Prospective comparative study of efficacy and toxicity of netilmicin and amikacin

Abstract

Eighty patients were treated with either amikacin or netilmicin in a prospective randomized study of serious gram-negative bacillary infections, including 11 due to gentamicin-resistant pathogens. Thirty-six treated with netilmicin and 35 treated with amikacin were evaluable for efficacy or toxicity, or both. The overall groups differed significantly only in age. There were no significant differences in efficacy of the two drugs. There were no statistically significant differences at the 95% level between the netilmicin group and the amikacin group with respect to nephrotoxic reactions (38 versus 28%, respectively) or ototoxic reactions (9 versus 25%, respectively). Further comparative trials of netilmicin and other aminoglycosides appear warranted before it is widely used.

Nonparallel nephrotoxicity dose-response curves of aminoglycosides

“…However, if more than one high-dose level is employed and renal histopathology is examined, a comparatively less steep dose-response slope has been suggested for netilmicin (10,21). The safety advantage predicted by such high-dose comparisons in rats has not extrapolated to the lower doses used in clinics, in which the nephrotoxicity of netilmicin cannot be differentiated from other aminoglycosides (1,15,20,22). Such a lack of extrapolation from high to low doses might be a function of a flatter dose-response slope.…”

“…Despite the advantages predicted in high-dose comparisons in rats, appreciable nephrotoxicity has been observed with netilmicin in clinics (1,15,20,22) and in rats at low multiples of the human dose. In addition, the slope of the nephrotoxicity dose-response curve of netilmicin was flatter and not parallel with the slopes of gentamicin and amikacin, confiming the suggestions made at high doses.…”

“…The distribution of casts excreted in the urine after 2 weeks of dosing and the terminal gross observations corroborated the flatter dose-response slope of netilmicin. Nephrotoxicity advantages predicted by high-dose comparisons with netilmicin in rats are apparently a function of its less steep dose-response slope and therefore may have no relevance to lower doses.When large multiples of the human dose of netilmicin are administered to rats, the drug is less nephrotoxic than gentamicin (2, 7, 10, 11, 13, 21), tobramycin (10,16,21), and amikacin (10), but netilmicin has appreciable nephrotoxicity in humans and cannot be differentiated from other aminoglycosides in clinics (1,15,20,22). Highdose toxicity comparisons in animals may be inappropriate for extrapolations to lower doses unless the slopes of their respective dose-response curves are linear and parallel (9).…”

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.…”

Discovery and development of new antimicrobial agents

“…The development of new aminoglycosides followed a pattern aimed at identifying SAR that blocked susceptible sites for enzymatic modification on the molecule while retaining the acceptable safety profile of the earlier agents (9,17). While many new analogs were tested clinically (33,126,138), amikacin remains one of the most useful due to the relatively infrequent occurrence of resistance encountered (13,107). Amikacin use was often restricted in many hospitals in hopes of preventing the emergence of resistant strains, but its use for empiric therapy in combination with beta-lactams has been widely adopted in centers where resistance to the older aminoglycosides is common.…”