1. health and fitness
2. disease

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
ACUTE KIDNEY INJURY (AKI)
I.
BACKGROUND
1, 2, 3
A. Sudden (hours to days) decline in excretory function of the kidney
B.
II.
Characterized by
i.
Dysregulation of fluids, electrolytes and acid-base balance
ii.
Decreased glomerular filtration rate (GFR)
iii.
Increase in serum creatinine (Scr)
EPIDEMIOLOGY/INCIDENCE
1, 2, 4
A. Associated with significantly high mortality and morbidity rates
B.
III.
Incidence
i.
Community-acquired : <1%
ii.
Hospital-acquired: ~9%
iii.
ICU-acquired: 30-67%
ETIOLOGY
1, 5, 6, 7
Figure 1: Pathophysiology of AKI
5
Aniemeke 2
Table 1: CLASSIFICATION, PATHPHYSIOLOGY AND CAUSES OF AKI
Classifications
Pathophysiology
Common causes
PRERENAL (25-60%)
Decreased renal perfusion
Volume depletion
Hepatorenal syndrome
Systemic vasodilation
INTRINSIC (35-70%)
Acute tubular necrosis
(ATN)
Ischemic or toxic tubular
damage
Ischemic insults
Nephrotoxic agents
Acute interstitial
nephritis (AIN)
Interstitial damage
Infections
Sarcoidosis
Lupus
POSTRENAL (<5%)
Urinary Obstruction
Prostate hypertrophy
Neurogenic bladder
Associated medications
NSAIDs
Cyclosporine
RAAS inhibitors
Tacrolimus
Vancomycin
Aminoglycosides
Methotrexate
Amphotericin B
Penicillin analogues
Cephalosporins
Sulfonamides
Ciprofloxacin
Acyclovir
Rifampin
Proton pump inhibitors
NSAIDs
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
Risk
Injury
Failure
GFR Criteria
1.5-fold increase in Scr or GFR decrease > 25%
2-fold increase in Scr or GFR decrease > 50%
3-fold increase in Scr or GFR decrease > 75% or Scr ≥ 4mg/dL, or acute
rise in Scr ≥ 0.5 mg/dL
Loss
ESRD
Complete loss of kidney function > 4 weeks
End-stage kidney disease (>3 months)
UO Criteria
UO < 0.5 mL/kg/h for ≥ 6 h
UO< 0.5mL/kg/h for ≥ 12 h
UO< 0.5mL/kg/h for ≥ 24 h or anuria for ≥ 12 h
K-DIGO Stage
1
AKIN CRITERIA
Scr Criteria
Increase in Scr to ≥ 0.3mg/dL or 1.5-to 2-fold from baseline
Increase in Scr to > 2-to 3-fold from baseline
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
K-DIGO CRITERIA
Scr Criteria
Increase in Scr to ≥ 0.3mg/dL or 1.5 to 1.9 times from baseline
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,
2
decrease in eGFR to < 35mL/min per 1.73m
UO< 0.3mL/kg/h for ≥ 24 h or anuria for ≥ 12 h
AKIN Stage
1
2
3
UO Criteria
UO < 0.5 mL/kg/h for ≥ 6 h
UO< 0.5mL/kg/h for ≥ 12 h
UO< 0.3mL/kg/h for ≥ 24 h or anuria for ≥ 12 h
UO Criteria
UO < 0.5 mL/kg/h for ≥ 6 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
Aniemeke 3
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
B.
1.
Methicillin-resistant Staphylococcus aureus (MRSA)
2.
Methicillin-resistant coagulase-negative staphylococci
3.
Non-vancomycin-resistant entercocci
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
V.
B.
Inhibition of peptidoglycan elongation and cross-linking
C.
Slowly bactericidal
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
Aniemeke 4
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
Author & Study
Design
19
Hidayat et al.,2006
(Prospective study)
Table 5: RISK FACTOR FOR VAN
Patient Characteristics
Treatment Groups
VAN Outcome
Risk Factor
Adult patients with hospitalacquired infections (MRSA)
n=95
Adult patients with suspected or
proven gram-positive infection
n=291; VM=246, Linezolid=45
Low trough (< 15mg/L) vs.
