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American Nephrology Nurses Association

Management of Common Types of Infections in Patients Receiving Chronic Renal Replacement Therapy. American Nephrology Nurses Association . Sarah Tomasello, PharmD, BCPS Clinical Associate Professor Rutgers, The State University of New Jersey Clinical Specialist – Nephrology

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American Nephrology Nurses Association

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  1. Management of Common Types of Infections in Patients Receiving Chronic Renal Replacement Therapy American Nephrology Nurses Association Sarah Tomasello, PharmD, BCPS Clinical Associate Professor Rutgers, The State University of New Jersey Clinical Specialist – Nephrology Robert Wood Johnson University Hospital New Brunswick, NJ stomasel@rci.rutgers.edu

  2. Outline of Presentation • Infections in patients on hemodialysis • Risk factors • Common “Bugs and Drugs” • Pharmacokinetic parameters and alterations • Administration and dosing • Monitoring therapy and altering regimen • Catheter related infections • Peritonitis

  3. Risk factors for Infection • Weakened immune function • Immunosuppressive agents, uremia • Indwelling catheters • Vascular Access • Catheter > AVG (arteriovenous graft) > AVG (arteriovenous fistula) • Presence as well as manipulation • Dialysis unit exposure • Care givers, patients • Comorbidities • Diabetes (~50%)

  4. Issues Related to Hemodialysis • Intermittent clearance • Generally three times a week • Vascular access • Type of filters • “High-Flux” • Filter re-use • Dialysis adequacy • Time on HD • Blood flow rate

  5. Common Drugs Used and Why? • Cephalosprins • Cefazolin, ceftazadime, ceftriaxone, • Quinolones • Levofloxacin, ciprofloxacin • Vancomycin • Aminoglycosides? • Gentamicin, tobramycin, amikacin • Long half-life (t ½)in ESRD patients • Can be dosed with/right after hemodialysis • What about “The WEEKEND”?

  6. Vancomycin • Glycopeptide • Empiric therapy for gram+ (MRSA) • Concerns • Resistance • 1 gram every week • 1 gram followed by 500mg Q HD

  7. Vanco • “Mississippi mud” • Crystalline Degradation Product 1 (CDP1) • Higher trough for resistant organisms or hard to penetrate areaaas • Assays • high performance liquid chromatography (HPLC) • Fluorescence polarization immunoassays (FPIA) Hu et al. Ther Drug Monitor 12 562-569, 1990

  8. Vancomycin Toxicities • “Red Man’s” Syndrome • Ototoxicity • Nephrotoxicity • Increased risk of toxicity with aminoglycoside antibiotics • Thrombocytopenia Rybak et al. Antimicrob Agents Chemother 1999;43:1549-1555

  9. Types of BacteriaCommon to dialysis patients bioweb.uwlax.edu/.../whatisbacteria.htm

  10. Properties of Dialyzable Drug* • Molecular weight • High-flux may eliminate drugs up to 5000 daltons • Vd • > 1 L/kg not readily dialyzed • Must be water soluble • Protein Binding • Highly protein bound (>96%) not as dialyzable • Watch “narrow therapeutic window” agents • Or saturated plasma proteins (toxicologic emergencies) * May be removed during dialysis

  11. Pharmacokinetic Parameters A = Absorption D = Distribution M = Metabolism E = Elimination/Excretion Alterations in Kidney Dysfunction

  12. Absorption and Bioavailability • DECREASED • Altered GI emptying (diabetes) • Altered pH (H2 antagonists, proton pump • Edema of GI tract (fluid overload) inhibitors, antacids) • Drug Interactions (antacids, iron, etc…) • INCREASED • Decreased first pass effect • Decreased metabolism by uremic toxins • Decreased enzymatic activity in kidney, liver, GI tract FOR ORAL MEDICATION ADMINISTRATION ONLY

  13. Volume of Distribution (Vd) • Plasma Protein Binding • Albumin is major plasma protein • Acidic drugs bind to albumin • Phenytoin, valproic acid, salicylates • Changes in albumin effect Vd • Alterations in binding sites Increased free concentrations (more effect?) vs Increased rate of clearance? (excreted more rapidly?) FYI! FYI!

