VANCOMYCIN FAILED MY KIDNEYS: NOW WHAT?

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VANCOMYCIN FAILED MY KIDNEYS NOW WHAT?

• Case presentation
• General Surgery Rotation
• Rajwant Minhas
• NOVEMBER 2011

2
Outline

• Learning Objectives
• Case
• Background Infected knee prosthesis and
  vancomycin induced nephrotoxicity
• Clinical Question
• Results
• Assessment
• Plan
• Monitoring
• Follow up

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Learning Objectives

• Understand the classification of
• Prosthetic joint infections
• Discuss alternate treatment options besides
  vancomycin to treat infected knee prosthesis
• Understand 3 differences with respect to MOA and
  ADRs b/w daptomycin, linezolid and tigecycline

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Patient Information

• NS 62 yo (53, 92 kg) IBW 51.9 kg
• Caucasian F
• Admitted Nov 1, 2011 for revision to knee
  arthroplasty
• C/C Knee pain
• HPI
• Left Oxford hemiarthroplasty 7 years ago
• Recently became hot, red swollen
• Acute pain in knee with pinching like pain, lasts
  for a while
• Difficulty doing stairs

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Patient Information
PMH MPTA
Left Oxford hemiarthroplasty 7 y ago HTN x years Primary prevention of cardiovascular event Dyslipidemia x years Furosemide 20 mg PO OD Amlodipine 5 mg PO OD Ramipril 5 mg PO OD Sprinolactone 12.5 mg PO OD ASA 81 mg PO OD Rosuvastatin 10 mg PO OD
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Patient Information
PMH MPTA
COPD Heartburn OA Migraine Fibromyalgia Sinus HA Seasonal allergies Fluticasone 250 mcg 2 puffs BID Ipratropium 20 mcg 2 puffs QID Salbutamol 100 mcg 2 puffs QID PRN Ranitidine 150 mg PO BID Ibuprofen 400 mg PO PRN Cetirizine 10 mg PO OD
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Patient Information

• Allergies NKDA
• FH Father HTN
• Mother Type II Diabetes, HTN
• SH
• Caffeine 3-4 cups coffee/day
• No alcohol
• Smoking 1 pack per day
• AAT
• Lives alone
• Retired
• Low salt diet

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Current Medications
Infected Knee Prosthesis Vancomycin 2 g IV Q12H
HTN Amlodipine 5 mg PO OD Ramipril 5 mg PO OD Furosemide 20 mg PO OD Spironolactone 12.5 mg PO OD
Dyslipidemia Rosuvastatin 10 mg PO OD
Nausea Dimenhydrinate 25-50 mg PO Q4H PRN Ondansetron 4 mg IV Q4-6 H PRN
Knee Pain Acetaminophen 650 mg PO Q6H Oxycodone 5-10 mg PO Q3-4 H PRN Morphine 5 mg IV Q4H Hydromorphone 0.1-0.4 mg IV Q10min PRN
Insomnia Zopiclone 3.75-7.5 mg PO HS PRN
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Review of Systems

• CNS Temp 36.9 C
• Resp
• RR 20
• CVS
• BP 141/59 mm Hg
• HR 71/min
• Fluids/Lytes/Heme
• WBC 8.2
• Neutrophils 5.7
• Hgb 84
• MSK/Skin/Extremities
• Knee X ray No signs of loosening of implant,
  degenerative changes at the patellofemoral joint
• Muscle spasm in left knee
• Immobility cast in place on left knee

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Review of Systems
Sept 26 Aspirate knee swab Coagulase negative Staph (CoNS) Sensitive to Cloxacillin, Vancomycin, Cefazolin
Nov 4 Joint fluid culture Coagulase negative Staph Sensitive to Vancomycin, Tetracycline, Tigecycline, Linezolid, Rifampin Resistant to Ampicillin, Cefazolin, Cloxacillin, Penicillin, Clindamycin
Aug 16 Knee arthroscopy, debridement Nov 1
Revision to arthroplasty, prosthesis
removed cement with vancomycin placed Nov 7
Discontinued Cefazolin 2g IV Q8H
Initiated Vancomycin 1500 mg IV Q12H
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Review of Systems
9/11 11/11 14/11
Creatinine 45 45 138
eGFR gt120 gt120 34
Vancomycin Dose 1500 mg IV Q12H 1750 mg IV Q12H 2000 mg IV Q12H
Vancomycin trough 7.9 11.4 41.5
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Medical Problem List

