Aminoglycoside antibiotics nephrotoxicity

Renal cell lines have been utilized to a limited extent for evaluation nephrotoxins. A rabbit kidney cell line (LLC-RKi) has been utilized for evaluating nephrotoxic antibiotics (Viano et al., 1983 Hottendorf et al., 1987 Williams et al., 1988). LLC-PKi cells have by far been the most widely employed cell line for studying drug-induced nephrotoxicity, specifically in the evaluation of aminoglycoside antibiotics (Hori et al., 1984 Schwertz et al., 1986 Williams et al., 1986b Holohan et al.,... 

Primary renal cell culture has been utilized to study a number of nephrotoxic agents including mercuric chloride (Inamoto et al., 1976), cadmium (Cherian, 1982), lead (McLachlin et al., 1980), cisplatin (Tay et al., 1988), aminoglycoside antibiotics... 

Hori, R., Yamamoto, S., H., Kohno, M. and Inui, K. (1984). Effect of aminoglycoside antibiotics on cellular functions of kidney epithelial cell line (LLC-PKi) a model system for aminoglycoside nephrotoxicity. Pharmacol. Exp. Ther. 230 742-748. 

Williams, P.D., Hottendorf, G.H. and Bennett, D.B. (1986a). Inhibition of renal membrane binding and nephrotoxicity of aminoglycosides. J. Pharmacol. Exp. Ther. 237 919-925. Williams, P.D., Laska, D.A. and Hottendorf, G.H. (1986b). Comparative toxicity of aminoglycoside antibiotics in cell cultures derived from human and pig kidney. In Vitro Toxicol. 1 23-32. 

Streptomycin must be given i.v. (pp. 278ff) like other aminoglycoside antibiotics. It damages the inner ear and the labyrinth. Its nephrotoxicity is comparatively minor. 

Paromomycin sulfate is an aminoglycoside antibiotic that until recently was used in parasitology only for oral therapy of intestinal parasitic infections (see previous text). It has recently been developed for the treatment of visceral leishmaniasis. A phase 3 trial in India showed excellent efficacy for this disease, with a daily intramuscular dosage of 11 mg/kg for 21 days yielding a 95% cure rate, and noninferiority compared with amphotericin. The drug was registered for the treatment of visceral leishmaniasis in India in 2006. In initial studies, paromomycin was well tolerated, with common mild injection pain, uncommon ototoxicity and reversible liver enzyme elevations, and no nephrotoxicity. Paromomycin is much less expensive than liposomal amphotericin or miltefosine, the other promising new therapies for visceral leishmaniasis. 

Another class of catamphiphilic drugs with high toxic potential is the aminoglycosides. Their nephrotoxicity is manifested by lethal injury to the proximal tubular cells by means of the induction of renal cortical lysosomal phospholipidosis. The toxic effect involves three steps the uptake of the antibiotics into the cells, the intralysoso-mal lipid storage, and, finally, cell necrosis. The aminoglycosides are highly water... 

Porter, G. A., and Bennett, W. M. 1989. Drug-induced renal effects of cyclosporine, aminoglycoside antibiotics and lithium Extrapolation of animal data to man. In Nephrotoxicity Extrapolation from in vitro to in vivo, and animals to man, ed. Bach, P. H. and Lock, E. A., 147-170. New York, London Plenum Press. 

Impairment of kidney function is a major adverse effect of the aminoglycoside antibiotics. In a survey of the use of antibiotics in a surgical service, aminoglycosides were given to 26 patients, of whom four developed nephrotoxicity (83). 

Marchewka Z, Dlugosz A. Enzymes in urine as markers of nephrotoxicity of cytostatic agents and aminoglycoside antibiotics. Int Urol Nephrol 1998 30(3) 339-48. 

Pauly DJ, Musa DM, Lestico MR, Lindstrom MJ, Hetsko CM. Risk of nephrotoxicity with combination vancomycin-aminoglycoside antibiotic therapy. Pharmacotherapy 1990 10(6) 378-82. 

Based on its considerable nephrotoxic potential, cisplatin should be given after, rather than before, other anticancer drugs and other drugs with a low therapeutic index (for example aminoglycoside antibiotics or bleomycin) that are primarily excreted in the urine in unchanged form. Concomitant use of potentially nephrotoxic agents (for example conventional amphotericin, tacrohmus) with cis-platin should be avoided (279,280). 

Since the discovery of streptomycin in 1944, aminoglycosides have endured as indispensable agents in the antimicrobial armamentarium. This is despite their well described potential for serious nephrotoxicity and otoxicity and the emergence of other classes of antibiotics with similar antibacterial spectrums. The major aminoglycoside antibiotics in... 

KojimaR, Ito M, Suzuki Y. Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (4). Effects oftobramycin alone and in combination with latamoxef on the stability of rat kidney lysosomal membranes. Jpn J Pharmacol 1987 43(1) 73-80. 

Major risk factors for renal toxicity in cancer patients include nephrotoxic chemotherapy drugs, age, nutritional status, concurrent use of other nephrotoxic drugs (e.g., aminoglycoside antibiotics), and preexisting renal dysfunction. Drugs with a high risk for renal toxicity include cisplatin, ifosfamide,... 

---