High trough (> 15mg/L)
High trough: 12%
Low trough : None
High trough
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%
21
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 VM dose
Concomitant
nephrotoxic
agents
Septic shock
High initial
trough
Bosso et al., 2011
(Prospective study)
22
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.,
23
2011
(Prospective study)
Elderly patients (median, 70 years),
with invasive infections
n=227
Loading dose, maintenance
dose
19%
High trough group: 24%
Low trough : 17%
Cano et al., 2012
(Retrospective study )
Adult ICU pneumonia patients
n=188
At least one dose of VM, and
trough levels were monitored
15.4%
Prabaker et al.,
25
2012
(Retrospective study)
Wunderink et al.,
26
2012
(Prospective study )
Adult patients with various
infections
n=348
Adult patients with MRSA
nosocomial pneumonia
n=448; VM=172, Linezolid=176
≥ 5 days of VM therapy
Overall: 8.9%
ICU stay
Low baseline
GFR
Malignancy
Prior episode
of AKI
Duration of
exposure
Aminoglycosi
de use
Contrast dye
Higher trough
Linezolid 600 mg q 12 h VM
15mg/kg q 12 h
VM (18.2%)
Linezolid (8.4%)
20
Lodise et al.,2008
(Retrospective study)
Lodise et al.,2009
(Retrospective study)
24
VM exposure
Higher trough
AKI, Acute kidney injury; VAN, vancomycin associated nephrotoxicity; VM, vancomycin; ICU, intensive care unit; Std, standard
Aniemeke 5
IX.
RISK FACTORS
9, 18
Table 6: RISK FACTOR FOR VAN
Comment
Larger vancomycin exposures
o Higher Troughs > 15 mg/L
o Increased exposure (increased area under the curve)
o Prolonged durations
History of acute kidney injury
Pre-existing renal insufficiency
Critically ill
Septic
Loop diuretics
Acyclovir
Amphotericin B
Aminoglycosides
Contrast dye
Disease-state specific nephrotoxicity
Obesity
African-American race
Treatment of complicated infections (HCAP, osteomyelitis, meningitis, endocarditis,
and bacteremia)
Factor
Vancomycin exposure-related
factors
Host-related factors
Concurrent nephrotoxins
Other factors
HCAP, health care associated pneumonia
PENICILLIN ASSOCIATED NEPHROTOXICITY
I.
BACKGROUND
A.
8, 27, 28
Penicillin
i. Oldest available pure antibiotic
ii. Isolated by Sir Alexander Fleming in 1928, from fungi, Penicillium notatum
iii. Primarily eliminated renally ~ 60-90%
II.
a.
10% glomerular filtration
b.
90% tubular secretion
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
Aniemeke 6
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.
V.
Mounting an immunogenic response developing into interstitial nephritis
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
Author & Study design
36
Pill et al., 1997
(Case report)
38
Tanaka et al.,1997
(Case report)
Sakarcan et al., 2001
(Case report)
29
39
Polderman et al., 2002
(Prospective, observational)
Liu et al., 2012
(Case report)
37
Table 7: EVIDENCE OF NEPHROTOXICITY
Patient Characteristics
Regimen
Intervention
51-year old woman with
PT, allopurinol,
6 days of PT + 7 days
acute leukemia
and VM
of VM/ allopurinol
11-year old with suspicion PT
4 days of PT treatment
of renal disease
13-year old with cystic
fibrosis
PT , levofloxacin,
cefuroxime
73 adult patients
PT group=43
Control group =40
PT vs. Control
(cephalosporins
or ciprofloxacin)
56-year old man with
osteomyelitis
PT
Two separate PT
treatments, 5 years
apart
36 hours of PT or
control
6 weeks of PT
Conclusion
AIN caused by PT
PT confirmed as
causative agent by
positive laboratory and
renal biopsy findings
PT identified as the
culprit of AIN
PT may cause or
aggravate electrolyte
disorders and tubular
dysfunction in ICU
patients when SCr levels
remain normal
PT can result in drug
induced AIN
VM, vancomycin; PT, piperacillin/tazobactam; AIN, acute interstitial nephritis; ICU, intensive care unit; SCr,serum creatinine
Aniemeke 7
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
Patient population
General medicine
ICU
Table 8: INCIDENCE OF AKI
VM (%)
PT (%)
4.9
11.1
6.0
12.2
VPT (%)
18.6
21.2
p value
0.005
0.279
VM, vancomycin; PT, piperacillin/tazobactam; VPT, vancomycin and piperacillin/tazobactam
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
III.

VPT group (40.5%)

VM group (9.0%)

p<0.001
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
Aniemeke 8
Meaney CJ, Hynicka LM, Tsoukleris MG. VAN in adult medicine patients: incidence, outcomes, and risk factors. Pharmacotherapy.2014;
42
34(7):653-61.
