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Vancomycin plus Piperacillin/Tazobactam….Bad for the Beans? Emmanuel U. Aniemeke, Pharm.D. PGY1 Pharmacy Resident University Health System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas Health Science College of Pharmacy Pharmacotherapy Education and Research Center The University of Texas Health Science Center San Antonio Pharmacotherapy Rounds February 27 th , 2015 LEARNING OBJECTIVES 1. Describe the pathophysiology, clinical presentation, and causes of acute kidney injury 2. Summarize the proposed mechanism of acute kidney injury associated with vancomycin and piperacillin/tazobactam 3. Evaluate the current literature regarding the risk of acute kidney injury while on combination vancomycin and piperacillin/tazobactam therapy 4. Provide practical recommendations regarding the combined use of vancomycin and piperacillin/tazobactam based on recently published literature
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Mar 13, 2018

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Page 1: Vancomycin plus Piperacillin/Tazobactam…sites.utexas.edu/pharmacotherapy-rounds/files/2015/09/aniemeke02...Vancomycin plus Piperacillin/Tazobactam….Bad for the Beans? Emmanuel

Vancomycin plus Piperacillin/Tazobactam….Bad

for the Beans?

Emmanuel U. Aniemeke, Pharm.D. PGY1 Pharmacy Resident

University Health System, San Antonio, Texas Division of Pharmacotherapy, The University of Texas Health Science College of Pharmacy

Pharmacotherapy Education and Research Center The University of Texas Health Science Center San Antonio

Pharmacotherapy Rounds February 27th, 2015

LEARNING OBJECTIVES

1. Describe the pathophysiology, clinical presentation, and causes of acute kidney injury

2. Summarize the proposed mechanism of acute kidney injury associated with vancomycin and

piperacillin/tazobactam

3. Evaluate the current literature regarding the risk of acute kidney injury while on combination vancomycin and

piperacillin/tazobactam therapy

4. Provide practical recommendations regarding the combined use of vancomycin and piperacillin/tazobactam

based on recently published literature

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ACUTE KIDNEY INJURY (AKI)

I. BACKGROUND 1, 2, 3

A. Sudden (hours to days) decline in excretory function of the kidney

B. Characterized by

i. Dysregulation of fluids, electrolytes and acid-base balance

ii. Decreased glomerular filtration rate (GFR)

iii. Increase in serum creatinine (Scr)

II. EPIDEMIOLOGY/INCIDENCE 1, 2, 4

A. Associated with significantly high mortality and morbidity rates

B. Incidence

i. Community-acquired : <1%

ii. Hospital-acquired: ~9%

iii. ICU-acquired: 30-67%

III. ETIOLOGY

1, 5, 6, 7

Figure 1: Pathophysiology of AKI

5

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Table 1: CLASSIFICATION, PATHPHYSIOLOGY AND CAUSES OF AKI

Classifications Pathophysiology Common causes Associated medications

PRERENAL (25-60%) Decreased renal perfusion Volume depletion Hepatorenal syndrome Systemic vasodilation

NSAIDs Cyclosporine RAAS inhibitors Tacrolimus

INTRINSIC (35-70%)

Acute tubular necrosis (ATN)

Ischemic or toxic tubular damage

Ischemic insults Nephrotoxic agents

Vancomycin Aminoglycosides Methotrexate Amphotericin B

Acute interstitial nephritis (AIN)

Interstitial damage Infections Sarcoidosis Lupus

Penicillin analogues Cephalosporins Sulfonamides Ciprofloxacin Acyclovir Rifampin Proton pump inhibitors NSAIDs

POSTRENAL (<5%) Urinary Obstruction Prostate hypertrophy Neurogenic bladder

Acyclovir Indinavir

NSAIDs, Non-steroidal anti-inflammatory drugs; RAAS, rennin-angiotensin-aldosterone system

IV. DEFINITION AND STAGING 1

Table 2: AKI STAGING

RIFLE CRITERIA

RIFLE Category GFR Criteria UO Criteria

Risk 1.5-fold increase in Scr or GFR decrease > 25% UO < 0.5 mL/kg/h for ≥ 6 h

Injury 2-fold increase in Scr or GFR decrease > 50% UO< 0.5mL/kg/h for ≥ 12 h

Failure 3-fold increase in Scr or GFR decrease > 75% or Scr ≥ 4mg/dL, or acute rise in Scr ≥ 0.5 mg/dL

