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Anti-infectives & Their Role inAcute Kidney Injury

Pharmacologic Implications inCritical Care Patients Across the

Lifespan

Teresa Etter MS, RN, CCNS-Rx


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Objectives

Identify the cumulative impact of commonICU medications on renal physiology

Define tools & clinical markers used toidentify AKI

Differentiate inflammatory and non-inflammatory adverse drug reactions

Describe the pharmacokinetics andpharmacodynamics of frequently used anti-infectives in critical care patients across thelifespan


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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


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Etiology

Pre-renal (azotemia)

Intrinsic

Glomerular

Tubular

InterstitialVascular

Post-renal


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Epidemiology

2-5% hospitalized adults

up to 30% of adult ICU

2-3% PICU10% NICU

4-15% adults undergoing CBP

5-8% children undergoing CBP

Prasad & Williams, 2008; AKIN, 2008


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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

Lerma, Kelly, Agraharker, 2009


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Pathologic Contributors

Low circulating volume

Low renal perfusion pressure

Low cardiac output

Systemic peripheral

vasodilatation Co-existing morbidities, CHF,

DM


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Medication Contributors

Vasopressors

Diuretics IV contrast

ACEs & ARBS

Anti-infectives


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Review

Occurs in all populations with asignificant mortality risk for ICU

patients Occurs in combination with

several pathophysiologic

processes that cause varyingtypes of injury

Treatment modalities compoundinjury risk


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Tubular Injury

Etiology

Ischemic

Toxic

Presentation

Urinary biomarkers Population significance


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Interstitial Injury

Etiology

Hypersensitivity

Drug side-effects

Presentation

Urinary biomarkers Population significance


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Courtesy of Wikipikia, 2008


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Physiologic Imbalances

Reaborptioninto vascular

system Na+, Cl-, K+

HCO3

H20

Glucose

Ability toconcentrate

urine Creatinine

Urea

K+

Antibiotics

Diuretics


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GFR

Declining creatinine levels latesign of deteriorating renal

functionAdults

MDRD

Pediatric & Neonatal Schwartz-Pedi (infants)


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Novel Urinary Biomarkers

Renal tubularcell proteins

(urine) KIM-1

NH3

Cyr61

Urinary low-molecular weight

proteins Cystatin C

NGAL

IL-18

Lerma, Kelly& Agraharker, 2009


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Review

Multiple etiologies may overlap

Ischemia, toxins, hypersensitivity

Drug-induced ATN usually dose-dependent & does not exhibitinflammatory S/S

AIN is usually a drug-inducedhypersensitivity that can induce a localor systemic inflammatory response


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Pharmacokinetics of Anti-

InfectivesAbsorption

Distribution

Protein binding

Metabolism

CYP interactions, metabolites

Elimination

Glomerular filtration, tubularsecretion


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Pharmacodynamics of

Anti-Infectives Efficacy

Minimum Inhibitory Concentration

(MIC) Time or dose-dependence

Post-antibiotic effects (PAE)

Safety Toxicity

Adverse effects


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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


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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


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PK/PD: Adult

Significance Extracellular fluid

Liver disease

Protein/albumin deficiency

Medication interactions

Pre-existing renal disease


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Review

Nephrotoxicity with multiple drugs,PK/PD & physiologic changes broughton by disease

Physiologic differences betweenpopulations impact drug metabolism

Goal-directed therapy must consider

Site of infection Susceptibility to organism

PK/PD of anti-infective


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Aminoglycoside:

Gentamicin Gm negative, including

pseudomonas

Moderate - prolonged PAE

Serious ADE: Nephrotoxicity

Common: Rash, pruritis, urticaria

Micromedex, 2010


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Beta-Lactam:

Piperacillin/Tazobactam Severe appendicitis or

peritonitis (Peds)

Minimal to no PAE

Serious:ATN, TIN,

thrombocytopenia Common: Rash, pruritis

Micromedex, 2010


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Cephalosporin:

Ceftriaxone Gram positive staph & strep

Minimal to no PAE

Serious: SJS, thrombocytopenia

Neonate: Ca-ceftriaxone precipitate

Common: Thrombocytosis,eosinophilia (inflammation)

Micromedex, 2010


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Quinolone: Levofloxacin

HA-pneumonia (MRSA,pseudomonas)

Anthrax exposure: pediatrics

Moderate - prolonged PAE

Serious: Nephrotoxicity, skinreactions

Common: Tendonitis

Micromedex,2010


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Sulfonamides:Trimethoprim/Sulfamethoxazole

E. Coli & strep pneumonia

Infants with HIV+ mothers

Serious: SJS, AIN, nephrotoxicity

Common:Allergic rash, urticaria

Micromedex,2010


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Azolide: Azithromycin

CA-pneumonia

Moderate -prolonged PAE

Serious: SJS, angioedema

Common: Rash, pruritis

Micromedex,2010


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Nitroimididazole:

MetronidazoleAnaerobic gm negative infections

CYP 2C9 inhibitor

Moderate to prolonged PAE

Serious: SJS, hypersensitivity

Common: Rash, pruritis, darkurine

Micromedex, 2010


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Lincosamides:

ClindamycinAnaerobic bacterial infections

Moderate prolonged PAE

Serious: SJS, thrombocytopenia

Common: Rash, pruritis, urticaria

Micromedex, 2010


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Oxazolididinone:

Linezolid Effective vs VRE & MRSA

Moderate prolonged PAE

Serious: SJS,thrombocytopenia

Common: Rash,thrombocytopenia

Micromedex, 2010


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References

Alper, A.B. (2009). Interstitial nephritis. Retrieved February9, 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 fromhttp://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 fromhttp://www.kdigo.org/guidelines/topicsummarized/CPG%20Summary%20by%20Topic_Acute%20Kidney%20Injury.html

Lerma, E.V., Kelly, B. & Agraharker, H. (2009). Acute tubularnecrosis. Retrieved February 11, 2010 from

http://emedicine.medscape.com/article/238064
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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 Medlinedatabase [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 fromhttp://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 tubulointerstitialnephritis. Retrieved February 11, 2010 fromhttp://nature.com/nrneph/journal/v3/n1/fig_tab/ncpneph0347_T2.html
http://merck.com/http://emedicine.medscape.com/article/768268http://emedicine.medscape.com/article/768268http://www.thefreelibrary.com/_/printPrintArticle.aspx?id=168164697http://www.thefreelibrary.com/_/printPrintArticle.aspx?id=168164697http://nature.com/nrneph/journal/v3/n1/fig_tab/ncpneph0347_T2.htmlhttp://nature.com/nrneph/journal/v3/n1/fig_tab/ncpneph0347_T2.htmlhttp://nature.com/nrneph/journal/v3/n1/fig_tab/ncpneph0347_T2.htmlhttp://www.thefreelibrary.com/_/printPrintArticle.aspx?id=168164697http://emedicine.medscape.com/article/768268http://merck.com/

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