Clinical Use Quiz

Elimination

A wide interpatient variation in the elimination of gentamicin, tobramycin, and amikacin has been reported. Variation is seen in patients with normal serum creatinine and creatinine clearance. The magnitude of variation is more pronounced in the initial phases of treatment and in patients treated for gram-negative sepsis as compared to normal volunteers. Thus, there tend to be substantial differences in pharmacokinetic parameters from patient to patient, but over an extended hospital stay such diferences may be seen within the same patient due to changes in renal function or hydration status.

Distribution Volume

Interpatient Variation

Aminoglycoside antibiotics distribute to a theoretical space similar to the extracellular fluid compartment. In normal volunteers, this compartment comprises about 20 to 35% of their body weight. However, the percent of body weight attributed to extracellular fluid changes with physiologic conditions.

For example, dehydration associated with gram-negative sepsis results in an extracellular fluid compartment that is less than 20 percent of body weight.

Newborn infants have a large extracellular fluid volume for their weight. Thus, their distribution often approximates 50 percent of their body weight. Distribution volume varies between patients, but all the aminoglycosides appear to vary consistently. This interpatient variation affects serum concentrations and the dose required.

Distribution volume changes with disease conditions, body composition and other variables such as age. Patients that are essentially at lean body weight will have a distribution volume of 20 to 35% of their body weight. Obese patients, because of the excess contribution of adipose tissue to the body weight but not to the overall distribution volume, will have a normal value of 10 to 20% of their body weight. Any situation resulting in a distribution volume of > 35% for a patient at lean body weight or > 20% for an obese patient should be thoroughly investigated for both biologic and artifactual causes before proceeding on to determining an appropriate dose and interval. Once Vd is determined for a specific patient, it may still change during the course of therapy.

The method of aminoglycoside analysis may also affect the calculated value for distribution volume. This may be particularly troublesome if, throughout the course of the week, your laboratory may switch methods for determining distribution volume or send after hour or weekend samples to another laboratory using a different method for aminoglycoside analysis.

If the laboratory totally converts to a new method for aminoglycoside analysis, the "normal range" for distribution volume may have to be altered to reflect the new method for analysis. As differences in quantitative methods become more evident with increasing concentrations of aminoglycoside, the clinician may encounter some difficulty in reproducing pharmacokinetic parameters derived while a patient was being treated with conventional or individualized therapy and then switched to single daily dosing.

The accurate calculation of distribution volume is dependent on knowing how much aminoglycoside the patient was supposed to receive and whether the patient actually received that dose. Antibiotic left in extension tubing or infiltrating may greatly compromise the quality of a pharmacokinetic study. Knowing the actual start and stop times for antibiotic infusion as well as whether the tubing was adequately flushed greatly improves the accuracy by which the calculation of distribution volume can be made.

Manufacturer production tolerances can also prove problematic in the accurate calculation of distribution volume. Investigators have reported that commercial lots of gentamicin and tobramycin labeled as 80mg (40 mg/mL) actually contain over 100mg of drug. Thus, patients may be routinely receiving up to 25% more drug than ordered. This could be very problematic in the preparation of 7mg/kg doses of gentamicin or tobramycin not only in terms of accurately determining volume but also in terms of the amagnitude of the actual peak concentration.

Another potential concern when evaluating pharmacokinetic parameters in patients receiving SDD therapy (7 mg/kg/day) is a recent report that the larger doses of aminoglycoside may be associated with a significant alpha or distribution phase, raising the question as to whether a one-compartment first order pharmacokinetic model is the appropriate method to characterize these serum concentration time data.

Determining Peak and Trough

Several factors influence peak and trough serum concentrations for each patient. The factors that you should consider include:

1. The patient's clinical condition,
2. The site of infection,
3. The relative sensitivity of suspected or isolated pathogen

**In patients with life-threatening infections, you would select a more aggressive regimen to achieve higher peak and trough concentrations.

PEAK AND TROUGH

PEAK is defined as the concentration immediately post-infusion.

TROUGH is the serum concentration immediately before the next doe. However, the TROUGH value used in calculations is obtained just before the last dose. Note: These values should be the same at steady-state.

