AMINOGLYCOSIDES

Pharmacokinetic Parameters and TDM Information

Parameter	Value				Reference
Elimination half-life* “t1/2”	0.5-3.0 hr (healthy young <30y, with normal renal function) 1.5-15.0 hr (healthy old >30y, with normal renal function) 0.5-2.5 hr (children) & 2-9 hr (neonates)				(1-6)
	Gentamicin           Tobramycin             Amikacin               Netilmicin
	2.0+3.0 hr                 2.2+1.0 hr                 2.3+0.4 hr             2.3+0.7 hr
Total body clearance* “TBC”	1.51+0.63 ml/min/kg (healthy young & normal renal function)				(1, 3-6)
	Gentamicin ml/min/kg	Tobramycin ml/min/kg	Amikacin ml/min/kg	Netilmicin ml/min/kg
	0.82Clcr+0.11	0.98Clcr+32%	1.3+0.6 =0.6Clcr+0.14	1.3+0.2
Volume of distribution “V”	0.15-0.25 L/kg hr (normal fluid status) 0.07-0.15 L/kg hr (dehydrated patients) 0.07-0.7 L/kg hr (dehydrated children) 0.2-0.7 L/kg hr (dehydrated neonates)				(1, 3-7)
	Gentamicin	Tobramycin	Amikacin	Netilmicin
	0.31+0.1L/kg	0.33+0.08L/kg	0.27+0.06L/kg	0.2+0.02L/k g

Plasma protein binding		Gentamicin	Tobramycin		Amikacin		Netilmicin		(3-6)
		< 10%
Urinary elimination		Gentamicin	Tobramycin		Amikacin		Netilmicin		(3-6)
		> 90%	90%		98%		80-90%
Therapeutic range#			Gentamicin	Tobramycin		Amikacin		Netilemicin		(3, 8)
	Peaks (mg/ml) Serious inf. Life-threat. inf.		6-8 8-10	6-8 8-10		20-25 25-30		6-8 8-10
	Troughs (mg/ml) Serious inf. Life-threat. inf.		0.5-1 1-2	0.5-1 1-2		1-4 4-8		0.5-1 1-2
Dosing***	Administration by either IM injection or IV bolus injection by 30 to 60 minutes intermittent infusions. Continuous IV infusion, although it is applicable but not save. The general daily dosage regimens for gentamicin, tobramycin and netilemicin are 3-5mg/kg/day “divided as 3 equal doses (infants 2-2.5mg/kg/day divided as 3 equal doses while children > 2 years the recommended dosage is 5mg/kg/day divided as  2 equql doses. The general daily dosage regimens for amikacin are 15mg/kg/day “divided as 2-3 equal doses. Dosage regimens should be decreased according to the degree of renal dysfunction in renal inpairment. However, the dose should be individualized									(1,2, 8-12)

*Aminoglycoside clearance is highly dependent on renal function. 
**Volume of distribution, is generally about 25% of the lean body weight, but highly variable
 #Several factors should be considered in selecting a desired peak and trough concentration: clinical condition, the site of infection, the relative sensitivity of the isolated or suspected pathogen, and the ratio between the peak serum concentration to the MIC. These suggested concentrations are general guidelines which may needed to be modified for selected patients.
*** Single daily doses of aminoglycosides have been recently recommended and it was effective and may be less toxic than multiple daily dose regimens as nephrotoxicity and ototoxicity have been argued to be related to exposure time. However, the clinical trial were limited to small patient numbers with mild infection, therefore, these clinical results are inconclusive and should not be extrapolated to routine clinical treatment.

Individualiz-ation of the dosage regimens*	Three post-infusion samples are collected for determining the pharmacokinetic parameters of each patient and upon which dosage regimes are individualized First serum sample should be collected 15-30min. post infusion for patients with normal renal function who received a 60 minute infusion and should be delayed 1-2hr post infusion for patients with renal dysfunction The 2nd & 3rd samples are obtained within the initial 2-3 hrs post-infusion for patients > 30y with normal renal function (3-4 hrs for older patients with normal renal dysfunction) For patients with renal impairment: four times serum creatinine estimates one half-life; the 2nd & 3rd samples should estimate t1/2. Calculations: From the line of best fit, the elimination rate constant (k) and the serum concentration on the regression line at zero time post-infusion (c¥)max. The drug distribution volume is calculated by the following equation: V=Ro/k[(1-e-kt1)/ (c¥max - c¥min. e-kt1)]. Where Ro is the infusion rate,t1 is the infusion period and (c¥)min is the predose concentration. τ ( dosing interval) –1/k ln[desired trough/ desired peak] + t1. The calculated dosage intervals are then rounded to clinically practical intervals of 4, 6, 8, 12, or 24 hours. The infusion rate in mg/hour = kV[desired peak][1-e-kτ/1-e-kt1]. The dose = Ro . t1	(1, 10)
Sampling(peak&troug h)	Peak: 30 minutes after completion of a 1/2-1 hr infusion             1 hr after IM administration Trough: Immediately prior the next IM or IV dose.	(10)

