Fidaxomicin (OPT-80) was approved by the U.S. FDA in May 2011 for
the treatment of Clostridium difficile-associated diarrhea (CDAD), joining
metronidazole and vancomycin as drugs recommended for treatment of
C. difficile infections (CDI). Fidaxomicin, also known as
lipiarmycin and tiacumicin, is an 18-membered macrolide natural
product that was first reported in mid-1970s and is produced by
fermentation. Fidaxomicin and its primary metabolite OP-1118,
which results from hydrolysis of the isobutyryl ester, are narrowspectrum
antibacterial agents with activity against gram-positive aerobic
and anaerobic organisms, but not against gram-negative organisms.
Fidaxomicin and OP-1118 exert their antibacterial activity by inhibiting
bacterial RNA polymerase, thereby inhibiting bacterial protein
synthesis.
The MIC90 (minimum inhibitory concentration to kill 90% of
bacteria) for fidaxomicin against C.difficile is 0.125–0.25 μg/mL; OP-
1118 is 4- to 16-fold less potent than the parent compound.
Fidaxomicin has been reported to spare native intestinal flora such as
Bacteroides spp. and as such, may prevent selection of drug-resistant
bacteria. Fidaxomicin is bactericidal to C. difficile and has a low
propensity for resistance development with no cross-resistance to
existing antibiotics. Fidaxomicin shows minimal systemic absorption following oral administration in preclinical studies and humans.
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Fidaxomicin is a recently marketed antibiotic with a confusing history dating back to its original isolation in 1975. Fidaxomicin is the major analogue of a family of macrocyclic lactones, isolated independently by three different groups from cultures belonging to three different genera (Actinoplanes, Dactylosporangium and Micromonospora) known as lipiarmycin A3, tiacumicin B and clostomicin B1, respectively. Fidaxomicin is a narrow spectrum antibiotic with excellent activity against Gram positive bacteria, notably Clostridium difficile. Fidaxomicin acts in the gastrointestinal tract without undue disruption to gut microbial flora.
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ChEBI: An 18-membered macrolide that is a fermentation product obtained from the Actinomycete Dactylosporangium aurantiacum. A narrow spectrum antibiotic used for treatment of Clostridium difficile-related infections.
Pharmaceutical Applications
Formerly known as difimicin. An 18-membered macrocyclic
compound related to the tiacumicin group of antibiotics
rather than conventional macrolides. It is active against
staphylococci (MIC 0.5–2 mg/L) and most anaerobic Grampositive
bacilli and cocci, but Gram-negative bacilli, including
Gram-negative anaerobes, are resistant. It is very poorly
absorbed when given orally and most interest surrounds its
activity against C. difficile (MIC 0.12–0.25 mg/L). Such data
as are presently available from clinical trials suggest that it is
as safe and effective in the treatment of C. difficile-associated
diarrhea as vancomycin.
