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Residency Project Pearls

Safety of extended infusion piperacillin-tazobactam plus vancomycin versus

standard infusion piperacillin-tazobactamplus vancomycin in general medicine

patients with a diagnosis of healthcarepatients with a diagnosis of healthcare associated pneumonia

Kati J. Khouri, Pharm.D.Joseph A. Levato, Pharm.D.

Rolla T. Sweis, Pharm.D., M.A., BCPS

Conflict of Interest

• The speaker has no actual or potential conflict of interest in relation to this presentation

Learning Objectives

1. Define acute kidney injury (AKI).

2. Recognize common medications that may b d l AKIcontribute to developing AKI.

Advocate Christ Medical Center (ACMC)

• Private, non-profit, 694-bed community teaching institution

• Nearly 1,000 affiliated physiciansl d• Level 1 trauma center, providing

emergency care for more than 95,000 patient visits annually

• Recognized by the American Nurses Credentialing Center as a Magnet Medical Center

Epidemiology

• According to United States data, the reported prevalence of hospital-acquired Acute Kidney Injury (AKI) is estimated to be up to 7.1%

• AKI has a poor prognosis with mortality ranging from 10%-80%

Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002; 39:930–936 Kaufman J, Dhakal M, Patel B, et al. Community-acquired acute renal failure. Am J Kidney Dis 1991; 17: 191-198Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983; 74:243-8 Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G. Risk factors and outcome of hospital-acquired acute renal failure. Clinical epidemiologic study. Am J Med 1987; 83:65-71 Liaño F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid Acute Renal Failure Study Group. Kidney Int 1998; 53:S16-24

Definition

• Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines define AKI as:– An absolute increase in serum creatinine (SCr) ofAn absolute increase in serum creatinine (SCr) of ≥0.3mg/dL within 48 hours, or

– ≥50% increase in SCr within seven days, or– A reduction in urine output

• Documented oliguria of < 0.5 ml/kg/hr for > 6 hours

Rocco, M. V., & Berns, J. S. (2012). KDOQI clinical practice guideline for diabetes and CKD: 2012 Update. American Journal of Kidney Diseases, 60(5), 850-886.

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Drug-Induced Acute Kidney Injury

• Complications lead to:– Increased hospital stay– Increased cost– Increased mortality

• Several medications have the potential to cause AKI such as:– Vasopressors– Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)– Diuretics– Antibiotics

Minejima, E., Choi, J., Beringer, P., Lou, M., Tse, E., & Wong-Beringer, A. (2011). Applying new diagnostic criteria for acute kidney injury to facilitate early identification of nephrotoxicity in vancomycin-treated patients. Antimicrobial agents and chemotherapy, 55(7), 3278-3283.Mehta, R., Kellum, J., Shah, S., Molitoris, B., Ronco, C., Warnock, D., & Levin, A. (2007). Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Critical care, 11(2), R31.

HCAP Treatment

• A combination of antibiotics is often recommended for empiric therapy of certain infections such as healthcare associated pneumonia (HCAP)– AmericanThoracic Society HCAP GuidelinesAmerican Thoracic Society HCAP Guidelines

• Anti-Pseudomonal beta-lactam + Vancomycin ± Anti-Pseudomonal fluoroquinolone or aminoglycoside

– ACMC• Piperacillin-Tazobactam (pip-tazo) + Vancomycin

American Thoracic Society. (2005). Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med, 171, 388-416.Dellit, T. H., Owens, R. C., McGowan, J. E., et.al (2007). Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clinical Infectious Diseases, 44(2), 159-177

Vancomycin

• Class– Glycopeptide

• EliminationR l– Renal

• Spectrum of activity– Gram positive organisms including methicillin-resistant

Staphylococcus aureus (MRSA)

Vancomycin. In: Lexi-drugs online [database on the Internet]. Hudson (OH): Lexicomp, Inc.; 2013 [updated 6 Jan 2011; cited 10 Mar 2014]. Available from: http://online.lexi.com.

Piperacillin-Tazobactam

• Class– Beta-lactam/beta-lactamase inhibitor

• Elimination– RenalRenal

• Spectrum of activity– Gram-positive organisms– Gram-negative organisms including Pseudomonas

aeruginosa– Anaerobes

Piperacillin-Tazobactam. In: Lexi-drugs online [database on the Internet]. Hudson (OH): Lexicomp, Inc.; 2013 [updated 6 Jan 2011; cited 10 Mar 2014]. Available from: http://online.lexi.com. Dellit, T. H., Owens, R. C., McGowan, J. E., et.al (2007). Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clinical Infectious Diseases, 44(2), 159-177

Piperacillin-Tazobactam Administration

• Standard Infusion Piperacillin-Tazobactam (SIPT)– Administered over 30 minutes– Dosing interval of every 6-8 hours

• E t d d I f i Pi illi T b t (EIPT)• Extended Infusion Piperacillin-Tazobactam (EIPT)– Administered over 4 hours– Dosing interval of every 8-12 hours

Kaufman, S. E., Donnell, R. W., & Hickey, W. S. (2011). Rationale and evidence for extended infusion of piperacillin–tazobactam. American Journal of Health-System Pharmacy, 68(16), 1521-1526.Yost, R. J., & Cappelletty, D. M. (2011). The Retrospective Cohort of Extended‐Infusion Piperacillin‐Tazobactam (RECEIPT) Study: A Multicenter Study. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 31(8), 767-775.

Extended Infusion

• Extending the administration time of beta-lactam antibiotics maximizes the time free drug is available at concentrations above the minimum inhibitory concentration (MIC)concentration (MIC)

• Pharmacodynamic dosing of beta-lactam antibiotics by extended infusion has been well referenced in the literature for years

Kaufman, S. E., Donnell, R. W., & Hickey, W. S. (2011). Rationale and evidence for extended infusion of piperacillin–tazobactam. American Journal of Health-System Pharmacy, 68(16), 1521-1526.Yost, R. J., & Cappelletty, D. M. (2011). The Retrospective Cohort of Extended‐Infusion Piperacillin‐Tazobactam (RECEIPT) Study: A Multicenter Study. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 31(8), 767-775.

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AKI Secondary to Vancomycin and Piperacillin-Tazobactam

• Penicillins have the potential to cause AKI such as acute interstitial nephritis

• Vancomycin’s nephrotoxic potential is not fully understood• Combination use may increase the risk of AKI compared to y p

administration of either agent alone• Safety data regarding extended infusion combination

therapy have been limited to mortality outcomes – Morbidity outcomes have not been fully evaluated

Mehta, R., Kellum, J., Shah, S., Molitoris, B., Ronco, C., Warnock, D., & Levin, A. (2007). Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Critical care, 11(2), R31.Kaufman, S. E., Donnell, R. W., & Hickey, W. S. (2011). Rationale and evidence for extended infusion of piperacillin–tazobactam. American Journal of Health-System Pharmacy, 68(16), 1521-1526.Yost, R. J., & Cappelletty, D. M. (2011). The Retrospective Cohort of Extended‐Infusion Piperacillin‐Tazobactam (RECEIPT) Study: A Multicenter Study. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 31(8), 767-775.

