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Are there any well controlled studies examining the risk of ototoxicity
from 5mg/kg once daily aminoglycosides vs. typical bayesian dosing schemes?
When I was pursuing my PharmD, some of the instructors taught that high
peaks were associated with ototoxicity. Lately, it seems that the
association is more a multiple of average trough X length of treatment.
(4mg/ml trough X 10 days treatment = 40; anything over 40 is risky) If
there aren't any published trials, have any of you with institutional
once-daily protocols done audiometry tests on the patients with 5mg/kg
dosing?
thanks,
Richard Rupchock Pharm D
Santa Rosa Memorial Hospital
Santa Rosa CA
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I hope that this is the correct format to respond to the above question.
In doing a work-up on the extended frequency ("once daily") aminoglycosides
dosing protocol, I do not recall reading a study where audiometry was used
to assess ototoxicity (auditory and vestibular). In one hospital where the
protocol (6 mg/kg) was instituted, patients were instructed to report any
hearing or balance changes to the RN or teams. No reports were received.
Nephro and ototoxicity may be related to the saturable transport and
accumulation of aminoglycosides within the inner ear and renal cortex.
With multiple daily dosing, persistent low serum concentrations slow tissue
clearance. The transient high levels obtained with extended frequency
dosing saturate the transport and reduce the uptake into the renal cortex
and inner ear. The longer interval between doses in extended frequency
dosing allows adequate clearance from these tissues, possibly preventing
toxicity. Could these references help?
Black FD, Pesznecker SC. Vestibular ototoxicity, clinical considerations.
Otolaryngologic Clinics of North America 1993; 26 (5): 713-736.
Brummet RE, Fox KE. Aminoglycoside induced hearing loss in humans.
Antimicrobial Agents and Chemotherapy 1989; 33 (6): 797-800.
Govaerts PJ, Ches J, Van De Heyning PH, Jorens PhG, et al. Aminoglycoside
induced ototoxicity, minireview. Toxicology Letters 1990; 52: 227-251.
Greg Soon, B.Sc(Pharm)
Peterborough Civic Hospital
Peterborough, ON, Canada
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We do baseline and serial audiograms and vestibular fxn tests when
aminoglycoside therapy extends beyond 2 weeks, regardless of the dosing
method employed.
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To Richard Rupchock
Data regarding ototoxicity of aminoglycosides is fairly shakey at best. To
date we believe that both duration of therapy and total dose are the two
main factors (similar to what you describe although not as specific). Other
factors may include: other ototoxic drugs, pre-existing hearing deficits,
receiving dialysis, being in hospital for long periods of time. Part of the
problem with assessing ototoxicity is the lack of sensitivity of the tests
that are currently undertaken, (ie simply asking the patient on the ward
whether he/she can hear you just doesn't quite pick up the subtleties of
hearing deficits). I think we are all eagerly awaiting comparative trials
of conventional versus once daily (where std 5mg/kg/d doses are used), and
once daily versus dose-individualised once daily dosing, when high tone
audiometry is being used as a sensitive index of ototoxicity.
I assume when you comment regarding "typical Bayesian dosing schemes" you
are referring to conventional dosing of aminoglycosides using Bayesian
methodology?
We do not use a standard 5 mg/kg dose of gentamicin/tobramycin at our
institution. All of our once daily doses are adjusted, using Bayesian
methods, targeting a goal Cmax and AUC. These principles have been
discussed in:
Barclay et al., Aust NZ J Med 1995; 25:230-5
Begg et al., Br J Clin Pharmac 1995; 39:605-9
Duffull et al., Br J Clin Pharmacol 1997; 43:125-35
While a standard 5 mg/kg/d dose of gentamicin/tobramycin might be a good
starting dose it would be inappropriate to assume that it would be suitable
for all patients. [In my experience doses required by patients may vary
from 2 to 12 mg/kg/day as a single dose.] It is our belief that dose
individualisation should be utilised with once daily dosing as it is with
conventional dosing techniques, until there is evidence to the contrary.
Do any of these comments help?
If you have any more specific points for discussion do not hesitate to
contact me directly.
Regards
Steve
----------------------------
Steve Duffull
Dept of Clinical Pharmacology
Christchurch Hospital
Private Bag 4710, CHCH
NZ
Ph +64 3 364 0900
Fax +64 3 364 0902
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Copyright 1995-2010 David W. A. Bourne (david@boomer.org)