Introduction and Evaluation of a Guideline for Vancomycin ... Reside… · doses of greater than 4 grams per day. However, total daily doses exceeding 4 grams are associated with

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PHARMACY RESIDENCY PROJECT

2018-2019

Introduction and Evaluation of a Guideline for Vancomycin Administered via

Continuous Intravenous (CIV) Infusion

Manuscript

August 26, 2019 (Version 5)

Richard Li, BSc, PharmD, RPh

Pharmacy Resident, Kingston Health Sciences Centre

Heather Wise, BSc(Pharm), RPh, ACPR

Critical Care Pharmacist, Kingston Health Sciences Centre

Susan McKenna, BScH, BScPhm, RPh, BCPS

Antimicrobial Stewardship Pharmacist, Kingston Health Sciences Centre

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ABSTRACT

Background: Vancomycin continuous intravenous (CIV) infusion is an alternative to intermittent

intravenous (IIV) dosing for patients in whom therapeutic levels are difficult to achieve, maintain, or

monitor. There is evidence from observational trials that vancomycin CIV is as effective as IIV with a

decreased risk of nephrotoxicity. At KHSC, there was formerly no standardized method for prescribing,

administering, or monitoring vancomycin CIV.

Objective: To implement a guideline and associated order set, then evaluate appropriateness, for the use

of vancomycin CIV in adult patients.

Methods: An institutional vancomycin CIV guideline and order set were developed with stakeholder

support. These were introduced to pharmacists and internal medicine residents through educational

rounds. Over 6 weeks, all patients receiving IV vancomycin were identified from the pharmacy

information system and reviewed to assess eligibility according to the guideline to receive vancomycin

CIV (i.e. unable to reliably achieve target levels on vancomycin IIV or upon recommendation from the

Infectious Diseases/Antimicrobial Stewardship services, and expected duration at least 7 days) and

determine whether it was actually prescribed. Pregnant/breastfeeding patients and those receiving dialysis

were excluded. No patient-specific interventions were made by the resident investigator.

Results: 139 patients prescribed IV vancomycin were screened to identify 24 patients who were eligible

for vancomycin CIV, none of whom were initiated on or transitioned from IIV to CIV. Of the 24 patients,

20 (84%) did not have a therapeutic serum vancomycin level by day 3 and 13 (54%) received a

concomitant nephrotoxin during vancomycin therapy. Three CIV-eligible patients were discharged home

on IV vancomycin.

Conclusions: While no patients were initiated on vancomycin CIV during the project timeline, the results

revealed that patients may experience delays in reaching therapeutic levels using IIV therapy. No patients

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were started inappropriately on vancomycin CIV. Future studies should explore barriers to initiation of

vancomycin CIV in patients who may benefit the most.

Key Words: Vancomycin, continuous infusion, guideline development, order set development

Abstract Word Count: 305

Manuscript Word Count: 2945

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BACKGROUND

Vancomycin is a glycopeptide antibiotic used to treat infections caused by Staphylococcus aureus

and other Gram-positive bacteria that are resistant to beta-lactams or is used in the case of allergy to beta-

lactams. It is traditionally given as an intermittent intravenous (IIV) infusion adjusted for body weight and

renal function. Current vancomycin guidelines recommend that a serum concentration of at least 10 mg/L

should be maintained to ensure adequate therapy, although a trough of 15 to 20 mg/L is recommended for

more serious, deep-seated infections.1

Rationale for Vancomycin CIV

While several pharmacodynamic models have been proposed to describe vancomycin’s bacterial

killing effect, data from various studies have identified the area-under-the-concentration-time-curve

(AUC) to minimum inhibitory concentration (MIC) ratio (AUC/MIC) as the most useful parameter to

predict treatment success.1 An AUC/MIC of greater than or equal to 400 mcg*h/mL is recommended by

the Infectious Diseases Society of America (IDSA) as a target to optimize clinical effectiveness of

vancomycin.1 AUC is difficult to estimate in a practical setting, thus trough concentrations are generally

used as a measurable surrogate marker. A trough concentration of between 15 to 20 mg/L is targeted to

reach an AUC/MIC of 400 mcg*h/mL based on an average MIC of 1 or below for Staphylococcus

aureus.1

The 2009 IDSA consensus guidelines on therapeutic monitoring of vancomycin concluded that

clinically adequate serum concentrations of vancomycin can be reliably reached using standard

intermittent infusion regimens. At the time, the guideline did not support vancomycin continuous

intravenous (CIV) infusion, as there was insufficient evidence to suggest that it could substantially

improve patient outcomes.1 Although several additional studies comparing vancomycin IIV and CIV have

been published since 2009, there is still a lack of definitive evidence that one infusion method is clinically

superior to the other. The most recent systematic review and meta-analysis of two randomized-controlled