The values we suggest as appropriate for peaks and troughs refer to STEADY STATE conditions.

TRADITIONAL DOSING VS. SINGLE DAILY DOSING (SDD)

Traditional Peak and Trough Concentrations

Single Daily Dosing (SDD)

This approach attempts to take advantage of the concentration dependent killing associated with aminoglycosides. This is achieved by adjusting peak concentrations to 10 times the bacterial MIC.

The current approach (Hartford nomogram) recommends a daily dose of 7 mg/kg/day for gentamicin or tobramycin. The goal is to produce a peak concentration of 20 to 25 mg/L.

This rationale is based on a worst case scenario of Pseudomonas aeruginosa with an MIC 50 (minimum concentration of antibiotic which inhibits 50% of bacteria) of 2 mg/L. (Remember: normal MIC range for aminoglycosides is approximately < 0.5 to 2.0 mg/L). Thus, a peak concentration of 20 mg/L (10 times the MIC) is recommended using this approach. A peak serum concentration of this magnitude can be accomplished using a gentamicin dose of 7 mg/kg/day.

The second goal of this strategy is to produce a period of time during the dosage interval when the aminoglycoside blood concentration is essentially zero. The reason is two-fold. 1) An aminoglycoside free interval will help to overcome adaptive resistance, and 2) Prevent tissue accumulation, reducing nephrotoxicity and ototoxicity.

Clinical data to date have not demonstrated that SDD is superior to conventional therapy in terms of efficacy or reducing toxicity.

SINGLE DAILY DOSING PEAK AND TROUGH CONCENTRATIONS

OTOXICITY

Ototoxicity is the progressive destruction of vestibular or cochlear sensory cells of the ear, with a direct affect on the 8th cranial nerve (vestibulocochlear nerve). Initial damage starts at the base of the cochlea where high frequency sounds are processed. At first, conversational hearing is not affected. If damage continues, the perception of low frequency sounds is involved. With severe toxicity, conversational hearing can be lost. The damage is usually bilateral. Sensory cells do not regenerate, so any hearing deficit is usually considered permanent.

The initial symptoms of cochlear damage include: tinnitus, a sensation of pressure or fullness in the ear, loss of high frequency hearing (measured by audiometry).

Vestibular dysfunction is manifested by: vertigo, nausea, vomiting, and nystagmus. The risk of ototoxicity appears to be different for different aminoglycosides.

Several factors associated with a higher incidence of ototoxicity are: duration of treatment, cumulative dose, average daily dose, concomitant use of furosemide or ethycrynic acid, underlying disease states, and previous exposure to aminoglycosides. Elderly patients have a higher risk of toxicity than young adults or pediatric patients. Additionally, patients with compromised renal function, particularly those requiring dialysis, are at increased risk.

INITIAL PATIENT SCREENING

In an attempt to critique the physician's initial order for aminoglycoside assuming traditional dosing, the following algorithmic approach should prove useful in translating limited laboratory and patient demographic information into estimates of pharmacokinetic parameters.

Knowing the patient's height can be used to calculate lean body weight (LBW):

For males, LBW = 50 + 2. 3 (# of inches over 5 feet) Kg
For females, LBW = 45 + 2.3 (# of inches over 5 feet) Kg

Example for a 5 foot 10 inch male the LBW = 73 Kg and for a 5 foot 10 inch female LBW = 68 kg.

Next the creatinine clearance (CrCl) can be calculated using the method of Cockcroft and Gault:

For males CrCl = (140 - age) * (LBW) / (72) * (Serum Creatinine) ml/min
For females CrCl = 0.85 * ((140 - age) * (LBW) / (72) * (Serum Creatinine)) ml/min

An estimate can then be made of the aminoglycoside elimination rate constant (Kd) using the Detli equation.

Kd = 0.0024 (CrCl) + 0.01 Hr-1

An estimate of the aminoglycoside half-life (t1/2) can then be made t1/2 = 0.693/Kd Hr

With this information available, an evaluation of the initial aminoglycoside dose and interval can be made. Again, it must be kept in mind that at this time we have no actual patient specific serum concentration time data to more precisely estimate these parameters. First, the dose can be evaluated on a mg/kg basis. Usually (not SDD), the dose should be approximately 1.5 mg/kg. If the patient is > 30% of their LBW, many clinicians will evaluate the dose using what is termed a dosing body weight. Dosing body weight (DBW) is calculated using LBW and actual body weight (ABW).