 *Many factors may change the clearance or the apparent volume of distribution during the course of aminoglycoside therapy and affect concentrations and dosage requirement. Therefore aminoglycoside therapy requires monitoring of serum creatinine or urea nitrogen, although, serum concentrations may rise before a change in serum creatinine is noted

 Relationship between Aminoglycoside Toxicity and Plasma Levels

Toxicity	Effect	Reference
Ototoxicity	It is largely irreversible. It results from progressive destruction of vestibular or cochlear sensory cells which are highly sensitive to damage by aminoglycosides. Aminoglycosides can accumulate in the otic fluids (pre- and endo-lymph of the inner ear) specially when the concentrations in the plasma are high. Diffusion back into the blood stream is very slow; the t1/2of aminoglycosides in the otic fluids is 5-6 times longer than in the plasma. Back diffusion is concentration-dependent and is facilitated only when the concentration of the drug in the plasma reaches a trough. Thus ototoxicity is more evident in patients with persistently continuos elevated plasma drug levels	(2, 13, 14)

Nephrotoxicity	Approximately 8-26% of patients who receive an aminoglycoside for more than several days will develop mild renal impairment. The renal damage is due to marked accumulation and avid retention of  aminoglycoside in the proximal tubular cells. The initial damage at this site is manifested by the excretion of enzymes of the renal tubular brush border. After several days there is a defect in renal concentrating ability, mild protienuria, and the appearance of hyaline and granular casts. While severe acute tubular necrosis may occur rarely, the most common significant finding is a mild rise in plasma creatinine, hypokalemia and hypophosphatemia are seen very infrequently. The impairment in renal function is almost always reversible, since the proximal tubular cells can regenerate. Nephrotoxicity correlates with the total amount of drug administered. Consequently, is more likely to be encountered with longer courses of therapy. Continuous infusion is more nephrotoxic than intermittant dosing	(1, 2, 15-19)
Constant plasma drug concentrations above a critical level, which is manifested by elevated trough serum concentrations correlate with aminoglycoside toxicity.		(1, 2)
In general, the dose-response data would indicate gentamicin to be the most toxic, followed by tobramycin and amikacin with similar degrees of toxicity, followed by netilmicin which is the least toxic.		(1)

 Typical Minimal Inhibitory Concentration in mg/ml of Aminoglycosides that will Inhibit 90% (MIC90%) of Clinical Isolates for Species

 

Species	Gentamicin	Tobramycin	Amikacin	Netilmicin
Citrobacter freundii	0.5	0.5	1	0.25
Enterobacter spp.	0.5	0.5	1	0.25
Escherichia coli	0.5	0.5	1	0.25
Klebsiella pneumoniae	0.5	1	1	0.25
Proteus mirabilis	4	0.5	2	4
Providencia stuartii	8	4	2	16
Pseudomonas aeruginosa	8	4	2	32
Serratia spp.	4	16	8	16
Enterococcus faecalis	32	32	>64	2
Staphylococcus aureus	0.5	0.25	16	0.25
References	(2, 20)

 Available Dosage Forms and Administration

Administration of gentamicin, tobramycin, amikacin and netilmicin are by either IM injection or IV bolus injection by 30 to 60 minutes intermittent infusions. Continuous IV infusion, although it is applicable but not save. They are available as parenteral injection, for IM, IV use or injections for IV infusion in different concentrations.  Also, parenteral injection for IV infusion in 0.9 Sodium Chloride solutions are available in different concentration for gentamicin and tobramycin.