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trials and nine observational studies found no difference in treatment failure or mortality between

vancomycin IIV and CIV.2

In patients with serious infections, attaining and maintaining therapeutic drug levels to ensure

optimal bacterial killing is of utmost importance. There is evidence to suggest that the probability of

attaining a trough concentration of 15 to 20 mg/L using currently recommended dosing guidelines (i.e. 15

mg/kg IV every 12 h) may be lower than 20%.3 Consequently, some clinicians have resorted to employing

doses of greater than 4 grams per day. However, total daily doses exceeding 4 grams are associated with a

higher likelihood of vancomycin-related nephrotoxicity.4 Additionally, a 2014 pharmacokinetic study

suggested that aiming for a trough target of at least 15 mg/L may put patients at unnecessary risk for

nephrotoxicity as many patients may achieve an AUC/MIC of 400 mcg*h/mL despite failing to reach the

desired target trough range.5 This study highlights the need to develop a more reliable method to measure

AUC/MIC during vancomycin therapy, as it is postulated to be the best predictor for efficacy.

A potential advantage of vancomycin CIV is reduced incidence of nephrotoxicity, especially in

critically ill patients who require aggressive dosing.2 Patients treated with vancomycin CIV are

consistently able to reach target therapeutic concentrations more frequently and in a more timely manner

than with IIV dosing.6-11 Furthermore, vancomycin CIV is associated with less variability in serum

concentrations and a longer time within the therapeutic range, thus lowering a patient’s risk for

inadequate therapy from subtherapeutic levels and nephrotoxicity from supratherapeutic levels. 6,8,11-13

CIV dosing also simplifies monitoring as there is no longer any concern about the timing of a serum

trough concentration, as levels can be measured at any time once steady state is reached.

Although neither practical nor necessary in all patients, vancomycin CIV is a clinically acceptable

alternative to traditional intermittent dosing for patients in whom therapeutic levels are difficult to

achieve, maintain, or monitor.

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Published Protocols for Vancomycin CIV

Several groups have published validated dosing tables or nomograms for vancomycin CIV,

primarily for the critically ill population.15-18 In most cases, a weight-based loading dose is given if the

patient is not already receiving vancomycin, then the daily dose is determined based on estimated

creatinine clearance, which correlates to vancomycin clearance. Most studies excluded patients receiving

renal replacement therapy.

Vancomycin CIV protocols differ in target steady state concentration (Css), dosing, and

monitoring procedures.19-22 However, most institutions recommend drawing a random vancomycin level

24 hours or more after initiation of the infusion, with a target Css range between 15 to 25 mg/L. In

accordance with previously published dosing tables and nomograms, loading doses are purely weight-

based while maintenance doses are generally determined based on estimated creatinine clearance.

Implementation of a Vancomycin CIV Protocol

At Kingston Health Sciences Centre (KHSC), vancomycin CIV is prescribed in selected patients.

However, there has been no standardized method for ordering and administering vancomycin CIV.

Clinicians wishing to initiate vancomycin CIV and monitor therapy did so in the absence of a guideline or

order set, potentially compromising patient safety. The lack of standardization in the manufacturing and

distribution process also created opportunities for error, such as when infusion rates were modified

without accounting for changes in drug concentration of a newly prepared infusion bag.

Thus, the current project implemented and evaluated the impact of a guideline and associated

order-set for the administration of vancomycin via continuous intravenous infusion at KHSC. The aim

was to characterize both the risks and the potential benefits of vancomycin CIV use after implementation.

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METHODS

Study Design

This two-phase research project guided the implementation and retrospective evaluation of

guideline-directed vancomycin CIV therapy at a 470-bed, acute care academic teaching hospital. By

definition, use of the guideline was encouraged but not mandatory and the vancomycin CIV use

evaluation was observational in nature. Approval from the Queen’s University Health Sciences and

Affiliated Hospitals Research Ethics Board was obtained prior to study commencement.

The first phase consisted of the development of an institutional guideline (Appendix 1) and

associated order set (Appendix 2) for vancomycin CIV with input from various stakeholder groups from

antimicrobial stewardship, internal medicine, pharmacy, nursing, and clinical laboratory services. In

addition, pharmacists and internal medicine residents were educated on the appropriate use of

vancomycin CIV.