• Acute Renal Failure
• Infected Knee Prosthesis
• DVT Prophylaxis
• Pain

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Drug Related Problems

• Actual NS is experiencing nephrotoxicity
  secondary to receiving vancomycin and would
  benefit from reassessment of her drug therapy.
• Potential NS is at risk of deep vein thrombosis
  and pulmonary embolism secondary to not receiving
  medication for DVT prophylaxis and would benefit
  from reassessment of her drug therapy
• Potential NS is at risk of experiencing
  cardiovascular event (MI, stroke) secondary to
  not receiving ASA for primary prophylaxis and
  would benefit from reassessment of her drug
  therapy.
• Potential NS is at risk of experiencing
  constipation, respiratory depression, confusion
  secondary to receiving morphine and oxycodone
  together for her pain and would benefit from
  reassessment her drug therapy.

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Infected Knee Prosthesis

• Heavy financial toll 50,000 per failed
  prosthesis
• Incidence 1-2 TKA
• Highest risk within first 3 months
• Risk factors Medical conditions
• Diabetes
• Obesity
• Rheumatoid arthritis
• Urinary tract infection
• Operative technique
• Prolonged operative time (gt 2.5 h)

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Infected Knee Prosthesis

• Other factors
• Immunosuppressive therapy
• Malnourishment
• Smoking
• Skin ulceration
• Previous surgery

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Classification of Infection According to Route

• Perioperative
• Haematogenous
• Contiguous

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Classification of Infection According to Onset of
Symptoms

• Early infection
• lt 3 months
• Acquired perioperatively
• Generally caused by S. aureus
• Delayed or low-grade infection
• 3-24 months
• Acquired during implant surgery
• Less virulent organisms (e.g. CoNS or P. acnes)
• Late infection
• gt24 months
• Haematogenous seeding from remote infections
• Most frequent foci Skin, respiratory, dental
  and UTIs

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Treatment Options

• Open débridement with retention
• Single-staged or 2-staged resection
  reimplantation of another prosthesis
• Resection arthroplasty
• Arthrodesis
• Antibiotic suppression
• Amputation

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Two-Stage Exchange

• Highest success rate gt90
• 1. Removal of prosthesis
• Immobilizer, antibiotic therapy
• If no difficult-to-treat microorganisms
• Short interval until reimplantation (2-4 wks)
• Temporary antimicrobial-impregnated bone cement
  spacer
• Difficult-to-treat longer interval (8 wks)
  without a spacer
• 2. Implantation of a new prosthesis during a
  later surgical procedure

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Vancomycin Induced Nephrotoxicity

• Nephrotoxicity defined as
• Determined by the clinical investigator
• An ? of 44.2 umol/L in SCr or gt50 baseline SCr
• or
• 3. A ? in CrCl to lt 50 mL/min or ? of gt 10mL/min
  from a baseline CrCl of lt 50 mL/min

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Vancomycin Induced Nephrotoxicity

• Elimination almost exclusively renal
• Onset 4-8 days from start of therapy
• Nephrotoxicity resolved in
• 50 of patients while on vancomycin
• 21 within 72 hrs of discontinuation
• Unclear whether high trough levels indeed cause
  ARF or vice-versa
• Concomitant nephrotoxic agents ? rates to as high
  as 35.

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Risk Factors for Vancomycin-Induced Nephrotoxicity
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Goals of Therapy

• NSs goals
• Restore functioning of her left knee
• Prevent another infection
• Go home
• Healthcare teams goals
• Painless, well-functioning knee arthroplasty
• Cure the current infection
• Restore baseline kidney function
• Prevent complications renal failure
• Minimize ADRs

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Clinical Question

• P In a 62 yo Caucasian F with infected knee
  prosthesis vancomycin induced nephrotoxicity
• I which antibiotic is safer vs.
• C vancomycin
• O in order to cure the knee prosthesis infection
  caused by CoNS

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Search Strategy Results

• Pubmed
• Ovid Embase
• Google
• Search Terms Infected knee prosthesis,
  treatment, tigecycline, daptomycin, linezolid,
  prosthetic joint infection
• Results
• Case reports
• Literature review
• Retrospective observational studies
• 1 SR for daptomycin