Observational Data• Hellwig et al.

– Retrospective evaluation of 735 adult patients– Compared patients on combination therapy of vancomycin +

pip-tazo vs. monotherapy of either agent alone – AKI defines as an increase in SCr of ≥ 0.5 mg/dL or a 50% . g

increase from baseline– Results

Hellwig T, Hammerquist R, Loecker B, et al. Retrospective evaluation of the incidence of vancomycin and/or piperacillin-tazobactam induced acute renal failure. Critical Care Medicine. December 2011. 39(12);79

Group General Medicine % AKI

Intensive Care Unit% AKI

Vancomycin monotherapy 4.9 6.0

Pip-tazo monotherapy 11.1 12.2

Combination therapy 18.6 21.2

Observational Data

• Balasubramanian et al.– Retrospective analysis of 226 adult patients– Compared patients on combination therapy of vancomycin + pip-

tazo vs. monotherapy of either agent alone – AKI defines as an increase in SCr of ≥ 0 5 mg/dLAKI defines as an increase in SCr of ≥ 0.5 mg/dL– Results

• No cases of nephrotoxicity were found among patients treated with vancomycin monotherapy

• Pip-tazo monotherapy– SIPT 4.4% vs. EIPT 2.2%

• Vancomycin + pip-tazo combination therapy– SIPT 22.7% vs. EIPT 19.6% incidence of AKI (p-value < 0.05)

Balasubramanian R, et al "Impact of concomitant use of vancomycin and piperacillin/tazobactam on nephrotoxicity in adult inpatients in a community hospital" ASPH 2013; Poster #5-43.

Change in Protocol

• In October 2012, ACMC transitioned from SIPT to an EIPT protocol

• Based on observational data and anecdotal experience from Infectious Disease physiciansexperience from Infectious Disease physicians, concern arose about the possible increase incidence of AKI in patients on combination therapy

Safety of extended infusion piperacillin-tazobactam plus vancomycin versus standard

infusion piperacillin-tazobactam plus p p pvancomycin in general medicine patients with a diagnosis of healthcare associated

pneumonia

Primary Objective

• To assess the incidence of AKI in patients on EIPT and vancomycin therapy versus SIPT and vancomycin in general medicine patients with a diagnosis of HCAPdiagnosis of HCAP

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Methods

• Single-center retrospective chart review• Institutional Review Board (IRB) approved• Analyzed subjects who were admitted to the hospital

with a diagnosis of HCAP from January 2012 to Marchwith a diagnosis of HCAP from January 2012 to March 2012 and compared them to similar subjects admitted with the same diagnosis from January 2013 to March 2013

• The baseline SCr was defined as the lowest SCr prior to initiating antibiotics

Primary Endpoint

• Incidence of AKI– AKI defined as an increase in serum creatinine of at least

0.5 mg/dL or a 50% increase in SCr from baseline

Statistical Methods

• Pearson Chi-square • Fisher’s exact test• Mann-Whitney U test• Computed utilizing SPSS® (Version 21)

Criteria

Inclusion Exclusion• Diagnosis of HCAP • Age less then 18 years• Age greater than or equal to 18 years • Patients on hemodialysis

• Received at least one dose of • Pregnancypiperacillin-tazobactam and vancomycin concomitantly

• General medicine patients (non-intensive care unit)

• A baseline serum creatinine level and a serum creatinine level post antibiotic initiation

Patient Enrollment

SIPTN=597

N= 130

467 subjects excluded

N=1035 subjects were assessed

EIPTN=438

N= 110

327 subjectsexcluded

Baseline CharacteristicsCharacteristic SIPT N=130 EIPT N=110 p-value

Average Age (years) 70.87 (20-104) 70.56 (22-95) 0.88

Male (%) 76 (58.0) 61 (55.0) 0.58

Average Weight (Kg) 78.4 (40-140) 76.5 (45-170) 0.68

A H i h ( ) 169 6 (140 0 190 5) 169 5 (144 7 190 5) 0 97Average Height (cm) 169.6 (140.0-190.5) 169.5 (144.7-190.5) 0.97

Average SCr mg/dL(Range)

1.1 (0.34-3.2) 1.2 (0.5-3.5) 0.25

Race (%)African American 46 (35.4) 43 (39.1) 0.55

Caucasian 82 (63.1) 58 (52.7) 0.11Hispanic 2 (1.5) 7 (6.4) 0.08

Non-Hispanic 0 (0) 2 (1.8) 0.20

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Baseline Characteristics

Comorbidities SIPTN=130

EIPTN=110

p-value

Hypertension (%) 87 (66.9) 87 (78.4) 0.048

Diabetes (%) 43 (33.1) 44 (39.6) 0.29

Hyperlipidemia (%) 37 (28.5) 30 (27.0) 0.80

CKD (%) 16 (12.3) 21 (18.9) 0.15

Cancer (%) 9 (6.9) 10 (9.0) 0.54

CHF (%) 26 (20.0) 28 (25.2) 0.33

COPD (%) 14 (10.8) 15 (13.5) 0.51

Baseline CharacteristicsNephrotoxic Agents SIPT

n=130EIPT

n=110p-value

IV Contrast (%) 17 (13.1) 23 (20.7) 0.11

NSAIDs (%) 7 (5.4) 4 (3.6) 0.51

ACEI/ARB (%) 31 (23.8) 28 (25.2) 0.80

Loop Diuretic (%) 36 (27.7) 34 (30.6) 0.62

Hydrochlorothiazide (%) 0 1 (0.9) 0.46

Spironolactone (%) 3 (2.3) 6 (5.4) 0.31

Aminoglycoside (%) 4 (3.1) 1 (0.9) 0.38

Antiviral (%) 1 (0.8) 5 (4.5) 0.09

Primary Outcome Results

SIPTN=130

EIPTN=110

p-value

SCr Increase of≥ 0.5mg/dL or by 50%

26 (20%) 11 (10%) 0.033

Patients with AKI SIPTN=26

EIPTN=11

p-value

Average Increase in SCr 1.33 ± 1.02 1.02 ± 0.61 0.52

Magnitude of SCr Change

Increase in SCr(mg/dL)

SIPTN=26 (%)

EIPTN=11 (%)

0.50 – 1.5 19 (73.1) 10 (90.9)1 51 – 2 5 4 (15 4) 01.51 2.5 4 (15.4) 02.51 – 3.5 2 (7.7) 1 (9.1)3.51 – 5.0 1 (3.8) 0

Average Vancomycin Dose and Levels

SIPTn=130

EIPTn=110

p-value

Average Total Daily Vancomycin Dose (Range)

1610 mg (375-6000) 1590 mg (500-3750) 0.85( g )Average VancomycinTrough (Range)

11.8 mcg/mL (2.9 -57.3) 12.6 mcg/mL (3.2-36.9) 0.10

Vancomycin Dose Ranges

Total Daily Vancomycin Dose (mg)

SIPTN=26 (%)

EIPTN=11 (%)

500-750 8 (30.7) 1 (9.1)1000- 1500 7 (26.9) 5 (45.4)1750 2000 8 (30 7) 2 (18 2)1750-2000 8 (30.7) 2 (18.2)3000-4000 1 (3.8) 3 (27.3)4500-6000 2 (7.7) 0

