5/5/2015
BACKGROUND
Vancomycin
“Vancomycin-associated
nephrotoxicity”: Is it truly the
vancomycin?
Karrine Roberts, PharmD
PGY2 Infectious Diseases Resident
Detroit Receiving Hospital, Detroit Medical Center
•
Glycopeptide antibiotic
•
Inhibits bacterial cell wall synthesis by
binding to terminal D-ala-D-alanine
portion of cell wall precursor
•
Active against Gram-positive
organisms
•
Most commonly used for methicillinresistant Staphylococcus aureus
(MRSA)
Vancomycin [package insert]. New York, NY: Pfizer; Rev 12/10
Lexi-Comp, Inc. (Lexi-DrugsTM ). Lexi-Comp, Inc.; February 27, 2015
J Antibiot (Tokyo). 2014 Jan;67(1):7-22
The speaker has no actual or potential conflicts of interest in relation to this presentation.
BACKGROUND
BACKGROUND
Vancomycin
Vancomycin-associated nephrotoxicity (VAN)
• Glycopeptide originally isolated from soil sample of Streptomyces
orientalis
• First approved for use in 1958 in order to treat penicillin-resistant
staphylococcal infections
• Early 1980s, dramatic increase in use (> 100 fold over next 2 decades)
•
•
•
Originally thought to be due to impurities in formulation (“Mississippi
mud”)
With improved purification methods, VAN considered infrequent (5-7%)
Guideline recommended to target higher trough levels (15-20 mcg/mL)
•
associatedmore
with nephrotoxicity
Significantly
VAN (up to 30-40%) reported with use of higher doses
•
Risk factors associated with VAN identified
•
lead to increased reports of nephrotoxicity and evaluation of risk factors
Risk factors associated with VAN
Vancomycin doses > 4 grams/day
Vancomycin trough levels > 20 mcg/mL
Concomitant nephrotoxins
History of kidney disease
Total body weight > 101.4 kg
Prolonged duration of therapy (> 7 days)
Admittance to the intensive care unit (ICU)
Levine, DP. Clin Infect Dis 2006;42(Suppl 1):S5-S12
BACKGROUND
Moellering RC, Jr. Clin Infect Dis 2006;42(Suppl 1):S3-S4
van Hal SJ, et al. Antimicrob Agent Chemother 2013;57:734-44
Lodise TP, et al. Antimicrob Agent Chemother 2008;52(4):1330-6
Elyasi S, et al. Eur J Clin Pharmacol 2012;68:1243-55
Liu, C et al. Clin Infect Dis. 2011 Feb 1;52(3):e18-55
Moh’d H, et al. South Med J. 2014 Jun;107(6):383-8
Rybak M, et al. Clin Infect Dis. 2009 Aug 1;49(3):325-7
BACKGROUND
Vancomycin-associated nephrotoxicity (VAN)
• Exact mechanism unknown
• Several proposed mechanisms
VAN at Detroit Medical Center (DMC)
• In 2013, DMC had an increase of suspected cases of VAN
•
•
– Proximal renal tubular cell necrosis
Rapid, often lead to fulminate renal failure
Some required renal replacement therapy
– Oxidative stress
• Multidisciplinary review panel met to assess VAN cases
– Mitochondrial damage
– Changes in expression of several transcripts from the complement and
inflammatory pathways
• Considered to be reversible
• Low incidence of residual damage with short term dialysis in only
3% and no patients needing long-term dialysis
•
•
•
Included pharmacists and physicians from numerous specialties
(nephrology, ICU, surgery, etc)
Exact role of vancomycin in the development of AKI was difficult to
ascertain due to confounding factors and multiple variables present
Concerns of potential bias if retrospectively review cases and compare to
alternatives
Shah-Khan F, et al. Int J Nephrol 2011;2011:436856
Oktem F, et al. Toxicology 2005;215:227-33
Dieterich C, et al. Toxicol Sci 2009;107:258-69
