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VANCOMYCIN FAILED MY KIDNEYS: NOW WHAT?
Case presentationGeneral Surgery Rotation
Rajwant MinhasNOVEMBER 2011
Outline
• Learning Objectives• Case• Background: Infected knee prosthesis and
vancomycin induced nephrotoxicity• Clinical Question• Results• Assessment • Plan• Monitoring• Follow up
Learning Objectives
1. Understand the classification of:
Prosthetic joint infections
2. Discuss alternate treatment options besides vancomycin to treat infected knee prosthesis
3. Understand 3 differences with respect to MOA and ADRs b/w daptomycin, linezolid and tigecycline
Patient Information• NS 62 yo (5’3”, 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
Patient InformationPMH 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
6
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
Patient Information
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
Current MedicationsInfected 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
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
Review of SystemsSept 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 removedcement with vancomycin placed
Nov 7: Discontinued Cefazolin 2g IV Q8H Initiated Vancomycin 1500 mg IV Q12H
Review of Systems
9/11 11/11 14/11
Creatinine 45 45 138
eGFR >120 >120 34
Vancomycin Dose 1500 mg IV Q12H 1750 mg IV Q12H 2000 mg IV Q12H
Vancomycin trough 7.9 11.4 41.5
Medical Problem List
• Acute Renal Failure
• Infected Knee Prosthesis• DVT Prophylaxis
• Pain
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.
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 (> 2.5 h)
Infected Knee Prosthesis
• Other factors
– Immunosuppressive therapy
– Malnourishment
– Smoking
– Skin ulceration
– Previous surgery
Classification of Infection According to Route
1. Perioperative
2. Haematogenous
3. Contiguous
Classification of Infection According to Onset of Symptoms
• Early infection: • < 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:• >24 months• Haematogenous seeding from remote infections• Most frequent foci : Skin, respiratory, dental and UTIs
Treatment Options
(1) Open débridement with retention
(2) Single-staged or 2-staged resection & reimplantation of another prosthesis
(3) Resection arthroplasty
(4) Arthrodesis
(5) Antibiotic suppression
(6) Amputation
Two-Stage Exchange• Highest success rate: >90%
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
Vancomycin Induced Nephrotoxicity
Nephrotoxicity defined as:
1. Determined by the clinical investigator
2. An ↑ of 44.2 umol/L in SCr or >50% baseline SCr
or
3. A ↓ in CrCl to < 50 mL/min or ↓ of > 10mL/min from a baseline CrCl of < 50 mL/min
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%.
Risk Factors for Vancomycin-Induced Nephrotoxicity
22
Goals of Therapy• NS’s goals:
– Restore functioning of her left knee– Prevent another infection– Go home
• Healthcare team’s goals– Painless, well-functioning knee arthroplasty– Cure the current infection– Restore baseline kidney function– Prevent complications: renal failure– Minimize ADRs
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
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
Alternatives to VancomycinDaptomycin 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 (<1.0%), 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
Leukopenia:3-4%
N, V, diarrhea, HA, dizziness, increase in hepatic enzymes
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.
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
Alternatives to VancomycinDaptomycin 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 (<1.0%), 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
Leukopenia:3-4%
N, V, diarrhea, HA, dizziness, increase in hepatic enzymes
Linezolid
• F=100%
• Excellent penetration into bone, fat, muscle, periarticular structures
• Elimination: – Nonrenal: 65%– Renal: 30%– Fecal: 5%– No dosage adjustment in renal insufficiency
Linezolid
• Documented case reports showing success in bone prosthesis infections
• 1. Retrospective study for chronic OM: – Cure rate 85% @ 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
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%, p=0.04)
Alternatives to VancomycinDaptomycin 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 (<1.0%), 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
Leukopenia:3-4%
N, V, diarrhea, HA, dizziness, increase in hepatic enzymes
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
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
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
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 <10
Random vancomycin
15.5
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
Monitoring
Monitoring point
What Who When
Infection Temperature
WBC, neutrophils, CRP
BP, HR
Nurse, Pharmacist, Physician Ongoing
Pain Nurse, Pharmacist Ongoing
MonitoringMonitoring 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 (>5 times ULN or 1000 units/L) or in asymptomatic patients CPK > 10 x ULN, muscle, joint pain
Nurse, pharmacist CPK weeklyMuscle pain: every day
Follow-Up
• Discharged on: Nov 28/11
• On outpatient IV therapy
Follow-Up
Monitoring parameter 30/11
Creatinine 81
eGFR 62
CRP <10
CPK 78
Review of Case
• Learning Objectives• Case• Background: Infected knee prosthesis and
vancomycin induced nephrotoxicity• Clinical Question• Results• Assessment • Plan• Monitoring• Follow up