Nephrotoxicity during

Vancomycin Therapy in
Combination with Piperacillin-
Tazobactam or Cefepime
Rutter wc et al. 2017
By Adilah & Chia Shook Ling
  Vancomycin – nephrotoxicity
 Prolonged vancomycin treatment duration eg. > 7 days
 Daily vancomycin dose > 4g

Introduction
Risk factor for  Other risk factors
nephrotoxicity  concomitant nephrotoxic agents administration eg. Loop
diuretics, acyclovir, NSAIDs
 obesity
  Addition of antipseudomonal beta lactams for hospitalised
patients
Introduction  Recent literatures – combined use of vancomycin (VAN) &
Piperacillin/Tazobactam (TZP) more nephrotoxic than VAN
monotherapy or combined use with Cefepime (FEP)
  Evaluate incidence of AKI with the two antibiotic regimens in
hospitalized patients
Study (a) Piperacillin/Tazobactam (TZP) with Vancomycin (VAN)
objective (b) Cefepime (FEP) with Vancomycin (VAN)
  Single-Center – University of Kentucky HealthCare Medical Center
(UKMC)
 Retrospective matched cohort study
 Study duration: 1 Sept 2010 – 1 Sept 2014

Study design
Primary outcome:
 Difference in AKI incidence between TZP-VAN and FEP-VAN
groups

AKI – evaluated using RIFLE criteria

 Inclusion criteria:
 Adult patients 18 yrs of age or older
 Hospitalised between 1 sept 2010 – 1 sept 2014
 Received TZP-VAN or FEP-VAN antibiotic combination for at least 48 hrs
Exclusion criteria:
 Patients with history of CKD or structural kidney disease required dialysis

Study Design  Experienced aki prior to antibiotic administration (within 48 hr of therapy

initiation or > 7 days after last dose of antibiotics)
 Underlying renal dysfunction (initial CrCl 30mL/min or less)
 Pregnant
 Diagnosed with cystic fibrosis
 Transferred from other hospital

Patient followed throughout their stay until discharge

  Demographic data,
 Visit details (LOS, primary diagnosis codes)
 Severity of underlying illness (charlson comorbidity index CCI)
 All serum creatinine levels determined per visit
(Initial serum creatinine concentration used as baseline)
Data collection  Patient’s hypotension exposure
 Receipt of other nephrotoxic agents, any receipt of intravenous
contrast agents.
 Dosing schedule of studied antibiotics
 Number of days of antibiotic therapy
 Primary outcome:
 Difference in AKI incidence between the group receiving TZP-VAN
and FEP-VAN

Study Secondary outcomes:

Outcomes  AKI incidence on the basis of dosing schemes & duration of

therapy
 Time to AKI from the time of initiation of therapy
 Hospital length of stay
 In-hospital mortality
 RIFLE criteria
 Consists of 3 severity classes (risk, injury & failure) & 2 outcomes
classes (loss of kidney function, end-stage kidney disease)
 Risk – decrease in GFR of at least 25%
Evaluation of  Injury – decrease in GFR of at least 50%
development  Failure – decrease in GFR of 75% or more
of AKI  Outcome classes require a diagnosis based on the duration of
renal dysfunction and were not evaluated in this study
* GFR estimated with the adjusted Cockfroft-Gault equation
Results

4193
10141 patients 2211 pts evaluated for
screened Evaluated for matched analysis
unmatched analysis

Met inclusion After balance up

criteria baseline covariates
Patient
demographic
& clinical
characteristics
Patient
demographic
and clinical
characteristics
Analysis for
Matched
Cohort
Matched
cohort
Multivariate
regression
results
Secondary
endpoints
• AKI occurred earlier in TZP group
• No significant difference in hospital length of stay or mortality
 TZP dosing FEP dosing
Antibiotic regimen regimen

dosing
regimen 3.375g 6hrly 4.5g 6hrly 2g 8hrly 2g 12hrly
(55.6%) (30.4%) (64.8%) (23.8%)

AKI
Incidence 20.1% 24.3% 13.4% 11.1%
Rate
 AKI incidence higher in TZP group
(21.4%)
• Range of AKI in current literature for TZP group :
9.5% - 34.8%

Discussion
AKI incidence in FEP group (12.5%)
• Similar with previous reports
• Lower compared to 1 study conducted by
Hammond et al. (28.8%)
 Incidence of AKI
TZP 32/109
(n=109) (29.3%)
• Moenster RP et N=139 P=0.099
al. 2014 4/30
FEP (n=30)
(13.3%)
n=139
Restrospective cohort study
Included DM patients with
osteomyelitis
Received VAN+TZP & TZP group
VAN+FEP for at least 72 hr (dose more than 9/24 (37.5%)
18g /day)
Incidence of AKI P=0.29
FEP group
(dose more than 3/17 (17.3%)
3g /day)
 Study objective: to evaluate observed incidence of AKI in adult
patients receiving TZP-VAN or FEP-VAN for more than 48 hrs

Gomes et al.
2014 VAN-TZP 34.8%
n=224
N=224 P<0.0001

Retrospective matched VAN-FEP 12.5%

cohort study

 There may be an association of TZP-VAN combination use with increased

risk of AKI
 Study objectives: To compare incidence of AKI development
Hammond et during therapy or within 72 hr after completion of therapy in
adult critically ill patients who received Vancomycin with
al. 2016 concomitant pip-tazo or cefepime.

TZP-VAN
n=122 32.7%
Retrospective cohort N=49 P= 0.647
study N=122
Duration: sept 2012 – dec FEP-VAN
28.8%
2014 N=73
AKI incidence rate: 37/122  Average treatment effect not significant showing no association between
(30.3%) AKI development and beta lactam choice (p=0.958)
 STUDY Moenster RP et Gomes et al. Hammond et al. Rutter wc et al.
al. 2014 2014 2016 2017

Population Restrospective Retrospective Retrospective Retrospective

cohort study matched cohort cohort study in matched cohort
Included DM study adult critically ill Single-Center-
patients with (n=224) patients Study over 4 years
osteomyelitis (n=122) (n=2211)
(n=139)

PICO Model Intervention Incidence of AKI

for receiving
Incidence of AKI
in adult patients
Incidence of AKI
development
AKI incidence in
the group
VAN+TZP at least receiving TZP- during therapy or receiving TZP-
72 hr VAN for more within 72 hr after VAN combination
than 48 hrs completion of for at least 48 hrs
TZP-VAN therapy

Comparison VAN+FEP FEP-VAN FEP-VAN FEP-VAN

Outcome VAN+TZP: VAN-TZP: TZP-VAN: TZP group:
32/109 (29.3%) 34.8% 32.7% (n=49) 21.4% (n=1633)
VAN+FEP: VAN-FEP: FEP-VAN: FEP group:
4/30 (13.3%) 12.5% 28.8% (n=73) 12.5% (n=578)
p = 0.099 p <0.0001 p = 0.647 p<0.0001
  Small sample sizes – lack of statistical power severely limit
application of findings from the previous studies
 Gomes et al. – confounding not adequately addressed in the
studies

Study In study by Rutter WC et al. 2017 –

 larger sample size
limitations  Utilize propensity score matching algorithm to control for
confounders
 AKI incidence difference maintained after controlling for
confounders
 Suggest that combined use of TZP with VAN is associated with
increase rates of AKI compared to FEP group
  AKI was significantly more common in patients receiving
vancomycin in combination with piperacillin-tazobactam than in
those receiving vancomycin in combination with cefepime.

Conclusion
 Reinforces the need for the judicious use of combination
empirical antimicrobial therapy.