Anti-infectives Their Role in Acute Kidney Injury

1. Anti-infectives & Their Role in Acute Kidney Injury Pharmacologic Implications in Critical Care Patients Across the Lifespan

2. Objectives Identify the cumulative impact of common ICU medications on renal physiology Define tools & clinical markers used to identify AKI Differentiate inflammatory and non-inflammatory adverse drug reactions Describe the pharmacokinetics and pharmacodynamics of frequently used anti-infectives in critical care patients across the lifespan

3. Definition Acute Kidney Injury Network Serum Creatinine increase within 48 hrs >/= 0.3 mg/dL 50% or 1 � times baseline Urine output decrease < 0.5 ml/kg/hr for > 6 hrs

4. Etiology Pre-renal (azotemia) Intrinsic Glomerular Tubular Interstitial Vascular Post-renal

5. Epidemiology 2-5% hospitalized adults up to 30% of adult ICU 2-3% PICU 10% NICU 4-15% adults undergoing CBP 5-8% children undergoing CBP

6. Mortality Adult ICU 20-50% medical 60-70% surgical 50-80% multi-organ failure 4-15% CBP NICU Up to 10% Pediatric ICU 2-3% 5-8% CBP

7. Pathologic Contributors Low circulating volume Low renal perfusion pressure Low cardiac output Systemic peripheral vasodilatation Co-existing morbidities, CHF, DM

8. Medication Contributors Vasopressors Diuretics IV contrast ACE�s & ARBS Anti-infectives

9. Review Occurs in all populations with a significant mortality risk for ICU patients Occurs in combination with several pathophysiologic processes that cause varying types of injury Treatment modalities compound injury risk

10. Tubular Injury Etiology Ischemic Toxic Presentation Urinary biomarkers Population significance

11. Interstitial Injury Etiology Hypersensitivity Drug side-effects Presentation Urinary biomarkers Population significance

13. Physiologic Imbalances ? Reaborption into vascular system Na+, Cl-, K+ HCO3 H20 Glucose ?Ability to concentrate urine Creatinine Urea K+ Antibiotics Diuretics

14. GFR Declining creatinine levels late sign of deteriorating renal function Adults MDRD Pediatric & Neonatal Schwartz-Pedi (infants)

15. Novel Urinary Biomarkers Renal tubular cell proteins (urine) KIM-1 NH3 Cyr61 Urinary low-molecular weight proteins Cystatin C NGAL IL-18

16. Review Multiple etiologies may overlap Ischemia, toxins, hypersensitivity Drug-induced ATN usually dose-dependent & does not exhibit inflammatory S/S AIN is usually a drug-induced hypersensitivity that can induce a local or systemic inflammatory response

17. Pharmacokinetics of Anti-Infectives Absorption Distribution Protein binding Metabolism CYP interactions, metabolites Elimination Glomerular filtration, tubular secretion

18. Pharmacodynamics of Anti-Infectives Efficacy Minimum Inhibitory Concentration (MIC) Time or dose-dependence Post-antibiotic effects (PAE) Safety Toxicity Adverse effects

19. PK/PD: Neonatal Significance > percentage of body water Low protein-binding capability CYP 20-70% of adult rates Glucuronidation depressed at birth GFR reduced at 0-1 month Tubular secretion immature

20. PK/PD: Pediatric Significance CYP activity exceeds adults from age 1-4 (adult levels by puberty) GFR from Cockcroft-Gault > 12 yrs

21. PK/PD: Adult Significance Extracellular fluid Liver disease Protein/albumin deficiency Medication interactions Pre-existing renal disease

22. Review Nephrotoxicity with multiple drugs, PK/PD & physiologic changes brought on by disease Physiologic differences between populations impact drug metabolism Goal-directed therapy must consider Site of infection Susceptibility to organism PK/PD of anti-infective

23. Aminoglycoside: Gentamicin Gm negative, including pseudomonas Moderate - prolonged PAE Serious ADE: Nephrotoxicity Common: Rash, pruritis, urticaria

24. Beta-Lactam: Piperacillin/Tazobactam Severe appendicitis or peritonitis (Peds) Minimal to no PAE Serious: ATN, TIN, thrombocytopenia Common: Rash, pruritis

25. Cephalosporin: Ceftriaxone Gram positive staph & strep Minimal to no PAE Serious: SJS, thrombocytopenia Neonate: Ca-ceftriaxone precipitate Common: Thrombocytosis, eosinophilia (inflammation)

26. Quinolone: Levofloxacin HA-pneumonia (MRSA, pseudomonas) Anthrax exposure: pediatrics Moderate - prolonged PAE Serious: Nephrotoxicity, skin reactions Common: Tendonitis

27. Sulfonamides: Trimethoprim/Sulfamethoxazole E. Coli & strep pneumonia Infants with HIV+ mothers Serious: SJS, AIN, nephrotoxicity Common: Allergic rash, urticaria

28. Glycopeptide: Vancomycin MRSA Moderate - prolonged PAE Serious: Renal failure, AIN, SJS, thrombocytopenia Common: Rash, urticaria, ? BUN, Cr

29. Azolide: Azithromycin CA-pneumonia Moderate -prolonged PAE Serious: SJS, angioedema Common: Rash, pruritis

30. Nitroimididazole: Metronidazole Anaerobic gm negative infections CYP 2C9 inhibitor Moderate to prolonged PAE Serious: SJS, hypersensitivity Common: Rash, pruritis, dark urine

31. Lincosamides: Clindamycin Anaerobic bacterial infections Moderate � prolonged PAE Serious: SJS, thrombocytopenia Common: Rash, pruritis, urticaria

32. Oxazolididinone: Linezolid Effective vs VRE & MRSA Moderate � prolonged PAE Serious: SJS, thrombocytopenia Common: Rash, thrombocytopenia

33. References Alper, A.B. (2009). Interstitial nephritis. Retrieved February 9, 2010 from http://emedicine.medscape.com/article/243597 Devarjan, pl & Woroniecki (2008). Acute tubular necrosis. Retrieved February 9, 2010 from http://emedicin.medscape.com/article/980830 Epocrates� Essentials clinical reference suite (2010). San Mateo, CA Howell, H.R., Brundige, M.L. & Langworthy, L. (2007). Drug-induced acute renal failure. U.S. Pharmacist 32(3): 45-50. retrieved online February 25, 2010 from http://www.uspharmicist.com/content/tabid/92/t/urology/c/10379/dnnprintmode/true/default.aspx?skinscr=[l]skins/us Kidney Disease: Improving Global Outcomes (2008). Acute kidney injury. Retrieved February 8,2010 from http://www.kdigo.org/guidelines/topicsummarized/CPG%20Summary%20by%20Topic_Acute%20Kidney%20Injury.html Lerma, E.V., Kelly, B. & Agraharker, H. (2009). Acute tubular necrosis. Retrieved February 11, 2010 from http://emedicine.medscape.com/article/238064

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