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Discussion

• In contrast to physician concerns prior to this study, there was a lower incidence of AKI in general medicine floor patients receiving vancomycin plus EIPT compared to vancomycin plus SIPT for the treatment of HCAP

• Average vancomycin doses and troughs were comparable between the groups

• Nephrotoxic agents were not confounding variables• No difference in baseline characteristics except for

hypertension

Limitations

• Single center study• External validity • Retrospective • Excluded ICU patients• Small patient sample size• Not evaluated

– Time to onset and resolution of AKI – Duration of therapy – Overlapping administration of both antibiotics– Different drug products used for the two groups

Conclusion

• There was a significantly lower incidence of AKI in general medicine patients diagnosed with HCAP on EIPT compared to the SIPT

Future Direction

• Larger, multicenter, prospective studies comparing EIPT + Vancomycin vs. SIPT + Vancomycin

• More prospective studies comparing other beta-lactam antibiotics in combination with vancomycinlactam antibiotics in combination with vancomycin should be conducted to further confirm these findings

Assessment Question #1

Which of the following statements is true?a. AKI is defined as an increase in serum creatinine of at least

0.5mg/dL or a 50% increase in serum creatinine from baselineb. AKI is defined as an increase in serum creatinine of at least

0 5mg/dL or a 30% increase in serum creatinine from baseline0.5mg/dL or a 30% increase in serum creatinine from baselinec. AKI is defined as in increase in serum creatinine of at least

1mg/dLd. AKI is defined as a 75% increase in serum creatinine from

baseline

Assessment Question #2

According to recent observational data, which of the following medications may contribute to the development of AKI when administered with Vancomycin?a. Dabigatranb. Piperacillin-Tazobactamc. Atenolold. Metronidazole

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Acknowledgements

• Joseph A. Levato, Pharm.D.• Rolla T. Sweis, Pharm.D., M.A., BCPS• Robert K. Mokszycki, Pharm.D., BCPS• Christopher Blair, Director of Research Services• Brian Maynard, Pharm.D. • Sarah Sienko, Pharm.D.

References• American Thoracic Society. (2005). Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J

Respir Crit Care Med, 171, 388-416.• Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis 2002; 39:930–936 • Kaufman J, Dhakal M, Patel B, et al. Community-acquired acute renal failure. Am J Kidney Dis 1991; 17: 191-198• Hou SH, Bushinsky DA, Wish JB, Cohen JJ, Harrington JT. Hospital-acquired renal insufficiency: a prospective study. Am J Med 1983; 74:243-8 • Shusterman N, Strom BL, Murray TG, Morrison G, West SL, Maislin G. Risk factors and outcome of hospital-acquired acute renal failure. Clinical epidemiologic

study. Am J Med 1987; 83:65-71 • Liaño F, Junco E, Pascual J, Madero R, Verde E. The spectrum of acute renal failure in the intensive care unit compared with that seen in other settings. The Madrid

Acute Renal Failure Study Group. Kidney Int 1998; 53:S16-24 Dellit, T. H., Owens, R. C., McGowan, J. E., et.al (2007). Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clinical Infectious Diseases, 44(2), 159-177.

• Rocco, M. V., & Berns, J. S. (2012). KDOQI clinical practice guideline for diabetes and CKD: 2012 Update. American Journal of Kidney Diseases, 60(5), 850-886.• Kaufman, S. E., Donnell, R. W., & Hickey, W. S. (2011). Rationale and evidence for extended infusion of piperacillin–tazobactam. American Journal of Health-, , , , y, ( ) p p J

System Pharmacy, 68(16), 1521-1526.• Piperacillin-Tazobactam. In: Lexi-drugs online [database on the Internet]. Hudson (OH): Lexicomp, Inc.; 2013 [updated 6 Jan 2011; cited 10 Mar 2014]. Available

from: http://online.lexi.com. • Vancomycin. In: Lexi-drugs online [database on the Internet]. Hudson (OH): Lexicomp, Inc.; 2013 [updated 6 Jan 2011; cited 10 Mar 2014]. Available from:

http://online.lexi.com. • Yost, R. J., & Cappelletty, D. M. (2011). The Retrospective Cohort of Extended‐Infusion Piperacillin‐Tazobactam (RECEIPT) Study: A Multicenter Study.

Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 31(8), 767-775.• Minejima, E., Choi, J., Beringer, P., Lou, M., Tse, E., & Wong-Beringer, A. (2011). Applying new diagnostic criteria for acute kidney injury to facilitate early

identification of nephrotoxicity in vancomycin-treated patients. Antimicrobial agents and chemotherapy, 55(7), 3278-3283.• Mehta, R., Kellum, J., Shah, S., Molitoris, B., Ronco, C., Warnock, D., & Levin, A. (2007). Acute Kidney Injury Network: report of an initiative to improve

outcomes in acute kidney injury. Critical care, 11(2), R31.• Min E, Box K, Lane J, et al. Acute kidney injury in patients receiving concomitant vancomycin and piperacillin/tazobactam. Critical Care Medicine. December 2011.

39(12);200.• Hellwig T, Hammerquist R, Loecker B, et al. Retrospective evaluation of the incidence of vancomycin and/or piperacillin-tazobactam induced acute renal failure.

Critical Care Medicine. December 2011. 39(12);79.

Questions

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Clinical Impact of Dual Antimicrobial Therapy in Critically

Ill Patients with Gram Negative Sepsis or Septic Shock

Mary Lenefsky, PharmDPGY-2 Critical Care Resident Midwestern

Chicago College of Pharmacy/Northwestern Memorial Hospital

Chicago, IL

The speaker has no actual or potential Conflict of Interest in relation to this presentation

Objectives

• Describe the rational behind using two active antimicrobial agents in patients with sepsis or septic shock

• List reasons antibiotics with overlapping coverage • List reasons antibiotics with overlapping coverage may be problematic

Sepsis: systemic host response to infection

Severe sepsis (organ dysfunction)

Septic shock (severe sepsis + hypotension not

Severe sepsis and septic shock kill 1

i 4 l

• Speed and appropriateness of therapy ultimately influence patient outcome

ypresponsive to fluids) in 4 people

Dellinger P, et al. Crit Care Med. 2013; 41:580-637.

Gram negative bacteremia

• Mortality ranges 20-60%1

• Initial coverage usually directed at P. aeruginosa

– Associated with higher mortality rates

• Initial regimens often include two agents active against P. aeruginosa

– 1989- lower mortality rates with combo vs. monotherapy2

– Not pertinent to current practice

2. Hilf, M et al. Am J Med. 1989; 87:540-46. 1. Johnson S, et al. Am J Health-Syst Pharm. 2011; 68:119-24.

What are the potential mechanisms?

• Potential mechanisms1,2

– Synergistic activity

– Broad coverage with agents with differing spectra of activity/resistance patterns

• Prevention of resistance development during antimicrobial therapy

1. Rodriguez A, et al. Crit Care Med. 2007; 35:1493-98. 2. Johnson S, et al. Am J Health-Syst Pharm. 2011; 68:119-24.

Potential issues

• Unnecessary use of antibiotics leads to– Resistance

– Increased adverse effects

– Increased costs

– Increased risk of superinfection

– Increased risk of C. difficile infection

Johnson S, et al. Am J Health-Syst Pharm. 2011; 68:119-24.

