SECTION V OTOTOXICITY, PREVENTION AND MONITORING1 A number of drugs can produce hearing loss and balance disturbances:  OTOTOXIC DRUGS Aminoglycoside Antibiotics Streptomycin Neomycin Kanamycin Gentamicin Tobramycin Amikacin Other Antibiotics Vancomycin Erythromycin (IV) Minocycline Cyclosporine Other Drugs Quinine Quinidine Salicylates (aspirin) Cisplatin  Loop Diuretics     furosemide (Lasix) Amphotericin B Radiocontrast (?) Vancomycin is a parenteral agent for severe gram-positive coccal infections.  It is potentially ototoxic and nephrotoxic if therapy is combined with aminoglycosides. Minocycline-induced vertigo is not uncommon; it is mild and transient.  Rare instances of transient hearing loss have been noted with erythromycin intravenous (not oral) doses exceeding 4 Gm/day.  All aminoglycoside antibiotics are ototoxic and nephrotoxic.  Streptomycin is considered more toxic to the vestibular system than to the cochlea, but the converse is so for neomycin and kanamycin.  Gentamicin and tobramycin toxicity is reported to be similar to that of streptomycin (more vestibulotoxic2).  Theoretically, amikacin should be similar to kanamycin (more cochlear toxic).  In practice, however, toxicity of all these agents appears to affect both vestibular and cochlear structures.1 Gentamicin (Garamycin), tobramycin (Nebcin), and amikacin (Amikin) are the "antipseudomonas aminoglycosides."  In practice, the risk of ototoxicity is dependent more on the care taken in administration than which of these three agents is selected. There are no indications for the use of kanamycin that outweigh its disadvantages of cochlear toxicity, nephrotoxicity, and ineffectiveness against pseudomonas organisms.  Neomycin is the most cochlear toxic of all drugs, so it is recommended for topical usage only.  Neomycin is a common ingredient in ear drops (Cortisporin, et al.)  Ototoxicity from neomycin in ototopicals in the middle ear is a possibility.  Parenteral therapy with neomycin is no longer a common practice.  Even topical therapy has resulted in hearing loss when large areas were treated, which allowed for high systemic absorption.  Examples include extensive burn therapy, peritoneal wound irrigations, and oral or rectal use as a bowel preparation, especially in patients with ulcerative colitis. Aminoglycosides are excreted almost entirely by the kidneys.  Therefore, impaired renal function prolongs the excretion time and results in high tissue concentrations that enhance the risk of ototoxicity.  Serum creatinine levels should be monitored before and during therapy.  SUGGESTED SCHEDULES FOR MONITORING RENAL FUNCTION OF PATIENTS  TREATED WITH AMINOGLYCOSIDES Patients with normal serum creatinine and Treatment course of 14 days or less:  determine serum creatinine at least twice a week. Treatment course of more than 14 days:  determine serum creatinine at least three times a week. Patients with elevated but stable serum creatinine:  determine serum creatinine at least every other day. Patients with rising or falling serum creatinine:  determine serum creatinine at least once a day. In patients with impaired renal function, the maintenance dose of an aminoglycoside is approximately half of the normal dose, and it is given at intervals (in hours) approximately four times the numerical value of the serum creatinine (in mg/100 ml).  Serum levels of aminoglycosides should also be monitored to detect elevated or increasing levels which may increase the risks of ototoxicity and nephrotoxicity. SUGGESTED SCHEDULES FOR DETERMINATION OF AMINOGLYCOSIDE SERUM LEVELS Normal renal function Peak level within first 1 to 2 days of therapy, or after 3rd dose Trough level within 1 week Subsequently, peak and trough levels approximately once a week Impaired but stable renal function Peak level within first 1 to 2 days of therapy, or after 3rd dose Trough level and another peak level within 1 week Subsequently, peak and trough levels approximately twice a week Impaired, unstable renal function Peak and trough levels after 1st dose Determination of serum levels as often as daily thereafter for as long as renal function remains unstable. Following any adjustments of dosage, peak and trough levels should be determined within 1 to 2 days. Peak serum levels are drawn 60 minutes after completion of an intravenous infusion or after an intramuscular injection.  