Phase two occurred between March 15th and April 26th, 2019 and all patients prescribed

intravenous vancomycin at the Kingston General Hospital (KGH) site were screened for potential

eligibility to receive vancomycin CIV based on guideline criteria.

Patient Population

All adult inpatients at the KGH site prescribed intravenous vancomycin during the evaluation

period were included in the study. Patients were excluded if they were receiving renal replacement

therapy, were pregnant or breastfeeding, or if they received less than 7 consecutive days of intravenous

vancomycin therapy.

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Study Outcomes

The primary outcome was the proportion of patients initiated on vancomycin CIV relative to the

number of patients eligible to receive vancomycin CIV.

Patients were considered eligible to receive CIV if they met one or more of the following criteria:

1) requiring a vancomycin IIV maintenance dose of greater than or equal to 4 grams in 24 hours

using existing dosing guidelines to reach target vancomycin serum levels and expected duration

of therapy is at least 7 days

2) unable to reliably achieve and/or maintain therapeutic targets using vancomycin IIV dosing

3) vancomycin CIV recommended by the KHSC Infectious Diseases or Antimicrobial Stewardship

at KHSC (asK) consult services

Secondary outcomes were:

1) the proportion of vancomycin CIV orders that were adherent to guideline dosing and monitoring

recommendations

2) the proportion of patients prescribed vancomycin CIV who:

a. achieved target serum concentration range within 24 or 48 hours of initiation of infusion

b. achieved at least one serum vancomycin concentration that was outside the target

therapeutic range (monitored until discharge, discontinuation of vancomycin CIV, or for

two weeks, whichever was shortest)

c. were initiated inappropriately on vancomycin CIV based upon guideline criteria relative

to the total number of patients who received vancomycin CIV

d. experienced at least one clinically significant interruption in vancomycin CIV therapy

e. experienced at least one instance where the vancomycin CIV was administered

concomitantly with a potentially incompatible intravenous medication

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Data Collection

Patients prescribed IV vancomycin were identified by the resident investigator through daily

medication usage reports generated using the BDM Pharmacy version 10.21.6 software system. Patients

with an active order for vancomycin IIV were reviewed between days 3 to 5 of therapy, then weekly until

discontinuation of vancomycin, discharge from KHSC, or the end of the data collection period.

Data relating to patient demographics, vancomycin dosing regimens, and vancomycin serum

levels were collected from the KHSC QuadraMed CPR electronic medical record, the BDM Pharmacy

version 10.21.6 software system, and patients’ bedside paper charts by the resident investigator. The data

were recorded using a standard data collection form depicted in Appendix 1. Patients’ target vancomycin

trough or steady state concentration range was obtained through chart review. If not documented, the

guideline defined target of 10 to 20 mg/L was used. When it was unclear whether eligibility criteria were

met for a patient, the resident investigator consulted co-investigators and a consensus was reached.

Data Analysis

All data were entered into a Microsoft Excel® file designed for this research project. Means,

medians, and standard deviations were calculated for continuous data such as age, weight, vancomycin

daily dosages, and vancomycin levels. Categorical data were reported as percentages and proportions.

Data that required statistical analysis were to be imported into IBM SPSS®. For comparative analysis of

continuous data either unpaired t-tests or Mann-Whitney U tests were to be conducted. A p-value of less

than 0.05 was to be considered statistically significant.

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RESULTS

A total of 139 patients prescribed IV vancomycin between March 20 and May 1, 2019 were

screened retrospectively to determine potential eligibility for CIV. Eighty-nine patients were excluded

because they received less than 7 days of intravenous vancomycin therapy, 20 patients were excluded due

to renal replacement therapy, and the remaining 30 patients were assessed for eligibility to receive CIV on

the basis of total daily dose, therapeutic level attainment, or involvement by Infectious Diseases or asK

(Figure 1).

Primary Outcome

None of the 24 patients deemed to be potentially eligible for CIV were initiated on vancomycin

CIV during the study period. Furthermore, no patients deemed ineligible for vancomycin CIV were

prescribed it. Therefore, none of the pre-defined secondary outcomes for this project were measurable.