Elyasi S, et al. Eur J Clin Pharmacol 2012;68:1243-55
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5/5/2015
BACKGROUND
CYCLING PILOT PROGRAM
VAN at Detroit Medical Center (DMC)
VAN at Detroit Medical Center (DMC)
• In order to assess these cases, several initiatives have taken place
• As a quality improvement initiative, a resistant Gram-positive
antimicrobial cycling pilot program was implemented at Sinai Grace
Hospital (SGH)
•
2013-2014 residency project assessing AKI among different generic vancomycin
products (Pfizer and Hospira)
• No difference of AKI between products
• Potential increased risk for those on concomitant piperacillin-tazobactam
•
Ongoing retrospective study assessing AKI between extended-infusion or
standard-infusion piperacillin-tazobactam, given in combination with vancomycin
•
Updated vancomycin pharmacy dosing guidelines and policy
•
•
•
Began November 1st, 2014
Involved monthly cycling between vancomycin with other resistant Grampositive antimicrobials for both empiric and definitive coverage
Goal: Eliminate confounding factors and multiple variables potentially
contributing to suspected cases of VAN and allow the institution to better
assess the independent impact of vancomycin on AKI
• Target area under the curve (AUC) for optimal patient outcomes
• Goal to assess if smaller doses can be given to achieve goal AUC targets rather than
using vancomycin troughs as a surrogate to the AUC
CYCLING PILOT PROGRAM
Indication
(by infection site)
Odd Months
Even Months
Pneumonia
Vancomycin
Linezolid 600 mg IV/PO every 12 hours
Vancomycin
Daptomycin 6 mg/kg IV daily unless
pneumonia still part of the differential, then
use Linezolid 600 mg IV/PO every 12 hours
(may consider higher doses of daptomycin
(8-10 mg/kg IV daily) in complicated
bacteremia, refractory bacteremia, or
endocarditis)
Bacteremia
Skin and skin structure
Vancomycin
Daptomycin 4 mg/kg IV daily
Urinary tract
Vancomycin
Linezolid 600 mg IV/PO every 12 hours
Intra-abdominal
Vancomycin
Linezolid 600 mg IV/PO every 12 hours
Sepsis (unknown source)
Vancomycin
Daptomycin 6 mg/kg IV daily or
Linezolid 600 mg IV/PO every 12 hours
Bone/Joint/Orthopedic
Vancomycin
Daptomycin 6 mg/kg IV daily
“Vancomycin-associated
nephrotoxicity”: Is it truly the
vancomycin?
Karrine Roberts, PharmD1
Ryan P. Mynatt, PharmD, BCPS AQ-ID1
Keith S. Kaye MD, MPH1,2
Michael J. Rybak, PharmD, MPH1,2,3
Kyle Murray, PharmD, BCPS1
Stacy Otremba, PharmD1
Mark Pangrazzi, PharmD1
Jason M. Pogue, PharmD, BCPS AQ-ID1,2
3Anti-Infective
Sinai-Grace Hospital
 404 bed, community teaching
hospital within the DMC
 Level II trauma center
 Designated trauma and stroke
center by Detroit Emergency
Medical Services (EMS)
 Affiliated with Wayne State
School of Medicine
 Located in Detroit, Michigan
1Department of Pharmacy Services, Detroit Medical Center, Detroit, Michigan
2Division of Infectious Diseases, Wayne State University, Detroit, Michigan
Research Laboratory, College of Pharmacy & Health Sciences, Wayne State University, Detroit, Michigan
METHODS
• IRB approved
• Retrospective cohort study
• Included ICU patients treated during the resistant Grampositive antimicrobial coverage cycling pilot program
• Two cohorts of patients
– Vancomycin (dosed per pharmacy dosing protocol)
– Alternatives (linezolid, daptomycin, or ceftaroline based on indication)