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Past research

• 2004- Baddour, et al.1

• 2007- Rodriguez, et al.2

• 2010- Martinez, et al. 3

• Post hoc analysis-possible benefit4

– Neutropenic patients

– Patients presenting with shock

2. Rodriguez A, et al. Crit Care Med. 2007; 35:1493-98.

4. Johnson S, et al. Am J Health-Syst Pharm. 2011; 68:119-24.

1. Baddour L, et al. Am J Resp Crit Care Med. 2004; 170:440-44.

3. Martinez J, et al. Antimicrob Agents Chemother. 2010; 54(9):3590-96.

Surviving sepsis 2012

Dellinger P, et al. Crit Care Med. 2013; 41:580-637.

Cochrane review

Cochrane Collaboration. 2014.

Self-assessment: Question 1

Double coverage of Pseudomonas has shown a mortality benefit in patients presenting with which of the following characteristics?

A. Liver transplant and neutropeniaB. Neutropenia and shockC. Kidney failure and neutropeniaD. Shock and kidney transplant

Self-assessment: Question 2

Potential outcomes of overusing antibiotics include

which of the following?

A. Increased risk of infection

B. Decreased risk of superinfection

C. Decreased risk of resistance

D. Decreased cost to the patient and the hospital

Northwestern Memorial Hospital• 894-bed Academic

Medical Center Hospital in downtown Chicago

• Primary teaching affiliate of N th t

Feinberg and Galter Pavilions Prentice Women’s Hospital

Northwestern University Feinberg School of Medicine

• 6 adult ICU’s • NSICU, CCU,

CTICU, SICU, NICU, MICU

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Our research project: study design

• Retrospective chart review

• January 1, 2013-December 31, 2013– Patients with ICD-9 Code for “Sepsis” or “Septic shock”

– Patients with positive blood culture for Gram Negative bacillus

• Cross referenced both reports

Methods

• Inclusion criteria– Admitted to an ICU within 24 hours of diagnosis of sepsis/septic

shock

– Total hospital stay at least 48 hours

– Positive GNR blood culture

• Exclusion Criteria – Patients with multi-drug resistant (MDR) organisms

– Those receiving triple active coverage

– No MIC/incomplete susceptibility data

– Palliative/not actively seeking care

M100-S23. CLSI. 2013; 33(1):1-200.

Study participants

• Double coverage– Beta-lactam and at least 1 dose of an aminoglycoside or

ciprofloxacin within 48 hours

– Active therapy determined by previously defined 2013 CLSI breakpoints

• Single coverage– Beta-lactam only

M100-S23. CLSI. 2013; 33(1):1-200.

Outcomes

• Primary outcome– In hospital mortality

• Secondary outcomes– Length of ICU stay

– Length of positive blood cultures

– Days of vasopressor use

– Days of steroid use

– Days of ventilator use

Statistical analysis

149 patients screened

68 patients excluded

80 patients included

34 encounters received single

coverage

47 encounters received double

coverage

ResultsTable 1. Baseline Demographics

Characteristic Singlecoverage (n=34)

Double coverage(n=47)

P value

Age- yr 61 +/- 16.8 62.6 +/- 14.9 0.638

Male sex 20 (44) 26 (55) 0.753

Systolic HF* 5 (15) 6 (13) 0.754

Diabetes 9 (27) 12 (26) 0.862

Coronary Artery Disease 4 (12) 10 (21) 0.289

Dialysis* 1 (3) 5 (11) 0.392

Autoimmune Disease* 1 (3) 7 (15) 0.131

On immunosuppression 9 (27) 14 (30) 0.807

*= Fisher’s exact test performed

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ResultsTable 1. Baseline Demographics

Characteristic Single coverage (n=34)

Double coverage(n=47)

P value

Known liver disease 9 (27) 5 (11) 0.063

History of liver transplant*

4 (12) 0 (0) 0.026

Current cancer 8 (24) 11 (23) 0.973

Central line on admission* 4 (12) 5 (11) 0.910

Prior hospitalization within 30 days

15 (44) 19 (40) 0.776

Surgery within 30 days 12 (35) 8 (17) 0.135

Antibiotic use within 30 days

14 (41) 15 (32) 0.652

*= Fisher’s exact test performed

ResultsTable 2. Characteristics When Diagnosed with Sepsis or Septic ShockCharacteristic Single

coverage (n=34)

Double coverage(n=47)

P value

SIRS criteria average 3.3 +/- 0.655 3.5 +/- 0.684 0.217

APACHE IV 56.4 +/- 26 62.8 +/- 33.1 0.351

ANC <500 cells/μL* 0 4 0.143

Serum creatinine baseline

*= Fisher’s exact test performed

S (mg/dL)

2.4 +/1 1.4 1.8 +/- 1.8 0.300

ALT (U/L) 123.4 +/- 226.1 61.5 +/- 75.4 0.090

AST (U/L) 122.1 +/- 175.7 67.7 +/- 122.8 0.120

Total bilirubin (mg/dL) 6.7 +/- 10.6 4.8 +/- 16.4 0.585

Direct bilirubin (mg/dL) 11.5 +/- 37.1 1.3 +/- 2.3 0.110

Lactate (mg/dL) 3.7 +/- 2.6 2.9 +/- 1.7 0.147

Results59% of patients received double coverage

Double Coverage Antibiotic (n=47)

94%

Aminoglycoside

Ciprofloxacin

ResultsGNRs in single coverage

Bacteria

Escherichia sp. (14)

Klebsiella sp. (7)

39%

19%

14%

Pseudomonas sp. (5)

Enterobacter sp. (3)

Proteus sp. (2)

Acinetobacter sp. (1)

Citrobacter sp. (1)

Stenotrophomonas sp. (1)

Serratia sp. (1)

Other (1)

ResultsGNRs in double coverage

Bacteria

Escherichia sp (22)

46%

17%

15%

Escherichia sp. (22)

Pseudomonas sp. (8)

Klebsiella sp. (7)

Enterobacter sp. (5)

Proteus sp. (4)

Serratia sp. (1)

Citrobacter sp. (1)

Results

6

7

8

9

ATI

ENT

S

PSA infections compared to mortality PSA infections compared to mortality

0

1

2

3

4

5

Single Coverage Double Coverage

NU

MB

ER O

F PA

Patients with PSA In hospital Mortality

20%

38%

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Results

20

25

30

IENTS

Source of GNR infectionSource of GNR infection

0

5

10

15

Urinary Tract Intra‐abdominal Other Unknown Lung IV Catheter

NUMBE

R OF PA

T

Frequency

Results: primary outcome

5

6

7

8

ATIENTS

In Hospital MortalityIn Hospital Mortality

P value= 0.504

0

1

2

3

4

5

In hospital mortality

NUMBE

R OF PAT

Single coverage Double coverage

21% 15%

Results: secondary outcomes

3

4

2.432.5

3

3.5

4

4.5

R OF DA

YS 

Secondary OutcomesSecondary Outcomes

1.03

1.51

0.21

1.421.15

1.49

1.11

0

0.5

1

1.5

2

Days of ICU stay (IQR)

