The aminoglycoside antibiotics are widely used for the treatment of severe gram-negative

infections such as pneumonia or bacteremia, often in combination with a β-lactam antibiotic.

Aminoglycosides are also used for gram-positive infections such as infective endocarditis

in combination with penicillins when antibiotic synergy is required for optimal

killing.

Aminoglycoside antibiotics are bactericidal, and the drugs exhibit concentrationdependent

bacterial killing. Antibiotics with concentration-dependent killing characteristically

kill bacteria at a faster rate when drug concentrations are higher. Also, 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. The mechanisms of action for aminoglycosides are binding to

the 30S ribosomal subunit inhibiting protein synthesis and misreading of mRNA causing

dysfunctional protein production.

The MIC for susceptible bacteria is higher for amikacin than it is for the other aminoglycosides.

Because the pharmacokinetics is similar for all these drugs, higher doses of amikacin are

needed to treat infections. The conventional method of dosing aminoglycoside antibiotics

is to administer multiple daily doses (usually every 8 hours). In order to take advantage of

concentration-dependent bacterial killing and the postantibiotic effect, extended-interval (usually the
total daily dose given once per day) aminoglycoside administration is also a

dosing option. Because of these two different methods of dosage administration, it is

important to identify which is being used when discussing serum concentration monitoring.

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 4-1). 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. Therapeutic steadystate

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 steady-state peak concentrations at the

lower end of this range (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 in the higher end of the range (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.

Therapeutic peak concentrations for amikacin are 15–30 μg/mL.

Keterangan gambar:

Concentration/time plot for gentamicin 120 mg given as a 1/2-hour infusion

(squares with solid line) and as a 1-hour infusion (circles with dashed line). 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 aminoglycosides are given as 1-hour infusions, 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.

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. The types of ototoxicity that aminoglycosides

cause are auditory and vestibular, and the damage is permanent. Aminoglycosides accumulate

in the lymph of the inner ear causing ongoing damage to cochlear or vestibular

sensory cells. Auditory ototoxicity usually is first noted at high frequencies (>4000 Hz) and is difficult to
detect using clinical means. Audiometry is required to detect high-tone

hearing loss and is seldom done in patient care areas. Older patients may have lost the

ability to hear in this range for other reasons. If aminoglycoside treatment is not discontinued

in individuals with high-frequency auditory ototoxicity, hearing loss will progress

to lower frequencies. As a result, aminoglycoside-induced hearing losses are not usually

detected until the patient is unable to detect sounds in the conversational frequency zone

(<4000 Hz). Often, the first sign of auditory ototoxicity is tinnitus. Vestibular ototoxicity

results in the loss of balance. Again, this type of ototoxicity is difficult to detect because

many patients treated with aminoglycosides are bed-bound. Besides loss of equilibrium,

headache, ataxia, nausea, vomiting, nystagmus, and vertigo can all be signs of vestibular

ototoxicity. Although this version of ototoxicity is also permanent, patients can often

compensate using visual cues, such as use of the horizon, to maintain balance and avoid

ataxia. In some studies, predose (“trough”) steady-state concentrations have been found
to be related to ototoxicity.5,6 However, peak steady-state concentrations have also been

elevated in these patients which clouds the relationship between serum concentrations

and this type of drug-induced adverse effect.

Extended-Interval Dosing

Because aminoglycoside antibiotics exhibit concentration-dependent bacterial killing

and the postantibiotic effect is longer with higher concentrations, investigators began

studying the possibility of giving a higher dose of aminoglycoside once daily.3,18,19 Generally,

these studies have shown comparable microbiologic and clinical cure rates for

many infections and about the same rate of nephrotoxicity (~5–10%) as with conventional

dosing. Auditory ototoxicity has not been monitored using audiometry in most of

these investigations, but loss of hearing in the conversational range as well as signs and

symptoms of vestibular toxicity have usually been assessed and found to be similar to

aminoglycoside therapy dosed conventionally. Based on this data, clinicians have begun

using extended-interval dosing in selected patients. For Pseudomonas aeruginosa infections

where the organism has an expected MIC ≈ 2 μg/mL, peak concentrations between

20 and 30 μg/mL and trough concentrations <1 μg/mL have been suggested.3 At the present

time, there is not a consensus on how to approach concentration monitoring using this

mode of administration. Some clinicians measure steady-state peak and trough concentrations

while others measure two steady-state postdose concentrations or a single

steady-state postdose concentration.

