Antibacterial activities, nephrotoxicity, and ototoxicity of a new aminoglycoside, Win 42122-2

Abstract

Win 42122-2 is a new aminoglycoside antibiotic obtained from a mutant strain of Micromonospora purpurea. In vitro and in vivo comparisons of Win 42122-2 with gentamicin and amikacin revealed that Win 42122-2 generally was less active than gentamicin against Pseudomonas and many Enterobacteriacae, especially Klebsiella and indole-negative Proteus. Against most gentamicin-susceptible isolates, Win 42122-2 was more active than amikacin. Gentamicin-resistant clinical isolates were usually resistant to Win 42122-2, although it was active against certain gentamicin-resistant organisms, depending upon the aminoglycoside-modifying enzymes harbored by the organism. However, Win 42122-2 was markedly less toxic than gentamicin in subacute nephrotoxicity studies in rats, ototoxicity experiments in guinea pigs, and ataxia determinations in cats. This series of antibacterial determinations and toxicity evaluations indicated that the reduced toxicity of the antibiotic may be sufficient to provide an improved therapeutic ratio over gentamicin and other aminoglycosides, even though Win 42122-2 is less potent than gentamicin against some bacteria.

In vitro studies with Win 42122-2: comparison with gentamicin, netilmicin, and amikacin

“…It is a complex of 2-hydroxygentamicin Cl (55%), C2a (10%), and C2 (35%), which is less active in vitro than gentamicin (GM) and generally inactive against GMresistant bacteria. However, it appears to be less toxic than GM in rats, guinea pigs, and cats (3). The reduced toxic potential of WIN may be greater than its reduced in-vitro potency.…”

“…However, comparative toxicological studies in a variety of animal species suggested that WIN was significantly less toxic than GM. Furthermore, the magnitude of the difference in toxicity was generally greater than the difference in potency (3). The development of a GM-like aminoglycoside with significantly reduced potential for toxicity would clearly be advantageous, especially for the treatment ofsevere disease due to gram-negative bacilli and infections that require long-term therapy, such as enterococcal endocarditis and the mycobacterioses.…”