  14. Volume of DistributionPlasma Protein Binding (cont.) • Alpha-1-acid glycoprotein (AAG) • Binds basic drugs • AAG up-regulated in kidney disease • “Expect” a decreased free-fraction • This has not been observed in vitro studies FYI! FYI!

  15. Causes of Hypoalbuminemia • Malnutrition • Nephrotic syndrome • Liver disease • Accumulation of competitive inhibitors • Uremic toxins • Metabolites (Normal serum albumin concentration ~4g/dL)

  16. Clinical Significance of Changes in Volume of Distribution: WATER • Increased fluid volume • Interdialytic weight gain • Effects drug “peak”concentration • Rapid fluid removal, • Redistribution (re-equilibrium) • Affects therapeutic drug monitoring (TDM) in serum

  17. Hemodialyzer • Selectively permeable membrane • Solute (drug) molecules pass through “selectively” based on MW and size • Composed of many types of fibers • Blood flows through 5000-20,000 hollow fibers • Dialysate flows on outside of fibers

  18. Hemodialysis System

  19. Hollow Fiber Dialyzer

  20. Definitions • Diffusion- passive movement of particles from high concentration to low concentration. Limited by filter. • Ultrafiltration- Removal of plasma water by a procedure • Convection-movement of particles with movement of water in which they are dissolved. Due to ultrafiltration, also limited by filter

  21. MW of Common Drugs • Digoxin: 781 Daltons • Vancomycin: 1,486 Daltons • Gentamicin: 149 Daltons • Cefazolin: 477 Daltons • Erythropoietin: 30,400 Daltons

  22. Molecular Weight High Flux Dialyzer Blood Dialysate MW cutoff < 5,000 daltons (up to 20,000?)

  23. Protein Binding albumin albumin albumin Blood Dialysate = Drug

  24. Protein Binding Normal Uremia albumin albumin albumin albumin albumin albumin albumin albumin albumin albumin albumin albumin “uremic slime” =Drug Competitive inhibitors

  25. Volume of Distribution Tissue Compartment Plasma Compartment Renal Elimination Or Dialysis

  26. Optimizing Therapy • Altering dose and dosing interval depends on efficacy and toxicity parameters • Peak effect for efficacy • aminoglycosides • Trough effect for efficacy/toxicity • digoxin, antiepileptics, aminoglycosides • Steady state for efficacy • antihypertensive agents • beta-lactam antibiotics

  27. GFR nl GFR Continuous Infusion Drug Concentration Steady State 24 hours 48 72 96 120 144

  28. kidney dysfunction Accumulation at same dose and dosing interval Drug Concentration Normal function Trough 24 hours 48 72 96 120 144

  29. Lower dose, same dosing interval Normal kidney function Decreased kidney function Drug Concentration Max effective dose Trough 24 96 hours 48 72 120 144

  30. Same dose, normal kidney function Extended interval in altered renal function Max effective dose Drug Concentration Trough Time (hrs)

  31. TIME Dependent Killing Example: Vancomycin HD TIW, MWF Slope=k

  32. Concentration Dependent Killing

  33. This is the dosing regimen we were trying to emulate. Matsuo et al. "Administration of Aminoglycosides to Hemodialysis Patients Immediately before Dialysis: a New Dosing Modality." Antimicrobial Agents and Chemotherapy 41.12 (1997): 2597-601. Print.