Days of positive blood cultures

Days of vasopressor therapy

Days of steroid therapy

Days of mechanical ventilation

NUMBE

R

Single Coverage Double Coverage

P- value 0.052

Limitations

• Retrospective

• Small sample size

• Single institutionSingle institution

• Institution bias

• PK/PD parameters not analyzed

• ICU’s may have different practices

Conclusions

• Double coverage with a beta-lactam and an aminoglycoside or ciprofloxacin was not associated with an improvement in hospital mortality (p=0.504)

• There was no difference in time to clearance of blood l ( 0 160)cultures (p=0.160)

• There was no difference in length of ICU stay (p=0.872)

• There was no difference between days of vasopressor therapy or days of mechanical ventilation (p=0.974, p=0.241)

Going forward

• Data from this study suggest there may not be a mortality benefit in sepsis/septic shock

• Things to consider

– Patient specific factors

– Your institution’s antibiogram

– PK/PD parameters

8/14/2014

6

Acknowledgements

• John Esterly, PharmD, BCPS, AQ-ID

• Bryan Lizza, PharmD, BCPS

• Erik J. Rachwalski, PharmD, BCPS

Clinical Impact of Dual Antimicrobial Therapy in Critically

Ill Patients with Gram Negative Sepsis or Septic Shock

Mary Lenefsky, PharmDPGY-2 Critical Care Resident Midwestern

Chicago College of Pharmacy/Northwestern Memorial Hospital

Chicago, IL

The speaker has no actual or potential Conflict of Interest in relation to this presentation

8/14/2014

1

Implementation of a Clinical Decision Support Tool to

Facilitate Formulary Medication Utilization

Kristopher Lozanovski, PharmDPGY2 Pharmacy Informatics ResidentNorthShore University HealthSystem

Evanston, Illinois

Disclosure

The author of this presentation has no actual or potential conflicts

f i t tof interest

NorthShore University HealthSystem

• Four community hospitals:– Evanston: 354 beds– Glenbrook: 173 beds– Skokie: 156 beds– Highland Park: 149 beds– Total: 832 beds

• NorthShore Medical Group• NorthShore Research Institute• NorthShore Foundation

Background:

Computerized Provider Order Entry yand

Clinical Decision Support

Computerized Provider Order Entry (CPOE)

• Direct entry of clinical orders within an electronic health record (EHR) by licensed clinicians with ordering privileges

• Allows for direct transmission of orders from providers to pharmacists for verification via a computer system

• Advantages:– Standardization of orders– Legible, complete orders– Integration of clinical decision support systems (CDSS)

Hoey P. The Pharmacy Informatics Primer. ASHP. 2008.

Clinical Decision Support System (CDSS)

• The use of health information technology to provide providers with intelligently filtered information to aid in the clinical decision making process

• Alerts healthcare providers during order placement and review via CPOE

• Common alerts– Drug-drug interactions– Drug-allergy interactions– Drug-disease interactions– Best practice alerts– Dose discrepancies

Fischer MA, Arch Intern Med. 2008;168:2433.Teich JM, Arch Intern Med. 2000;160:2741.

8/14/2014

2

Potential Advantages and Disadvantages of CDSS

Disadvantages Advantages

Alert DesensitizationProvides automatic up to date and evidence based practices

Can be perceived as a threat li i l j d

Reduced clinical practice i ito clinical judgment variation

Promote over-reliance on software

Improved patient safety and quality of care

Time-consuming Facilitate workflowMaintenance, support, training Decrease costs

Fischer MA, Arch Intern Med. 2008;168:2433.Teich JM, Arch Intern Med. 2000;160:2741.

Background:

Formulary Medicationsandand

Formulary Decision Support

Medication Cost Management• Medication expenditures are the largest component of every

health system pharmacy's operating budget

• Formulary medications: – Reviewed and evaluated for safety for use within the institution– Orderable drug record completely built for CPOE– Stocked by the pharmacy for immediate use– Reduced costReduced cost

• Non-formulary medications:– Not reviewed or evaluated for safety for use within the institution– Orderable drug record not completely built for CPOE– Not readily stocked by the pharmacy for immediate use– Higher cost

Sweet BV, et al. Am J Health Syst Pharm. 2001; 58(18): 1746.

Formulary Decision Support

• The use of CDSS functionality to improve formulary compliance– Guides clinicians toward prescribing formulary medications

over non-formulary options

• Potential options: – Include only formulary options in the CPOE order catalog

– Indicate the medication as “non-formulary” when ordering the medication

– Display a pop-up alert when the clinician attempts to order a non-formulary medication while providing a selectable list of alternative formulary options

Kuperman GJ, et al. JAMIA. 2007; 14(1): 29.

Efficacy of Formulary Decision Support

• Fischer MA, et al. (2008)– Study the effect of e-prescribing with formulary decision support

over a 18 month period– Results:

• Formulary medications: +6.6% (95% CI: +5.9% to +7.3%)• Non formulary medications: 5 2% (95% CI: 5 9% to 4 5%)• Non-formulary medications: - 5.2% (95% CI: -5.9% to -4.5%)

• Teich JM, et al. (2000)– Study the effect of a pop-up formulary decision support alert on

histamine H2 antagonist prescribing over a 24 month period– Results:

• Preferred agent use: Increased from 15.6% to 81.3% (P<0.001)Fischer MA, Arch Intern Med. 2008;168:2433.Teich JM, Arch Intern Med. 2000;160:2741.

Project Objective

• Implement a dynamic formulary decision support tool within the electronic health record to facilitate formulary compliance at the point of order entry

8/14/2014

3

Methods

• Proof of concept• Form taskforce• Preliminary review and testing• Communication and implementation• Analysis

Current Prior to Admission (PTA) Medication Prescribing Workflow

Nurse obtains andNurse obtains and inputs medication history into EHR

Patient admitted to hospital

Providers place prior to admission orders

Current Pharmacy Workflow• Non-formulary medication ordered:

– Pharmacist may contact physician suggesting formulary alternatives

– Patient may supply own medication for usePharmacy may borrow medication from another– Pharmacy may borrow medication from another facility

– Pharmacy may purchase the medication

• Notify nursing and prescriber reason for the delay in dispensing the medication

Potential Impact

Average total orders(Ordered: 10/1/2013 – 01/31/2014)

Average non-formulary PTA orders

(Ordered: 10/1/2013 – 01/31/2014)

Average % non-formulary PTA

orders

181 437 4 195 2 3%181,437 4,195 2.3%

Pharmaceutical Subclass(Ordered: 10/1/2013 – 01/31/2014)