References (1, 8-10)

 Absorption

Aminoglycosides are very poorly absorbed from GIT. Less than 1% of the dose is absorbed following either oral or rectal administration. The drugs are not inactivated in the intestine and they are eliminated quantitatively in the feces. Absorption from GIT may be increased in cases of GIT diseases. Also, long-term oral or rectal administration may result in accumulation of aminoglycosides to toxic levels in patients with renal failure. Instillation of these drugs into body cavities may results in rapid absorption and toxicity. Topical applications of aminoglycosides for long periods to large wounds, burns or cutaneous ulcers may also lead into toxication specially in patients with renal insuffeciency. All of the aminoglycosides are absorbed rapidly from IM sites of injection. Peak concentrations in plasma occur after 30-90 minutes and are similar to those observed 30 minutes after completion of an intravenous infusion of an equal dose over a 30-minute period. Absorption from IM injection may be reduced in critically ill patients due to poor perfusion

References (2, 21, 22)

Assay Methods

Method	References
Microbiological assay	(1, 23, 24)
Radioimmunoassay (RIA)	(1)
Radioenzymatic immunoassay (REA)	(25)
Homogenous enzyme multiplied immunoassay (EMIT)	(1, 26)
Flourescence immunoassay (FIA)	(1)
Gas-liquid chromatography (GLC)	(1, 27)
High-performance liquid chromatography (HPLC)	(28)

 Homogenous EMIT and FIA methodologies have been substantially improved and now represent the two most common assay methods used to measure serum aminoglycosides in the clinical laboratories

Factors Affecting Plasma Levels

Factor*	Effect(s)
Renal function	It affects greatly, the plasma levels of aminoglycosides. There is a statistical highly significant correlation between serum creatinine or creatinine clearance and aminoglycoside elimination. Plasma levels increase as the renal functions impaired.
Age	In healthy adults, cardiac output, renal blood flow, and glomerular filtration decreases with increasing age. Pharmacologic agents which are primarily eliminated by glomerular filtration rate are influenced by these physiologic change. Elimination and clearance of aminoglycosides decrease with increasing age therefore plasma concentrations consequently increase with age increase.
Distribution volume	Aminoglycosides distribute primarily to the extracellular fluid compartment which approximates 20-25% of body weight. This physiologic space is susceptible to changes that my occur during the course of treatment. For examples, patients in initial phases of gram-negative sepsis are febrile, nauseated and vomiting and consequently, are dehydrated. As a result the extracellular fluid compartment and drug volume are decreased. In contrast, patients with congestive heart failure, patients with peritonitis and patients receiving IV hyperalimentation have initially large volume of distribution. This volume is changed during the course of treatment as a result of correcting the dehydration or removing the excess fluids. When volume of distribution decreases, the elimination rate increases and the half-life decreases and vice versa. These changes are all independent of any change in occurring with serum creatinine or other markers of renal function.

Hematocrit	There is linear relationship between the reciprocal of hematocrit and drug half-life. Hematocrit is altered by changes in patient’s fluid status.
Ideal body weight	The drug’s distribution volume increases with increasing excess wieght, presumably due to distribution into extracellular water within the adibose tissue.
Gender	Elimination rate for gentamicin is faster in female than male. Females had a lower volume of distribution probably because of decreased muscle mass and decreased extracellular fluid per unit of weight.
Obstetric patients	The extracellular fluid compartment, total body water, cardiac output, renal flow and glomerular filtration are all increased during the later phases of pregnancy and may cause an increase in the elimination rate of aminoglycosides.
Burn patients	Hemodynamic changes secondary to burn (burn patients are hypermetabolic), appear to explain why these patients have an extremely rapid rate of aminoglycoside elimination. In addition, the extracellular fluid compartment in burn patients can be extremely large immediately post-injury. Consequently, an occasional patient who develops gram-negative sepsis early in the course of burn resuscitation may have an extremely high distribution volume and a prolonged half-life, even though renal function tests are normal. After post burn diuresis, the volume of distribution returns to normal.
Pediatric patients	The elimination rate of aminoglycosides in pediatric patients is rapid

Internal medicine patients	A large number of internal medicine patients with normal serum creatinine concentration had gentamicin half-life of less than 2.5 hours. However, a substatial number of these patients had prolonged elimination rates of the drug and required a marked dosage reduction.
Ascites	Patients with ascites have an extremely high distribution volume and thus have a prolonged half-life, even though renal function tests are normal.
Geriatric patients	Elderly patients have a progressive decrease in glomerular filtration rate with increasing age. However, serum creatinine may be misleading indicator of glomerular filtration and aminoglycoside elimination since the endogenous production of createnine decreases with increasing age.
Surgery/ Critically ill patients	A wide interpatient variation exist among surgical patients who develop gram-negative sepsis. Surgical patients with infections have many underling medical complications that may alter the elimination rate of aminoglycosides. Also, critically ill patients may have early signs of organ failure or may in verse be hypermetabolic.
Cystic fibrosis	Patients with cystic fibrosis are hypermetabolic and have higher glomerular filteration rate, therefore they eliminate aminoglycosides very rapidly.
Neonates	The newborn, specially the premature patient, experienced very dynamic changes in physiologic parameters such as cardiac output, renal blood flow, renal function and extracellular fluid. Consequently, the distribution volume, clearance and half-life vary substantially from day to day, and therapeutic concentrations are extremely difficult to attain and maintain
Gynecologic patients	The elimination rate of aminoglycosides with gynecologic infections is generally rapid and dosage requirements are generally increased in this group of patients
References	(1, 29-32)

