Because Gentamicin Is Solely Eliminated in the Urine, and Is Nephrotoxic, Renal Failure and Toxic Gentamicin Levels Can Quickly Develop.
As the proximal tubule cells become exposed to gentamicin, renal cell damage can occur, with loss of renal function. Although it is the theory of Once Daily Dosing that there is an eight hour period where the serum gentamicin level is practically zero that gives the renal cells a time to rest and regenerate, nephrotoxicity can and does occur in patients on Once Daily Dosing. Because gentamicin is not metabolized, but is excreted in the urine, any loss of renal function without a concomitant decrease in the dose administered will inevitably lead to some increase in the average daily serum gentamicin concentration. Increasing serum gentamicin levels promote further nephrotoxicity, and a vicious circle of increasing serum gentamicin levels and increasing nephrotoxicity results. I have reviewed cases where the serum creatinine level rose from normal to over 3.0 within 3 to 4 days. While gentamicin induced nephrotoxicity is usually transient, and resolves with discontinuance of the drug, the vestibular damage that can result from high serum gentamicin levels secondary to acute nephrotoxicity is usually permanent.
For gentamicin to be used safely, health care professionals must carefully monitor kidney function and check for symptoms of vestibulopathy (damage to the vestibular system). Additionally, they must monitor their patient closely for any symptoms of vestibular disturbance, such as nausea, vertigo, tinnitus, or bouncing vision.
Many physicians and health care providers are under the mistaken impression that they can safely give patients one large dose of gentamicin a day without monitoring patients for side effects. This common misperception can be traced to misinterpretation of the results of a single medical study, referred to as the Hartford Study. Health care providers' eagerness to save money by giving one, rather than three, doses of gentamicin daily may have also played a role in establishing the common but mistaken idea that one a day dosing of gentamicin eliminates potential side effects.
In fact, patients receiving gentamicin must be monitored closely. Physicians are encouraged to monitor concentrations of the drug in patients' blood to prevent the development of excess gentamicin blood levels. While monitoring alone will NOT ENSURE that ototoxicity will not develop, it can detect subtle rises in gentamicin levels and decreased renal function which foreshadow rapidly developing renal shutdown and excessive gentamicin buildup. Without careful monitoring, it is recommended that gentamicin not be used for more than three days.
Monitoring alone will NOT prevent the occurrence of permanent vestibular loss. Many physicians and pharmacologists hold the mistaken notion that if a patient is being monitored, and that if there is no increase in serum gentamicin levels to "abnormal" or toxic levels, and if there is no rise of serum creatinine to "abnormal" levels, their patient is immune to developing ototoxicity. While monitoring and appropriate intervention can prevent a number of ototoxic events from occurring, continuous exposure to "normal" serum levels of gentamicin for extended periods can be toxic to vestibular hair cells. MONITORING DOES NOT ELIMINATE THE NEED FOR CONSIDERING APPROPRIATE DOSING AND LENGTH OF TREATMENT ISSUES.
Monitoring Renal Function Prior to a patient receiving gentamicin, baseline renal function must be determined. Since gentamicin is eliminated solely in the urine and is not metabolized, dosing is dependent on renal function. Moreover, it is critically important to have a baseline from which to monitor ongoing renal function. Assume that laboratory normals for creatinine at a particular institution are .6 to 1.4 mg/ml. A patient with a baseline creatinine of .6 whose serum creatinine level rises to 1.3 over the first week of gentamicin therapy is most probably experiencing gentamicin induced nephrotoxicity which will soon spiral out of control and lead to excessive serum gentamicin levels, whereas the patient with a baseline creatinine of 1.3 that remains stable over the first week is not.
For a person receiving gentamicin over 7-10 days, checking renal function every 2 to 4 days is reasonable: It is far better to catch an incipient nephrotoxicity sooner rather than later. Cohen & Powderly: Infectious Diseases, 2nd ed., Mosby 2004 at 1812 recommends: "If once-daily aminoglycoside therapy is continued beyond 4 days, a random concentration should be obtained on the fifth day, and then weekly thereafter. Serum creatinine should be measured every 2–3 days." [emphasis supplied]
Monitoring serum gentamicin levels
For traditional three times a day dosing, serum gentamicin monitoring involves taking a blood draw immediately after infusing gentamicin, and then immediately before the next dose. These levels are referred to as "peak" and "trough" levels. The figure below demonstrates the theoretical blood levels resulting from 3 times a day dosing vs once-a-day or ODA dosing. The concept of obtaining peak and trough levels is based on the notion that in order to effectively kill the target organism, a certain peak concentration is necessary. On the other hand, high trough levels allow more exposure of the vestibular hair cells to gentamicin, and are to be avoided. For traditional 3 times a day dosing, this concept makes sense.
Most laboratories reports list "normal ranges" for peak and trough levels for three times a day administration , usually 5 to 10 µg/mL for peak concentration, and <2 µg/mL for trough concentration. These have no application to ODA dosing, as is evidenced in the Figure.
For ODA dosing, it is expected, and is part of the theoretical framework underlying the concept of ODA dosing, that the serum gentamicin level should be at or very close to 0 for the last 6-8 hours of the 24 hour period. In ODA dosing, "trough" levels, if taken, should be <.5 µg/mL. Many physicians and pharmacologists erroneously assume that as long as the trough level for ODA is less than the level printed on the laboratory slip, they are safe.
Ototoxicity has been related to total exposure to gentamicin: the area under the time-dose curve times the days of exposure. In order to best estimate the area under the time dose curve for ODA dosing, the concept of a "random" or 6-10 hour post infusion emerged. Adjustment of dosing based on random levels is key to the Hartford approach, and the use of the Hartford nomogram. See gentamicin dosing Since the Hartford nomogram is based on 7mg/kg/day, it is inapplicable to lower dosing regimes such as 5 mg/kg/day. If one monitors random levels when giving less than 7 mg/kg/day, and applies the Hartford nomogram without adjustment, adjustments in dosing should produce serum levels that are the equivalent of 7 mg/kg/day.
Monitoring the Patient's Symptoms
The patient must be monitored closely for any signs of vestibulopathy. In order for a patient to self-report any such symptoms, the physician or person administering the gentamicin must be acutely aware of symptoms of impending ototoxicity: ringing in the ears, any sense of imbalance, nausea, "dizziness," jittery or bouncing vision, or a sense of fullness in the ears.
Many authors recommend the use of serial audiograms to detect high frequency hearing loss, which may foreshadow frank vestibular symptoms. Dobie RA; Black FO; Pezsnecker SC; Stallings VL, Hearing loss in patients with vestibulotoxic reactions to gentamicin therapy., Arch Otolaryngol Head Neck Surg 132(3): 253-7 (2006) (abstract), Esterhai JL Jr Gentamicin-induced ototoxicity complicating treatment of chronic osteomyelitis. Clin Orthop Relat Res - 01-AUG-1986(209): 185-8 (abstract), Fausti SA, High-frequency audiometric monitoring for early detection of aminoglycoside ototoxicity. J Infect Dis - 01-JUN-1992; 165(6): 1026-32 (abstract).
In the event that ototoxic signs appear, Gentamicin MUST be immediately discontinued, absent the presence of severe, unavoidable, life threatening consequences if gentamicin is discontinued.