Average # of non-formulary

orders per month

Estimated # of non-formularyannual orders

Salicylates 393 3531Oil Soluble Vitamins 285 2562

Multivitamins 185 1659

Common prior to admission medication pharmaceutical subclasses

Potential Impact

Iron 170 1524Calcium 169 1515

Angiotensin II Receptor Antagonists 144 1296Prostatic Hypertrophy Agents 100 894

Urinary Antispasmodics 90 807Prostaglandins – Ophthalmic 69 618

Cobalamins 66 591

Proof of Concept

• Formulary decision support– Pop-up alert that appears when a clinician orders a non-

formulary prior to admission medication

– Only affects orders placed through the admission medication reconciliation processmedication reconciliation process

• Goals:– Reduce prior to admission non-formulary ordering– Reduce call volume between pharmacists and providers

8/14/2014

4

Proof of Concept

• Dynamic functionality: – If the non-formulary medication has the same

generic medication available on formulary:

• Generic equivalents are suggested

ExampleInput by nurse (prior to admission):

Prior to admission medication list:

© 2014 Epic Systems Corporation. Used with permission

© 2014 Epic Systems Corporation. Used with permission

Formulary decision support (generic equivalent):

Example

The ordering provider can select one of the suggested formulary alternatives or continue with the original order– If the original order is continued, a reason for using the

non-formulary medication is required

© 2014 Epic Systems Corporation. Used with permission

Proof of Concept

• Dynamic functionality: – If the non-formulary medication has no generic

formulation available on formulary:

• Alternate formulary medications are suggested based h ti l b l f th d don pharmaceutical subclass of the ordered non-

formulary medication

• This functionality can be suppressed by specific pharmaceutical subclasses

ExampleInput by nurse (prior to admission):

Prior to admission medication list:© 2014 Epic Systems Corporation. Used with permission

Prior to admission medication list:

© 2014 Epic Systems Corporation. Used with permission

Formulary decision support (generic equivalent):

Example

The ordering provider can select one of the suggested formulary alternatives or continue with the original order– If the original order is continued, a reason for using the

non-formulary medication is required

© 2014 Epic Systems Corporation. Used with permission

8/14/2014

5

Taskforce

• Health Information Technology (HIT)

• Pharmacy Super Users (HIT Liaisons)

• Pharmacy Clinical Specialists• Pharmacy Clinical Specialists

• Inpatient Physicians and Medical Residents

Preliminary Review• Pharmaceutical subclass

– Supplied by data vendor

• Determination of pharmaceutical subclasses to suppress– Assessed each subclass using annual ordering reports– Suppression considerations:

• Relevant to prior to admission medicationsp• Safety• Multiple mechanisms of action • User friendly

– Overall: 346 / 439 subclasses suppressed ( 79%)

• Testing and Troubleshooting

Preliminary Review• Determination of the verbiage displayed in the

alert– Displayed alternatives may not be therapeutically

equivalent– Clinical judgment should be used when selecting a

formulary alternativeformulary alternative– Addressing potential issues:

• “Continue with Original Order” disabled• Matching dose and frequency to original order

• Pharmacy and Therapeutics for approval

ExampleDisplayed formulary decision support alert:

© 2014 Epic Systems Corporation. Used with permission

Communication and Implementation

• Communicate with on-site trainers– Nurses– Inpatient physicians (hospitalists, residents)– Pharmacists

• Implementation: March 11, 2014

Results• Analysis periods:

– Pre-implementation : 82 days (12/18/2013 - 03/10/2014)– Post-implementation : 82 days (03/11/2014 - 05/31/2014)

• A chi-squared test was used to determine statistical significance (p < 0.05)

Total number of medication Number of non-Timeframe orders

(formulary + non-formulary)formulary medication

ordersPercentage p-value

Pre-implementation 470,351 10,227 2.2 %

Post Implementation 531,476 8,328 1.6 %

Percent reduction in non-formulary ordering: -27.9 % < 0.0001

8/14/2014

6

Pharmaceutical Subclass

# of non-formularyorders(Pre-

implementation)

# of non-formulary orders

(Post-implementation)

Percent change p-value

Multivitamins 313 77 -78.2 % <0.0001

Angiotensin II Receptor Antagonists 255 165 - 42.7 % <0.0001

Prostatic HypertrophyAgents 155 126 - 28.1 % 0.0058

Common prior to admission medication pharmaceutical subclasses

Results

Agents

Urinary Antispasmodics 150 142 -16.2 % 0.1301

Prostaglandins – Ophthalmic 118 135 +1.24 % 0.9215

Cobalamins 130 45 - 69.4 % <0.0001

Folic Acid / Folates 60 43 - 36.6 % 0.0215

ACE Inhibitors 66 29 - 61.1 % <0.0001

Artificial Tears and Lubricants 91 68 - 33.9 % 0.0094

Antihistamines – Non-Sedating 43 17 - 65.0 % 0.0001

Limitations• Impact on non-formulary medication

ordering also affected by a second project– Prior to admission preference list– Implemented on the same day with this project

• Small subset of non-formulary orders yplaced outside of admission processes not affected

• Subjective criteria for selecting pharmaceutical subclasses to suppress

Conclusion

• The use of formulary decision support has the potential to reduce non-formulary prior to admission medication ordering

Future Directions• Further assess impact on non-formulary

ordering

• Evaluate additional pharmaceutical• Evaluate additional pharmaceutical subclasses for intervention

Assessment Question #1• Which of the following is a potential

disadvantage of clinical decision support?

A. Improved patient safetyB. Alert desensitizationC. Enhanced quality of careD. Medication cost reduction

Assessment Question #2• Which of the following criteria is necessary

to support dynamic formulary clinical decision support alert functionality when suggesting formulary alternatives?

A. Pharmaceutical subclassB. Route of administrationC. Ordering provider typeD. Name of the medication

8/14/2014

7

Acknowledgements• Muriel Forbes, PharmD

– Clinical specialist – Pharmacy Informatics, Project Preceptor• Lynn Boecler, PharmD, MS

– Senior Director, Pharmacy Services• Hina Patel, PharmD, BCPS

– Clinical Manager• Jenny Szparkowski, PharmD, BCPS

– Clinical Specialist – Pharmacy Informatics• Jillian Lesniewski• Jillian Lesniewski

– Senior Applications Analysts

Presenter Contact Information:Kristopher Lozanovski, PharmDNorthShore University HealthSystemklozanovski@NorthShore.org

References

• Heffler S Smith S Keehan S et al. Health spending projections through 2013. Health Aff (Millwood) 2004; ((suppl Web exclusives)) W4-79- 93

• Fischer MA, Vogeli C, Stedman M, et al. Arch Intern Med. 2008; 168(22):2433-2439.

• Teich JM, Merchia PR, Schmiz JL, et al. Effects of computerized physician order entry on prescribing practices. Arch Intern Med. 2000; 160:2741-7.

Implementation of a Clinical Decision Support Tool to

Facilitate Formulary Medication Utilization

Kristopher Lozanovski, PharmDPGY2 Pharmacy Informatics ResidentNorthShore University HealthSystem

Evanston, Illinois

8/14/2014

1

A Retrospective Review of a Renal Sparing Protocol (RSP) in Orthotopic

Liver Transplantation (OLT)

ICHP Annual Meeting 2014

Presented by: Brett J Pierce PharmD

PGY-2 Solid Organ Transplant Resident

The speaker has no actual or potential conflict of interest in relation to this presentation

ObjectivesIdentify adverse effects associated with immunosuppressive agents.

