VANCOMYCIN FAILED MY KIDNEYS: NOW WHAT?

1. 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

3. 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

4. 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

5. Patient Information

6. Patient Information

7. 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

8. Current Medications

9. 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

10. Review of Systems 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

11. Review of Systems

12. Medical Problem List Acute Renal Failure Infected Knee Prosthesis DVT Prophylaxis Pain

13. 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.

14. 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)

15. Infected Knee Prosthesis Other factors Immunosuppressive therapy Malnourishment Smoking Skin ulceration Previous surgery

16. Classification of Infection According to Route Perioperative Haematogenous Contiguous

17. 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

18. Treatment Options Open débridement with retention Single-staged or 2-staged resection & reimplantation of another prosthesis Resection arthroplasty Arthrodesis Antibiotic suppression Amputation

19. 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.Implantationof a new prosthesis during a later surgical procedure

20. Vancomycin Induced Nephrotoxicity Nephrotoxicity defined as: Determined by the clinical investigator 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

21. 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%.

22. Risk Factors for Vancomycin-Induced Nephrotoxicity

23. 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

24. 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

26. 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

27. Alternatives to Vancomycin

28. 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.

29. 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

30. Alternatives to Vancomycin

31. Linezolid F=100% Excellent penetration into bone, fat, muscle, periarticular structures Elimination: Nonrenal: 65% Renal: 30% Fecal: 5% No dosage adjustment in renal insufficiency

32. 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

33. 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)

34. Alternatives to Vancomycin

35. 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

36. 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

37. 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

38. Follow-Up Vancomycin dose held on Nov 14/11 Daptomycin started on Nov 18/11 : 6mg/kg IV q48h

39. 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

40. Monitoring

41. Monitoring

42. Follow-Up Discharged on: Nov 28/11 On outpatient IV therapy

43. Follow-Up

44. Review of Case Learning Objectives Case Background: Infected knee prosthesis and vancomycin induced nephrotoxicity Clinical Question Results Assessment Plan Monitoring Follow up