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Alternatives to Vancomycin
Daptomycin Linezolid Tigecycline
Active against Gram ve Bactericidal, conc. dependent killing, significant post-antibiotic effect Gram ve Bacteriostatic enterococci, staphylococci Bactericidal streptococci MRSA, VRE Gram ve, gram ve, anaerobic aytpicals Bacteriostatic
Indicated for cSSIs, Bacteremia, right-sided native valve endocarditis caused by MSSA or MRSA SSIs, cSSIs without concomitant OM due to S. aureus cSSIs, cIAIs
SEs reversible dose-related myalgias weakness (lt1.0), anemia, edema, GI adverse effects, hyper or hypotension neuropathy, serotonin syndrome Myelosuppression thrombocyopenia, anemia 6-7 of patients, more common after 2 wks of therapy Leukopenia3-4 N, V, diarrhea, HA, dizziness, increase in hepatic enzymes
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Daptomycin

• Faster killing of S. aureus (including MRSA)
  Enterococci (including VRE) vs. vancomycin.
• In vitro Clinical association b/w vancomycin
  exposure daptomycin heteroresistance in S.
  aureus 
• Conc. in bone lower than vancomycin, probably
  due to high protein binding (92)
• Inactive nontoxic metabolites, 53-59 excreted
  in urine
• Overlapping musculoskeletal toxicity b/w statins
  daptomycin advised not to use concomitantly.

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Daptomycin Systematic Review of Case Reports
Case Series

• Patients with bone or joint infections
• Most failed on another antibiotic before
• Cure in 12/20 (60) with total joint arthroplasty
• Case report (Antony et al.)
• 7 patients with reduced renal function tx with
  4mg/kg Q 48H, all cured
• Effective against MDR gram ve OM joint
  infections even in cases where other first line
  agents have failed
• Frequent emergence of resistance

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Alternatives to Vancomycin
Daptomycin Linezolid Tigecycline
Active against Gram ve Bactericidal, conc. dependent killing, significant post-antibiotic effect Gram ve Bacteriostatic enterococci, staphylococci Bactericidal streptococci MRSA, VRE Gram ve, gram ve, anaerobic aytpicals Bacteriostatic
Indicated for cSSIs, Bacteremia, right-sided native valve endocarditis caused by MSSA or MRSA SSIs, cSSIs without concomitant OM due to S. aureus cSSIs, cIAIs
SEs reversible dose-related myalgias weakness (lt1.0), anemia, edema, GI adverse effects, hyper or hypotension neuropathy, serotonin syndrome Myelosuppression thrombocyopenia, anemia 6-7 of patients, more common after 2 wks of therapy Leukopenia3-4 N, V, diarrhea, HA, dizziness, increase in hepatic enzymes
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Linezolid

• F100
• Excellent penetration into bone, fat, muscle,
  periarticular structures
• Elimination
• Nonrenal 65
• Renal 30
• Fecal 5
• No dosage adjustment in renal insufficiency

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Linezolid

• Documented case reports showing success in bone
  prosthesis infections
• 1. Retrospective study for chronic OM
• Cure rate 85 _at_ 12 wks, 78.8 at follow-up
• 2. Retrospective, nonrandomized observational
  study
• 14 patients with infected total joint
  arthroplasty
• Treated by 1 or 2 stage revision linezolid
  course
• Result Infection resolved 100
• 3. Prospective observational study
• 9 patients OM
• 2 patients periprosthetic infections
• Pathogen Multiresistant CoNS
• 6 wks therapy
• Result 100 remission at mean follow-up of 24
  months

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Tigecycline

• No human trials found involving OM
• Animal studies May have a role in bone infection
• 28 days of treatment in rabbits with OM
• Tigecycline/oral rifampicin 100 infection
  clearance
• Alone 90
• Jaksic et al.
• Febrile neutropenic patients with cancer
• Vancomycin more nephrotoxic (2.3 vs 0.3,
  p0.04)

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Alternatives to Vancomycin
Daptomycin Linezolid Tigecycline
Active against Gram ve Bactericidal, conc. dependent killing, significant post-antibiotic effect Gram ve Bacteriostatic enterococci, staphylococci Bactericidal streptococci MRSA, VRE Gram ve, gram ve, anaerobic aytpicals Bacteriostatic
Indicated for cSSIs, Bacteremia, right-sided native valve endocarditis caused by MSSA or MRSA SSIs, cSSIs without concomitant OM due to S. aureus cSSIs, cIAIs
SEs reversible dose-related myalgias weakness (lt1.0), anemia, edema, GI adverse effects, hyper or hypotension neuropathy, serotonin syndrome Myelosuppression thrombocyopenia, anemia 6-7 of patients, more common after 2 wks of therapy Leukopenia3-4 N, V, diarrhea, HA, dizziness, increase in hepatic enzymes
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Summary

