Tobramycin Level

Tobramycin is an aminoglycoside antibiotic that is used for treatment of infections of susceptible strains of aerobic gram-negative bacteria that are resistant to less-toxic antibiotics. In particular, it has been more commonly used for definitive or empirical treatment of Acinetobacter, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Providencia stuartii, and sometimes Serratia. ^{[1, 2]}

Normal findings ^[3] :

• Therapeutic level: 5-10 mcg/mL
• Toxic level: > 12 mcg/mL

No standard reference range exists for a tobramycin level when administered as a single-daily dose. Instead, serum concentrations are taken hours after infusion (please see below) and are either plotted graphically onto a nomogram or encoded onto a computer to generate a 24-hour area under the curve (AUC). A final, but less validated, method involves checking a level at the end of the anticipated dosing interval to ensure that it is less than 1 mcg/mL. ^{[4, 5]}

For the nomogram method: One serum concentration 6-14 hours after the start of the infusion. Use the nomogram below and adjust as directed. ^{[1, 6, 7]}

For the 24-hour area under the curve (AUC) method, 2 serum concentrations are taken: The first is 1 hour after infusion and the second is 6 hours after infusion. A computer program then generates a 24-hour AUC and recommends the appropriate dose or interval change (please see below for links to free programs online). ^{[1, 6, 7]}

Another commonly used method is to check for a trough level before the second dose would have been given, with the goal of keeping the trough level < 1 mcg/mL. ^[2]

Conventional (multiple-daily) dosing

For tobramycin administered in multiple daily doses (usually every 8-12 hours), peak and trough levels guide tobramycin dosing. Peak levels are used to adjust the tobramycin dose per administration and should be within the reference range to be considered therapeutic. Subsequent tobramycin doses are either increased or decreased to attain levels within this range. ^{[1, 8]}

Trough levels, on the other hand, are used to modify the dosing intervals. The goal is to keep the trough levels below the designated reference value to prevent accumulation and toxicity. ^{[1, 2]}

Extended interval (single-daily) dosing

Tobramycin administered using an extended interval is monitored and adjusted using a 24-hour AUC, a nomogram, or based on an end of interval level. A 24-hour AUC, as aforementioned, is computer-generated and derived from 2 serum concentrations (at 1 and 6 hours after finish or start of IV infusion) and provides computer-generated recommendations on dose adjustments. ^{[1, 7, 2, 9]} Examples of computerized AUC methods that are available online for free include Aladdin and TCIWorks.

Another method using a nomogram plots a single serum concentration taken 6-14 hours after the end of the IV infusion onto a graph (see below). This is less accurate than the computer-based method but requires only one drug level and is more readily available. It is well-studied only in adults and has been demonstrated to work well in patients with normal or mildly impaired renal function (creatinine clearance between 60-90 mL/min/1.73 m2); caution should be taken in interpreting results of patients with more severe renal impairment. Dosing interval changes, namely whether to maintain the usual 24-hour administration interval or to increase it to every 36-48 hours, are based on where the serum concentration falls on the nomogram. If a level falls on the border between 2 dosing intervals, the longer is chosen because efficacy will likely be preserved and the chances of level accumulation and toxicity will be minimized. ^{[1, 7, 2, 10, 9]}

Another simple, commonly used method is to check the trough level at the end of the dosing interval, before the second dose. One obvious drawback is that you cannot confirm that the dose is appropriate until the second dose is due. When the level is less than 1 mcg/mL, the dose and interval can safely be continued. If the dose is elevated, then longer intervals will be needed and, if significantly elevated, one may need to use one of the above methods to determine an alternate regimen. This method is less reliable compared with the other methods, and caution is required in interpreting its results. A study on patients with cystic fibrosis showed that the extended-interval dosing resulted in higher drug levels in excess of those associated with the multiple-daily dosing, despite having a trough level at goal. ^[4]

Serum tobramycin

See the list below:

• Specimen: Blood

• Container: Red-top tube

• Collection method: Routine venipuncture (at least 5 mL); finger-prick (< 0.5 mL) ^[11]

Collection times are as follows:

• Conventional (multiple-daily) dosing: Ideally, peak and trough levels should be collected when the antibiotic is presumed to be in steady-state, which is usually around the third dose. Collect blood for peak level 30-60 minutes after completion of an intravenous dose or 60-90 minutes after an intramuscular dose. Collect blood for trough level within 30 minutes of the next dose. ^{[12, 6]}

• Extended interval (single-daily) dosing: Serum random levels can be measured after the first dose of the antibiotic. As elucidated above, collect a 1-hour and 6-hour post-infusion serum for the computer-based method, and a single serum sample between 6-14 hours from the start of infusion for the nomogram method. ^{[12, 6, 13]} Serum “trough” or “end-interval” levels are collected within 30 minutes of the subsequent dose. Do not use the tobramycin trough reference ranges provided above, as these are standardized for conventional dosing. (The goal with this method is < 1 mcg/mL.)

• For both dosing methods, serum levels are usually repeated every 3-7 days or more frequently when clinically warranted.

Description

Tobramycin is an aminoglycoside antibiotic that is used for treatment of infections of susceptible strains of aerobic gram-negative bacteria that are resistant to less-toxic antibiotics. In particular, it has been more commonly used for definitive or empirical treatment of Acinetobacter, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Providencia stuartii, and sometimes Serratia. ^{[1, 2]}

Tobramycin, which is administered parenterally, either intravascularly or intramuscularly, reaches peak serum concentrations in 30-90 minutes. Conventional (multiple-daily) doses of this aminoglycoside do not usually lead to accumulation except in patients with renal impairment and in neonates. Dosage for such patients must, therefore, be adjusted accordingly. ^{[1, 2]}

Extended interval (single daily) dosing has the theoretical advantage of minimizing the risk of toxicity while still optimizing bacterial killing with delivery of fewer but higher doses of the antibiotic. At the end of each dosing interval, tobramycin level is expected to reach very low serum concentrations (< 1 mcg/mL) but still continues to have antibacterial activity (also called postantibiotic effect), making the single-daily dosing a feasible alternative regimen. Please see the image below that shows differences in serum concentration over time between the 2 dosing regimens. ^[14]

Like other aminoglycosides, tobramycin has intrinsic toxicity. It can cause reversible nonoliguric nephrotoxicity, irreversible vestibulocochlear toxicity, and neuromuscular blockade, among others. ^{[12, 2]}

Indications/Applications

Serum tobramycin levels are recommended in the following settings: ^{[12, 7, 15, 16]}

• Premature infants and neonates up to 3 months

• Patients with impaired renal function, fluctuating renal function, on dialysis, or those who are critically ill

• Co-existence of disease states known to increase toxicity, such as, but not limited to dehydration, volume depletion, hypotension, concurrent liver disease, metabolic acidosis, hypokalemia, and hypomagnesemia

• Dose change or if planning on prolonged therapy (>3 days for single-daily dosing, or >7 days for multiple-daily dosing)

• Signs or symptoms of toxicity

• If tobramycin is coadministered with drugs known to potentiate toxicity

Considerations

Evaluate renal function regularly, assess need for prolonged therapy, and monitor symptoms consistent with vestibulocochlear toxicity.

Use of finger-prick sampling, instead of venous sampling, can be considered for therapeutic drug monitoring of tobramycin.