Timothy C. Hain, MD
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|Figure 3: The level of gentamicin in the blood can be predicted reasonably well from patient weight and kidney function. The plot to the left shows simulated blood levels of gentamicin for a typical person with normal kidney function and average size, using a dose of 120 mg of gentamicin every 8 hours. The area under the curve (see text) over 50 hours for this regimen is about 175mg.|
Nevertheless, it is very uncommon for gentamicin otototoxicity to develop with with less than 1 week of treatment suggesting that toxicity might be more closely related to the total dose than peak dose. Prazma et al (1976) found ototoxicity due to Tobramycin to be both proportional to total dose and peak level. In other words, the same total dose arrived at through two different regimen was more toxic for the regimen with the higher peak levels. Against the idea that toxicity correlates with total dose, F.O. Black et al (2001) did not find a correlation between total aminoglycoside dose and ototoxicity. However, their numbers were small and a correlation could have easily been missed. Also, total dose may be the wrong measure as exposure of the ear to gentamicin is presumably correlated to blood level rather than dose. Blood levels are a function of dose, timing, kidney function, and volume of distribution.
Thus a refinement of this idea is that ototoxicity is proportional to the "area under the curve", or AUC, meaning the integral of the gentamicin blood level. This idea is attractive, as it would fit well with the general thought that aminoglycoside ototoxicity is due to diffusion from the blood compartment into an inner ear compartment, which binds gentamicin strongly and for very long periods. Beaubian et al (1989, 1991) has presented strong evidence for this idea using another aminoglycoside, Amikacin, in an animal model. Against this idea is that in humans, Fee did not find that area under the curve (related to total dose, kidney function and volume of distribution) correlated with ototoxicity (Fee, 1980). Fee suggested that there were other, yet unknown factors, operative.
|Figure 4: In this simulation of once/day dosing, notice that peak levels are much higher than for the every 8 hour dosing simulation in figure 3. Nevertheless, this regimen is equally effective and may even be less ototoxic. This suggests that ototoxicity is not directly related to the peak level. The "area under the curve" (see text) for 50 hours of this regimen is similar to the every 8 hour dosing schedule of figure 3, about 225 mg.|
Extended Interval Dosing: There is other evidence for the AUC concept. It is now well known that a high peak dose is not necessarily harmful. A recent trend is to administer gentamicin on a once/day or longer schedule because bacterial killing is a stronger function of concentration than time. Details about how this is done using a nomogram called the "Hartford Nomogram" is found in in a paper written by Nicolau et al. Other algorithms are discussed by Begg and Barclay (1995). Peak levels are much higher than the levels expected for three times a day dosing, and targets for three time/day dosing as discussed above are inappropriate for once/day dosing. Instead, levels drawn at known times from the administration, typically 6-10 hrs after the last dose, are used to adjust the interval of dosing using a nomogram.
According to Begg (1995), trough levels are not needed for once-daily dosing. Most evidence suggests that ototoxicity is less for once/day dosing than more frequent dosing (Begg and Barclay, 1995). This line of evidence again suggests that high-peak levels are not necessarily ototoxic, but rather it is the total dose or some other factor that is important. It also possible that toxicity might be related to a combination of peak dose and total dose, or that toxicity is a complex function of peak and total dose, potentiating medications and genetic suceptibility. The few human studies done to date, all necessarily retrospective of course, are not powerful enough to clearly distinguish between these possibilities.
If we accept the idea, so far unproven in humans, that the AUC predicts ototoxicity more closely than peak and trough levels, then a group that would be expected to have more ototoxicity than the norm are individuals with poor kidney function. Because the blood level of gentamicin decays much more slowly, the AUC is greater.
|Figure 5. This simulation represents blood levels in an individual with renal impairment such that the time constant of gentamicin is increased to 8 hours rather than the usual 2 hours. With every 8 hour dosing, out to about 50 hours, the peak drug level climbs with each dose. The area under the curve for this regimen over 50 hours is 519, roughly twice as much as for simulations shown in figures 3 and 4, of persons with normal renal function.|
Figure 5 above represents this situation in a person with severe renal disease. This, however, is an unrealistic simulation as ordinarily blood levels are monitored and dose reduced. If the dose were halved after the first "loading" dose, the peak levels can be kept below 8, but the trough levels are always above 4, and the AUC at 50 hours is only modestly elevated (303) compared to a similar regimen in persons with normal renal function. Only a few studies have been done regarding the prevalence of ototoxicity in persons with renal disease (Gendeh 1993; Dayal 1979). While ototoxicity does appear more commonly in this population, other factors such as underlying medical disease as well as previous courses of ototoxic medications are difficult to separate out. Another possibly confounding factor is that when doses are adjusted downward or drug is given less frequently, patients may succumb to their infection more often.