Prospective randomized double-blind comparison of nephrotoxicity and auditory toxicity of tobramycin and netilmicin

Abstract

Netilmicin or tobramycin was administered to 197 patients in a prospective randomized double-blind trial. Of these patients, 140 recipients of nine or more doses of netilmicin or tobramycin could be evaluated for nephrotoxicity. Fifty-five patients were able to cooperate in the administration of serial audiograms. Nephrotoxicity of similar severity developed in 7 of 73 (9.6%) recipients of tobramycin and in 7 of 67 (10.4%) recipients of netilmicin (P > 0.05). Mild or slight auditory toxicity developed in 5 of 28 (17.8%) recipients of tobramycin and in 2 of 27 (7.4%) recipients of netilmicin (P > 0.05).Toxicity is the major limiting factor in the clinical usefulness of aminoglycosides (16,26). In experimental animals the nephrotoxicity and ototoxicity of netilmicin are lower than those of the other aminoglycosides (3,6,9,11,18,20,22,25, 36 Florence, Italy, 1981), and in a large prospective randomized trial (15) the ototoxicity of netilmicin was lower than that of tobramycin (P = 0.037). In four prospective randomized studies reported so far, however, the rates of toxicity of netilmicin, gentamicin, and amikacin have been similar (2,4,10,17).Adult patients with possible or documented sepsis, urinary or biliary tract infection, or pneumonia and for whom an aminoglycoside was considered indicated by a doctor other than one of the investigators were candidates for entry into the trial. Informed consent was obtained in each case. Patients allergic to aminoglycosides or infected with an organism known to be resistant to tobramycin or netilmicin or who had received an aminoglycoside in the previous 30 days were not entered into the study. The trial was prospective and controlled. Drug assignments were random (a computer-generated table was used), and a double-blind evaluation of toxicity was performed. Serum aminoglycoside measurements and appropriate dosage changes were supervised by an nonblinded member of the investigative group. The patient and the clinical investigator (J.M.G.) responsible for the evaluation of each case did not know which aminoglycoside had been given. Antibiotic therapy other than aminoglycosides and nonantibiotic therapy were not controlled in trial protocol. The loading dose of tobramycin and netilmicin was 1.7 mg per kg of total body weight given intravenously over 20 or 30 min. Maintenance doses were initially adjusted for renal function according to a nomogram * Corresponding author.

Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides

“…We found a significant trend toward a lower ototoxic potential for netilmicin; this has also been found in some experimental models (5,8,14,20,27) and in several, but not all, open and randomized clinical studies (4,10,15,18,21,38,40). Several factors have been identified by univariate statistical techniques as predisposing individuals to auditory toxicity (4,9,13,16,18,22,28,35,37,41).…”

“…Other predisposing factors such as male sex or advanced age have also been identified in clinical and experimental studies (4,6,9,13,16,22,28,29,35,37,41). A trend toward a lower ototoxic potential for netilmicin has been confirmed in several randomized and open clinical studies (10,15,18,38,40). However, the risk factors for ototoxicity developing in patients given netilmicin have not been analyzed.…”

“…The aminoglycoside trials were designed to compare the toxicity of tobramycin and amikacin (trial 1) and tobramycin and netilmicin (trials 2 and 3). The details of trials 1 and 2 have been published (10,11). The design of trials 2 and 3 was exactly the same.…”

Cumulative and acute toxicity of repeated high-dose tobramycin treatment in cystic fibrosis

“…This may reflect the fact that the general condition of the patients improves considerably during therapy and that the first measurement is impaired because of diminished alertness level, a phenomenon also observed by Gatell et al (11), or because of noisy respiration. However, the preferential damage by aminoglycosides to reception of the highest frequencies (6) is evidenced by the reduction in hearing thresholds in that frequency range.…”

Aminoglycoside-induced hearing loss in humans

“…Most studies consider ototoxicity to have occurred if at any time after a base-line audiogram has been obtained an increase occurs in the auditory threshold of 15 dB or more at any two frequencies (38,45,52,53,55,58,61,72) or 20 dB at one or more frequencies (5, 21,25,27). Some investigators consider a 15-dB or greater change at any frequency to represent ototoxicity (4, 29,40,50,76,[80][81][82][83]94), and others use some combination of criteria (10,32,33,66). The basis for accepting a 15-dB change in threshold as a meaningful change is that it is standard procedure to use 5-dB steps in sound intensity when obtaining auditory thresholds.…”