UO< 0.5mL/kg/h for ≥ 24 h or anuria for ≥ 12 h

Loss Complete loss of kidney function > 4 weeks

ESRD End-stage kidney disease (>3 months)

AKIN CRITERIA

AKIN Stage Scr Criteria UO Criteria

1 Increase in Scr to ≥ 0.3mg/dL or 1.5-to 2-fold from baseline UO < 0.5 mL/kg/h for ≥ 6 h

2 Increase in Scr to > 2-to 3-fold from baseline UO< 0.5mL/kg/h for ≥ 12 h

3 Increase in Scr to > 3-fold from baseline or ≥ 4mg/dL (≥ 354 μmol/L) with an acute increase of at least 0.5 mg/dL or on RRT

UO< 0.3mL/kg/h for ≥ 24 h or anuria for ≥ 12 h

K-DIGO CRITERIA

K-DIGO Stage Scr Criteria UO Criteria

1 Increase in Scr to ≥ 0.3mg/dL or 1.5 to 1.9 times from baseline UO < 0.5 mL/kg/h for ≥ 6 h

2 Increase in Scr 2 to 3 times from baseline UO< 0.5mL/kg/h for ≥ 12 h

3 Increase in Scr 3 times from baseline or ≥ 4mg/dL (≥ 354 μmol/L) or initiation of renal replacement therapy or in patients < 18 years, decrease in eGFR to < 35mL/min per 1.73m

2

UO< 0.3mL/kg/h for ≥ 24 h or anuria for ≥ 12 h

GFR, glomerular filtration rate ;Scr, Serum creatinine; OU, Urine output; RRT, Renal replacement therapy; AKIN, Acute Kidney Injury Network; K-DIGO, Kidney Disease Improvement Global Outcomes

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VANCOMYCIN ASSOCIATED NEPHROTOXICITY (VAN)

I. BACKGROUND 8, 9, 10

A. Vancomycin

i. Glycopeptide antibiotic

ii. Early formulation of vancomycin contained significant impurities, nicknamed “Mississippi mud”

iii. Subsequent formulations increased the purity, reducing the severities of toxicity

iv. Cornerstone antibiotic for management of severe gram-positive infections

1. Methicillin-resistant Staphylococcus aureus (MRSA)

2. Methicillin-resistant coagulase-negative staphylococci

3. Non-vancomycin-resistant entercocci

B. Primary renal excretion

i. Glomerular filtration and active tubular secretion (90%)

ii. Hepatic conjugation (~10%)

II. MECHANISM OF ACTION 8

A. Inhibits cell wall synthesis of gram-positive bacteria

B. Inhibition of peptidoglycan elongation and cross-linking

C. Slowly bactericidal

V. ADVERSE EFFECTS 8, 11, 12

A. Nephrotoxicity (5-43%)

B. Infusion reactions: “Redman syndrome”

C. Drug fever

D. IgA bollous dermatosis

VI. POSTULATED MECHANISM OF VAN 9, 13, 14, 15, 16, 17

A. Drug-induced oxidative stress

B. Mitochondrial damage in the proximal renal tubular cell

C. Proximal renal tubular cell necrosis

D. Contribution to complement pathway and inflammation

E. Believed to be mostly reversible

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VII. INCIDENCE OF VAN 9, 13, 14,15, 16, 17

A. Incidence ranges from 5 - 43 %

B. Associated with

i. Prolonged hospitalization

ii. Increased mortality

iii. Need for renal replacement therapy

VIII. EVIDENCE OF VAN

Table 5: RISK FACTOR FOR VAN

Author & Study Design

Patient Characteristics Treatment Groups VAN Outcome Risk Factor

Hidayat et al.,200619

(Prospective study) Adult patients with hospital-acquired infections (MRSA) n=95

Low trough (< 15mg/L) vs. High trough (> 15mg/L)

High trough: 12%

Low trough : None

High trough

Lodise et al.,200820

(Retrospective study)

Adult patients with suspected or proven gram-positive infection n=291; VM=246, Linezolid=45

