Development and validation of a vancomycin protocol that utilizes calculated Area Under

the Curve-based dosing

John Talili, Pharm.D., PGY-1 Pharmacy Resident

Institution: Southeast Hospital

Residency Director: Susan Boswell, Pharm.D.

Project Mentors: Ryan Mattes, Pharm.D.

Daniel Nelson, Pharm.D.

Adnan Omanovic, Pharm.D.

Conflict of interest

• No conflicts of interest to disclose

Background

• The dosing of vancomycin is complex due to adverse effects• 2009 Infectious Diseases Society of America (IDSA) Vancomycin

Therapeutic Guidelines• Optimal target is an Area Under the Curve (AUC)/Minimum Inhibitory

Concentration (MIC) ratio of ≥ 400 mg*hr/L• AUC ≥ 600 mg*hr/L associated with increased risk of nephrotoxicity • Complicated infections: Target trough of 15-20 mg/L to achieve goal AUC• Trough concentrations < 10 mg/L encourages resistance• 15 - 20 mg/kg dosing IV every 8 – 12 hours (actual body weight)• Loading dose of 25 – 30 mg/kg for seriously ill patients

Rybak et al. Clin Infect Dis. 2009 Aug 1;49(3):325-7.

Background

Hale CM, et al. J Pharm Pract. 2017;30(3):329-335.Neely MN, et al. Antimicrob Agents Chemother. 2018;62(2).Finch NA, et al. Antimicrob Agents Chemother. 2017;61(12).

Lack of evidence to support that higher vancomycin trough levels provide benefit

Targeting troughs of ≥ 15 – 20 mg/L are not more likely to achieve AUC/MIC ≥ 400 mg*hr/L than troughs ≥ 10 – 15 mg/L

Aggressive vancomycin trough targets are associated with increased risk of nephrotoxicity

Switching from a trough-based to AUC-based monitoring is associated with lower nephrotoxicity

Background

Rybak MJ, et al. Am J Health Syst Pharm. 2020 Mar 19.

Background

• Need for research• Previous Southeast Hospital protocol utilized trough-based monitoring

• A previous study at Southeast Hospital: trough-based monitoring exceeded the recommended AUC in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia

• Institutions were making or have made the switch to AUC-based monitoring

Background

• Objective• To develop and validate an Area Under the Curve-based vancomycin dosing

protocol

• Anticipated Impact• Decreased risk of nephrotoxicity while achieving a target AUC of 400 – 600

mg*hr/L• Provide a new protocol according to updated literature

Mogle BT, et al. Int J Antimicrob Agents. 2018 Dec;52(6):805-810.Gregory ER, et al. J Pharm Pract. 2019 Mar 10; 897190019834369.Meng L, et al. Pharmacotherapy. 2019 Apr;39(4):433-442.

Methods

• Study Design: Prospective cohort chart review

• This study was approved by the SoutheastHEALTH Institutional Review Board

Inclusion Criteria Exclusion Criteria• Patients at least 18 years old

• Required to have received intravenous vancomycin for at least 24 hours

• Two vancomycin levels drawn to evaluate AUC

• Dialysis patients

• Surgical prophylaxis patients

• Outpatient Antibiotic Therapy (OPAT) Patients

Rybak MJ, et al. Am J Health Syst Pharm. 2020 Mar 19.

Methods

• Acute Kidney Injury definition per Kidney Disease: Improving Global Outcomes (KDIGO) 2012

• An increase in serum creatinine (SCr) of ≥ 0.3 mg/dL within the 48 hours preceding vancomycin initiation

Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. Kidney inter., Suppl. 2012; 2: 1–138.

Methods

• Research project development

IRB Approval Protocol Development

P & T Committee approval

Calculator development and education

Study initiation and data collection

Data analysis

Methods

• Protocol DevelopmentTwo-point sampling using trapezoidal rule(Any two levels within a single dosing interval)

Vancomycin dosed by pharmacy

Pharmacists calculated an initial dose and timed the administration of vancomycin

An AUC of 400 to 600 mg*hr/L was targeted and maintained

Initial vancomycin levels were obtained after the second dose

Monitoring and dose adjustments documented electronically and by kinetics monitoring sheet

𝐴𝐴𝐴𝐴𝐴𝐴24 = �𝑡𝑡𝑖𝑖𝑖𝑖𝑖𝑖 ×(𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶+𝐶𝐶𝐶𝐶𝑖𝑖𝑖𝑖)2

+ �𝐶𝐶𝐶𝐶𝐶𝐶𝐶𝐶 −𝐶𝐶𝐶𝐶𝑖𝑖𝑖𝑖𝑘𝑘𝑒𝑒

× 𝑁𝑁𝑁𝑁𝐶𝐶𝑁𝑁𝑒𝑒𝑁𝑁 𝑜𝑜𝑖𝑖 𝑑𝑑𝑜𝑜𝑑𝑑𝑒𝑒𝑑𝑑𝐷𝐷𝐶𝐶𝐷𝐷

𝑘𝑘𝑒𝑒 =ln𝐴𝐴1𝐴𝐴2∆𝑡𝑡

Mogle BT, et al. Int J Antimicrob Agents. 2018 Dec;52(6):805-810.Meng L, et al. Pharmacotherapy. 2019 Apr;39(4):433-442.Rybak MJ, et al. Am J Health Syst Pharm. 2020 Mar 19.

