tiacumicin

OBJECTIVE: To review the chemistry, pharmacology, microbiology, pharmacodynamics, pharmacokinetics, clinical efficacy, tolerability, drug interactions, dosing, and administration of fidaxomicin (FDX). DATA SOURCES: A search of PubMed using the terms "fidaxomicin," "OPT-80," "PAR-101," "OP-1118," "difimicin," "tiacumicin," and "lipiarmycin" was performed. All English-language articles from 1983 to November 2013 were reviewed for relevance. Bibliographies of all articles were reviewed as well as the manufacturer's Web site to further identify relevant information...

The co-identity of the antibiotics lipiarmycin A3 obtained from Actinoplanes deccanensis and tiacumicin B obtained from Dactylosporangium aurantiacum was unambiguously demonstrated through a number of experimental means. Spectroscopic analyses performed on both the antibiotics themselves and on their derivatives showed no difference between the two series of compounds. Moreover, unambiguous confirmation of the postulated identity of the two compounds was achieved by chemical degradation of lipiarmycin A3 and isolation of (3S,4R)-pentane-1,3,4-triol triacetate whose relative configuration was assigned by comparison with the authentic erythro and threo pentane-1,3,4-triol triacetates, obtained by chemical synthesis...

The first members of the tiacumicin family of antibiotics, encompassing more than 40 compounds, were isolated in 1975. Structurally, the core aglycon is an 18-membered macrolactone having two conjugated diene units, one isolated double bond, 5 stereogenic centers and most often, at least one glycosidic linkage. Tiacumicin B, a RNA synthesis inhibitor, is a narrow-spectrum antibiotic against clostridia. For the treatment of Clostridium difficile infection (CDI), it has the same cure rate as vancomycin but with lower relapse rate and was approved by the FDA in May 2011...

OBJECTIVE: To evaluate the pharmacology, microbiology, safety, and efficacy of fidaxomicin for treatment of Clostridium difficile infections (CDI). DATA SOURCES: Literature was identified through Ovid MEDLINE (1948-December 2011) and International Pharmaceutical Abstracts (1970-December 2011) using the search terms fidaxomicin, OPT-80, PAR-101, OP-118, difimicin, tiacumicin, lipiarmycin, Clostridium difficile, Clostridium difficile infection, Clostridium difficile-associated diarrhea, and cost...

BACKGROUND: Fidaxomicin, a macrolide antibiotic, was the first medication for the management of Clostridium difficile infections (CDI) to be approved by the US Food and Drug Administration in more than 20 years. OBJECTIVE: This article reviews published literature on fidaxomicin for management of CDI, including its chemistry, spectrum of activity, pharmacokinetic properties, pharmacodynamics, therapeutic efficacy, adverse events, dosing, administration, and pharmacoeconomic considerations...

The 18-membered macrocyclic glycoside tiacumicin B, an RNA polymerase inhibitor, is of great therapeutic significance in treating Clostridium difficile infections. The recent characterization of the tiacumicin B biosynthetic gene cluster from Dactylosporangium aurantiacum subsp. hamdenensis NRRL 18085 revealed the functions of two glycosyltransferases, a C-methyltransferase, an acyltransferase, two cytochrome P450s, and a tailoring dihalogenase in tiacumicin biosynthesis. Here we report the genetic confirmation and biochemical characterization of TiaS5 as a sugar-O-methyltransferase, requisite for tiacumicin B biosynthesis...

The RNA polymerase inhibitor tiacumicin B is currently undergoing phase III clinical trial for treatment of Clostridium difficile associated diarrhea with great promise. To understand the biosynthetic logic and to lay a foundation for generating structural analogues via pathway engineering, the tiacumicin B biosynthetic gene cluster was identified and characterized from the producer Dactylosporangium aurantiacum subsp. hamdenensis NRRL 18085. Sequence analysis of a 110,633 bp DNA region revealed the presence of 50 open reading frames (orfs)...

OBJECTIVE: To optimize the production of tiacumicin B in Dactylosporangium aurantiacum NRRL 18085, we developed a genetic manipulation system for disrupting genes involved in tiacumicin biosynthesis. METHODS: We developed a method of conjugation to transfer exotic DNA pSET152 into D. aurantiacum NRRL 18085. Using the PCR-targeting system, we disrupted a putative tiacumicin halogenase gene in vitro by "in-frame deletion" in E. coli, and then the resulting cosmid was transferred into D...

OBJECTIVE: To evaluate the efficacy and safety of fidaxomicin for the treatment of Clostridium difficile infection. DATA SOURCES: Literature retrieval was accessed through MEDLINE (1966-January 2010) and International Pharmaceutical Abstracts (1970-January 2010) using the terms OPT-80, difimicin, PAR-101, fidaxomicin, tiacumicin, lipiarmycin, and Clostridium difficile. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles published in English that were identified from the data sources were evaluated and pertinent information was included...

