Fidaxomicin (Dificid®): a new class of antibiotics

Fidaxomicin is the first of a new class of antibiotics called macrocycles. This antibiotic has a narrow antibacterial spectrum and is bactericidal against Clostridium difficile. These properties are achieved by inhibition of an RNA polymerase at a site distinct from that of rifamycins. Fidaxomicin has also been found to inhibit sporulation in vitro. No cross-resistance with any other antibiotic class has been discovered. However, some mutations of RNA polymerase are associated with reduced susceptibility to fidaxomicin.

Fidaxomicin is highly specific, affecting faecal concentrations of C. difficile with little to no effect on normal microflora. This may explain the lower recurrence rate in patients treated with fidaxomicin compared to vancomycin. Fidaxomicin has a prolonged in vitro post-antibiotic effect (approximately six to ten hours), which allows for twice daily dosing. Fidaxomicin has minimal systemic absorption, exerting its actions locally throughout the gastrointestinal tract. Plasma concentrations of fidaxomicin and its main metabolite, OP-1118, are in the nanogram/ml range following oral administration of therapeutic doses. The majority of the administered dose is excreted in the faeces. Formation of this microbiologically active metabolite occurs primarily by hydrolysis at the isobutyryl ester. Metabolism of fidaxomicin and its metabolite are independent of cytochrome P450 enzymes. Therefore, no dosage adjustments are required when co-administered with medicines that are substrates of this pathway.

Fidaxomicin was registered by the Therapeutic Goods Administration (TGA) in January 2013 for the treatment of C. difficile associated diarrhoea in adults. To reduce the development of drug-resistant bacteria, Fidaxomicin should only be used to treat infections proven, or strongly suspected, to be caused by C. difficile. The antibiotic must not be used to treat systemic infections as its absorption is poor. Caution is required when using fidaxomicin in patients with pseudomembranous colitis or life-threatening C. difficile infection, as there is currently limited clinical data to demonstrate its efficacy compared to other accepted therapies. Data also lacks in patients with concomitant inflammatory bowel disease. Therefore, caution is required due to the risk of enhanced absorption that may lead to systemic adverse reactions.

Systemic absorption is minimal, thus, side effects to fidaxomicin tend to be confined to the gastrointestinal tract. The most common adverse effects are nausea, constipation, vomiting, and abdominal pain. More severe effects such as gastrointestinal haemorrhage, anaemia, and neutropenia have been observed in clinical trials. However, they were not considered to be drug-related by the investigators. It is a pregnancy category B1 drug, indicating that there is insufficient data related to use during pregnancy, although available information shows no evidence of increased foetal damage. Safety and effectiveness have not been established in children; thus, it is not recommended for paediatric patients.

The normal dose of fidaxomicin is 200mg twice daily for ten days and may be taken without regard to food. No dose adjustment is required for the elderly, patients with renal or hepatic impairment, or in patients undergoing dialysis. The use of fidaxomicin is limited to the treatment of confirmed C. difficile infection due to its narrow spectrum of activity and low systemic absorption. The Therapeutic Guidelines: Antibiotic acknowledge “there is evidence that fidaxomicin is associated with lower rates of recurrence compared to vancomycin, but data for its use in severe disease are lacking and it is currently expensive.” For this reason, the guidelines still recommend the use of metronidazole or vancomycin for C. difficile infection.