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