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Chapter 4

Chapter 4. REFERENCE: APPLIED CLINICAL PHARMACOKINETICS Slideshow by: lecturer HADEEL DELMAN. THE AMINOGLYCOSIDE ANTIBIOTICS. ABOUT AMINOGLYCOSIDE. Concentration-efficacy relationships The pharmacodynamic properties of aminoglycosides are: Concentration-dependent killing

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Chapter 4

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  1. Chapter 4 REFERENCE: APPLIED CLINICAL PHARMACOKINETICS Slideshow by: lecturer HADEEL DELMAN

  2. THE AMINOGLYCOSIDEANTIBIOTICS

  3. ABOUT AMINOGLYCOSIDE • Concentration-efficacy relationships • The pharmacodynamic properties of aminoglycosides are: • Concentration-dependent killing • Significant post-antibiotic effect

  4. post-antibiotic effect • The post antibiotic effect is the phenomenon of continued bacterial killing even though serum concentrations have fallen below the minimum inhibitory concentration (MIC). • Because the post antibiotic effect is concentration-dependent for the aminoglycosides, higher drug concentrations lead to a longer post antibiotic effect.

  5. Administration When given by IV infusion over 30 minutes, aminoglycosides follow a 3-compartment pharmacokinetic model; alpha (distribution), ß (elimination), ɣ (tissue release).

  6. (squares with solid line) 1/2-hour infusion(circles with dashed line)1-hour infusion. When given as a 1/2-hour infusion, end of infusion concentrations are higher because the serum and tissues are not in equilibrium. A 1/2-hour waiting time for aminoglycoside distribution to tissues is allowed before peak concentrations are measured. If given as 1-hour infusions, distribution has an opportunity to occur during the infusion time, and peak concentrations can be obtained immediately. That mean the peak always measured after 1 hr

  7. Time of measuring peak and trough • Peak steady-state concentrations always measured after 1 hr • Trough steady-state concentrations obtained within 30 minutes of the next dose

  8. Aminoglycoside antibiotics are given by to methods: • The conventional method • Extended-interval dosing

  9. The conventional method • The conventional method of dosing is to administer multiple daily doses (usually every 8 hours) • Steady-state peak concentration: • 5–10 μg/mL for gentamicin, tobramycin, or netilmicin • 15–30 μg/mL for amikacin • Steady-state trough concentration: • < 2 μg/mL for gentamicin, tobramycin or netilmicin. • < 5 μg/mL for amikacin

  10. Aminoglycoside toxicity • Exceeding peak steady-state concentrations of 12–14 μg/mL for gentamicin, tobramycin, or netilmicin or 35–40 μg/mL for amikacin when using conventional dosing leads to an increased risk of ototoxicity. • Trough steady-state concentrations above 2–3 μg/mL for tobramycin, gentamicin, or netilmicin or 10 μg/mL for amikacin predispose patients to an increased risk of nephrotoxicity.

  11. Extended-interval dosing • Extended-interval dosing (usually the total daily dose given once per day) take advantage of concentration-dependent bacterial killing and the post antibiotic effect. • Steady-state peak concentration: • 20–30 μg/mL for gentamicin, tobramycin, or netilmicin • Steady-state trough concentration • < 1 μg/mL

  12. Toxicity does not increase in patients with extended-interval dosing of aminoglycosides? 1-Diffusion of drug out of tissue into the blood which avoids drug accumulation in the ear and kidney. 2-The uptake mechanisms into the ear and kidney may be saturable, so that high peak serum concentrations of aminoglycosides may not result in high renal or ear tissue concentrations.

  13. CLINICAL MONITORING PARAMETERS • White blood cell counts and body temperatures • Chest x-ray in pneumonia • In the intra-abdominal infection, abdominal pain and tenderness • Wound infection the wound should be less inflamed with less purulent discharge. • Aminoglycoside steady-state peak and trough serum concentrations should be measured in 3–5 estimated half-lives in conventional dosage approaches. • Extended-interval aminoglycoside therapy (two steady-state postdoseconcentrations, only a steady-state trough concentration, a single aminoglycoside serum concentration 6–14 hours after a dose) • Serum creatinine concentrations should be used to detect nephrotoxicity. • Clinical signs and symptoms of auditory ototoxicity.

  14. EFFECTS OF DISEASE STATES AND CONDITIONS ONAMINOGLYCOSIDE PHARMACOKINETICS AND DOSING

  15. OBESITY • Lipophilicdrugs tend to partition into adipose tissue, and the volume of distribution in obese patients for these drugs can be dramatically larger than in normal weight patients. Examples diazepam, carbamazepine. • Hydrophilic drugs tend to not distribute into adipose tissue so that the volume of distribution is notdifferentin obese and normal weight patients. Examples digoxin, cimetidine, and ranitidine.

  16. Obesity may affect: • Extracellular fluid & V ---- (↑Aminoglycoside, ↔ Digoxin and vancomycin) • GFR & Cl ---- (↑Aminoglycoside, vancomycin, cimetidine) • Hepatic Cl ----- (↑diazepam,↓methylprednisolone, ↔carbamazepine and cyclosporine)

  17. Obesity ----→ t1/2 • t1/2 = (0.693 ⋅ V) / Cl

  18. Methods to initiate aminoglycoside therapy • The pharmacokinetic dosing method • The Hull and Sarubbinomogram • The Hartford nomogram • Literature-based recommended dosing

  19. The pharmacokinetic dosing method 1-Most flexible. It allows for individualized target serum concentrations to be chosen for a patient, so 2- It can be used for both conventional and extended-interval dosing.

