Fluconazole – not just any anti-fungal
Fluconazole is a triazole antifungal agent which came into use in the late 1980s. It has a different chemical structure to its predecessor, ketoconazole, and is safer systemically. It is licensed for the treatment of topical fungal infections in the mouth, skin and genitals and for invasive, systemic fungal infections in otherwise healthy people. Its other main use is in prevention of fungal infections in people who are immunocompromised. Its mode of action is probably due to its ability to block a process essential for the formation of the fungal cell membrane.
Oral yeasts are present in about a third of the general population but its prevalence in people with advanced cancer increases to between 50% and 90%, which makes it unsurprising that oral fungal infections are more common in our patients where it is estimated to affect up to 30%. Previous antibiotic and cytotoxic therapy along with dry mouth can dramatically alter the general colonisation of the oral cavity which makes it much more susceptible to fungal infection. Evidence suggests that only oral and not systemic antibiotics or steroids are associated with the development of oral thrush.
However, many people are treated for what looks like an oral fungal infection without confirmation of the diagnosis by sending swabs to the microbiology lab. Perhaps there is a perception that oral suspensions are innocuous and whilst nystatin is used as a topical treatment with no absorption from the gastrointestinal tract, fluconazole suspension is a liquid formulation of a therapeutic dose in the same way as most other liquid medicines, so we need to consider side effects and drug interactions as well as antimicrobial stewardship.
The recommended dose for adults with mucosal candidiasis is 50mg daily for 7 – 14 days. This may be extended for other mucosal infections such as oesophagitis and candiduria, and the dose can be increased to 100mg daily for ‘unusually difficult infections’. For patients who may find a longer course problematic, there is a 150mg capsule used as a single dose for vulval candidiasis which may be considered as an off-licence option.
There is a NICE Clinical Knowledge Summary for the treatment of oral candidiasis. For adults it suggests miconazole should be used first line and if not suitable, then nystatin. Fluconazole is suggested as third line or if the infection is extensive (suggested by pain on swallowing) or severe. The dose recommended is 50mg daily for 7 days. For patients who are immunocompromised, the choice of agent is the same but if the infection persists, they suggest extending the course for 14 days, increasing the dose to 100mg and swabbing to ensure you have identified the causative organism.
The common side effects of fluconazole include headaches, abdominal pain, nausea, vomiting and diarrhoea, and rashes. Less common are anaemia, decreased appetite, seizures, dizziness, taste changes, constipation, cholestasis, myalgia and fatigue.
Fluconazole is only partially metabolised in the liver and about 90% is excreted unchanged. People with moderate to severe renal impairment should have a 50% dose reduction. It should be used with care for patients with liver dysfunction as it has been associated with rare cases of hepatic toxicities. It is known to affect levels of some liver enzymes and it is an inhibitor of some of the cytochrome enzymes which break down other drugs, (namely P450 and, more strongly, CYP2610). Other drugs that use these enzymes for breakdown may then remain active for longer and there are many notable drug interactions (see Figure 1. left). It is important to note that the potential for these interactions persists for 4-5 days after the course has ended. It is also essential to consider the effects of both stopping and starting fluconazole when patients are taking medicines likely to interact.
Another consideration is that fluconazole has a known risk of QT prolongation. This is a relatively new area of concern in palliative care since we appreciate several of the drugs we commonly use also have this propensity. We have featured this in a recent newsletter and individual centres will have their own approaches to how they prescribe these drugs individually and in combination.
There is some evidence to show that systemic antifungal treatments are more effective than topicals although nystatin is a good choice for mild oral candidiasis. Fluconazole is preferred over other -azole antifungals and for patients who cannot take nystatin. Resistance has become a problem with antifungals in the same way as antibiotics. There is evidence of cross-resistance and local policies should be consulted when considering hospice formularies.
Lastly, the cost of fluconazole as quoted in the British National Formulary (BNF) shows the capsules to be much more economical than the oral liquid. A 7-day course at 50mg daily using generic oral liquid costs approximately £20 whereas capsules cost just pennies.