower average daily doses and significantly lower mean trough concentrations. Additionally, it was found that in approximately 35% of cases, AUCs were therapeutic at ≥400, with a correlating trough value <15 mg/L, which is consistent with previous studies. Before the transition in monitoring practice, this therapeutic discordance between the trough and AUC₂₄ values may have resulted in inappropriate dose adjustments, greater vancomycin exposure, and an increased risk of nephrotoxicity.

In another retrospective cohort at a tertiary care center, AUC-based monitoring resulted in fewer dose increases compared to a trough-based monitoring cohort.²¹ Similarly, in the present study, AUC-guided dosing resulted in significantly more patients in the therapeutic range. The AUC-based monitoring group resulted in a trend towards fewer patients requiring dose adjustments after vancomycin initiation and patients in the AUC-based monitoring group required fewer dose adjustments during therapy.

AUC₂₄ has previously been shown to be the best indicator for clinical effectiveness, but this has not been demonstrated in smaller hospital settings.³ While the present study did not demonstrate superior efficacy between monitoring types, this is likely due to limitations with enrollment and the study design which was primarily to demonstrate a lack of harm. It is important for facilities to monitor efficacy outcomes from a quality assurance standpoint when implementing major practice changes.

There are limitations to consider when interpreting the results of this study. Notably, there are limitations inherent to the single-center, quasi-experimental study design which lacks the ability to account for confounding variables. Unidentified variables may have contributed to the patients who experienced nephrotoxicity. For example, observed nephrotoxicity may have been due to inherent disease processes rather than directly related to vancomycin therapy. Another limitation of this study is the small sample size. Given the already low rates of AKI, a much larger population would be needed to detect a clinically significant difference. While the appropriateness of serum levels is routinely assessed in clinical practice, these were not specifically studied for this project. Some facilities have voiced a concern with the added time required for AUC/MIC monitoring and this outcome was beyond the scope of this study. Finally, microbiology data were not recorded for bactericidal cure. However, anecdotally speaking, proven culture data was rare among both cohorts.

Conclusion

The transition from trough-based monitoring to AUC/MIC based vancomycin monitoring was associated with similar treatment efficacy, similarly low rates of AKI, a higher proportion of levels within the therapeutic range, and a trend toward lower vancomycin exposures in a single, primary medical center.

Footnotes

Acknowledgments

Jennifer Stark, PharmD, BCPS, FCCP and Brad Hodge, PharmD are acknowledged for their roles in this project and manuscript.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Disclosure

This material is the result of work supported with resources and the use of facilities at the Veterans Health Care System of the Ozarks. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Andrea V Eads, PharmD

Jennifer L Cole, PharmD, BCPS, BCCCP, FCCP

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