  34. Dosing Tobramycin “Pre-HD” 310mg post HD

  35. Tobramycin Course *Dose was held on 9/10

  36. Drug Dosing for Hemodialysis • Use recommendations from literature* • Dose for CrCl < 10-15 ml/min on HD • IV IDEALLY given TIW during/after HD • Supplemental dose post-HD if needed • Daily Dialysis • Very little literature (use professional judgment) • MONITOR • Subjective and objective efficacy and toxicity • Therapeutic drug monitoring if available (and PK calculations) *See previous slides 30-32

  37. Drug Levels in HD (Dialyzable) Cpeak Cpre-HD K off HD Conc K on HD Next Dose ctrough Pre HDHDEnd HD Time

  38. Redistribution Phenomenon Koff HD Kon HD Conc Pre HD HD End HD Time

  39. POINTS TO REMEMBER • MONITOR!!! • Therapeutic drug levels (if appropriate) • MUST be taken at the proper times • Subjective and objective signs of efficacy and toxicity • Watch for idiosyncratic or “expected” adverse drug events

  40. Risk factors for Infection in Peritoneal Dialysis • Patient technique • Provider technique • Immunocompetence • Cormorbid disease states

  41. Peritonitis • Incidence • 1 episode for every 12-24 patient months • Signs and Symptoms • Cloudy drainage • Abdominal pain • Fever • Nausea/vomiting • Fever > 37ºC • Diagnostic criteria • Dialysate WBC count > 100/mm3 (> 50% PMNs) • Organism on culture?

  42. Drug Regimens to Treat Peritonitis • Several review articles on drug delivery using intraperitoneal route (IP) • Watch for compatibility issues* • Use International Society of PD Guidelines for the treatment of PD related peritonitis** • Use primary literature *Intraperitoneal administration of drugs in peritoneal dialysis patients: A review of compatibility and guidance for clinical use peritoneal dialysis international 2009;29:5–15 .**International ad hoc committee on peritoneal dialysis related infections. International society for peritoneal dialysis - guidelines for the treatment of peritonitis in adults. Peritoneal dial int 2005;25:107-131.

  43. Treatment of Peritonitis • Give intraperitoneally (IP) if possible • Empiric therapy • Cover both gram positive and negative • Combination first and third generation cephalosporin • Cefazolin and ceftazidime • Narrow coverage based on culture report • not always cultured • Complications • Fibrosis and scarring

  44. Peritoneal Dialysis Catheter Infections • Incidence • Once per 1-2 patient years • Organisms • staph aureus, staph epi, pseudomonas • Prophylaxis for nasal carriers of Staphylococcus aureus? • rifampin 300 mg BID x 5 days every three months • intranasal mupiricin BID x 5 days every month • exit-site mupiricin topically every day

  45. PD Dialyzability Factors • Inflamed peritoneum during infection • Blood flow - may affect drug transfer • Dwell time • Residual renal function • Dialysate dextrose concentration- increase causes more ultrafiltration • Generally, high drug absorption but low drug clearance for PD

  46. Dosing Drugs for Patients on PD • Molecular size- not as important as HD, increased permeability • PB- highly PB not removed • Vd- Increased Vd means less removed, more absorbed into the body • Water solubility- required for removal • Ionization- highly ionized neither absorbed or removed

  47. Common Agents to Treat Peritonitis • Tables from ISPD guidelines 2005 update

  48. Issues Related to IP Administration • Patient education • Compatibility • Clearance • Increased peritoneal membrane permeability during acute infection • Decreased permeability with fibrosis and sclerosis secondary to infection and inflammation

  49. Catheter-Related Bacteremia (CRB) • “Biofilm infection” • Catheter removal creates a requirement for the use of temporary catheters and risk of their associated complications • Multiple procedures, hospitalization period, increased costs • Loss of central venous entry site • Dialysis patients must continue to receive dialysis treatments, therefore, catheter removal is not a feasible option Beathard GA et. al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21(6):528-538

  50. Incidence of CRB • Rate is less than uncuffed catheters • Tunneled catheters: 1.6-5.5 episodes/1000 days • Uncuffed cathers: 3.8-6.6 episodes/1000 days • Morbidity and mortality due to metastatic infections: 3.2%-50% Beathard, et al. Infection associated with tunneled hemodialysis catheters. Sem Dial. 2008; 21 (6):528-538

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