Vancomycin and Piperacillin/Tazobactam Combination TherapyZosyn Renal... · ©2016 MFMER | slide-4 Question 1 • As a provider, I am concerned about the risk of AKI when using vancomycin

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Vancomycin and Piperacillin/Tazobactam Combination Therapy:The Renal Wringer?

Logan Olson, PharmDPGY1 Pharmacy Resident

Pharmacy Ground RoundsOctober 11th, 2016

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Objectives• Describe the mechanisms by which vancomycin

and piperacillin/tazobactam could cause acute kidney injury

• Discuss current evidence regarding AKI in the setting of vancomycin and piperacillin/tazobactam combination therapy

• Identify strategies to reduce risk of AKI in patients requiring broad spectrum antibiotics

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Question 1• As a provider, I am concerned about the risk of

AKI when using vancomycin and piperacillin/tazobactam combination therapy

• A – Yes• B – No

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Objective 1

Describe the mechanisms by which vancomycin and piperacillin/tazobactam could cause acute kidney injury

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Vancomycin• Acute tubular necrosis

VancomycinOxygen Free Radical

Hazlewood KA, et al. Am J Med. 2010;123(2):182-193

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Vancomycin• Acute tubular necrosis

Hazlewood KA, et al. Am J Med. 2010;123(2):182-193

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Vancomycin• Associated nephrotoxicity

• Reported in 0-5% of patients in the 1980s• Recent studies suggest:

• 1% - 3.8% incidence• Targeting low trough levels

• 12% - 42.6% incidence• Targeting high trough levels

Hazlewood KA, et al. Am J Med. 2010;123(2):182-193

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Piperacillin/Tazobactam• Interstitial nephritis

UreaSodium

Water

McCormic H, et al. Am J Health Syst Pharm. 2015;72:s25-s30

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Piperacillin/Tazobactam• Interstitial nephritis

McCormic H, et al. Am J Health Syst Pharm. 2015;72:s25-s30

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• Interstitial nephritis

Piperacillin/TazobactamEosinophils and Neutrophils

InflammationMcCormic H, et al. Am J Health Syst Pharm. 2015;72:s25-s30

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Piperacillin/Tazobactam• Associated nephrotoxicity

• < 1%• No difference between intermittent and

extended infusion strategies

Joshi M, et al. Respiratory Medicine. 2006;100(9):1554-1565McCormick H, et al. Am J Health Syst Pharm. 2015;72:s25-s30

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Vancomycin + Piperacillin/Tazobactam

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Objective 2

Discuss current evidence regarding AKI in the setting of vancomycin and piperacillin/tazobactam combination therapy

Risk Factors for AKI

Exposures

Sepsis

Critical Illness

Burns

TraumaMajor Surgery

Nephrotoxic Drugs

Radiocontrast Agents

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

Risk Factors for AKI

Susceptibilities

Dehydration/ Volume

Depletion

Advanced Age

Female

Black RaceCKD

Chronic Diseases

Diabetes Mellitus

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

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Burgess, et al. 2014

Burgess LD, et al. Pharmacotherapy. 2014;34(7):671-676

Retrospective Cohort (n=191)

Vancomycin (n=99)

Vancomycin + Pip/Tazo (n=92)

Incidence of nephrotoxicity within 7 days of vancomycin initiation

Pip/Tazo = Piperacillin/Tazobactam

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Burgess, et al. 2014Description Vancomycin (n=99) Combination

Group (n=92) P value

Mean Age (SD) 56.3 (±15.9) 60.7 (±15.1) -

Concomitant Nephrotoxins 71 (71.7%) 74 (80.4%) -

Vancomycin Trough Concentrations (µg/ml)

16.5 ± 8.2 17.6 ± 8.4 -

Sepsis 10 (10.1%) 15 (16.3%) -

Severe Sepsis 2 (2.0 %) 4 (4.4%) -

Septic Shock 1 (1.0%) 6 (6.5%) -

Sepsis Total 13 (13.1%) 25 (27.2%) -

Nephrotoxicity 8 (8.1%) 15 (16.3%) 0.041

SD = Standard DeviationBurgess LD, et al. Pharmacotherapy. 2014;34(7):671-676

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• Retrospective matched cohort (n=224)

Vancomycin + Pip/Tazo(n=112)

Vancomycin + Cefepime (n=112)