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)
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)
Population
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
Endpoints
Outcomes
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
Chi-square test or fisher exact test for categorical variables analysis
Statistical 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
n=125 adult patients ; Nephrotoxicity group (n=17) , No nephrotoxicity group (n=108)
Age (mean) : 50.9 ± 15.5
Results
Strengths
Table 9: KEY DIFFERENCES IN CHARACTERISTICS OF STUDY GROUP
Variable
Nephrotoxicity (n=17) No nephrotoxicity (n=108)
2
BMI (kg/m )
22.1
26
Baseline CrCl (ml/min) mean
91.5 ± 26.7
83.5 ±27.7
VM daily dose (mg/kg)
29.3± 9.5
26.2 ± 7.4
Daily dose >4g, n (%)
2 (11.8)
4 (3.7)
Trough ≥ 15mg/L, n (%)
6 (46.20)
28 (32.6)
Hypotensive event, n (%)
3 (17.7)
1 (0.9)
Eosinophilia, n (%)
5(29.4)
1 (0.9)
Skin/Skin Structure Infection,
5 (29.4)
51(47.2)
n (%)
PT treatment, n (%)
13 (76.5)
45 (41.7)
p value
0.049
0.267
0.1291
0.188
0.360
0.008
<0.001
0.170
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
Focused on one level of patient care (internal medicine patients), hence reducing confounding variables
Aniemeke 9
Limitations
Authors Conclusion
Take Home Points
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
Use of concomitant piperacillin-tazobactam is significantly associated with development of nephrotoxicity
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 piperacillin43
tazobactam. Pharmacotherapy. 2014; 34(7):670-6.
To determine whether the addition of piperacillin-tazobactam leads to an increased incidence of nephrotoxicity
Objective
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
Outcomes
Statistical Analysis
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
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
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
Aniemeke 10
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
Strengths
Limitations
Authors Conclusion
Take Home Points
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
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
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
Patients receiving VPT therapy have a significantly increased risk of developing nephrotoxicity
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
44
in diabetics: piperacillin-tazobactam as compared with cefepime. Clin Microbiol Infect. 2014;20(6):O384-9.
Objective
To compare the potential rate of AKI between VPT and VC
Design
Single-center, retrospective cohort study (January 1, 2006 – December 31, 2011)
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
Population
Baseline CrCl ≤ 40 mL/min
3
Baseline blood urea nitrogen (BUN)/SCr ratio ≥20:1, or absolute neutrophil count <500 cells/mm
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
Aniemeke 11
Statistical
Analysis
Results
therapy
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
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
Strengths
Limitations
Authors
Conclusion
Take Home
Points
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
Homogeneity in disease states ( diabetic patients treated for osteomyelitis)
Longer duration of treatment
Inclusion of patients with stable renal function at baseline
Single centered, retrospective, small study
Study failed to achieve power
Heterogeneity between number of patients on VPT vs. VC
Although no statistical difference was found in the rates AKI between groups and in the subgroup analysis, VPTtreated patients did develop AKI
Diabetic patients with higher risk of renal insufficiency at baseline
Too many confounding variables to conclude confirmed AKI
Aniemeke 12
Gomes DM, Smotherman C, Birch A, et al. Comparison of acute kidney injury during treatment with VM in combination with piperacillin45
tazobactam or cefepime. Pharmacotherapy. 2014; 34(7):662-9.
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)
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
Population
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
Primary endpoint
Rates of AKI for patients treated between both arms according to the Acute Kidney Injury Network (AKIN)
Outcomes
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)
Nonparametric Wilcoxon rank sum, Chi-square test or Fisher exact test for categorical data
Statistical Analysis
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
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
0.79± 0.24
0.74 ±0.22
0.413
(mg/dl)
ICU admission, n (%)
39 (34.8)
60 (53.6)
0.005
Nephrotoxin (NSAIDs), n (%)
12 (10.7)
25 (22.3)
0.019
Results
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
Strengths
Unmatched data, the incidence of AKI was higher in the VPT (34.8%) versus VC (12.5%),(OR 3.74, 95% CI 1.897.39);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
Large study
Aniemeke 13
The use of propensity score matching to match baseline characteristics
Limitations
Authors Conclusion
Take Home Points
IV.
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
There is an increased risk of developing acute kidney injury with patient’s receiving VPT therapy compared to
VC therapy
Baseline population were similar after matching i.e., propensity score matching
AKI may develop between 4-5 days
Advocates streamline of therapy
SUMMARY OF LITERATURE
A. Study limitations
V.
i.
Retrospective, unblinded studies
ii.
Lack of randomization
iii.
Lack of power or inability to achieve power
iv.
Heterogeneity in patient groups
LITERATURE BASED CONCLUSION
A. AKI developed from the combination VPT therapy is reversible
B.
C.
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
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
Aniemeke 14
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APPENDIXES
Appendix A:
Table 1: CHARLSON COMORBIDITY INDEX SCORING SYSTEM
COMORBIDITY COMPONENT
Score
1
2
3
6
AGE
Score
0
1
2
3
4
46
Condition
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)
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
Moderate or severe liver disease
Metastatic solid tumor
AIDS (not just HIV positive)
Age range (years)
<40
41-50
51-60
61-70
71-80
ECG, electrocardiogram; CVA, cerebrovascular accident; TIA, transient ischemic attack; AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus.
Aniemeke 17