âVancomycin-associated nephrotoxicityâ: Is it truly
Transcription
âVancomycin-associated nephrotoxicityâ: Is it truly
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 1 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) 2 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 3 5/5/2015 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 4 5/5/2015 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