• Baseline SCrwithin 24 hours of admission

• Treated for ≥ 48 hours

• ≥ 1 Vancomycin trough

Primary Outcome:Incidence of AKI

Definition: AKIN Criteria

Gomes, et al. 2014

(KDIGO) Acute Kidney Injury Work Group. Kidney inter., Suppl. 2012; 2: 1–138Gomes DM, et al. Pharmacotherapy. 2014;34(7):662-669

SCr = Serum CreatinineAKIN = Acute Kidney Injury NetworkAKI = Acute Kidney InjuryPip/Tazo = Piperacillin/Tazobactam

AKIN Criteria

Serum Creatinine Urine Output

≥ 0.3mg/dL or

≥ 1.5 - 2-fold from baseline

< 0.5ml/kg/h for > 6 hours

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Gomes, et al. 2014

Description Vancomycin + Cefepime (n=112)

Vancomycin + Pip/Tazo (n=112) P value

Age 50.4 52.4 0.344Male 57.1% 58.9% 0.787Weight 83.2 kg 91.5 kg 0.004SCr at antibiotic start 0.74 mg/dl 0.79 mg/dl 0.413

ICU during admission 64.3% 46.4% 0.009

Contrast 45.5% 42.0% 0.59

Diabetes Mellitus 22.3% 38.4% 0.009

Mean days of antibiotic therapy 6.7 7.1 0.003

AKI incidence 12.5% 34.8% < 0.0001

Gomes DM, et al. Pharmacotherapy. 2014;34(7):662-669SCr = Serum CreatininePip/Tazo = Piperacillin/TazobactamAKI = Acute Kidney Injury

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Gomes, et al. 2014

Description Vancomycin + Cefepime (n=55)

Vancomycin + Pip/Tazo (n=55) P value

Age 52.1 51.4 0.875Male 47.3% 43.6% 0.834Weight 85.8 kg 89.1 kg 0.467SCr at antibiotic start 0.74 mg/dl 0.75 mg/dl 0.776

ICU during admission 52.7% 52.7% 1.000

Contrast 32.7% 34.6% 1.000

Diabetes Mellitus 30.9% 32.7% 1.000

Mean days of antibiotic therapy Not provided Not provided -

AKI incidence 10.9% 36.4% < 0.003

Gomes DM, et al. Pharmacotherapy. 2014;34(7):662-669SCr = Serum CreatininePip/Tazo = Piperacillin/TazobactamAKI = Acute Kidney Injury

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Limitations

Single Center

Severity of Illness

Score

SepsisAKI type

Gomes, et al. 2014

• Conclusion: Results suggest ↑ risk• Unknown variables ↓ confidence

AKI = Acute Kidney Injury Gomes DM, et al. Pharmacotherapy. 2014;34(7):662-669

Moenster, et al. 2013

Diabetics with

osteomyelitis

Vancomycin + Pip/Tazo

(n=109)

Vancomycin + Cefepime

(n=30)

Hammond,et al. 2016

ICU

Vancomycin + Pip/Tazo

(n=49)

Vancomycin + Cefepime

(n=73)

Retrospective Cohorts

Development of AKIAKI = Acute Kidney InjuryPip/Tazo = Piperacillin/TazobactamICU = Intensive Care Unit

Moenster RP, et al. Clin Microbiol Infect 2014; 20: O384–O389389Hammond DA, et al. Pharmacotherapy. 2016;36(5):463-471

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32.729.328.8

13.3

0

5

10

15

20

25

30

35

40

45

50

Hammond Moenster

Perc

ent o

f Pat

ient

s (%

)

Incidence of AKI

Vancomcyin + Pip/Tazo Vancomycin + Cefepime

P = 0.761 P = 0.09

Moenster RP, et al. Clin Microbiol Infect 2014; 20: O384–O389389Hammond DA, et al. Pharmacotherapy. 2016;36(5):463-471

AKI = Acute Kidney InjuryPip/Tazo = Piperacillin/Tazobactam

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Vancomycin + Pip/Tazo (n=59)

Vancomycin + Cefepime or Meropenem

(n=26)

Peyko, et al. 2016• Prospective Cohort (n=85)

Pip/Tazo, cefepime, or meropenem ≥ 72 hours with steady state vancomycin trough

SCr = Serum CreatinineAKI = Acute Kidney InjuryPip/Tazo = Piperacillin/Tazobactam

Primary Outcome:Development of AKI

Definition: AKIN Criteria

Exclusion CriteriaRenal replacement therapy

Baseline SCr > 2.5 mg/dL

Peyko V, et al. J Pharm Pract. 2016; [Epub ahead of print]

