Chemotherapeutic Evaluation of 5-Episisomicin (Sch 22591), a New Semisynthetic Aminoglycoside

Abstract

5-episisomicin (Sch 22591) is a novel semisynthetic aminoglycoside with a spectrum and potency similar to gentamicin in its activity against susceptible bacterial strains, but with increased potency against Pseudomonas, Providencia , and Proteus rettgeri . It is also more active than tobramycin and amikacin against these last-mentioned species. Against resistant strains, Sch 22591 is significantly more active than gentamicin or tobramycin. Against resistant gram-negative bacteria other than Pseudomonas , Sch 22591 has activity similar to that of amikacin, but Sch 22591 is more potent. Against Pseudomonas strains, it is active against most gentamicin- and tobramycin-resistant strains and is more active than the other three antibiotics. Some Pseudomonas strains are resistant to Sch 22591, but susceptible to amikacin. Against a selection of aminoglycoside-resistant staphylococci, Sch 22591 has very good activity against strains resistant to tobramycin, amikacin, and gentamicin. The superior in vitro potency of Sch 22591 against Pseudomonas has been confirmed in vivo in experimental infections in mice. Absorption in dogs is similar to that of other aminoglycoside antibiotics. The acute toxicity of Sch 22591 in mice is greater than that of gentamicin; its vestibular toxicity potential and nephrotoxicity potential in cats and rats appear to be similar to those of gentamicin.

Activity of 5-Episisomicin Compared with That of Other Aminoglycosides

“…Although it had the best activity of the agents tested against bacteria resistant by virtue of a permeability barrier, the concentrations could only be achieved in urine and not in blood. The recent studies by Waitz et al (10) indicate that the in vitro observations concerning 5-episisomicin are confirned in protection experiments in animals. However, it appears that 5-episisomicin is not less toxic in the experimental animal.…”

Comparison of aminoglycoside resistance patterns in Japan, Formosa, and Korea, Chile, and the United States

“…The plates were slowly thawed at 4°C before inoculation with 5 p,l of 1:100 dilutions of 24-h cultures. The MIC, the lowest drug concentration at which no visible growth was observed, was determined after 24 and 48 h. In addition to gentamicin, tobramycin, amikacin, netilmicin, and dibekacin, aminoglycosides tested included sisomicin (Schering Corp.), 2'-N-ethyl-netilmicin (Schering Corp.), 6'-N-ethyl-netilmicin (Schering Corp.), astromicin (fortimicin; Kyowa Hakko), HAPA-gentamicin B (Sch 21420; Schering Corp. [15]), 5-episisomicin (Sch 22591; Schering Corp. [24]), and apramycin (Eli Lilly & Co.).…”

Aminoglycosides: Ancient and Modern

“…Other researchers have carried out similar types of mutant-feeding studies with other aminoglycosides; some years later, workers at Schering-Plough isolated D Ϫ mutants of Micromonospora inyouensis that were blocked in the production of sisomicin and employed medium supplementation with a variety of DOS to produce analogues of this aminoglycoside. This work led to the identification of a compound, 5-episisomicin that had improved antibacterial activity compared to gentamicin and also inhibited certain classes of gentamicin-resistant bacteria; it eventually became the basis of a useful therapeutic agent [14]. We found that 5-episisomicin has very good potency in blocking certain ribozyme-based reactions.…”