Standard VM dose (< 4g/day) , High VM dose (> 4g/day) and Linezolid for > 48 hours

High doses: 34.6%

Standard dose 10.9%

Linezolid : 6.7%

High VM dose

Concomitant nephrotoxic agents

Septic shock

Lodise et al.,200921

(Retrospective study)

Adults patients with suspected or proven gram-positive infection n=166; High dose=27,Std dose=139

VM for > 48hours, with ≥ 1 VM trough level collected within 96 hours of therapy

12.7% High initial trough

Bosso et al., 201122

(Prospective study)

Adult patients with MRSA infections n=288

Low vs. high trough, (< 15mg/L vs. > 15mg/L)

High trough group: 29.6%

Low trough : 8.9%

High troughs

Race (black)

Minejima et al., 2011

23

(Prospective study)

Elderly patients (median, 70 years), with invasive infections n=227

Loading dose, maintenance dose

19%

High trough group: 24%

Low trough : 17%

ICU stay

Low baseline GFR

Malignancy

Prior episode of AKI

Cano et al., 201224

(Retrospective study )

Adult ICU pneumonia patients n=188

At least one dose of VM, and trough levels were monitored

15.4% Duration of exposure

Aminoglycoside use

Prabaker et al., 2012

25

(Retrospective study)

Adult patients with various infections n=348

≥ 5 days of VM therapy Overall: 8.9% Contrast dye

Higher trough

Wunderink et al., 2012

26

(Prospective study )

Adult patients with MRSA nosocomial pneumonia n=448; VM=172, Linezolid=176

Linezolid 600 mg q 12 h VM 15mg/kg q 12 h

VM (18.2%)

Linezolid (8.4%)

VM exposure

Higher trough

AKI, Acute kidney injury; VAN, vancomycin associated nephrotoxicity; VM, vancomycin; ICU, intensive care unit; Std, standard

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IX. RISK FACTORS 9, 18

PENICILLIN ASSOCIATED NEPHROTOXICITY

I. BACKGROUND

8, 27, 28

A. Penicillin

i. Oldest available pure antibiotic

ii. Isolated by Sir Alexander Fleming in 1928, from fungi, Penicillium notatum

iii. Primarily eliminated renally ~ 60-90%

a. 10% glomerular filtration

b. 90% tubular secretion

II. MECHANISM OF ACTION 8

A. Inhibits cell wall synthesis

B. Binds irreversibly to the penicillin-binding-proteins

C. Inhibition of peptidoglycan elongation and cross-linking

D. Rapid bactericidal time-dependent killing

III. ADVERSE EFFECTS 8

A. Acute interstitial nephritis

B. Gastrointestinal upset

C. Hypersensitivity reactions

Table 6: RISK FACTOR FOR VAN

Factor Comment

Vancomycin exposure-related factors

Larger vancomycin exposures o Higher Troughs > 15 mg/L o Increased exposure (increased area under the curve) o Prolonged durations

Host-related factors History of acute kidney injury

Pre-existing renal insufficiency

Critically ill

Septic

Concurrent nephrotoxins Loop diuretics

Acyclovir

Amphotericin B

Aminoglycosides

Contrast dye

Other factors Disease-state specific nephrotoxicity

Obesity

African-American race

Treatment of complicated infections (HCAP, osteomyelitis, meningitis, endocarditis, and bacteremia)

HCAP, health care associated pneumonia

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IV. POSTULATED MECHANISM OF NEPHROTOXICITY 29, 30, 31, 32

A. Dimethoxyphenylpenicilloyl (DPO) binding to host renal structural protein

B. Formation an antigen-protein complex (hapten) along the tubular basement membrane

C. Mounting an immunogenic response developing into interstitial nephritis

V. PIPERACILLIN-TAZOBACTAM (PT) 33, 34, 35

A. Extended-spectrum semisynthetic penicillin combined with β-lactamase inhibitor

B. Approved by the FDA in 1993

C. Composed at an 8:1 ratio of piperacillin and tazobactam

D. FDA Indications

i. Nosocomial pneumonia

ii. Intra-abdominal infections

iii. Skin and soft tissue infections

iv. Pelvic inflammatory disease

v. Septicemia

vi. Neutropenic fever

vii. Osteomyelitis

viii. Septic arthritis

VI. EVIDENCE OF PIPERACILLIN-TAZOBACTAM ASSOCIATED NEPHROTOXICITY

Table 7: EVIDENCE OF NEPHROTOXICITY

Author & Study design Patient Characteristics Regimen Intervention Conclusion

Pill et al., 199736

(Case report) 51-year old woman with acute leukemia

PT, allopurinol, and VM

6 days of PT + 7 days of VM/ allopurinol

AIN caused by PT

Tanaka et al.,199738

(Case report)

