Anti-infectives & Their Role in Acute Kidney Injury

Pharmacologic Implications in Critical Care Patients Across the Lifespan

Teresa Etter MS, RN, CCNS-Rx

Objectives

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

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
AKIN, 2008

Etiology

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

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
Prasad & Williams, 2008; AKIN, 2008

Mortality

Adult ICU 20-50% medical 60-70% surgical 50-80% multiorgan failure 4-15% CBP
Lerma, Kelly, Agraharker, 2009

NICU Up to 10% Pediatric ICU 2-3% 5-8% CBP

Pathologic Contributors

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

Medication Contributors

Vasopressors Diuretics IV contrast ACEs & ARBS Anti-infectives

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

Tubular Injury

Etiology Ischemic Toxic Presentation Urinary biomarkers Population significance

Interstitial Injury

Etiology Hypersensitivity Drug side-effects Presentation Urinary biomarkers Population significance

Courtesy of Wikipikia, 2008

Physiologic Imbalances

Reaborption

into vascular system

Na+, Cl-, K+ HCO3 H20 Glucose

Ability to concentrate urine

Creatinine Urea K+ Antibiotics Diuretics

GFR

Declining creatinine levels late sign of deteriorating renal function Adults

MDRD

Pediatric & Neonatal

Schwartz-Pedi (infants)

Novel Urinary Biomarkers

Renal tubular cell proteins (urine)

KIM-1 NH3 Cyr61

Urinary lowmolecular weight proteins Cystatin C NGAL IL-18

Lerma, Kelly& Agraharker, 2009

Review

Multiple etiologies may overlap

Ischemia, toxins, hypersensitivity

Drug-induced ATN usually dosedependent & does not exhibit inflammatory S/S AIN is usually a drug-induced hypersensitivity that can induce a local or systemic inflammatory response

Pharmacokinetics of AntiInfectives

Absorption Distribution
Protein binding

Metabolism
CYP interactions, metabolites

Elimination
Glomerular filtration, tubular secretion

Pharmacodynamics of Anti-Infectives

Efficacy
Minimum Inhibitory Concentration (MIC) Time or dose-dependence Post-antibiotic effects (PAE)

Safety
Toxicity Adverse effects

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

Sinxadi & Mcilleron, 2007

PK/PD: Pediatric Significance

CYP activity exceeds adults from age 1-4 (adult levels by puberty) GFR from Cockcroft-Gault > 12 yrs

Sinxadi & Mcilleron, 2007

PK/PD: Adult Significance

Extracellular fluid Liver disease Protein/albumin deficiency Medication interactions Pre-existing renal disease

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

Aminoglycoside: Gentamicin

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

Micromedex, 2010

Beta-Lactam: Piperacillin/Tazobactam

Severe appendicitis or peritonitis (Peds) Minimal to no PAE Serious: ATN, TIN, thrombocytopenia Common: Rash, pruritis
Micromedex, 2010

Cephalosporin: Ceftriaxone

Gram positive staph & strep Minimal to no PAE Serious: SJS, thrombocytopenia
Neonate: Ca-ceftriaxone precipitate

Common: Thrombocytosis, eosinophilia (inflammation)

Micromedex, 2010

Quinolone: Levofloxacin

HA-pneumonia (MRSA, pseudomonas) Anthrax exposure: pediatrics Moderate - prolonged PAE Serious: Nephrotoxicity, skin reactions Common: Tendonitis
Micromedex,2010

Sulfonamides:

Trimethoprim/Sulfamethoxazole

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

Micromedex,2010

Glycopeptide: Vancomycin

MRSA Moderate - prolonged PAE Serious: Renal failure, AIN, SJS, thrombocytopenia Common: Rash, urticaria, BUN, Cr
Micromedex,2010

Azolide: Azithromycin

CA-pneumonia Moderate -prolonged PAE Serious: SJS, angioedema Common: Rash, pruritis

Micromedex,2010

Nitroimididazole: Metronidazole

Anaerobic gm negative infections CYP 2C9 inhibitor Moderate to prolonged PAE Serious: SJS, hypersensitivity Common: Rash, pruritis, dark urine
Micromedex, 2010

Lincosamides: Clindamycin

Anaerobic bacterial infections Moderate prolonged PAE Serious: SJS, thrombocytopenia Common: Rash, pruritis, urticaria

Micromedex, 2010

Oxazolididinone: Linezolid

Effective vs VRE & MRSA Moderate prolonged PAE Serious: SJS, thrombocytopenia Common: Rash, thrombocytopenia

Micromedex, 2010

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). Druginduced 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/1 0379/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%20S ummary%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

References (cont.)

Merck Manual Online. Retrieved from http://merck.com Micromedex Healthcare Series [Intranet database]. Version 5.1 Greenwood Village, Colo:Thomson-Reuters (Healthcare) Inc. Plakogiannis, R. & Nogid, A. (2007). Acute interstitial nephritis associated with co-administration of vancomycin & ceftriaxone: case series & review of the literature [Abstract]. Retrieved February 24, 2010 from Ovid Medline database [Intranet database] Quinn, A. & Sinert, R.H. (2009). Metabolic acidosis. Retrieved February from http://emedicine.medscape.com/article/768268 Sinxadi, P. & Mcilleron, H. (2007). Principles of dosing in young children. Clinical Pharmacology. Retrieved online from http://www.thefreelibrary.com/_/printPrintArticle.aspx?id=168164697 Tune, B.M. (1994). Renal tubular transport & nephrotoxicity of beta lactam antibiotics: structure-activity relationships. [Abstract]. Retrieved February 24, 2010 from Ovid Medline database Vaseemuddin, M., Schwartz, M.M., Dunea, G. & Kraus, M.A. (2007). Idiopathic hypocomplementemic immune-complex-mediated tubulointerstitial nephritis. Retrieved February 11, 2010 from http://nature.com/nrneph/journal/v3/n1/fig_tab/ncpneph0347_T2.html