1. The aminoglycoside antibiotics

2. Introduction Semisynthetic Antibiotic
Aminoglycosides exhibit concentration-dependent killing. The higher the peak, the more effective
Aminoglycosides have a concentration-dependent postantibiotic effect. The postantibiotic effect is the phenomenon of continued bacterial killing even though serum concentrations have fallen below the minimum inhibitory concentration (MIC). Because the postantibiotic effect is concentration-dependent for the aminoglycosides, higher drug concentrations lead to a longer postantibiotic effect

3. Spectrum of Activity
Fairly broad spectrum of activity with some Gram + activity and very good Gram – activity
Used for the treatment of:
severe gram-negative infections such as pneumonia or bacteremia, often in combination with a β-lactam antibiotic.
gram-positive infections such as infective endocarditis in combination with penicillins

4. Two Dosing Approaches
Conventional Dosing
Extended-Interval Dosing

5. When given as a 1/2-hour infusion (squares with solid line) , 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 aminoglycosides are given as 1-hour infusions (circles with dashed line), distribution has an opportunity to occur during the infusion time, and peak concentrations can be obtained immediately
In either case, concentrations 1 hour after the infusion was initiated are similar.

6. Conventional Dosing
Dose to achieve a target peak and trough concentration
Dosing intervals generally range from every 8 (good renal function) to 24 hours (poor renal function)

7. Conventional Dosing
Aminoglycoside antibiotics are given as short-term (1/2–1 hour) infusions
If a 1-hour infusion is used, maximum end of infusion “peak” concentrations are measured when the infusion is completed (Figure)
If a 1/2-hour infusion is used, serum concentrations exhibit a distribution phase so that drug in the blood and in the tissues are not yet in equilibrium
Because of this, a 1/2-hour waiting period is allowed for distribution to finish if a 1/2-hour infusion is used before peak concentrations are measured

8. Conventional Dosing: Target steady state peak concentrations
Therapeutic steady state peak concentrations for gentamicin, tobramycin, and netilmicin are generally 5–10 μg/mL for gram-negative infections
Infection sites with more susceptible bacteria, such as intraabdominal infections usually can be treated with lower steady-state peak concentrations (typically 5–7 μg/mL)
Infection sites that are difficult to penetrate and with bacteria that have higher MIC values, such as pseudomonal pneumonia usually require steady-state peak concentrations (typically 8–10 μg/mL)
When gentamicin, tobramycin, or netilmicin are used synergistically with penicillins or other antibiotics for the treatment of gram-positive infections such as infective endocarditis steady-state peak concentrations of 3–5 μg/mL are often times adequate

9. Suggested Target Peak Concentrations (mg/L) (gentamicin or tobramycin)
Types of infections
Suggested Target Peak Concentrations (mg/L) (gentamicin or tobramycin)
Abdominal infections
6-8
Bacteremia
Empiric therapy in cystic fibrosis
8-12
Endocarditis, Bacterial (prevention & treatment)
gram positive (synergy: 1mg/kg/q8hrs)
3-5
gram negative
8-10
Eye infections
Meningitis
Neutropenic patients
6-10
Peritonitis
Pneumonia
Skin and soft tissue infections
Urinary tract infections
4-6

10. Conventional dosing: Steady state trough concentration
Steady-state trough (Cssmin) concentrations should be <2 μg/mL to avoid toxicity

11. Conventional dosing: 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 (predose or minimum concentrations usually obtained within 30 minutes of the next dose) above 2–3 μg/mL for tobramycin, gentamicin, or netilmicin or 10 μg/mL for amikacin predispose patients to an increased risk of nephrotoxicity

12. Extended-Interval Dosing
Not included

13. Volume of distribution
Adult with normal renal function, Adult with renal failure, Burns patients:
V= 0.26 L/kg (ABW)
Obesity (>30% over IBW) with normal renal function:
V= 0.26 [IBW + 0.4(ABW-IBW)]
Cystic fibrosis
V= 0.35 L/kg
Acites/overhydration
V= (0.26 DBW) + (ABW-DBW)
DBW is patient’s dry weight (DBW) before ascitic fluid accumulated

14. Elimination rate constant

15. Elimination rate constant
The elimination rate constant (ke) for aminoglycoside antibiotics increases in proportion with creatinine clearance (CrCl).
The equation for this relationship is:
ke (in h−1) = (CrCl in mL/min)

16. Time of Sampling
Peak concentration: 1 hr after the start of a hr infusion
Trough within 30 min prior to dose
Target concentrations should be at steady-state (after 3-5 half-lives)

17. Initial dosage determination
Calculate CrCl
Calculate Ke
Calculate Vd
Calculate Tau:
T: infusion duration, t’: time of Cmax relative to infusion end
Calculate the dose:

18. Use of aminoglycoside serum concentrations to alter dosages
Pharmacokinetic Concepts Method

19. Pharmacokinetic Concepts Method
Requirements: 2 concentrations obtained at steady-state: C1 and C2 at t1 and t2
Calculate K
Calculate Vd: using C1 and t1 (t1 is the time relative to end of infusion):

20. Pharmacokinetic Concepts Method
Calculate Tau:
T: infusion duration, t’: time of Cmax relative to infusion start
Calculate the dose:

21. PQ is a 75-year-old, 62-kg (5 ft 9 in) male with gram-negative sepsis
PQ is a 75-year-old, 62-kg (5 ft 9 in) male with gram-negative sepsis. His current creatinine clearance is 43 ml/min, and it has been stable since admission. Compute a gentamicin dose for this patient to provide a steady-state peak concentration of 8 μg/mL and a steady-state trough concentration of 1.5 μg/mL using conventional dosing.

22. Patient PQ (please see problem 1) was prescribed gentamicin 110 mg every 12 hours. Steady-state gentamicin concentrations were obtained before and after the fourth dose, and the peak concentration (obtained 1/2 hour after a 1/2-hour infusion of gentamicin) was 9.5 μg/mL while the trough concentration (obtained within 1/2 hour before dosage administration) was 3.0 μg/mL. Compute a revised gentamicin dose for this patient to provide a steady-state peak concentration of 8 μg/mL and a steady state trough concentration of 1 μg/mL using conventional dosing.