11-year old with suspicion of renal disease

PT 4 days of PT treatment PT confirmed as causative agent by positive laboratory and renal biopsy findings

Sakarcan et al., 200129

(Case report)

13-year old with cystic fibrosis

PT , levofloxacin, cefuroxime

Two separate PT treatments, 5 years apart

PT identified as the culprit of AIN

Polderman et al., 200239

(Prospective, observational)

73 adult patients PT group=43 Control group =40

PT vs. Control (cephalosporins or ciprofloxacin)

36 hours of PT or control

PT may cause or aggravate electrolyte disorders and tubular dysfunction in ICU patients when SCr levels remain normal

Liu et al., 201237

(Case report)

56-year old man with osteomyelitis

PT 6 weeks of PT PT can result in drug induced AIN

VM, vancomycin; PT, piperacillin/tazobactam; AIN, acute interstitial nephritis; ICU, intensive care unit; SCr,serum creatinine

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VANCOMYCIN PLUS PIPERACILLIN/TAZOBACTAM ASSOCIATED NEPHROTOXICITY

I. CLINICAL QUESTION

A. Does the combination therapy of vancomycin and piperacillin/tazobactam (VPT) increase the risk

incidence of nephrotoxicity?

II. ABSTRACT EVALUATION

A. Hellwig et al. 40

i. Retrospective evaluation of 735 adult patients over a 6 month period

ii. Compared patients who received VM alone versus PT alone versus combination therapy of VPT for

more than 48 hours

iii. AKI defined as increase of serum creatinine greater than 0.5 mg/dL or a 50% increase from

baseline

iv. Result

B. Min et al. 41

i. Evaluation of 140 surgical ICU patients over one year

ii. Compared patients on the combination therapy of VPT versus monotherapy of VM alone for at

least 48 hours

iii. AKI defined as increase of serum creatinine more than 1.5 times baseline during antibiotic therapy

iv. Result

Incidence of AKI

VPT group (40.5%)

VM group (9.0%)

p<0.001

III. LITERATURE REVIEW

A. Meaney et al. Pharmacotherapy 2014

B. Burgess et al. Pharmacotherapy 2014

C. Moenseter et al. Clin Micro Biol Infect 2014

D. Gomes et al. Pharmacotherapy 2014

Table 8: INCIDENCE OF AKI

Patient population VM (%) PT (%) VPT (%) p value

General medicine 4.9 11.1 18.6 0.005

ICU 6.0 12.2 21.2 0.279 VM, vancomycin; PT, piperacillin/tazobactam; VPT, vancomycin and piperacillin/tazobactam

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Meaney CJ, Hynicka LM, Tsoukleris MG. VAN in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy.2014; 34(7):653-61.

42

Objective To determine the incidence, time-course, outcomes, and risk factors of VM among adult internal medicine patients

Design Single-center, retrospective cohort study, (January 1, 2009-December 31 , 2009)

Population

Inclusion

Men or women ≥ 18 years

Admitted to an internal medicine service, treated with VM for ≥72 hours

Exclusion

Patients diagnosed with AKI or chronic kidney disease (CKD)

Initial Scr ≥1.4 mg/dL for women and ≥1.5 mg/dL for men

Diagnosis of kidney injury due to causes other than VM therapy

Outcomes

Endpoints

Incidence of nephrotoxicity: Increase in Scr by 0.5mg/dl or 50% above baseline

The outcome of the nephrotoxicity event, described as either return to Scr to baseline (defended as within 20% of the baseline value), development of CKD or dialysis dependence