• Limitations of studies
• No RCTs
• Very few patients with MRCoNS
• Different patient characteristics
• Mixed bone/joint infections vs. prosthetic
  infections
• Trials of other antibiotics vs. first trial
• DAP coadministered with other antibiotics
• Bactericidal vs. static
• More information on DAP vs. linezolid,
  tigecycline
• DAP Some resistance

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Initial Assessment

• Prosthetic knee infection improved since
  admission
• Renal function worse over past 24 hours
• Do not agree with current drug therapy for knee
  infection
• Patient compliant in hospital

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Plan

• Drug Hold Vancomycin therapy
• Review DAP vs. linezolid vs. tigecycline
• Non-drug Hydration
• Monitor
• Urine output x 48 hours
• SCr, eGFR, BUN
• Ototoxicity, N,V, diarrhea

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Follow-Up

• Vancomycin dose held on Nov 14/11
• Daptomycin started on Nov 18/11 6mg/kg IV q48h

Monitoring parameter 15/11 16/11 17/11 21/11 24/11
Creatinine 165 183 168 133 128
eGFR 27 24 27 35 37
CRP 75 lt10
Random vancomycin 15.5
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Final Assessment Plan

• Agree with current therapy of DAP
• Hold statin while on DAP
• Renal function improved over past 24 hours
• Patient compliant in hospital
• Continue monitoring renal function and
  signs/symptoms of myopathy

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Monitoring
Monitoring point What Who When
Infection Temperature WBC, neutrophils, CRP BP, HR Nurse, Pharmacist, Physician Ongoing
Pain Nurse, Pharmacist Ongoing
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Monitoring
Monitoring point What Who When
GI adverse effects N, V, diarrhea, constipation Nurse Ongoing

Renal function eGFR, SCr Pharmacist, Physician Every 2 days until back to baseline
Edema Swelling in limbs Nurse, Pharmacist, Physician Ongoing
Anemia Hgb Physician, Pharmacist Ongoing
Hypokalemia K levels Physician, Pharmacist Ongoing
Myopathy ?in CPK (gt5 times ULN or 1000 units/L) or in asymptomatic patients CPK gt 10 x ULN, muscle, joint pain Nurse, pharmacist CPK weekly Muscle pain every day
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Follow-Up

• Discharged on Nov 28/11
• On outpatient IV therapy

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Follow-Up
Monitoring parameter 30/11
Creatinine 81
eGFR 62
CRP lt10
CPK 78
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Review of Case

• Learning Objectives
• Case
• Background Infected knee prosthesis and
  vancomycin induced nephrotoxicity
• Clinical Question
• Results
• Assessment
• Plan
• Monitoring
• Follow up

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References

• 1. Jacofsky DJ, Campbell MD. The Infected Total
  Knee Arthroplasty Part 1 Identification and
  Diagnosis in the Primary Care Setting. Hospital
  Physician. January 2006. p. 29-36
• Available from http//www.turner-white.com/member
  file.php?PubCodehp_jan06_knee.pdf
• 2. Jacofsky DJ, Campbell MD. The Infected Total
  Knee Arthroplasty Part 2 Management Options. Feb
  2006 .p. 29-36. Available from
  http//www.turner-white.com/memberfile.php?PubCode
  hp_feb06_knee.pdf
• 3. Gupta A, Biyani M, Khaira A. Vancomycin
  nephrotoxicity myths and facts. 2011 69(9)
• p.379-383.
• 4. Hazlewood KA, Brouse SD, Pitcher WD, Hall RG.
  Vancomycin-Associated Nephrotoxicity Grave
  Concern or Death by Character Assassination? Am J
  Med. 2010 Feb 123(2) 182.e1. doi 10.1016/j.amjme
  d.2009.05.031
• 5. Falagas ME, Giannopoulou KP, Ntziora F,
  Papagelopoulos PJ. Daptomycin for treatment of
  patients with bone and joint ifnections a
  systematic review of the clinical evidence.
  International Journal of Antimicrobial Agents 30
  2007 .p.202-209.
• 6. Trampuz A, Zimmer W. Prosthetic joint
  infections update in diagnosis and treatment.
  Swiss Med Wkly 2005 135243-251
• 7. Oussedik S, Haddad FS. The use of linezolid in
  the treatment of infected total joint
  arthroplasty. The Journal of Arthroplasty 2008
  23(2)273-279.