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5/5/2015
METHODS
METHODS
•
Inclusion criteria
Exclusion criteria
•
Admitted to the ICU
•
•
Between the ages of 18 to 99
Hemodialysis or other renal
replacement therapy
•
Received a resistant Grampositive antimicrobial > 24
hours
•
Acute kidney injury or severe renal
dysfunction
Data collected
– Demographics, co-morbid conditions, site of infection, microbiological data,
pertinent laboratory data, concomitant nephrotoxins, concomitant antimicrobials
administered, and ICU admission and discharge dates
•
– Serum creatinine greater than 2
mg/dL and a creatinine clearance
less than 30 mL/min
•
Oral vancomycin for Clostridium
difficile
•
Meningitis/CNS infection indication
•
Died or were discharged within 48
hours
Concomitant nephrotoxins included
– ACE-I/ARB*, acyclovir, aminoglycosides, amphotericin B, calcineurin inhibitors,
colistin, IV contrast, loop diuretics, NSAIDs**, and vasopressors
•
Acute kidney injury (AKI) definition
– AKIN (Acute Kidney Injury Network) criteria definition
– Abrupt (within 48 hours) reduction in kidney function
– Absolute increase in serum creatinine of ≥ 0.3 mg/dL or ≥ 50% (1.5-fold form baseline),
or a reduction in urine output (documented ≤ 0.5 mL/kg per hour for > 6 hours)
*Angiontension converting enzyme inhibitors/angiotension receptor blockers
**Non-steroidal anti-inflammatory drugs
OUTCOMES
STATISTICS
• Primary
• Categorical data
Molitoris BA et al. Nat Clin Pract Nephrol 2007;3:439–442
– Chi-squared or Fisher’s Exact test when appropriate
– Compare the incidence of acute kidney injury (AKI)
• Secondary
• Continuous data
– Length of stay (LOS)
– Student’s t-test or Wilcoxon Rank Sum test when appropriate
– In-hospital mortality
– Duration of therapy (days)
• P-value < 0.05 considered significant
– Adverse events
– Thrombocytopenia, Clostridium difficile, creatine phosphokinase
elevations
RESULTS
• Multi-variable analysis will be done to assess independent
effect once total sample is complete
RESULTS
Vancomycin Group
Alternatives Group
119
Screened
91
Screened
Baseline characteristics
Vancomycin
(n = 37)
Alternatives
(n = 42)
P-value
Age, median (IQR)
63 (50-72)
62.5 (56.0-71.8)
0.58
Male Gender, N (%)
23 (67%)
17 (40%)
0.07
32 (86.5%)
39 (92.9%)
0.46
Characteristic
African American ethnicity, N (%)
82
Excluded
49
Excluded
Median Charlson Comorbidity Index, N (IQR)
3 (2-5)
4 (3-6)
0.19
61.4 (43.6-88.0)
55.8 (36.5-69.28)
0.29
2 (5.4%)
7 (16.7%)
0.16
Patients with CrCl 30 - 60 mL/min, N (%)
16 (43.2%)
17 (40.5%)
0.82
Patients with CrCl > 60 mL/min, N (%)
19 (51.4%)
18 (42.9%)
0.50
1 (0-2)
1 (0-2)
0.57
10 (27.0%)
7 (16.7%)
0.29
Median baseline CrCl, mL/min (IQR)
Patients with CrCl < 30 mL/min, N (%)
37
Included
42
Included
Median # concomitant nephrotoxins (IQR)
Severe Sepsis/Septic Shock
CrCl = Creatinine clearance
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RESULTS
RESULTS
Antibiotics Used
Gram-positive Antimicrobial
Vancomycin, N (%)
• Gram-positive antimicrobial Indications
Vancomycin
(n = 37)
Alternatives
(n = 42)
37 (100%)
0 (0%)
Linezolid, N (%)
0 (0%)
39 (92.9%)
Daptomycin, N (%)
0 (0%)
2 (4.8%)
Ceftaroline, N (%)
0 (0%)
1 (2.4%)
Vancomycin
(n = 37)
Alternatives
(n = 42)
Piperacillin/tazobactam, N (%)
14 (37.8%)
10 (23.8%)
Cefepime, N (%)
18 (48.6%)
23 (54.8%)
Meropenem, N (%)
3 (8.1%)
1 (2.4%)