Statistical Analysis

Chi-square test or fisher exact test for categorical variables analysis

Student t-test for continuous, normally distributed data

Wilcoxon Rank Sum test for non-normal continuous data and ordinal data

Multiple regression analysis for bivariate assessment resulted in p value <0.20

Covariates identified as potential confounders and non significant covariates were included in the regression models

Results

n=125 adult patients ; Nephrotoxicity group (n=17) , No nephrotoxicity group (n=108)

Age (mean) : 50.9 ± 15.5

Table 9: KEY DIFFERENCES IN CHARACTERISTICS OF STUDY GROUP

Variable Nephrotoxicity (n=17) No nephrotoxicity (n=108) p value

BMI (kg/m2) 22.1 26 0.049

Baseline CrCl (ml/min) mean 91.5 ± 26.7 83.5 ±27.7 0.267

VM daily dose (mg/kg) 29.3± 9.5 26.2 ± 7.4 0.1291

Daily dose >4g, n (%) 2 (11.8) 4 (3.7) 0.188

Trough ≥ 15mg/L, n (%) 6 (46.20) 28 (32.6) 0.360

Hypotensive event, n (%) 3 (17.7) 1 (0.9) 0.008

Eosinophilia, n (%) 5(29.4) 1 (0.9) <0.001

Skin/Skin Structure Infection, n (%)

5 (29.4) 51(47.2) 0.170

PT treatment, n (%) 13 (76.5) 45 (41.7) 0.008

Cumulative incidence of VAN: 13.6% (17/125)

Nephrotoxicity developed at a median of 4.5 days (IQR: 2.2-4.9) and peaked at 5.7 days (IQR: 3.8-9.6)

Acute hypotensive events, creatinine clearance, Charlson Comorbidity index (refer to appendix 1), and use of PT were associated with VAN

PT was associated with 5.36-fold increased odds of VAN (95% CI 1.41-20.5) after controlling for acute hypotensive events, creatinine clearance, Charlson Comorbidity index

Concomitant nephrotoxic drugs included; ACEI, allopurinol, acyclovir, aminoglycoside, ampohotericin, ganciclovir, IV contrast agent, loop diuretic, NSAID, TMP-SMX, tenoforvir, and beta-lactams

Strengths Focused on one level of patient care (internal medicine patients), hence reducing confounding variables

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Limitations Retrospective, unblinded

Small sample size within the nephrotoxic group, hence limited data on significant differences in occurrence of the risk factors between groups

Large type II error on variable analysis

Stability of Scr was not assessed before the patient were entered into the study

Wide confidence intervals, low precision

Exclusion of treatment related variables, such as dose, trough concentrations, patient weight ≥ 101.4kg or 2 or more concomitant nephrotoxic agents in the regression model

Authors Conclusion Use of concomitant piperacillin-tazobactam is significantly associated with development of nephrotoxicity

Take Home Points Higher acuity patients are at risk for VAN

Nephrotoxicity was seen after 4 days of therapy

AKI developed from VPT is reversible

Burgess LD, Drew RH. Comparison of the incidence of VAN in hospitalized patients with and without concomitant piperacillin-tazobactam. Pharmacotherapy. 2014; 34(7):670-6.

43

Objective

To determine whether the addition of piperacillin-tazobactam leads to an increased incidence of nephrotoxicity in patients receiving VM

To explore potential confounding factors that may increase the risk of VAN

Design Single-center, retrospective cohort study (July 1, 2009-July 1, 2012)

Population

Inclusion

Men or women ≥ 18 years , who received a minimum of 48 hours of IV VM with or without PT for any indication

Patients with four SCr values measured on four separate days during admission

Exclusion

Patients with underlying renal dysfunction , defined as: o Scr >1.5 mg/dL or a creatinine clearance (CrCl) of < 30 mL/min based on the Cockcroft-Gault equation o Any previous history of renal replacement therapy o Recent history of AKI: 1.5-fold increase in SCr from baseline and before the initiation of VM

Outcomes

Primary endpoint

Incidence of nephrotoxicity: defined as a minimum 1.5-fold increase in the patient's SCr based on the maximum measured SCr value within the first 7 days of VM treatment from the SCr measured within 48 hours before initiating VM