Recognize the need for renal sparing protocols and strategies that they employ.

Renal Dysfunction in OLT

Renal dysfunction is commonly seen with liver disease

Among cirrhotics:

44% have acute tubular necrosis (ATN)

17% have hepato-renal syndrome (HRS)

Acute renal failure complicates up to 60% of OLTs

Increases morbidity and mortality

Increases length of hospital stay

End stage renal disease (ESRD) increases mortality 40%

3Trotter JF, et al. Liver Transpl. 2013 Aug;19(8):826-42.

Tacrolimus (TAC)

Forms drug-protein complex FKBP12

Inhibits calcineurin phophatase

P t T C ll ti ti

Mechanism of Action

ClassificationCalcineurin inhibitor (CNI) Tacrolimus Calcineurin

NFAT

Prevents T-Cell activation

4

Adverse EffectsNeurotoxicity

Hyperglycemia

Hyperkalemia

Hypertension

Nephrotoxicity

IL2 Production

T-Cell Activation

Tacrolimus Induced Nephrotoxicity

Tacrolimus induced nephrotoxicity occurs in 17-44% of OLTs

Tacrolimus binding proteins are concentrated in renal tissues

Toxicity occurs by multiple methods:Direct renal toxicity via:

Epithelial vacuolization Antiproliferative effectsInterstitial fibrosisRenal vasospasm

5

Trotter JF, et al. Liver Transpl. 2013 Aug;19(8):826-42. Randhawa PS, et al. Adv Anat Pathol. 1997 Jul;4(4):265-276.

Mycophenolate (MMF)

Inhibits inosine monophosphate dehydrogenase

Prevents de novo purine synthesis

Inhibits T and B cell proliferation

Mechanism of Action

S Phase

6

Adverse EffectsGI Intolerance

Myelosuppression

Opportunistic Infections

8/14/2014

2

Question #1

Which of these is a side effect that may be caused by mycophenolate?

A. Tremor

B. Hyperglycemia

C. Neutropenia

D. Constipation

7

Protocol Comparison

Non-Renal Sparing (NRS)Renal Sparing Protocol

(RSP)

Induction Methylprednisolone Day 0 Methylprednisolone Day 0

MaintenanceTacrolimus

Prednisone Taper

TacrolimusPrednisone TaperM h l t

pMycophenolate

Tacrolimus Start

Post-Op Day 0 Post-Op Day 3

Initial TAC Target Trough

8-10ng/ml 5-8ng/ml

8

RSP Inclusion Criteria

SCr > 1.5mg/dL?

CrCl <60mL/min?

9

Use Renal Sparing Protocol

On Renal Replacement

Therapy?

SCr increase >50% from

baseline

Existing Literature

Renal Sparing effect of decreased CNI exposure is well documented

MMF has been used extensively in patients receiving OLT

What Is Known?

What is Published?

1

Goralczyk AD, et al. Am J Transplant. 2012 Oct;12(10):2601-7.

What is Published?

Eight trials compare low-dose CNI + MMF with standard dose CNI

Of these 2 looked at de novo MMF

Neither evaluated delayed initiation of TAC

Rao et al.Population

84 OLT Patients at Northwestern Memorial Hospital

42 Renal Sparing Protocol (RSP)

42 Simultaneous Liver Kidney (SLK)

Treatment

1

Rao V, et al. Transplant Proc. 2013 Jan-Feb;45(1):320-2.

NMH Renal Sparing Protocol

LD-Delayed TAC + HD-MMF + Prednisone

ResultsSCr improved at 1 year in both groups

Similar death, rejection, and infection rates

Question #2

What method do renal sparing protocols employ?

A. Using increased doses of steroids

B. Decreasing renal exposure to tacrolimus

C. Decreasing renal exposure to mycophenolate mofetilg p y p

D. Using alternative methods for opportunistic infection prophylaxis.

8/14/2014

3

Study Question

Does the use of a renal sparing protocol put OLT patients at a higher risk of acute rejection within the first year after transplant?

Primary Question

1

Secondary QuestionDoes the addition of high-dose mycophenolate, increase the occurrence of neutropenia, thrombocytopenia, and gastrointestinal side effects?

Outcome Measures

Occurrence of acute rejection within one year of transplantPrimary Outcome

Secondary OutcomesOccurrence of:

Neutropenia –ANC<1000

Thrombocytopenia – PLTs<150,000

1

GI Side Effects – Leading to discontinuation of MMF

Opportunistic Infections:Cytomegalovirus (CMV)

Herpes SymplexVirus (HSV)

Pneumocystis Pneumonia (PCP)

Aspergillosis

Candidiasis

Study Population – Inclusion/Exclusion

Adult, deceased donor, OLT patients at NMH

Transplanted between 2010-2012

Inclusion Criteria

Exclusion CriteriaNon-DeNovo RSP start

1

Deviated from protocol

Prior transplant recipients

Previously received immunosuppression

End Stage Liver Disease (ESLD) due to autoimmune hepatitis

Study Site

Northwestern Memorial Hospital

894 Bed academic medical center

Level 1 trauma center

46,000 inpatient admissions per year

Kovler Organ Transplantation Center

Established 1964

>1300 OLTs to date110-130 per year

90% Deceased Donors

Statistics

This study was approved by the Northwestern University Investigational Review Board

Continuous variables were analyzed with Student's t-test andWilcoxan Rank-Sum test

Categorical variables were analyzed with Chi-square and Fisher's Exact

All data were analyzed with Epi-Info 7.1.3; Atlanta, GA

233 Total Patients

16 Autoimmune Hepatitis14 Multiple Transplants

16 Non-DeNovo RSP Start40 Deviated from protocol

147 Patients Included

79 RSP 68 NRS

8/14/2014

4

Baseline DemographicsRSP N=79 NRS N=68 P

Mean Age (yrs) 55.9 STD(11.0) 58.0 STD(8.3) 0.20

Male (%) 51 (64.6%) 50 (73.4%) 0.24

White (%) 56 (70.9%) 46 (67.7%) 0.67

Black (%) 9 (11.4%) 6 (8.8%) 0.61

Hispanic (%) 12 (15 2%) 13 (19 1%) 0 40

1

Hispanic (%) 12 (15.2%) 13 (19.1%) 0.40

MELD Score at Transplant

Median: 29 IQR: (25.0-36.0) Min:15, Max: 47

Median: 20.5 IQR: (17.0-26.0) Min:11, Max:47

< 0.01

Serum Creatinine at Transplant

Median: 1.95 IQR:(1.46-2.62)

Min:0.63, Max:2.62

Median 1.05IQR: (0.8-1.21)

Min:0.49, Max:3.9< 0.01

CMV Serology At Transplant

RSP N=79 NRS N=68 P

D+/R- (High Risk) 14 (17.7%) 12 (17.6%) 0.80

D+/R+ (Intermediate Risk)

37 (46.8%) 34 (50.0%) 0.79

D-/R+ (IntermediateRi k)