Trough levels are drawn 30 minutes before the next dose. DOSAGE OF AMINOGLYCOSIDES IN ADULTS WITH NORMAL AND IMPAIRED RENAL FUNCTION (from Lerner and Matz1 and Sanford Guide4) Aminoglycoside INITIAL DOSEa,c "LOAD" DESIRABLE SERUM LEVEL (ìg/ml) MAINTENANCE DOSEa,d All Adults Peaka Troughb Normal Renal Function Impaired Renal Functione After Each Hemodialysis Gentamicin IV Tobramycin IV TID Dosing ONCE DAILYf DOSING 2 (to 3c) mg/kg 4-10 1-2 1.7 mg/kg q 8 hr 0.8-1.0 mg/kg at intervals (hr) approximately 4 times the serum creatininee (mg/100 ml) 50% of the initial dose 5.1 (to 7a)  mg/kg 16-24 < 1  5.1 mg/kg q 24 hr  Amikacin IV TID DOSING ONCE DAILYf DOSING 7.5 mg/kg 15-30  5-10  7.5 mg/kg 2.5-3.0 mg/kg at intervals (hr) approximately 4 times the serum creatininee (mg/100 ml) 50% of the initial dose 15 mg/kg  56-64  < 1 a Some infections may require higher dosage and serum levels. b  Patients with impaired renal function may have higher trough levels. c  An initial loading dose higher than the maintenance dose is given to patients with impaired renal function or for whom rapid onset of maximum therapy is essential (e.g., septic shock).  Most patients with normal  renal function receive the lower maintenance dose for the initiation of  therapy. d  For obese patients, the appropriate dosage may be less than that indicated  on a body weight basis. e  For example, if the serum creatinine is 3.0 mg/100 ml, the maintenance dose  would be given every 12 hours. f  Once daily dosing of high doses of aminoglycosides appears to induce less oto-nephrotoxicity than multiple dosing and may be as effective for therapy.3 Factors which increase the risk of ototoxicity include the following: Impaired renal function Prolonged treatment course (over 10 days) Concomitant use of loop diuretics such as ethacrynic acid or furosemide (Lasix) Concomitant use of other nephrotoxic or ototoxic drugs (vancomycin et al., Section I.J.) Advanced age Previous aminoglycoside therapy Sensorineural hearing loss It is impractical to perform audiological or vestibular function tests on all patients who receive aminoglycosides.  The numbers are too large, and many patients are too ill to respond to the tests.  However, such tests are especially important in patients at high risk (as above) and in those for whom loss of inner ear function would create a major handicap (e.g., a piano tuner, a ballet dancer).  Audio-vestibular testing should be performed prior to therapy or within the first 3 days.  Audiograms performed within 72 hours of the onset of therapy are still considered baseline, since ototoxicity does not occur before then.  During therapy, testing should be done weekly.  Patients should be questioned daily about symptoms such as decreased hearing, tinnitus, fullness, dysacousis, dizziness, problems of ocular fixation, and nausea. Patients whose serum levels exceed the recommended levels or those who develop nephrotoxicity or symptoms of ototoxicity should be tested, and the drug dosages should be adjusted.  Although ototoxicity may be irreversible and may progress after cessation of therapy, in some patients discontinuation of the drug results in some increment of improvement. NOTE:   Tables and text for this section were adapted from S. A. Lerner and G. J. Matz1 and are used by permission of the American Journal of Otolaryngology and Otolaryngology, Head and Neck Surgery. REFS: Lerner, Matz:  Am. J. Otolaryng. 1980; 1:169.  Otolaryng., Head, Neck Surg. 1979; 87:222. Fee:  Laryngoscope 1980; 90:Supple. No. 24. Nordstrom: J. Antimic.  Chemoth. 1990; 25:159-173. Gilbert, et al.:  The Sanford Guide to Antimicrobial Therapy 2002, page 71.