Since large doses of aminoglycoside are given as a single dose with this mode of

administration, two additional adverse effects become of concern. Because of the manufacturing

process used to produce aminoglycoside antibiotics, very low residual amounts

of gram-negative endotoxin are sometimes present in the commercial product. Reports

of infusion-related hypotension in patients receiving extended-interval aminoglycosides

during the late 1990s have been attributed to the amount of toxin administered at one

time. Acute neuromuscular blockade, usually associated with concurrent administration

of anesthetics or neuromuscular blockers, is also a possible adverse effect of aminoglycosides

associated with high drug concentrations. Because of the high peak concentrations

achieved using extended-interval dosing, surgical and intensive care patients should be

monitored for this possible adverse effect.

BASIC CLINICAL PHARMACOKINETIC PARAMETERS

The aminoglycosides are eliminated almost completely (≥90%) unchanged in the urine

primarily by glomerular filtration (Table 4-1). These antibiotics are usually given by

short-term (1/2–1 hour) intermittent intravenous infusions, although they can be given

intramuscularly. When aminoglycosides are given intramuscularly they exhibit very good

bioavailability of ~100% and are rapidly absorbed with maximal concentrations occurring

about 1 hour after injection. Exceptions to this situation are patients who are hypotensive or

obese. Hypotensive patients shunt blood flow away from peripheral tissues, such as muscle,

to provide maximal blood flow to internal organs. As a result, intramuscularly administered

drugs may be malabsorbed in hypotensive patients, such as those with gram-negative

sepsis. Care must be taken with obese individuals to use a long enough needle to penetrate

subcutaneous fat and enter muscle tissue when administering aminoglycoside antibiotics.

Drug injected into poorly perfused fatty tissue will likely be malabsorbed. Oral

bioavailability is poor (<10%) so systemic infections cannot be treated by this route of

administration. Plasma protein binding is low (<10%).

Manufacture recommended doses for conventional dosing in patients with normal renal

function are 3–5 mg/kg/d for gentamicin and tobramycin, 4–6 mg/kg/d for netilmicin, and

15 mg/kg/d for amikacin. These amounts are divided into three equal daily doses for gentamicin,

tobramycin, or netilmicin, or two or three equal daily doses for amikacin. Extended-interval
doses obtained from the literature for patients with normal renal function are 4–7 mg/kg/d for

gentamicin, tobramycin, or netilmicin and 11–20 mg/kg/d for amikacin.3,19–26,33–38

EFFECTS OF DISEASE STATES AND CONDITIONS ON

AMINOGLYCOSIDE PHARMACOKINETICS AND DOSING

Nonobese adults with normal renal function (creatinine clearance >80 mL/min, Table 4-1) have

an average aminoglycoside half-life of 2 hours (range: 1.5–3 hours), and the average aminoglycoside

volume of distribution is 0.26 L/kg (range: 0.2–0.3 L/kg) in this population.39–42

The volume of distribution is similar to extracellular fluid content of the body, and fluid balance

will be an important factor when estimating the aminoglycoside volume of distribution

for a patient. Patients who have been febrile due to their infections for 24 hours or more

may be significantly dehydrated and have lower volumes of distribution until rehydrated.

Because aminoglycosides are eliminated primarily by glomerular filtration, renal dysfunction

is the most important disease state that affects aminoglycoside pharmacokinetics.

43,44 The elimination rate constant decreases in proportion to creatinine clearance

because of the decline in drug clearance (Figure 4-2).45,46 This relationship between renal

function and aminoglycoside elimination will form the basis for initial dosage computation.

Because the kidney is the organ responsible for maintaining fluid

and electrolyte balance in the body, patients with renal failure are sometimes overhydrated.

