Measuring Peaks and Troughs: Gentamicin, Vancomycin, Chloramphenicol

Therapeutic drug monitoring is used to prevent or decrease the risk of toxic effects of medication. Monitoring serum concentrations of most antibiotics is unnecessary because these drugs are effective over a  wide range of serum levels, therapeutic levels are achieved easily, and levels associated with toxicity rarely are encountered when standard dosing schedules are employed and patients have normal clearance mechanisms. However, certain antibiotics, especially chloramphenicol, vancomycin, and the aminoglycosides, have narrow therapeutic windows and are associated with potential adverse reactions. Therefore, careful monitoring of serum concentrations of these drugs is critical.

Measurement of serum drug levels can help determine the dose and frequency of administration that allow for maximum therapeutic benefit with minimum toxicity. Appropriately timed blood samples are essential for accurate interpretation of serum drug levels. The best times to obtain blood samples for most parenterally administered antibiotics is 30 minutes after a 20- to 30-minute intravenous infusion, when the level is presumed to be highest (peak level), and immediately before the next dose, when the level is presumed to be lowest (trough level). For oral antibiotics, peak levels should be obtained 30 minutes to 1 hour after oral liquid or 1.5 hours following oral capsule administration.

The principles of therapeutic drug monitoring are based on two pharmacokinetic parameters: volume of distribution (Vd) and half-life (t1/2). Vd is the hypothetical volume within which the drug is distributed and is used to determine the dose required to maximize activity. The t1/2 reflects the rate of drug elimination and, thus, is used to determine the most appropriate frequency of dosing. The blood sample obtained 1 hour after completing the infusion provides information about the Vd after the drug has begun to be dispersed  through the body but before significant amounts have been eliminated. The trough level, drawn immediately before the next dose, helps to determine elimination kinetics and t1/2.

- Peak level provides info about Vd. Trough levels determines elimination kinetics and t 1/2.

A level drawn 30 minutes after completing a gentamicin infusion will not be a reliable indicator of Vd because not enough time has passed for drug distribution to begin. Serum samples drawn 90, 120, or 150 minutes after completing the infusion are not as reliable as a sample obtained 1 hour after completing the infusion because drug elimination will have begun.

Aminoglycoside antibiotics (eg, gentamicin, tobramycin, amikacin) have a high profile of toxic side effects, such as nephrotoxicity and ototoxicity. Although aminoglycoside-induced renal injury usually is reversible, ototoxicity, characterized by both auditory and vestibular nerve damage, is not. Individual risk factors may contribute to the development of toxicity, but the major association with organ damage is elevated peak and trough serum drug concentrations. Sustained peak serum gentamicin concentrations of more than 12 to 14 mg/L and trough serum concentrations of more than 2 mg/L have been associated with a  significantly increased risk of both toxicities.

Monitoring of serum aminoglycoside peak and trough concentrations has been shown to decrease the incidence of nephrotoxicity, although these toxicities still can occur in patients whose serum concentrations are in the desired therapeutic range. Thus, regular monitoring of levels is recommended to assure the adequacy of the dosing regimen and to monitor for drug accumulation and potential toxicity. Serial trough concentrations correlate better than peak levels with the rising tissue accumulation of drug during a course of treatment.

Peak and trough serum concentrations should be measured following the fifth or sixth dose of the aminoglycoside. If these levels are appropriate, serial trough concentrations should be obtained every 4 to 7 days, depending on the clinical status of the patient. Sustained elevation of the trough concentration in excess of 25% over a 2- to 4-day period has been found to place patients at measurable risk for aminoglycoside-induced toxicity.

Dosages can be altered relatively simply if appropriately obtained peak and trough serum concentrations are available. If peak serum values are high or low, the total daily dose should be reduced or increased by 10% to 20%, respectively, while maintaining the same interval of administration. If trough levels (obtained just prior to infusion of the next dose) are too high or low, the dosing interval should be prolonged or shortened, respectively, while maintaining the same total daily dose. If both values are abnormal, the entire dosage regimen should be changed accordingly.

Chloramphenicol no longer is used widely in the United States because it can induce a rare, idiopathic, and irreversible form of bone marrow suppression that clearly does not correlate with serum concentrations. If chloramphenicol is used, monitoring of serum concentrations is important to avoid the major dose-related toxicities of reversible bone marrow suppression and the "gray baby syndrome." Reversible bone  marrow suppression, usually affecting the erythroid series, has been associated with peak chloramphenicol concentrations of more than 25 mcg/mL. The "gray baby syndrome" of neonates, characterized by  abdominal distention, vomiting, flaccidity, cyanosis, and circulatory
collapse, is associated with serum chloramphenicol levels exceeding 50 mg/L. The syndrome also has been recognized in toddlers and following accidental overdoses in adults.

Vancomycin dose-related adverse drug reactions are very similar to those seen with aminoglycosides. Nephrotoxicity and ototoxicity have been associated with high serum levels of vancomycin, but use of newer and more purified preparations of the drug has reduced the incidence of these adverse reactions. Unfortunately, the data supporting a cause-and-effect relationship between serum levels of the drug and either its efficacy or its reported toxicities are not very convincing, and some experts now advocate abandoning the practice of checking serum vancomycin levels. If levels are measured, serum should be obtained 2 to 3 hours following a 30- to 60-minute infusion to allow the antibiotic to distribute fully among tissue compartments. Peak and trough serum drug concentrations should be maintained at 25 to 40 mg/L and 5 to 10 mg/L, respectively.

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