  20. To calculate initial dose by pharmacokinetic dosing method I- calculating the estimated pharmacokinetic parameter A- Elimination rate constant estimate B-Volume of distribution estimate II- Selection of pharmacokinetic model and equations: III-Steady-state concentration selection and dose

  21. A-Elimination rate constant estimate Ke (in h−1) = 0.00293(CrCl in mL/min) + 0.014

  22. B-Volume of distribution estimate Volume of distribution without disease states and conditions that change this parameter is: ✓ If a patient weighs less than their ideal body weight, actual body weight is used to estimate volume of distribution. ✓ For patients whose weight is between their ideal body weight and 30% over ideal weight, actual body weight can be used to compute estimated volume of distribution, Vd= 0.26 L/kg

  23. B-Volume of distribution estimate • In patients who are more than 30% above their IBW, • In patients who are overhydrated or have ascites: V = 0.26[IBW + 0.4(TBW-IBW)] V = (0.26 ⋅ DBW) + (TBW − DBW)

  24. Selection of pharmacokinetic model and equations:

  25. NOTE: • Loading doses should be considered for patients with creatinine clearance values below 60 mL/min. ▪ One approach is to use different equations depending upon the renal function of the patient so use • (Intermittent intravenous infusion for creatinine clearances >30 mL/min, while Intravenous bolus for creatinine clearances ≤30 mL/min). ▪ Alternatively, intermittent intravenous infusion equations can be used for all patients regardless of renal function.

  26. Steady-state concentration selection • Aminoglycoside selected based on site and severity of infection as well as the infecting organism. • Severeinfections, such as gram-negative pneumonia or septicemia, that need highminimum inhibitory concentration (MIC) • Peak steady-state serum concentrations of : • 8–10 μg/mL for gentamicin, tobramycin, or netilmicin • 25–30 μg/mL for amikacin • When using conventional dosing.

  27. Steady-state concentration selection • Moderateinfections with organisms that display lower MIC values, such as intra-abdominal infections are usually treated with: • 5–7 μg/mL (gentamicin, tobramycin, or netilmicin) • 15–25 μg/mL (Amikacin) • Aminoglycosides in combination with penicillinsor other antibiotics for the treatment of gram positive infections such as infective endocarditis, steady-state peak concentrations of : • 3–5 μg/mL for gentamicin, tobramycin, or netilmicin • 12–15 μg/mL for amikacin.

  28. Steady-state concentration selection • For conventional dosing, • Steady-state trough concentrations should be maintained • <2 μg/mL for tobramycin, gentamicin, and netilmicin or • <5–7 μg/mL for amikacin. • For extended-interval dosing, • Steady-state trough concentrations should be • <1 μg/mL for gentamicin, tobramycin, and netilmicin.

  29. Example 1 JM is a 50-year-old, 70-kg (5 ft 10 in) male with gram-negative pneumonia. His current serum creatinine is 0.9 mg/dL, and it has been stable over the last 5 days since admission. Compute a gentamicin dose for this patient using conventional dosing. 1. Estimate creatinine clearance. • stable serum creatinine + not obese. • The Cockcroft-Gaultequation can be used to estimate CrCl: • CrClest = [(140 − age)BW] / (72 ⋅ SCr) = [(140 − 50 y)70 kg] / (72 ⋅ 0.9 mg/dL) CrClest = 97 mL/min

  30. 2. Estimate elimination rate constant (ke) and half-life (t1/2). • The elimination rate constant versus creatinine clearance relationship is used to estimate the gentamicin elimination rate for this patient: • ke = 0.00293(CrCl) + 0.014 = 0.00293(97 mL/min) + 0.014 = 0.298 h−1 • t1/2 = 0.693/ke = 0.693/0.298 h−1 = 2.3 h

  31. 3. Estimate volume of distribution (V) • The patient has no disease states or conditions that would alter the volume of distribution from the normal value of 0.26 L/kg: • V = 0.26 L/kg (70 kg) = 18.2 L

  32. 4. Choose desired steady-state serum concentrations. • Gram-negative pneumonia patients treated with aminoglycoside antibiotics require: • steady-state peak concentrations (Cssmax) equal to 8–10 μg/mL; • steady-state trough (Cssmin) concentrations should be <2 μg/mL to avoid toxicity. • Set: Cssmax = 9 μg/mL and • Cssmin= 1 μg/mL.

  33. 5-Use intermittent intravenous infusion equations to compute dose (Table 4-2). • Calculate required dosage interval (τ) using a 1-hour infusion: • τ = [(lnCssmax − lnCssmin) / ke] + t′ • = [(ln 9 μg/mL − ln 1 μg/mL) / 0.298 h−1] + 1 h • = 8.4 h 8 h • k0 = CssmaxkeV[(1 − e−keτ) / (1 − e−ket′)] • k0 = (9 mg/L ⋅ 0.298 h−1 ⋅ 18.2 L){[1 − e−(0.298 h−1)(8 h)] / [1 − e−(0.298 h−1)(1 h)]} • = 172 mg 170 mg

  34. So… • The prescribed maintenance dose would be 170 mg every 8 hours.

  35. 6. Compute loading dose (LD), if needed. • LD = k0/(1 − e−keτ) = 170 mg / [1 − e−(0.298 h−1)(8 h)] = 187 mg • As noted, this loading dose is only about 10% greater than the maintenance dose and wouldn’t be given to the patient. Since the expected half-life is 2.3 hours, the patient should be at steady state after the second dose is given.

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