Methods

• Study period: January 2020 through March 2020• Data Collection

• Age• Gender• Dose and frequency of vancomycin• Serum Creatinine, Creatinine Clearance (Cockroft-Gault)• Vancomycin levels to evaluate AUC• AUC values• Patients with concurrent nephrotoxic drugs

Methods

Intravenous contrast dye Loop diuretics Amphotericin B Polymyxins Vasopressors

Chavada R, et al. Antimicrob Agents Chemother. 2017;61(5)Finch NA, et al. Antimicrob Agents Chemother. 2017;61(12):1-10Luther MK, et al. Crit Care Med. 2018;46(1):12-20Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. Kidney inter., Suppl. 2012; 2: 1–138

• Nephrotoxic Drugs Aminoglycosides Angiotensin-converting enzyme

inhibitors (ACE-Is) Angiotensin receptor blockers (ARBs) Nonsteroidal anti-inflammatory drugs

(NSAIDs) Piperacillin-tazobactam

Methods

• Data Collection• Weight definitions and usage (per Renal Dosing Policy at Southeast

Hospital): • Actual body weight (ABW): used for dosing vancomycin (i.e. 15 mg/kg)• Ideal body weight (IBW): used for calculating creatinine clearance (CrCl)

if IBW < ABW• IBW males = 50 kg + 2.3 x inches > 60 inches• IBW females = 45.5 kg + 2.3 x inches > 60 inches

• Adjusted/obese body weight (OBW): used for calculating the CrCl if patient is > 20% over ideal body weight

• OBW = IBW + 0.4 (ABW – IBW)

Methods

Percentage of patients on vancomycin that achieved the goal target AUC of 400 to 600 mg*hr/L

AUC levels in patients that experienced an acute kidney injury (AKI)

Percentage of patients that experienced an AKI

Percentage of patients that experienced an AKI while on defined nephrotoxic medications

• Endpoints

Statistical Analysis

• Utilization of spreadsheet• Data collection• Evaluation of endpoints

• Statistical Methods (Descriptive Statistics)• Measures of central tendency (mean, median, mode)• Measures of variability [range, inter-quartile range (IQR)]

Results - Demographics

Sample Size

Included 122

Excluded 136

Gender (n=122)

Male 82

Female 40

Patient Age (Years)

Mean 64.7

Median 66.5

Range 27 - 94

Total Body Weight (kg)

Mean 91.5

Median 85.3

Range 32-167.8

IQR 74.5-107.7

Results - Demographics

Top 5 Infections/Indications

Hospital-Acquired Pneumonia

31

Skin and Soft Tissue 26

Pneumonia – Unspecified 18

Sepsis - Empiric 11

Community-Acquired Pneumonia

6

Top Culture Results

No growth 88

Methicillin-resistant Staphylococcus

aureus

8

Methicillin-sensitive Staphylococcus

aureus

8

Coagulase-negative Staphylococcus

4

Enterococcus faecalis

3

Proteus mirabilis 3

Results - Endpoints

AUC Levels (<400 mg*hr/L) (n = 26)

AUC Levels (>600 mg*hr/L) (n = 36)

Mean 348.7 Mean 683.8

Median 368.5 Median 666

Range 174-398 Range 604-906

IQR 340.8-390.5 IQR 624.3-719.5

Results - Endpoints

AUC Levels in AKI (mg*hr/L) (n = 15)

Mean 596.13

Median 606

Range 411-764

IQR 539-643.5

Levels Within Target Range

7

Levels Above AUC of 600 8

Results - Endpoints

Nephrotoxic Medications in Patients with AKI

Piperacillin-Tazobactam 7

Furosemide 1

Torsemide 1

Losartan 1

Total Body Weight (kg) in AKI

Mean 105.2

Median 107

Range 73.4-135

IQR 90.8-110.5

Strengths & Limitations

Strengths Limitations

• Provides a protocol according to updated literature

• Updated monitoring plan for patients on vancomycin

• More frequent monitoring of vancomycindosing

• Two-level method only provides a snapshot of patient

• Single center, observational study

• Emergency department dosing

• Multiple calculator updates

• Pharmacist calculator user-error/clinical judgment

Conclusions

• Rate of achieving goal AUC could be attributed to the limitations of the monitoring method (two-level provides snapshot)

• Higher AUC levels can increase the risk of AKI

• The combination of vancomycin and piperacillin-tazobactam is associated with increased AKI risk

• Additional studies that account for the limitations of this study and inclusion of a larger sample size is warranted

Challenges for Implementation

• Education of nurses of switch to two-level monitoring• Pharmacist communication with nurses on floors• Nursing education sheets distributed• Medication safety handouts distributed

• Multiple updates to calculator

Next Steps

• Continue to utilize and improve our calculator and process

• Comparison analysis of AKI rates pre- and post-implementation

• Emergency Department communication and education

• Purchasing a Bayesian calculator and compare to two-level dosing

Development and validation of a vancomycin protocol that utilizes calculated Area Under

the Curve-based dosing

John Talili, Pharm.D., PGY-1 Pharmacy Resident

Institution: Southeast Hospital

Residency Director: Susan Boswell, Pharm.D.

Project Mentors: Ryan Mattes, Pharm.D.

Daniel Nelson, Pharm.D.

Adnan Omanovic, Pharm.D.