Body weight can be an effective way to detect overhydration in a patient. If the

usual weight of the patient is 70 kg when they are in normal fluid balance, known as the
patient’s “dry weight,” and the patient is currently 75 kg with signs and symptoms of

overhydration (pedal edema, extended neck veins, etc.), the additional 5 kg of weight

could be considered extra fluid and added to the estimated volume of distribution for the

patient. Since 1 L of water weighs 1 kilogram, the estimated volume of distribution for

this patient would be 18.2 L using the patient’s dry weight (V = 0.26 L/kg ⋅ 70 kg = 18.2 L)

plus 5 L to account for the additional 5 kg of extra fluid yielding a total volume of distribution

equal to 23.2 L (V = 18.2 L + 5 L = 23.2 L). Care would be needed to alter the

estimated volume of distribution toward normal as the excess fluid was lost and the

patient’s weight returned to its usual value.

Aminoglycosides are relatively polar molecules with good water solubility. Because of

this, they do not enter adipose cells to any significant extent. However, in patients who

weigh more that 30% over their ideal body weight, the volume of distribution for aminoglycosides

increases because of the additional extracellular fluid contained in adipose tissue

(Figure 4-3).
Liver disease patients with ascites have additional extracellular fluid due to accumulation

of ascitic fluid.65–67 Since aminoglycosides pass into ascitic fluid, the volume of distribution

is increased in these patients. The approach to estimating an initial volume of

distribution is similar to that used in renal failure patients who are fluid overloaded. The

weight of the patient when ascitic fluid is not present is known as the patient’s dry

weight. If this value is not known and the patient is not obese, ideal body weight can be

used as an estimate of the dry weight.

DRUG INTERACTIONS

Most important drug interactions are pharmacodynamic, and not pharmacokinetic, in

nature. Vancomycin,14,17,87 amphotericin B,17 cyclosporin,88 and furosemide12,16,17 enhance

the nephrotoxicity potential of the aminoglycosides. Each of these agents can cause

nephrotoxicity when administered alone. When these drugs are administered concurrently

with an aminoglycoside, serum creatinine concentrations should be monitored on a daily

basis. Additionally, serum concentrations of vancomycin or cyclosporin, as well as the

aminoglycoside, should be measured. Loop diuretics,89,90 including furosemide,

bumetanide, and ethacrynic acid, can cause ototoxicity, and an increased incidence of this

adverse effect has been reported when aminoglycosides have been coadministered. If
aminoglycoside antibiotics are administered with loop diuretics, clinical signs and symptoms

of ototoxicity (auditory: decreased hearing acuity in the conversational range, feeling

of fullness or pressure in the ears, tinnitus; vestibular: loss of equilibrium, headache,

nausea, vomiting, nystagmus, vertigo, ataxia) should be monitored daily.

Aminoglycosides have intrinsic nondepolarizing neuromuscular blocking activity and

may prolong the effects of neuromuscular blocking agents such as succinylcholine.91

Surgical and intensive care patients receiving neuromuscular blockers and aminoglycosides

should be monitored for this potential adverse effect. As previously discussed, penicillins

(primarily penicillin G, ampicillin, nafcillin, carbenicillin, ticarcillin) can inactivate

aminoglycosides in vivo and in blood specimen tubes intended for the measurement

of aminoglycoside serum concentrations.50–54 These two classes of drugs can also inactive

each other in intravenous administration bags and syringes and should not be mixed together.

DAFTAR PUSTAKA

Applied Clinical Pharmacokinetics.2008. The McGraw-Hill Companies, Inc.

Goodman andGilman. 2006. The Pharmacological Basis of Therapeutics. New York: McGraw-Hill.

Jackson GG, Arcieri G. 1971. Ototoxicity of gentamicin in man: a survey and controlled analysis of

clinical experience in the United States.

Barclay ML, Duffull SB, Begg EJ, et al. 1995. Experience of once-daily aminoglycoside dosing

using a target area under the concentration-time curve. Aust N Z J Med.

Krieger JA, Duncan L. 1999. Gentamicin contaminated with endotoxin. N Engl J Med.