20 (25.3%) 16 (23.5%) 0.99

Baseline Demographics

2

Risk)D-/R- (Low Risk) 8 (10.1%) 6 (8.8%) 0.70

ESLD Etiology

RSP N=79 NRS N=68 P

Hepatitis C 27 (34.2%) 33 (48.5%) 0.08

Alcoholic Liver Disease 21 (26.6%) 16 (23.5%) 0.67

Cryptogenic Cirrhosis 10 (12.7%) 1 (1.47%) 0.02

RejectionRejection Within 1 Year

RSP N=79 NRS N=68 P

Total 19 (24.1%) 15 (22.1%) 0.92

Biopsy Proven AcuteRejection (BPAR)

10 (12.7%) 4 (5.9%) 0.26

Empirically Treated 9 (11.4%) 11 (16.2%) 0.40

2

24.1%

12.7% 11.4%

22.1%

5.9%

16.2%

0%

10%

20%

30%

Total BPAR Empiric

RSP NRS

NeutropeniaNeutropenia Within 1 Year

RSP N=79 NRS N=68 P

Total 39 (49.4%) 15 (22.5%) <0.01

Moderate (500≤ANC<1000) 18 (22.8%) 10 (14.7%) 0.22

Severe (0<ANC<500) 21 (26.6%) 5 (7.4%) <0.01

50%

22.80%14.70%

26.60%

7.40%

0%10%20%30%40%50%

RSP NRS

Severe

Moderate

Opportunistic InfectionsOpportunistic Infections Within 1 Year

RSP N=79 NRS N=68 PTotal 21 (26.6%) 8 (11.8%) 0.02

CMV 13 (16.5%) 5 (7.4%) 0.09

HSV 4 (5.1%) 1 (1.5%) 0.37Aspergillosis 3 (3.8%) 2 (2.9%) 0.99p g ( ) ( )Candidiasis 1 (1.2%) 0 (0%) 0.99

NRSRSP CMV

HSV

Aspergillosis

Candidiasis

MMF DiscontinuationRSP patients who stopped MMF due to adverse affects:

Total Patients: N=7 (8.9%)

GI Issues: N=2 (2.5%)

Neutropenia: N=5 (6.3%)

8/14/2014

5

Renal Function/ThrombocytopeniaSerum Creatinine

RSP N=79 NRS N=68 P

SCr at Transplant Median 1.95 IQR (1.46-2.62)

Median 1.05IQR (0.8-1.21)

< 0.01

SCr at 3 months 1.36 STD (0.54) 1.18 STD (0.40) 0.03

SCr at 6 months 1.44 STD (0.61) 1.19 STD (0.29) <0.01

SCr at 12 months 1.40 STD (0.80) 1.18 STD (0.30) 0.040

∆ From Baseline Median Decrease 0.65IQR (0.17-1.52)

Median Increase 0.15IQR (-0.38-0.15)

< 0.01

Thrombocytopenia

RSP N=79 NRS N=68 P

Total 7 (8.9%) 8 (11.8%) 0.56

LimitationsRetrospective study design

Tacrolimus levels were not recorded

Limited to patients during the protocol period

Unable to analyze biopsy proven rejection only

Moving Forward

Results presented to P&T Committee

Data shared with transplant group

Drafted manuscript

Submit for academic publication

Summary

Renal impairment is commonly associated with ESLD

Tacrolimus is an effective immunosuppressant, but can cause significant nephrotoxicity

A l i l ili i hi h d h l d l d A renal sparing protocol utilizing high dose mycophenolate, and low dose, delayed initiation tacrolimus does not appear to put patients at a higher risk of rejection within 1 year following transplant

A renal sparing protocol does appear to cause higher rates of opportunistic infections and neutropenia

Acknowledgements

Thank you to the following:

Chad L. Richardson, PharmD

Milena McLaughlin, PharmD, MSc, BCPS, AAHIVP

Marc Scheetz, PharmD, MSc, BCPS AQ-ID

John Esterly, PharmD, BCPS AQ-IDy

Noelle RM Chapman, PharmD, BCPS

Michael Postelnick, RPh BCPS AQ-ID

Josh Levitsky, MD.

A Retrospective Review of a Renal Sparing Protocol (RSP) in Orthotopic

Liver Transplantation (OLT)

ICHP Annual Meeting 2014

Presented by: Brett J Pierce PharmD

PGY2 Solid Organ Transplant Resident

The speaker has no actual or potential conflict of interest in relation to this presentation

8/14/2014

6

References

1. Trotter JF, Grafals M, Alsina AE. Early use of renal-sparing agents in liver transplantation: a closer look. Liver Transpl. 2013 Aug;19(8):826-42.

2. Randhawa PS, StarzlTE, Demetris AJ. Tacrolimus (FK506)-Associated Renal Pathology. Adv Anat Pathol. 1997 Jul;4(4):265-276.

3. Goralczyk AD, Bari N, Abu-AjajW, Et Al. Calcineurin inhibitor sparing with mycophenolate mofetil in liver transplantion: a systematic review of randomized controlled trials. Am J Transplant. 2012 Oct;12(10):2601-7.J p ; ( )

4. Rao V, Haywood S, Abecassis M, Levitsky J. A non-induction renal sparing approach after liver transplantation: high dose mycophenolate mofetil with delayed, low-dose tacrolimus. Transplant Proc. 2013 Jan-Feb;45(1):320-2.

5. Boudjema K, Camus C, Saliba F.Reduced-dose tacrolimus with mycophenolate mofetil vs. standard-dose tacrolimus in liver transplantation: a randomized study. Am J Transplant. 2011 May;11(5):965-76.

MMF Dose Post Tx Total Daily Dose (mg)

3 months (N=72)  1458.3 STD (508.73)

Immunosuppression

6 months (N=67)  1313.43 STD (498.75)

12 months (N=65)  1153.8 STD (529.76)

Prednisone Dose3 months post Tx

RSP (N=74)5.87 STD 3.14

NRS (N=65)15.29 STD 3.91

P0.02

RSP Group (N=79)

NRS Group (N=68)

P

Death Within 1 Year of 

Transplant (%)6 (7.6%) 6 (8.8%) 0.79

Ti t

Death and Time to Rejection

Time to Rejection (Weeks)

Median 3IQR1‐24

Median 1 IQR1‐4

0.06

Neuberger et al. Boudjema et al.

525 OLT PatientsPatient

Population195 OLT patients

A: TAC (≥10ng/ml)B:TAC (≤8ng/ml) + MMF

C: Daclizumab + MMF/TAC (≤8ng/ml,

POD5)

Treatment A:TAC (≥12ng/ml) + MMFB:TAC (≤10ng/ml) + MMF

)

Change in eGFR at 1yearPrimary

Outcome(s)

Acute rejectionRenal dysfunction

Arterial hypertensionDiabetes

Daclizumab induction with delayed, LI-TAC and MMF

improved renal outcomes with no change in safety or efficacy

Conclusions

LI-TAC and MMF reduces the occurrence of renal

dysfunction and the risk of graft rejection.

Neuberger JM, et al. Am J Transplant 2009; 9:327–336.Boudjema K, et al. Am J Transplant. 2011 May;11(5):965-76.