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Peyko, et al. 2016

DescriptionVancomycin + Cefepime or

Meropenem (n=26)

Vancomycin + Pip/Tazo (n=59) P value

Pneumonia 34.6% 47.5% 0.271UTI 15.4% 3.4% 0.047IAI 7.7% 0% 0.031Sepsis of unknownorigin/bacteremia 3.9% 10.2% 0.328

SSTI 19.2% 20.3% 0.906Osteomyelitis 3.9% 11.9% 0.243Other 15.4% 6.8% -

Peyko V, et al. J Pharm Pract. 2016; [Epub ahead of print] UTI = Urinary Tract InfectionIAI = Intra-abdominal InfectionSSTI = Skin and Soft Tissue Infection

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Peyko, et al. 2016

DescriptionVancomycin + Cefepime or

Meropenem (n=26)

Vancomycin + Pip/Tazo (n=59) P value

Age 74 74.8 0.814Male 57.7% 44.1% 0.701Baseline SCr 1.2 mg/dl 1.0 mg/dl 0.193Nephrotoxic agents 38.5% 33.9% 0.685Vasopressor 15.4% 13.6% 0.823Diabetic 50% 32.2% 0.118CKD at baseline 19.2% 20.3% 0.906Vancomycin troughs 18.3 µg/mL 16.6 µg/mL 0.331Development of AKI 7.7% 37.3% 0.005

Peyko V, et al. J Pharm Pract. 2016; [Epub ahead of print]

SCr = Serum CreatinineCKD = Chronic Kidney DiseasePip/Tazo = Piperacillin/TazobactamAKI = Acute Kidney Injury

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Limitations

Degree of

Sepsis

Antibiotic Selection

Small sample

size AKI type

Single Center

Peyko, et al. 2016

• Conclusion: Results suggest ↑ risk• Small sample size and unknown variables ↓

confidenceAKI = Acute Kidney Injury

Peyko V, et al. J Pharm Pract. 2016; [Epub ahead of print]

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So where does this leave us?

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Objective 3

Identify strategies to reduce risk of AKI in patients requiring broad spectrum antibiotics

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Risk Reduction Strategies

Minimize

Vasopressors

High Dose Diuretics

NSAIDS

Bently ML, et al. Crit Care Med. 2010 Jun;38(6 Suppl):S169-74NSAIDS = Non-Steroidal Anti-Inflammatory Drugs

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Risk Reduction Strategies

Continually Reassess

Antibiotics Indicated?

Deescalation

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Risk Factors for AKI• Vancomycin

• High-dose regimens• > 4g/day

• High trough serum level• Duration of therapy

• > 1 week incidence 6-21%• > 2 weeks incidence up to 30%

Elyasi S, et al. Eur J Clin Pharmacol. 2012 Sep;68(9):1243-55

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Risk Reduction Strategies

Target lower trough goals

when possible

Minimize doses >4g

per day

Minimize Vancomycin

Exposure

Elyasi S, et al. Eur J Clin Pharmacol. 2012 Sep;68(9):1243-55

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Question 2• What is the proposed mechanism for

vancomycin-associated nephrotoxicity?• A – Acute Glomerulonephritis• B – Acute Interstitial Nephritis• C – Acute Tubular Necrosis

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Question 3• Which of the following is not a risk factor for

AKI?• A – Sepsis• B – Male gender• C – Critical illness• D – Advanced Age

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Question 4• Which of the following is an appropriate

intervention to decrease risk of AKI in the setting of vancomycin + pip/tazo combination therapy?

• A – Avoiding high dose diuretics• B – Deescalation following cultures and

sensitivities• C – Utilizing lower vancomycin trough goals• D – All of the above

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Question 5• As a provider, I am concerned about the risk of

AKI when using vancomycin and piperacillin/tazobactam combination therapy

• A – Yes• B – No

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Summary• The mechanism by which the combination of

vancomycin and pip/tazo may cause AKI is currently unknown

• Studies are inconclusive regarding increased risk of AKI with combination therapy

• The risk of AKI can be reduced by avoiding nephrotoxic medications, continually reassessing antibiotic therapy, and limiting vancomycin exposure

Pip/Tazo = Piperacillin/TazobactamAKI = Acute Kidney Injury

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Questions & Discussion

Logan Olson, PharmDPGY1 Pharmacy Resident

olson.logan@mayo.edu