All 24 patients met vancomycin CIV eligibility criteria based on inability to reliably achieve

and/or maintain therapeutic targets using vancomycin IIV. Fifteen patients (63%) had at least one sub-

therapeutic vancomycin serum level and 12 patients (50%) achieved at least one supra-therapeutic

vancomycin level at some point during vancomycin IIV therapy. The range of vancomycin levels was

between less than 5 mg/L and 35.1 mg/L. Eligibility for vancomycin CIV based on requiring more than or

equal to 4 grams of vancomycin in 24 hours was met by only a single patient (4%) receiving 1.5 grams

intravenously every 8 hours (4.5 grams in 24 hours). KHSC Infectious Diseases consult service was

involved in the care of 8 patients (33%) who were eligible to receive vancomycin CIV; however, it was

never recommended. (Table 1)

Characteristics of CIV-Eligible Patients

Most of the 24 vancomycin CIV eligible patients were admitted to the critical care medicine or

internal medicine services (Figure 2), were between 50 and 79 years of age and weighed between 60 and

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99 kilograms. (Table 2). There were significantly more male patients (16 of 24 patients; 67%). Seventeen

patients (71%) did not have any degree of renal impairment, defined as an average calculated creatinine

clearance of greater than or equal to 90 mL/min based on the Cockcroft-Gault equation. (Table 2)

Characteristics of Vancomycin Therapy in CIV-Eligible Patients

The most common indication for intravenous vancomycin in the CIV-eligible population was

bacteremia (8 of 24 patients; 33%), followed by respiratory tract infection (5 of 24 patients; 21%) and

osteomyelitis (4 of 24 patients; 17%). (Figure 3) Methicillin-resistant Staphylococcus aureus (MRSA)

was the most commonly isolated or suspected pathogen, with 9 patients (38%) being treated for a

confirmed MRSA infection and 2 patients (8%) being treated empirically. Enterococcus faecium (3

patients; 13%) and Staphylococcus epidermidis (4 patients; 17%) were also isolated in a minority of

cases. (Figure 4) One CIV-eligible patient received vancomycin for Enterococcus faecalis pneumonia due

to a documented allergy to penicillin. In addition, 14 patients (58%) received a concomitant intravenous

nephrotoxin at some point during IV vancomycin therapy, the most common medication being

piperacillin/tazobactam (7 patients).

A total daily vancomycin IIV dose of 3 or more grams was initially prescribed to 6 of 24

vancomycin CIV eligible patients (25%). Eleven CIV-eligible patients (46%) eventually required at least

3 grams of vancomycin per day at some point during therapy. Moreover, 5 patients required 3.75 grams

per day and 1 patient was prescribed a total daily dose of 4.5 grams. (Table 3) Three CIV-eligible patients

were eventually discharged home on prolonged courses of IV vancomycin, none of whom required

greater than 3 grams of vancomycin per day during the hospital stay. The KHSC Infectious Diseases

consult service was initially involved in the care of two of these patients but were no longer involved at

the point of discharge.

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DISCUSSION

Despite the availability of a guideline and order set, none of the 24 patients meeting institutional

eligibility criteria were initiated on or transitioned from vancomycin intermittent to continuous

intravenous (CIV) infusion. Some of the barriers to adoption of CIV could have been perceived patient

acceptance by prescribers, interference with physiotherapy and activity, total daily doses just below cutoff

criteria of 4 grams, and anticipated discontinuation of IV vancomycin within 7 days.

While the pharmacists at KHSC received education and guidance on the appropriate use of

vancomycin CIV through practice rounds, physician-based education was only provided to Internal

Medicine residents. Therefore, it is possible that prescribers from other clinical services, including

Critical Care and Orthopedic Surgery, were not aware of the availability of a guideline and order set for

vancomycin CIV.

Although pharmacists were encouraged to consider the use of vancomycin CIV in eligible

patients, the 1-week run-in period between order set availability and data collection may have been too

short for them to become comfortable making recommendations to the medical teams. Furthermore, a

data collection period of 6 weeks may have been insufficient to capture the infrequent prescribing of

vancomycin CIV.

The results also highlight the limitations of the current practice of vancomycin IIV dosing at

KHSC, as all of the CIV eligible patients who were chart reviewed did not achieve clinically acceptable

vancomycin serum levels by day 3 of therapy. This is especially concerning as many of these patients

were receiving treatment for severe and/or deep-seated infections that necessitate prolonged courses of

effectively dosed antimicrobial therapy (e.g. bacteremia, pneumonia, and osteomyelitis). However, this

research project was not designed to assess adherence to the existing dosing guideline for vancomycin

IIV.

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In addition, a large proportion of patients, some of whom were also receiving

piperacillin/tazobactam concomitantly, experienced a supra-therapeutic level while on vancomycin IIV.