Aztreonam, N (%)
0 (0.0%)
4 (9.5%)
No anti-pseudomonal agent, N (%)
2 (5.4%)
4 (9.5%)
Concomitant Anti-pseudomonal Agent
Alternatives Group
Vancomycin Group
Pneumonia 59.5%
Pneumonia 48.6%
Sepsis 23.8%
Sepsis* 29.7%
SSSI 4.8%
Endocarditis 2.4%
SSSI 5.4%
Endocarditis 2.7%
Bone/Joint 2.7%
Bone/Joint 2.4%
Itra-abdominal 5.4%
Itra-abdominal 0%
Other 2.4%
Other 5.4%
Bacteremia 4.8%
SSSI = skin and skin structure infection
*Sepsis = Sepsis of unknown origin
RESULTS
STUDY LIMITATIONS
• Interim analysis
Outcomes
Outcome
Vancomycin
(n = 37)
Alternatives
(n = 42)
P-value
AKI, N (%)
8 (21.6%)
8 (19.1%)
0.79
AKI resolved, N (%)
7 (87.5%)
4 (50%)
0.33
5 (3-9)
4.5 (3-7)
0.43
Median duration of therapy (DOT), days (IQR)
Median DOT if MRSA not isolated, days (IQR)
Median length of hospital stay, days (IQR)
Median length of ICU stay, days (IQR)
Mortality, N (%)
6 (3-7)
4 (3-6)
0.16
14 (10-16.3)
12 (7-17)*
0.58
9 (4.75-11.25)
7 (4-12)
0.58
4 (10.8%)
4 (9.8%)*
1.00
Vancomycin
(n = 37)
Alternatives
(n = 42)
P-value
Thrombocytopenia, N (%)
5 (13.5%)
9 (21.4%)
0.39
Clostridium difficile infection, N (%)
2 (5.4%)
1 (2.4%)
0.60
Creatine phosphokinase elevations, N (%)
2 (5.4%)
6 (14.3%)
0.27
Adverse effects
• Retrospective data collection
• Patients may have received a single dose of
vancomycin in the ED prior to ICU admission
• Changes in vancomycin dosing policy to target AUC
rather than trough values
• Shortage of piperacillin/tazobactam changed
consistency of concomitant use
• Only ICU patients included
*Does not include patients still hospitalized
CONCLUSIONS
• Based on current available data, firm conclusions as
to the independent impact of vancomycin on AKI in
these ICU patients cannot be drawn
FUTURE DIRECTIONS
• Continuation of the pilot to achieve higher sample
size for comparison
• Cost analysis to be done in final analysis
• Interim results show similar incidence of acute
kidney injury between treatment groups
• Multi-variable analysis to assess independent
impact of vancomycin on AKI
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LEARNING QUESTION #1
LEARNING QUESTION #2
Which of the following statements regarding vancomycinassociated nephrotoxicity (VAN) is false?
The following are risk factors associated with
vancomycin-associated nephrotoxicity
a. VAN was originally thought to be due to the impurities in
the original formulations of the products
b. Pathogenesis of VAN is thought to partly be due to
oxidative stress causing necrosis of the proximal tubule
c. This toxicity is considered to be irreversible and
permanent
d. More aggressive dosing strategies that target higher
vancomycin troughs have been associated with
increased incidence of VAN
a.
b.
c.
d.
Concomitant nephrotoxic agents
Longer duration of therapy (> 7 days)
Vancomycin doses greater than 4 grams daily
All of the above
ACKNOWLEDGEMENTS
• Thank you to all co-investigators
• Special thanks to the following
pharmacists at Sinai Grace Hospital for
helping with implementation of the protocol
• Jason Pogue, PharmD, BCPS-AQ ID
• Mark Pangrazzi, PharmD
• Stacey Otremba, PharmD
“Vancomycin-associated
nephrotoxicity”: Is it truly the
vancomycin?
Karrine Roberts, PharmD
PGY2 Infectious Diseases Resident
Detroit Receiving Hospital, Detroit Medical Center
The speaker has no actual or potential conflicts of interest in relation to this presentation.
5