DBW = LBW + 0.4 (ABW-LBW) Kg

Again, a value of approximately 1.5 mg/kg would be considered appropriate if it is necessary to use DBW. If the prescriber is significantly above or below this value, the prescriber should be contacted with a suggested modification to the dosing strategy.

The appropriateness of the dosage interval can be evaluated using the estimate of the patient's half-life. Generally, the dosage interval for traditional or individualized dosing approximates two to three half-lives. Thus, if the patient had an estimated half-life of 3.5 hours, an appropriate dosage interval would be 2 * 3.5 = 7 hr or 3 * 3.5 = 10.5 hr plus an hour for the infusion. In this example, a dosage interval of 8 or 12 hrs would seem appropriate. Remember in looking at the dosage interval the drug infusion must be included in your decision. For example, if the patient receives their dose of aminoglycoside from 0800 to 0900, the true peak occurs at 0900, and the true trough occurs at 1600 or the distance between the peak and the trough is 7 hours.

If the dosage interval appe ars to be too short or too long, the prescriber should be contacted to change the interval.

If you are satisfied that the dose and dosage interval are appropriate or have changed them to your satisfaction, we are ready to consider the question of doing levels. Before any attempt is made to obtain levels, a question should be asked as to how long the patient will receive parenteral antibiotics. For example, an 18 year old woman with pyelonephritis is likely to receive IV therapy only as long as she cannot take antibiotics orally. It would not be advisable to obtain levels in this situation.

Generally, you have two options to monitor the patient's aminoglycoside therapy. The first option is to do a "trough"/"peak" study. To do this, the patient must be at steady state which means that they have received the drug for 3 to 5 half-lives on time and on schedule. This means that if the patient is to receive drug three times during the day at 0800, 1600, and 2400, that schedule has been maintained and the drug was actually given at those times. The patient must also have stable renal function and their volume or hydration status should be stable. Generally, an aminoglycoside level is ordered approximately 30 minutes before and 30 minutes after the next dose. With "trough"/"peak" studies, the trough must be used twice in calculating the necessary pharmacokinetic parameters. First an actual trough concentration is determined prior to the antibiotic infusion. Second the "trough" must also serve as the second post infusion point so that a line may be drawn providing a slope or the -Kd value. The trough is placed in the appropriate spatial time relationship by determining the distance in hours between the previous peak concentration and the current "trough" value. Because each dose of aminoglycoside forms its own serum concentration time curve and that, by definition, steady-state means that a saw-tooth pattern of these serum concentration time curves has been established with each of the curves superimposable over the other, the "trough" can be placed as the second post infusion value by graphing it the same distance from the current peak concentration as the trough was from the former peak concentration.

The second option for monitoring the patient is to do series kinetics. Series kinetics does not require that the patient be at steady-state as if the patient has received aminoglycoside before you will obtain a "trough" prior to the next dose and the Kd or t1/2 is measured using 2 or 3 actual post infusion serum concentrations (i.e., you will not attempt to place the trough as a post infusion point). The "trough" is obtained within 30 minutes of the next dose. No trough is required if the patient is being studied following the first dose (.e., trough = 0 mg/L). Obviously, a minimum of two post infusion points are required. Optimal sampling strategies suggest that these two points be spaced by approximately 1.5 half-lives. Thus, if you estimate the patient's half-life to be 3.5 hours, the two post infusion points should be separated by about 5 hours (1.5 * 3.5). If the drug infusion were scheduled from 0800 to 0900 and the first post infusion point was obtained at 0930, the second post infusion point should be obtained at approximately 1430. While two points will generate a line, many clinicians may feel uncomfortable with just 2 post infusion points in a series pharmacokinetic study. If a third point is desired, it should be obtained at a halfway point between the first and third post infusion levels. Thus in our example, if three post infusion points were required, suggested times might be 0930, 1200, and 1430. Obviously, additional points add inconvenience, discomfort, and cost to the patient's care.