Secondary endpoints

Incidence of nephrotoxicity in adult hospitalized patients receiving VM intravenous therapy with and without the following risk factors: o Any use of concomitant nephrotoxic agents o Advanced age o A measured or estimated steady-state VM trough concentration of 15 μg/ml or greater o Elevated Charlson Comorbidity Index, or a total VM dosage of 4 g/day or greater in the first 7 days of

therapy

Statistical Analysis

n= 180 patients per group required to achieve a statistical power of 80% to detect a 15% difference between the VPT group (25%) and VM group (10%)

Chi-square test for the association of the addition of PT to the incidence of nephrotoxicity

Univariate logistic regression analysis for the main exposure variable of PT addition and potential risk factors for nephrotoxicity

Multivariate logistic regression model to assess the association of nephrotoxicity with addition of PT

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Results

Table 10: Demographic and Clinical Characteristics by Treatment Group

Description VM (n=99) VPT (n=92)

Males n (%) 48 (48.5) 54 (58.7)

Age (mean) 56.3± 15.9 60.7± 15.1

Concomitant nephrotoxins n (%) 71 (71.7) 74 (80.4)

Charlson Comorbidity Index 3 4

ICU admission n (%) 19 (19.2) 14 (15.2)

Sepsis: VM group n (%) 10 (10.1) 15 (16.3)

Severe sepsis n (%) 2 (2.0) 4 (4.4)

Septic shock n (%) 1 (1.0) 6 (6.5)

Outcome Analysis

Table 11: OUTCOME ANALYSIS OF TREATMENT GROUP

Description VM (n=99) VPT (n=92) p value

Incidence of nephrotoxicity (%) 8 (8.0) 15 (16.3) 0.041

Secondary Endpoint (Univariate analysis)

Variable Odds ratio (OR) 95% Confidence Interval

Age 0.98 0.95-1.01

Concomitant nephrotoxic agents 1.16 0.41-3.33

VM trough concentrations ≥15μg/mL 3.67 1.49-9.03

The multivariate analysis of VPT resulted in an OR of 2.48 ( p=0.032, CI >1.11); one-sided T-test

VM troughs (mean) were similar between groups and no patient in either group received 4g/day or more of VM

Only measured or estimated trough concentration of ≥15mg/L was associated with an increased risk of nephrotoxicity

Strengths Large study

Stability of Scr was assessed before the patient were entered into the study

Inclusion of patients with stable renal function in the study at baseline minimize the impact of treatment duration being a confounder

Limitations Retrospective, unblinded

Duration of exposure of patient to nephrotoxic agents or comorbid conditions were not stated

Notable differences between groups in the incidence of sepsis

Data on the number of patients receiving which specific other nephrotoxic agents not provided

Authors Conclusion Patients receiving VPT therapy have a significantly increased risk of developing nephrotoxicity

Take Home Points Trough concentrations ≥15mg/L increased incidence of nephrotoxicity

Power analysis is flawed because it is based on unproven data

Significant difference in treatment groups (i.e., severe sepsis, septic shock)

Severity of illness increases risk of AKI

Moenster RP, Linneman TW, Finnegan PM, et al. Acute renal failure associated with VM and β-lactams for the treatment of osteomyelitis in diabetics: piperacillin-tazobactam as compared with cefepime. Clin Microbiol Infect. 2014;20(6):O384-9.

44

Objective To compare the potential rate of AKI between VPT and VC

Design Single-center, retrospective cohort study (January 1, 2006 – December 31, 2011)

Population

Inclusion

Diagnosis of diabetes

Diagnosis of osteomyelitis with determination to treat by an infectious disease physician

Treatment with either VPT or VC for at least 72h

Exclusion

Baseline CrCl ≤ 40 mL/min

Baseline blood urea nitrogen (BUN)/SCr ratio ≥20:1, or absolute neutrophil count <500 cells/mm3

Recipient of IV acyclovir, amphotericin B, any aminoglycoside or any vasopressor concurrently or within 48 h of antibiotic initiation

Outcomes Rate of AKI: Increase in baseline Scr of 50% or 0.5mg/dL between the two groups of patients o Patients were stratified into high-dose (≥3 g of cefepime per 24 h, or ≥ 18 g of PT per 24 h) or non-high-dose