Although this project did not aim to evaluate drug-induced nephrotoxicity, concurrent intravenous use of

vancomycin and piperacillin/tazobactam may increase the risk of acute kidney injury more than threefold

compared to vancomycin monotherapy. 23

The vancomycin IIV maintenance dosage of 4 grams per day was used as a threshold for

vancomycin CIV eligibility based on observational data suggesting that total daily doses exceeding 4

grams are associated with a higher likelihood of vancomycin-related nephrotoxicity. 4 Consequently, only

1 patient met the threshold dosage-based eligibility criteria for vancomycin CIV. However, using a

decreased threshold dosage of 3 grams per day would have identified 5 additional patients as vancomycin

CIV-eligible, all of whom received a daily dosage of 3.75 grams at some point during the study period

(only 6% below the original threshold dosage of 4 grams). As the AUC/MIC target of 400 mcg*h/mL

may be achieved even at a lower target serum concentration of 15 mg/L, it may have been reasonable to

initiate these 5 additional patients on vancomycin CIV.

The 3 vancomycin CIV-eligible patients who were discharged home on IV vancomycin may

represent missed opportunities for transition to CIV as the necessary equipment to run a continuous IV

infusion in these patients is already available in the form of a continuous ambulatory IV infusion pump

(e.g. CADD device). Vancomycin CIV has been studied in the setting of outpatient antimicrobial therapy

(OPAT) and identified as a clinically acceptable alternative to IIV in several observational trials.13,24,25

The usage of vancomycin CIV in patients who are prescribed OPAT could drastically simplify therapeutic

drug monitoring due to no longer requiring coordination of outpatient visits to coincide with trough

timings. Inappropriately timed serum vancomycin levels measured in the outpatient setting may result in

unnecessary dosage adjustments that place patients at risk for therapeutic failure or toxicity.

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CONCLUSION

In this retrospective evaluation of guideline-directed vancomycin CIV therapy at KHSC, there

was no appropriate prescribing of vancomycin CIV, despite most patients meeting institutional eligibility

criteria based on inability to achieve or maintain therapeutic targets using vancomycin IIV dosing.

Additionally, there was no inappropriate usage of vancomycin CIV therapy. Future studies should aim to

explore reasons for lack of vancomycin CIV adoption in specific patient populations, such as patients who

are anticipated to be discharged home on OPAT.

Furthermore, as the visibility of the vancomycin CIV guideline and order set increases, there

should be an effort to provide just-in-time support by pharmacists and the asK team to ensure appropriate

usage of vancomycin CIV therapy at the point of prescription. Once enough time has lapsed to capture

future vancomycin CIV prescriptions (e.g. 6 months to 1 year), the methods outlined in this project could

contribute to a continuous quality improvement initiative to ensure that the use of vancomycin CIV

therapy at KHSC is properly evaluated.

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REFERENCES

1. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of

consensus recommendations from the infectious diseases Society of America, the American Society of

Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2009

Aug; 49(3):325-7.

2. Hao JJ, Chen H, Zhou JX. Continuous versus intermittent infusion of vancomycin in adult patients: A

systematic review and meta-analysis. Int J Antimicrob Agents 2016 Jan;47(1):28-35.

3. Drusano G et al. Vancomycin dose recommendations for HAP, VAP, or HCAP and attainment of

vancomycin trough concentrations of 15-20 mg/L: cognitive dissonance. IDSA Annual Meeting

(Abstract 447) 2007 Oct.

4. Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per

day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother 2008

Apr;52(4):1330-6.

5. Neely AP, Melanson SE, Carty MG, et al. Are vancomycin trough concentrations adequate for optimal

dosing? Antimicrob Agents Chemother 2014;58(1):309-16.

6. Wysocki M, Delatour F, Faurisson F et al. Continuous versus intermittent infusion of vancomycin in

severe Staphylococcal infections: a prospective multicenter randomized study. Antimicrob Agents

Chemother 2001 Sep;45(9):2460-7.

7. Bissell BD, Riggi G and Morrison C. Evaluation of continuous infusion vancomycin administration in

a critically ill trauma population. J Intensive Care Med 2018 Jan.

8. van Maarseveen EM, Gipmans S, Vasbinder E et al. Switching from intermittent to continuous

infusion of vancomycin in critically ill patients: toward a more robust exposure. Ther Drug Monit

2016 Jan;38(3):398-401.

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9. Lin H, Bukovskaya Y, De Moya M et al. Vancomycin continuous infusion versus intermittent infusion

during continuous venovenous hemofiltration: slow and steady may win the race. Ann Intensive Care

2015 May;5:10.

10. Tafelski S, Nachtigall I, Troeger U et al. Observational clinical study on the effects of different dosing

regimens on vancomycin target levels in critically ill patients: continuous versus intermittent

application. J Infect Public Health 2015 Jul-Aug;8(4):355-63.