BACKGROUND: Clostridium difficile-associated diarrhoea has become a major problem over the last years. Increasing incidence and more severe clinical cases initiated the search for new treatment options. OBJECTIVE: OPT-80, also known as tiacumicin B, lipiarmycin or PAR-101, is a macrocyclic antimicrobial with little or no systemic absorption after oral administration and narrow activity spectrum against Gram-positive aerobic and anaerobic bacteria. METHODS: Data on OPT-80 available from published studies, presentations at conferences and the manufacturer were collected and reviewed...

Clostridium difficile-associated diarrhea usually occurs as a complication of antibiotic treatment. Recent data shows an increase in incidence rate of CDAD and higher rates of morbidity, colectomy and death. The management of CDAD involves discontinuing the inciting antibiotic agent and treatment with metronidazole or vancomycin. The reduced response rates and higher recurrence rates with metronidazole treatment reported in recent studies raise the question of the effectiveness of metronidazole therapy. After each recurrence, the risks for further relapses grow even bigger (after two recurrences, the risk being greater than 50%) and the management of recurrent CDAD becomes a challenge...

Natural products have played a pivotal role in antibiotic drug discovery with most antibacterial drugs being derived from a natural product or natural product lead. However, the rapid onset of resistance to most antibacterial drugs diminishes their effectiveness considerably and necessitates a constant supply of new antibiotics for effective treatment of infections. The natural product templates of actinonin, pleuromutilin, ramoplanin and tiacumicin B, which are compounds undergoing clinical evaluation, represent templates not found in currently marketed antibacterial drugs...

Several novel tiacumicin derivatives containing bromine have been produced by the addition of inorganic bromine to the fermentation broth of Dactylosporangium aurantiacum subsp. hamdenesis. Structures were elucidated employing mass spectrometry and NMR spectroscopy. Antibacterial activity of the bromotiacumicins is comparable to that of the parent compounds.

Several novel tiacumicin derivatives containing bromine have been produced by the addition of inorganic bromine to the fermentation both of Dactylosporangium aurantiacum subsp, hamdenensis. Structures were elucidated employing mass spectrometry and NMR spectroscopy. Antibacterial activity of the bromotiacumicins is comparable to that of the parent compounds.

A new method is described for the selective isolation of species of Myxococcus directly from soil by dilution plating. The method involves suppression of competing microorganisms with antibiotics combined with air drying and wet heat treatment of soils. Fungi were eliminated by supplementing the plating medium with cycloheximide and nystatin. Non-sporulating bacteria were controlled by air drying soils and then heating aqueous soil dilutions for 10 min at 56 degrees C. The predominant sporulating bacteria in soil, Streptomyces and Bacillus, were suppressed by adding either tiacumicin B, ristocetin or vancomycin to the medium...

Recent findings on the epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Clostridium difficile-induced colitis (CDIC) are discussed. CDIC is a gastrointestinal disorder that results from colonization by and overgrowth of C. difficile. Among patients in the community who are treated with an oral antimicrobial, only 1 to 3 individuals per 100,000 develop CDIC, compared with as many as 1 per 100 hospitalized patients treated with an antimicrobial. The requirements for CDIC are (1) a readily available source of C...

A novel complex of Gram-positive antibiotics has been isolated from the fermentation broth and mycelium of Dactylosporangium aurantiacum subsp. hamdenesis subsp. nov. The structures of these six compounds were deduced employing UV, MS, IR, and extensive 1D and 2D homonuclear and heteronuclear NMR experiments. Each component contained a highly unsaturated 18-membered macrolide ring. Components differed from one another by minor structural variations in the macrolide ring and by the number and esterification pattern of glycosidically bound sugars...

A complex of 18-membered macrolide antibiotics has been discovered in the fermentation broth of strain AB718C-41. The producing culture, isolated from a soil sample collected in Hamden, Connecticut, was identified as a strain of Dactylosporangium aurantiacum and was designated D. aurantiacum subsp. hamdenesis subsp. nov. The antibiotic complex was produced in a New Brunswick 150-liter fermentor using a medium consisting of glucose, soybean oil, soybean flour, beef extract and inorganic salts. Several of the antibiotics were active against sensitive and multiple antibiotic-resistant strains of pathogenic Gram-positive bacteria...

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 microgram/ml for tiacumicin B, 0.25 to 1 microgram/ml for tiacumicin C, and 0.5 to 1 microgram/ml for vancomycin. The resistance frequency for both compounds against C. difficile was less than 2.8 x 10(-8) at four and eight times the MIC. The in vivo activities of the tiacumicins against two strains of C. difficile were compared with that of vancomycin in a hamster model of antibiotic-associated colitis...