In vitro and in vivo evaluation of tiacumicins B and C against Clostridium difficile

Abstract

Tiacumicins B and C are members of a novel group of 18-membered macrolide antibiotics with in vitro activity against Clostridium difficile. The MICs against 15 strains of C. difficile were 0.12 to 0.25 ,ug/mI for tiacumicin B, 0.25 to 1 ,ug/ml for tiacumicin C, and 0.5 to 1 ,ug/ml for vancomycin. The The tiacumicins are a group of 18-membered macrolide antibiotics originally isolated from the fermentation broth of Dactylosporangium aurantiacum subsp. hamdenensis (7,16). Tiacumicin B, the major antibiotic component produced by this culture, contains an unsaturated 18-membered macrolide ring with a seven-carbon sugar at carbon 11 and a 6-deoxy sugar at carbon 20 (Fig. la). This compound is apparently identical to one of the lipiarmycins, a previously described group of antibiotics produced by Actinoplanes deccanensis (1, 10, 12), and to clostomicin Bi, an antibiotic from Micromonospora echinospora (9). Tiacumicin C differs in the position of butyrate esterification on the seven-carbon sugar (Fig. lb). Tiacumicin C appears to be identical to clostomicin B2, a member of the clostomicin complex isolated from M. echinospora (9).A preliminary report on the biological properties of the tiacumicins indicated that tiacumicin B has moderate activity against pathogenic strains of Staphylococcus aureus, Streptococcus pyogenes, and Enterococcus faecium and demonstrated that it has limited, but potent, activity against several anaerobic bacteria (16). In the same study, tiacumicin C was found to have a similar spectrum of activity but to be less potent than tiacumicin B.The present study was designed to examine the in vitro activities of the tiacumicins against Clostridium difficile and to evaluate the efficacies of these compounds in treating antibiotic-associated pseudomembranous colitis caused by * Corresponding author. In vitro potency. MICs in Wilkins-Chalgren agar were determined by a standard twofold agar dilution procedure (13).Effect of serum and pH on in vitro activity. The effects of 50% hamster serum and at pHs 6.5, 7.3, and 8.0 on the in vitro potencies of the tiacumicins in Wilkins-Chalgren broth were determined by a microdilution method (13). To separate the effect of pH from the effect of serum, the pHs of the serum samples were adjusted to 7.3 prior to testing.Effect of hamster cecal contents on in vitro activity. The bioavailabilities of the tiacumicins in the presence of normal hamster cecal contents were determined by a previously described methodology (13). Briefly, MICs and MBCs of

In Vitro Activity of OPT-80 against Clostridium difficile

“…The MICs of OPT-80 for C. difficile reported by Theriault et al and Swanson et al were higher than those determined in this study (10,11). The treatment of CDAD with OPT-80 in a hamster model published by Swanson et al showed a higher efficacy than the treatment with vancomycin.…”

“…Also, OPT-80 has been shown to inhibit RNA synthesis by the Escherichia coli and Bacillus subtilis RNA polymerases (9). OPT-80 shows little or no systemic absorption (10). Earlier studies showed some activity against gram-positive aerobic and anaerobic organisms.…”

“…Antibiotic levels in the ceca of the hamsters were reported to be 248 g/g at a 6-h time point. Doses as low as 0.2 mg/kg prevented the development of fatal colitis in clindamycin-treated hamsters (10). Since OPT-80 lacks activity against gram-negative bacteria, its potency to affect the colonization resistance within the gut must be anticipated to be low.…”

“…Gram-negative species were not inhibited by OPT-80 (11). Swanson et al (10) studied the activity of OPT-80 in vitro against 15 strains of C. difficile and observed MICs with a range of 0.12 to 0.25 g/ml. In a hamster model for pseudomembranous colitis, OPT-80 was capable of completely preventing the lethality of the animals and prevented the occurrence of relapses (10).…”

The ups and downs of drug discovery: the early history of Fidaxomicin

“…In the hamster model, 4 which was later improved by Jeff Alder to develop an impressive data package, all vancomycin-treated animals died shortly after treatment ceased, whereas tiacumicin B-treated animals survived without apparent development of colitis. Recurrence of the infection is a major drawback of vancomycin treatment of colitis, and, on the basis of our results, Jake Clement delivered a presentation to Abbott management proposing Tiacumicin B as a product candidate.…”