11. Hong LT, Goolsby TA, Sherman DS et al. Continuous infusion vs intermittent vancomycin in

neurosurgical intensive care unit patients. J Crit Care 2015 Oct;30(5):1153.e1-6.

12. Schmelzer TM, Christmas AB, Norton JH et al. Vancomycin intermittent dosing versus continuous

infusion for treatment of ventilator-associated pneumonia in trauma patients. Am Surg 2013

Nov;79(11):1185-90.

13. Vuagnat A, Stern R, Lotte A et al. High dose vancomycin for osteomyelitis: continuous vs.

intermittent infusion. J Clin Pharm Ther 2004 Aug;29(4):351-7.

14. Saugel B, Nowack HC, Hapfelmeier A et al. Continuous intravenous administration of vancomycin in

medical intensive care unit patients. J Crit Care 2013 Feb;28(1):9-13.

15. Pea F, Furlanut M, N Camilla, et al. Prospectively validated dosing nomograms for maximizing the

pharmacodynamics of vancomycin administered by continuous infusion in critically ill patients.

Antimicrob Agents Chemother 2009 May;53(5):1863-7.

16. van Maarseveen EM, Bouma A, Touw DJ, et al. Design and prospective validation of a dosing

instrument for continuous infusion of vancomycin: a within-population approach. Eur J Clin

Pharmacol 2014 Nov;70(11):1353-9.

17. Baptista JP, Roberts JA, Sousa E, et al. Decreasing the time to achieve therapeutic vancomycin

concentrations in critically ill patients: developing and testing of a dosing nomogram. Crit Care 2014

Dec;18(6):654.

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18. Sin JH, Newman K, Elshaboury RH, et al. Prospective evaluation of a continuous infusion

vancomycin dosing nomogram in critically ill patients undergoing continuous venovenous

haemofiltration. J Antimicrob Chemother 2018 Jan;73(1):199-203.

19. Sunnybrook Health Sciences Centre. Continuous Infusion (CIV) Vancomycin – Guidelines for use.

Last updated: 2016 Jan.

20. University of Wisconsin Hospitals and Clinic Authority. Intravenous Vancomycin Use – Adult –

Inpatient/ Ambulatory Clinical Practice Guideline. Last updated: 2018 May.

21. Scottish Antimicrobial Prescribing Group. Intravenous Vancomycin Use in Adults (Continuous

Infusion). Last updated: 2017 Jan.

22. National Health Service (NHS) Trust: St George’s University Hospitals and Epston and St Helier

University Hospitals. Guidelines for the Use of Vancomycin by Continuous Infusion in Critical Care

Areas. Last updated 2017 Sep.

23. Luther MK, Timbrook TT, Caffrey AR, et al. Vancomycin plus piperacillin-tazobactam and acute

kidney injury in adults: A systematic review and meta-analysis. Crit Care Med 2018 Jan;46(1):12-20.

24. Ingram PR, Lye DC, Fisher DA et al. Nephrotoxicity of continuous versus intermittent infusion of

vancomycin in outpatient parenteral antimicrobial therapy. Int J Antimicrob Agents 2009 Dec;

34(6):570-4.

25. Verrall AJ, Llorin R, Tam VH et al. Efficacy of continuous infusion of vancomycin for the outpatient

treatment of methicillin-resistant Staphylococcus aureus infections. J Antimicrob Chemother 2012

Dec;67(12):2970-3.

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Figure 1. Process of Screening Patients Receiving Vancomycin Intermittent Intravenous Infusion (IIV)

to Determine Eligibility for Vancomycin Continuous Intravenous Infusion (CIV) Therapy

19

Figure 2. Distribution of Vancomycin Continuous Intravenous Infusion Eligible Patients by Admitting

Service (n = 24)

Figure 3. Distribution of Vancomycin Continuous Intravenous Infusion Eligible Patients by Infection

Type (n = 24)

Critical Care

29%

Internal Medicine

25%

Orthopedic

Surgery

17%

Hematology

Oncology

13%

Cardiac Surgery

4%

General Surgery

4%

Radiation

Oncology

4%

Urology

4%

0 1 2 3 4 5 6 7 8 9

Urinary Tract

Skin & Soft Tissue

Prosthetic Joint

Intra-abdominal

Osteomyelitis

Respiratory Tract

Bacteremia

Number of Patients

Typ

e of

Infe

ctio

n

20

Figure 4. Distribution of Vancomycin Continuous Intravenous Infusion Eligible Patients by Organism

