1. Use of antibacterial agents in renal failure R2 박준민

2. Introduction The kidney is the major organ for maintaining fluid and electrolyte homeostasis. Changes in renal function → effects on the pharmacology of antibacterial agents Reviews the pharmacokinetics of antibacterial agents in patients with normal and decreased renal function.

3. Pharmacokinetics Bioavailability - Degree that a drug is absorbed into the systemic circulation after extravascular administration - Decreased in renal insufficency : nausea, vomiting, diabetic gastroparesis, and intestinal edema, conversion of urea to ammonia by gastric urease, antacids, or the use of alkalating agents, such as bicarbonate and citrate, decreased small bowel movement

4. Pharmacokinetics Metabolism - First-pass hepatic metabolism may be diminished in uremia leading to increased serum levels of oral antibacterial agents - Impaired plasma protein binding increases the level of free drug - Increases the amount of drug available for elimination By dialysis or hepatic metabolism

5. Pharmacokinetics Distribution - Volume of distribution(Vd) : amount of drug in the body/plasma concentration : protein-binding drug → small Vd : lipid soluble drug → large Vd

6. Pharmacokinetics Elimination - The rate of elimination of most antibacterial agents follows first-order kinetics - Proportional to the amount of drug in the body - Rate of elimination= K x amount of drug in the body = K x Vd x plasma conc. - Plasma drug clearance= K x Vd - T 1/2 = ln2/K= 0.693/K = (0.693)(Vd)/plasma drug clearance ∴ Vd ∝ 1/plasma drug clearance

7. Pharmacokinetics Creatinine clearance - The rate of elimination of drugs by the kidney depends on the glomerular filtration rate (GFR) - A 24-hour urine collection allows accurate determination of the endogenous creatinine clearance, which is a close approximation to the GFR - Serum creatinine alone is not a reliable measure of creatinine clearance(ex. Elderly, debilitated pt.)

8. Pharmacokinetics Estimation of creatinine clearance - The equation of Cockroft and Gault - Creatinine clearance in males = {(140-age) total body weight in kg}/(72 x serum creatinine) - In females the clearance is 85% of this value - The equation of Pesola et al - Use ideal body wt. instead of total body wt. - Ideal body wt.= 50kg + 2.3kg /inch(over 5 ft) [male] = 45.5kg + 2.3kg/inch(over 5ft) [female]

9. Dosing of antibacterial agents in renal failure Initial dose - Based on extracellular fluid volume - Not altered in the presence of decreased renal function - Ascites, edema: large dose - Dehydration: small dose - 4 maintenance doses are required to achieve a steady dose

10. Dosing of antibacterial agents in renal failure Maintenance dose - After the loading dose, subsequent maintenance doses frequently require modification in patients with decreased renal function. - Dose reduction or interval extension

23. Dosing of antibacterial agents in renal failure Once-daily aminoglycoside - Aminoglycoside : Treatment of certain gram-negative bacteria : High side effect profile and prolonged postantibiotic effect - Once daily aminoglycoside therapy → reduce nephrotoxicity and ototoxicity → reduce costs and prolonged postantibiotic effect (Hatala et al: meta - analysis)

24. Dosing of antibacterial agents in renal failure -Once daily aminoglycoside therapy : PID, gram-negative bacteremia, UTI, febrile neutropenia, gynecologic infections, respiratory infections (effective) : pregnancy, Cl cr < 20mL/min, bone and joint infections, central nervous system infections, infective endocarditis, obesity, burns, solid organ transplantation (non effective) : initial dose is based on Cl cr

25. Intermittent dosing cefazolin with hemodialysis - Hemodialysis patients with suspected bloodstream or vascular infections, vancomycin and gentamicin are frequently given as empiric therapy. - Limitation of vancomycin use : emergence of vancomycin-resistant enterococcus and concerns for increasing resistance of S aureus to glycopeptides Dosing of antibacterial agents in renal failure

26. Intermittent dosing cefazolin with hemodialysis - Cefazolin can be administered on either a weight- based or fixed-dose schedule after each dialysis session and can provide a safe and effective alternative to vancomycin for susceptible organisms (Kuypers et al, Sowinski et al, Fogel et al)

27. Dosing of antibacterial agents in renal failure Serum levels - Useful d/t potential toxicity - Esp. vancomycin, aminoglycoside - Vancomycin : Conc.-independent killing effect : Serum level does not consistently correlated with toxicity : Debate on serum level use

28. Dosing of antibacterial agents in renal failure - Aminoglycoside : Conc.-dependent killing effect : Level must be followed d/t nephrotoxicity - Peak level, trough level, random level

29. Dosing of antibacterial agents in renal failure Dialysis - Start when renal failure progress to the point of uremia or inadequate urine output - Cl cr < 15mL/min for diabetic pt. < 10mL/min for nondiabetic pt.

30. Adverse effect of antibacterial agents in renal failure Inappropriate dose and pathologic changes associated with uremia Neurotoxicity - Psychosis, hallucination, myoclonus, seizure - Penicillin, imipenem, b-lactam, acyclovir, amantadine, quinolone Ototoxicity - Erythromycin

31. Adverse effect of antibacterial agents in renal failure Hypoglycemia - Sulfonamide : structural similarity of hypoglycemic agent Platelet aggregation abnormality - High doses of penicillin Vit K deficiency - Penicillin, cephalosporin

32. Adverse effect of antibacterial agents in renal failure Spontaneous achilles tendon rupture - Fluoroquinolones Hepatotoxicity - Tetracycline

33. Reference