Transcript Use of antibacterial agents in renal failure

Use of antibacterial agents
in renal failure
R2 박준민
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.
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
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
Pharmacokinetics
Distribution
- Volume of distribution(Vd)

: amount of drug in the body/plasma concentration
: protein-binding drug → small Vd
: lipid soluble drug → large Vd
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
- T1/2= ln2/K= 0.693/K
= (0.693)(Vd)/plasma drug clearance
∴ Vd ∝1/plasma drug clearance
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.)
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]
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
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
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)
Dosing of antibacterial agents in renal
failure
- Once daily aminoglycoside therapy
: PID, gram-negative bacteremia, UTI, febrile
neutropenia, gynecologic infections, respiratory
infections (effective)
: pregnancy, Clcr < 20mL/min, bone and joint
infections, central nervous system infections,
infective endocarditis, obesity, burns, solid organ
transplantation (non effective)
: initial dose is based on Clcr
Dosing of antibacterial agents in renal
failure

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

Intermittent dosing cefazolin with hemodialysis
- Cefazolin can be administered on either a weightbased 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)
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
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
Dosing of antibacterial agents in renal
failure

Dialysis
- Start when renal failure progress to the point of
uremia or inadequate urine output
- Clcr < 15mL/min for diabetic pt.
< 10mL/min for nondiabetic pt.
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
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
Adverse effect of antibacterial agents in
renal failure

Spontaneous achilles tendon rupture
- Fluoroquinolones

Hepatotoxicity
- Tetracycline
Reference