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therapy

Statistical Analysis

n= 200 patients per group was required to achieve a statistical power of 80%, to detect a 19% difference between groups

Chi-square test or Fisher’s extract test to compare non-parametric data

Student’s t-test to evaluate parametric data, an alpha of <0.05was considered significant

Results

n=139: VPT =109, VC=30 o High dose therapy : VPT=32 ,VC=17

Baseline Characteristics

Table 12: KEY DIFFERENCES IN BASELINE CHARACTERISTICS

Characteristics VPT (n=109) VC (n=30) p value

Age (years) 62.8 58.4 0.03

Haemoglobin A1c 6.6 4.9 0.05

Loop diuretics, n (%) 25 (22.9) 14 (46.6) 0.008

Contrast dye, n (%) 14 (12.8) 3 (10) 0.036

Average CrCl at initiation (ml/min) 72 80.02 0.06

High-dose therapy recipient, n (%) 24 (22) 17 (56.6) <0.05

Outcome Analysis

25.9% (36/139) of all patients developed AKI o High dose therapy : AKI: 33% (12/36) , no AKI: 28.1% (29/103)

No statistical differences between average total duration, average VM troughs or use nephrotoxic agents (loop diuretics, ACEI or contrast dye) between patients who developed AKI and those who did not

Figure 2: Frequency of AKI by groups

The multivariate analysis showed that only weight and average VM trough were found to have a significant impact on the development of AKI

The use of high-dose β-lactam therapy did not affect the likelihood of developing AKI

The choice of using PT increased the likelihood of developing AKI, but this finding was not statically significant

Strengths Homogeneity in disease states ( diabetic patients treated for osteomyelitis)

Longer duration of treatment

Inclusion of patients with stable renal function at baseline

Limitations Single centered, retrospective, small study

Study failed to achieve power

Heterogeneity between number of patients on VPT vs. VC

Authors Conclusion

Although no statistical difference was found in the rates AKI between groups and in the subgroup analysis, VPT-treated patients did develop AKI

Take Home Points

Diabetic patients with higher risk of renal insufficiency at baseline

Too many confounding variables to conclude confirmed AKI

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Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with VM in combination with piperacillin-tazobactam or cefepime. Pharmacotherapy. 2014; 34(7):662-9.

45

Objective To evaluate the observed incidence of AKI in adult patients receiving either piperacillin-tazobactam and vancomycin (VPT) or cefepime-vancomycin (VC) for more than 48 hours, without preexisting renal insufficiency

Design Single-center, retrospective matched cohort study (January 21, 2012 - October 15, 2012)

Population

Inclusion

Men or women aged ≥ 18 years, who had a baseline Scr within 24 hours of admission

Patients with at least one VM trough level, and had received treatment with VPT or VC for at least 48 hours during admission

The combination of these agents was initiated no more than 48 hours apart

Exclusion

Patients currently receiving dialysis, history of CKD (stage III or higher) or structural kidney disease (e.g., one kidney, kidney transplant, kidney tumor), or renal insufficiency (CrCl < 60 ml/min at admission

Current pregnancy, incarceration, treatment with investigational medications or ≥ one dose of intermittent (> 30 min) PT infusion

Febrile neutropenia and meningitis infections

Outcomes

Primary endpoint

Rates of AKI for patients treated between both arms according to the Acute Kidney Injury Network (AKIN) guidelines during therapy or within 72 hours after combination therapy was discontinued

Secondary endpoints

Time to AKI from initiation of combination therapy and hospital length of stay (LOS)

Statistical Analysis

Nonparametric Wilcoxon rank sum, Chi-square test or Fisher exact test for categorical data

n= 112 patients per group was required to achieve a statistical power of 80% to detect a 15% difference between the VPT group (25%) and VC group (10%)

Propensity score to control for potential bias and balance observed covariates among the two groups

Greedy matching algorithm to match patients with comparable propensity scores

Results

Baseline Characteristics

643 records reviewed

n=224; VPT=112, VC=112

Table 13: BASELINE CHARACTERISTICS (UNMATCHED DATA)

Characteristics VPT (n=112) VC (n=112) p value

Age (mean) 52.42± 13.91 50.37 ± 14.27 0.344

Weight (kg) 91.54± 26.33 83.15± 27.76 0.004

Scr at start of antibiotics (mg/dl)

