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CLINICAL PHARMACOKINETICS OF THE AMINOGLYCOSIDES |
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1. Introduction.
2. Pharmacokinetic Overview.
3. Therapeutic drug monitoring.
4. Adverse effects.
5. Dosage calculation.
6. Conclusion.
7. Clinical example.
1. Introduction:
Eg. Gentamicin, Tobramycin, Kanamycin, Retilmicin, Amikacin.
Treatment of choice for life-threatening gram-negative infections due to organisms such as Pseudomonas aeruginosa, Klebsiella, Enterobacteria and Serratia.
Eg.
- Urinary tract infections.
- Septicaemia.
- Infected burns.
- Pneumonia.Often used in combination with a penicillin.
2. Pharmacokinetic Overview:
(a) Absorption:
Not absorbed after oral administration
must be administered parenterally to treat systemic infections.
(b) Distribution:
Water soluble compounds that rapidly distribute into the ECF and highly perfused tissues, and concentrate in the kidneys.
Vd ~ 0.25 L/kg (0.1 - 0.5 L/kg).
Plasma protein binding negligible (< 20%).
(c) Elimination:
Eliminated almost entirely by the kidney via glomerular filtration.
Because of the narrow therapeutic margins of these drugs, dosage should be reduced in patients with renal impairment (see later).
Renal function Half-life (hr) Normal 0.5 - 5 (average 2) Abnormal 1 - 70
3. Therapeutic Drug Monitoring:
Desirable plasma levels:-
Time Level (mg/ml) Peak¶ 5 - 8 Trough < 2 ¶ 1hr after IM dose/30 mins after completion of IV infusion.
4. Adverse Effects:
- Nephrotoxicity
- Ototoxicity
Uncommon:
- NM blockade
- Skin rashes
- Blood dyscrasias
(a) Nephrotoxicity - (~ 2 - 10%):
- Often difficult to distinguish from other causes of renal dysfunction in patients with serious illnesses.
- Exact mechanism unknown. Aminoglycosides accumulate in proximal cortical cells of kidney
- Cl
.
- Often reversible with discontinuation of drug.
- Risk factors:-
- Prolonged therapy (cumulative dose).
- Elevated trough plasma levels.
- Pre-existing renal disease.
- Advanced age.
- Elevated peak plasma levels.
(b) Ototoxicity - (~ 2 - 26%):
- Can impair both auditory and vestibular function
- Often difficult to detect in seriously ill patients.
- Risk factors:-
- Generally as for nephrotoxicity.
- Often irreversible/partially reversible.
5. Aminoglycoside Dosage
Administration:
Generally diluted in 100ml normal saline and infused IV over 30 minutes, to avoid transiently high peak plasma levels.
(a) Loading dose:
~ 2mg/kg should be administered to all patients, irrespective of renal function.
(b) Maintenance doses:
Dosage must be selected according to individual renal function.
(i) Normal renal function:
~ 1 - 1.5 mg/kg (ie. ~ 80mg) every 8 hours.
(ii) Renal impairment:
Alternatives:-
- Prolong the interval between normal doses - and/or
- reduce the dose but maintain a normal dosage interval (NB. In general, the dose must be > 40mg in order to obtain satisfactory peak levels).
Nomogram approach:
Suggested maintenance dosage schedules for Gentamicin, Tobramycin and Netilmicin according to creatinine clearance (loading dose 2-3 mg/kg)
Creatinine clearance¶ (ml/sec)
Percentage of normal maintenance dose§
Interval (hours between normal maintenance doses b Gentamicin Netilmicin or Tobramycin
> 1.67
100
8
12
1.17 - 1.67
80
9 - 11
12 - 14
0.92 - 1.17
65
12 - 13
15
0.75 - 0.92
55
14 - 15
16
0.67 - 0.75
50
16 - 17
20
0.58 - 0.67
40
18 - 20
24
0.50 - 0.58
35
21 - 24
30
0.42 - 0.50
30
22 - 28
36
0.33 - 0.42
25
29 - 32
42
0.25 - 0.33
20
33 - 41
48
0.17 - 0.25
15
42 - 52
54
< 0.17
10
> 53
> 60
¶ Measured or assessed from the formula:
(140 - age) X weight (kg) Creatinine clearance (ml/sec) = _________________________________
48,869 X plasma creatinine (mmol/L) NB. x 0.85 for women
§ The normal maintenance dose for both Gentamicin and Tobramycin ranges from 1.0 to 1.7mg/kg 8 hourly and for Netilmicin is 2mg/kg 12 hourly.
Eg. A 68 year old female (49kg), serum creatinine 0.11mmol/L, suspected septicaemia. Loading dose and initial maintenance dose of Gentamicin?
(c) Clearance approaches:
F x D C = ___________
Cl x - Creatinine clearance approach - (Refer also to renal failure lectures):
Aminoglycosides are almost entirely eliminated by the renal route, so that Gentamicin and creatinine clearance are similar over a wide range of renal function (fe
1.0).
(ie. Cl = Cl
D/
= C
X Cl
C or D = ______________________
mg/day 1,000 Where Cl
Eg. Previous patient
Cl
334ml/min
2 x 34 x 60 x 24 = ______________________
mg/day 1,000
NB Assumptions:
Based on a mean steady-state level of 2
g/ml
Drug clearance and creatinine clearance remain equal.
- Individual drug clearance estimation:
- Give loading dose infusion (R
).
- Measure at least two Gentamicin levels after the infusion.
- Plot 10g C Vs time.
- Estimate k (and t½).
- Estimate Co (conc. at end of infusion).
- Calculate Vd:-
R )
Vd = ________________
k X Co Where R
is duration of infusion (hr).
Now, Cl = k x Vd
- Estimate
1 C = __
ln ______
+ tinf k C C
= desired peak
C= desired trough
Round
(eg. 6, 8, 12, 18, 24, 48hrs).
- Calculate R
(1 - e )
R = Cl x C _________
mg/hr (1 - e and convert to total dose (given tinf).
NB Requires accurate recording of infusion times and blood collection times.
6. General Conclusions:
- The aminoglycosides are important antibiotics in the treatment of life-threatening Gram-negative microbial infections.
- They have narrow therapeutic margins.
- Since they are almost exclusively eliminated by the kidney, dosage must be reduced in patients with renal impairment.
- Several methods can be used to estimate the dosage requirements of individual patients.
- Since these methods only provide initial estimates of the maintenance dosage requirements, plasma level monitoring should be performed to determine more accurate dosage refinements.
- Renal function should also be routinely monitored.
7. Clinical example:
A 65 year old male (68kg) presents to Accident and Emergency with weakness and confusion, abdominal pain, and fever. The patient is hypotensive (105/60) and has a tachycandia (95/min). The tentative diagnosis is septic shock. Initial orders include blood culture, urine cultures and sputum gram stain.
Urgent admission tests reveal a serum creatinine of 0.19mmol/L. A loading dose infusion of Gentamicin (100mg over 30 mins) is administered.
What initial maintenance dose would you recommend, using:-
(a) Nomogram approach, and
(b) creatinine clearance approach?
Two serum Gentamicin levels are performed after the infusion:-
Time after infusion (hr) Gentamicin level ( 1.0 5.3 4.2 3.6 Calculate the patient’s clearance of Gentamicin from these data.
What dosage regimen would you recommend to achieve a peak steady-state level of 7mg/ml and a trough of 1mg/ml?
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