VANCOMYCIN FAILED MY
KIDNEYS: NOW WHAT?
Case presentation
General Surgery Rotation
Rajwant Minhas
NOVEMBER 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 Information
PMH
MPTA
•Left Oxford hemiarthroplasty 7 y ago
•HTN x years
Furosemide 20 mg PO OD
Amlodipine 5 mg PO OD
Ramipril 5 mg PO OD
Sprinolactone 12.5 mg PO OD
•Primary prevention of cardiovascular
event
ASA 81 mg PO OD
•Dyslipidemia x years
Rosuvastatin 10 mg PO OD
Patient Information
PMH
MPTA
•COPD
Fluticasone 250 mcg 2 puffs BID
Ipratropium 20 mcg 2 puffs QID
Salbutamol 100 mcg 2 puffs QID PRN
•Heartburn
•OA
•Migraine
•Fibromyalgia
•Sinus HA
Ranitidine 150 mg PO BID
•Seasonal allergies
Cetirizine 10 mg PO OD
Ibuprofen 400 mg PO PRN
6
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 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
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 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
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 VancomycinInduced Nephrotoxicity
High
dose/trough
Long duration
Concomitant
nephrotoxins
Vancomycin
Nephrotoxicity
ICU stay
Vasopressors
High APACHE
II score
Obesity
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 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, rightsided 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 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, rightsided 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 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, rightsided 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
Random
vancomycin
15.5
<10
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
Nurse, Pharmacist, Physician
Ongoing
Nurse, Pharmacist
Ongoing
WBC, neutrophils, CRP
BP, HR
Pain
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 (>5 times ULN or 1000
units/L) or in asymptomatic
patients CPK > 10 x ULN,
muscle, joint pain
Nurse, pharmacist
CPK weekly
Muscle 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