0.79± 0.24 0.74 ±0.22 0.413

ICU admission, n (%) 39 (34.8) 60 (53.6) 0.005

Nephrotoxin (NSAIDs), n (%) 12 (10.7) 25 (22.3) 0.019

Table 14: PREVALENCE AND DURATION OF ACUTE KIDNEY INJURY (UNMATCHED DATA)

Variables VPT (n=39) VC (n=14) p value

Highest VM trough prior to AKI (mcg/ml) 22.6 24.3 0.52

In ICU at AKI onset, n (%) 11 (28.2) 9(64.3) 0.017

Days to AKI from Combination start, mean 4.97± 3.1 4.85± 2.9 0.975

Total days of AKI, mean outcome of AKI at discharge 7.6± 6.8 10± 14.8 0.0626

Resolved, n (%) 16 (41) 3 (21.4) 0.190

Insult still present, n (%) 23 (59) 11(78.6) 0.190

Unmatched data, the incidence of AKI was higher in the VPT (34.8%) versus VC (12.5%),(OR 3.74, 95% CI 1.89-7.39);p<0.0001

Matched data: o n=110; VPT=55, VC=55 o Propensity scores were estimated using age, weight, SCr, and estimated Clcr at baseline and

antibiotics, admission unit and service, comorbidities, Charlson Comorbidity index, antibiotics allergies and indication

o Incidence of AKI higher in the VPT (36.4%) versus VC (10.9%) , (OR 5.67, 95% CI 1.66-19.33);p=0.003

Strengths Large study

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IV. SUMMARY OF LITERATURE

A. Study limitations

i. Retrospective, unblinded studies

ii. Lack of randomization

iii. Lack of power or inability to achieve power

iv. Heterogeneity in patient groups

V. LITERATURE BASED CONCLUSION

A. AKI developed from the combination VPT therapy is reversible

B. While the data supporting the incidence of AKI with VPT therapy is limited, the risk of AKI may be higher in:

a. Patient with higher acuity of illness

b. Patients on combination VPT therapy for ≥ 4 days

C. Antibiotic de-escalation by day 3, is imperative to decrease the risk of AKI

D. Larger, randomized , multicenter trials are needed to provide further evidence of harm

The use of propensity score matching to match baseline characteristics

Limitations

Retrospective, unblinded

The retrospective design of the study makes it difficult to distinguish if the changes in the patients’ renal function is as a result of the disease progression or as a result of the combination therapy

Data were not collected for all risk factors that predisposed the patients to drug-induced AKI e.g. treatment with vasopressors, the presence of hypotension, sepsis, hypoalbuminemia, volume depletion, or high severity illness score

Urine eosinophils or data from kidney biopsies were not collected to classify the type of AKI

Authors Conclusion There is an increased risk of developing acute kidney injury with patient’s receiving VPT therapy compared to VC therapy

Take Home Points Baseline population were similar after matching i.e., propensity score matching

AKI may develop between 4-5 days

Advocates streamline of therapy

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APPENDIXES

Appendix A:

Table 1: CHARLSON COMORBIDITY INDEX SCORING SYSTEM46

COMORBIDITY COMPONENT

Score Condition

1 Myocardical infarction (history, not ECG changes only) Congestive heart failure Peripheral vascular disease (includes aortic aneurysm ≥6cm) Cerebrovascular disease: CVA with mild or no residual or TIA Dementia Chronic Pulmonary disease Connective tissue disease Peptic ulcer disease Mild liver disease (without portal hypertension, includes chronic hepatitis) Diabetes without end-organ damage (excludes diet-controlled alone)

2 Hemiplegia Moderate or severe renal disease Diabetes with end-organ damage(retinopathy, neuropathy, or brittle diabetes) Tumor without metastases (exclude if >5years from diagnosis) Leukemia (acute or chronic) Lymphoma

3 Moderate or severe liver disease

6 Metastatic solid tumor AIDS (not just HIV positive)

AGE

Score Age range (years)

0 <40

1 41-50

2 51-60

3 61-70

4 71-80

ECG, electrocardiogram; CVA, cerebrovascular accident; TIA, transient ischemic attack; AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.