 *(Several factors have been reported to alter the disposition of aminoglycosides and thereby influence serum concentrations and dosage requirements)

 References

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2.     Chambers, H. F. and Sande, M. A. The Aminoglycosides. In “Goodman & Gilman’s: the Pharmacological Basis of Therapeutics”. Hardman, J. G.; Molinoff, P. B.; Ruddon, R. W. and Gilman, A. G. (Eds.). McGraw-Hill, New York, St.Louis, San Francisco, Auckland, Lisbon, London, Madrid, Mexico City, Milan, Montereal, New Delhi, San Juan, Singapore, Sydney, Tokyo, Toronto, 9^th ed., 1103 (1996).

3.     Matzke, G. R.; Millikin, S. P. and Kovarik. Variability in Pharmacokinetic Values for Gentamicin, Tobramycin and Netilmicin in Patients with Renal Insufficiency. Cli Pharm., 8, 800 (1989).

4.     Bauer, L. A. and Bloutin, R. A. Influence of Age o Amikacin Pharmacokinetics in Patients without renal disease. Comparison with Gentamicin and Tobramycin. Eur J Clin Pharmacol. 24, 639 (1983).

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12. Strum, A. W. Netilmicin in the Treatment of Gram-Negative Bacteremia: Single Daily Versus Multiple daily Dosage. J Infect Dis., 159, 931 (1989).

13. Huy, P. T. B.; Meulemans, A.; Wassef, M.; Manuel, C.; Strekers, O. and Amiel, C. Gentamicin Persistence in Rat Endolymph and Perilemph after a Two-Days Constant Infusion. Antimicrob Agents Chemother., 23, 344 (1983).

14. Brummett, R. E. and Fox, K. E. Studies of Aminoglycoside Ototoxicity in Animal Models. In “ the Aminoglycosides: Microbiology, Clinical Use and Toxicity”. Whelton, A. and Neu, H. C. (Eds.). Marcel Dekker, Inc., New York, 419 (1982).

15. Smith, C. R.; Baughman, K. L.; Edwards, C. Q.; Rogers, J. F. and Lietman, P. S. Controlled Comparison of Amikacin and Gentamicin. N Engl J Med., 296, 349 (1977).

16. Smith, C. R.; Lipsky, J. J.; Laskin, O. L.; Hellman, D. B.; Millits, E. D.; Longstreth, J. and Lietman, P. S. Double-Blind Comparison of the Nephrotoxicity and Auditory toxicity of Gentamicin and Tobramycin. N Engl J Med., 302, 1106 (1980).

17. Aronoff, G. R.; Pottratz, S. T.; Brier, M. E.; Walker, N. E.; Fineberg, N. S.; Glant, M. D. and Luft, F. C. Aminoglycosides Accumulation Kinetics in Rate Renal Parenchyma. Antimicrob Agents Chemother., 23, 74 (1983).

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19. Patel, V.; Luft, F. C.; Yum, M. N.; Patel, B.; Zeman, W. and Kleit, S. A. Enzymuria in Gentamycin-Induced Kidney Damage. Antimicrob Agents Chemother., 7, 364 (1975).

20. Wiedeman, B. and Atkinson, B. A. Susceptibility to Antibiotic: Species Incidence and Trends. In “ Antibiotics In Laboratory Medicine”. Lorian, V., (Ed.). Williams & Wilkins, Baltimore, 3^rd ed., 962 (1991).

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22. Breen, K. J.; Bryant, R. E.; Levinson, J. D. and Schenker, S. Neomycin Absorption in Man. Ann Intern Med., 76, 211 (1972).

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29. Dee, T. H. and Kozin, F. Gentamicin and Tobramycin Penetration into Synovial Fluid. Antimicrob Agents Chemother., 12, 548(1977).

30. McCracken, G. H. Clinical Pharmacology of Gentamicin in Infants 2 to 24 Months of Age. Am J Dis Chil., 124, 884 (1972).

31. Gill, M. A. and Kem J. W. Altered Gentamicin Distribution in Ascitic Patients. Am J Hosp Pharm., 36, 1704 (1979).

32. Michaelsen, H. and Bergan, T. Pharmacokinetics of Netilmicin in Children with and without Cystic Fibrosis. Antimicrob Agents Chemother., 19(6), 1029 (1981).

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