Isolated or Suspected (n = 24)

Table 1. Patient Eligibility Based on Institutional Criteria for Vancomycin CIV (n = 24)

Number of Patients (%)

Criterion 1 ≥ 4 grams in 24 hours (at any time on IIV) 1 4%

Criterion 2

Serum vancomycin level out of target range

(at any time on IIV)

24 100%

Sub-therapeutic level (at any time on IIV) 15 63%

On Day 3

Between Day 3 and 7

Between Day 7 and 141

15 63%

7 29%

1 17%

Supra-therapeutic level (at any time on IIV) 12 50%

On Day 3 (all between 20.1 and 25 mg/L) 5 21%

Between Day 3 and 7

Between 20.1 and 25 mg/L

Between 25.1 and 29.9 mg/L

Greater than 30.0 mg/L

8 33%

4 17%

2 8%

2 8%

Between Day 7 and 141

(all between 20.1 and 25 mg/L)

3 50%

Criterion 3 Recommendation by ID (at any time on IIV) 0 0%

Recommendation by asK (at any time on IIV) 0 0% 1 Only 6 patients remained on vancomycin IIV at 14 days

0 1 2 3 4 5 6 7 8 9 10

General gram positives (empiric)

Enterococcus spp. (empiric)

E. faecalis (confirmed)

E. faecium (confirmed)

S. epidermidis (confirmed)

MRSA (empiric)

MRSA (confirmed)

Number of Patients

Org

an

ism

Iso

late

d o

r S

usp

ecte

d

21

Table 2. Characteristics of Vancomycin Continuous Intravenous Infusion Eligible Patients (n = 24)

Category Number of Patients (%) Median (Range)

Age (years) Greater than or equal to 80 2 8%

63.5 (20-87)

65-79 8 33%

50-64 7 29%

30-49 4 17%

Less than 30 3 13%

Gender

Female 8 33% N/A

Male 16 67%

Weight (kg)

Greater than or equal to 100 4 17%

80.6 (53-120)

80-99 10 41%

60-79 9 38%

Less than 60 1 4%

Average Calculated Creatinine Clearance (mL//min) 1

Greater than or equal to 90 17 71%

N/A2 60-89 4 17%

40-59 1 4%

Less than 40 2 8% 1 The patient’s calculated creatinine clearance averaged over all review days during IV vancomycin therapy

Based on online calculator: https://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation 2 Median and range not reported as many patients’ estimated creatinine clearances calculated based on serum creatinine

values were unrealistically high (e.g. greater than 200 mL/min)

Table 3. Comparison of Initial Daily Vancomycin Doses and Highest Total Daily Doses Required

During Therapy in Vancomycin Continuous Intravenous Infusion Eligible Patients (n = 24)

Total Daily Dose Number and Percentage of Patients

(Initial Dose)

Number and Percentage of Patients

(Highest Dose)

0.5 grams 1 4% 1 4%

1 gram 1 4% 1 4%

1.5 grams 1 4% 1 4%

2 grams 10 41% 7 29%

2.5 grams 5 21% 3 13%

3 grams 4 17% 5 21%

3.75 grams 2 8% 5 21%

4.5 grams 0 0% 1 4%

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APPENDIX 1: KHSC Vancomycin Continuous Intravenous (CIV) Infusion Guideline

23

24

25

26

27

28

APPENDIX 2: KHSC Vancomycin Continuous Intravenous (CIV) Infusion Order Set

29

30

31

APPENDIX 3: Vancomycin CIV Eligibility & Use Data Collection Form

Attending Service: _________________________________

GENERAL INFORMATION

Age

Gender ☐M ☐F Antibiotic allergies and reaction

Height (cm)

Weight (kg) Day 1 of any IV vancomycin therapy

GENERAL INFORMATION – WEEKLY REVIEW

Day of review

☐3 ☐4 ☐5

Day of review

☐7 ☐9

☐8 ☐10

Day of review

☐14 ☐16

☐15 ☐17

Day of review

☐21 ☐23

☐22 ☐24

Day of review

☐25 ☐27

☐26 ☐28

Most recent serum creatinine (mcmol/L)

Creatinine clearance (mL/min)1

Creatinine trend ☐stable

☐trending up

☐stable

☐trending up

☐stable

☐trending up

☐stable

☐trending up

☐stable

☐trending up Indication for IV vancomycin

Concomitant nephrotoxins

☐Yes:

☐No

☐Yes:

☐No

☐Yes:

☐No

☐Yes:

☐No

☐Yes:

☐No On active ID list or ASK2 involvement

☐ID ☐ASK

☐Neither

☐ID ☐ASK

☐Neither

☐ID ☐ASK

☐Neither

☐ID ☐ASK

☐Neither

☐ID ☐ASK

☐Neither 1 Estimated using Cockcroft-Gault equation (in mL/min) with calculator from mdcalc.com (using adjusted body weight if overweight/obese) 2 Antimicrobial Stewardship at KHSC

EXCLUSION CRITERIA (met at any time during review)

☐Receiving renal replacement therapy

☐Pregnant or breastfeeding

☐Expected duration of therapy less than 7 days

Explain:

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GENERAL ADMINISTRATION DATA: INTERMITTENT IV INFUSION

Day of review

☐3 ☐4 ☐5

Day of review

☐7 ☐9

☐8 ☐10

Day of review

☐14 ☐16

☐15 ☐17

Day of review

☐21 ☐23

☐22 ☐24

Day of review

☐25 ☐27

☐26 ☐28

Current vancomycin dosing

Therapeutic target (mg/L)

Source of information ☐Guideline

☐Patient chart, by:

☐Guideline

☐Patient chart, by:

☐Guideline

☐Patient chart, by:

☐Guideline

☐Patient chart, by:

☐Guideline

☐Patient chart, by:

Criterion 1: Requiring an II vancomycin maintenance dose of greater than or equal to 4 grams in 24 hours (via existing dosing guidelines or upon serum level monitoring directed to reach a target of 15 to 20 mg/L) and expected duration of therapy is at least 1 week. Criterion 2: Unable to reliably achieve and/or maintain therapeutic targets using II vancomycin dosing. Criterion 3: CI vancomycin prescribed by KHSC Infectious Disease consult service or Antimicrobial Stewardship at KHSC (ASK).

PRIMARY OUTCOME: ELIGIBILITY FOR CONTINUOUS IV INFUSION

Day of review

☐3 ☐4 ☐5

Day of review

☐7 ☐9

☐8 ☐10

Day of review

☐14 ☐16

☐15 ☐17

Day of review

☐21 ☐23

☐22 ☐24

Day of review

☐25 ☐27

☐26 ☐28

Criterion 1 ☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met Criterion 2 ☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met Criterion 3 ☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met

☐Met

☐Not Met

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LD: Loading dose MD: Maintenance dose

CONTINUOUS IV INFUSION DATA

☐New start ☐Transition, day of therapy when transitioned:

Most recent serum creatinine (mcmol/L) and throughout Creatinine clearance (mL/min) Creatinine trend

☐stable

☐trending up

Eligibility criteria met for use ☐Criterion 1 ☐Criterion 2 ☐Criterion 3 ☐None (inappropriate)

Type of line used (specify) ☐Central (eg. PICC): ☐Peripheral:

LD MD1 MD2 MD3 MD4 MD5 MD6 MD7 MD8

Dose (mg)

N/A

Date started

Time started

Concentration (mg/mL)

N/A

Rate (mL/h)

Rate (mg/h)

Steady state vancomycin level (mg/L)

Date drawn

Time drawn

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SECONDARY OUTCOME: ADHERENCE TO GUIDELINE

Order set used? ☐Yes ☐No

Adherent to initial dosing and monitoring guidelines? ☐Yes ☐No

If NOT adherent and for transitions from intermittent vancomycin, mark all that apply:

☐No empiric dose reduction when transitioning ☐ Incorrect timing of first vancomycin level

☐Other reason(s):

If NOT adherent and for NEW continuous vancomycin starts, mark all that apply:

☐Incorrect (or no) loading dose ☐Incorrect maintenance dose

☐Incorrect timing of first vancomycin level ☐Other reason(s):

SECONDARY OUTCOME: TARGET ATTAINMENT

Target attained within 24 hours? ☐Yes ☐No

Target attained within 48 hours? ☐Yes ☐No

SECONDARY OUTCOME: INTERRUPTION OF THERAPY

Was the continuous IV infusion interrupted at any time? ☐Yes ☐No

Describe reasons for interruption (also document if multiple interruptions occurred)

SECONDARY OUTCOME: IV INCOMPATIBILITY

List any incompatible IV medications3

Were any incompatible IV medications given using the same line (or Y-site)? ☐Yes ☐No

3 Incompatible medications include: Piperacillin/tazobactam, ceftazidime, imipenem, cloxacillin, moxifloxacin, propofol, valproic acid, phenytoin, theophylline, methylprednisolone, furosemide

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