How to use antifungals appropriately?

We are now familiar with the main classes of antifungals. But how do we use them appropriately? Antimicrobial stewardship aims to reduce unnecessary and inappropriate prescribing and to minimize the harms of adverse drug effects and resistance. The main stewardship principles can be summarised in the following two principles:

1. Start smart, then focus
2. Right drug, right time, right dose, right route and right duration

Start smart, then focus

The “Start smart, then focus” principle mainly focuses on the treatment of an acutely unwell patient, especially with presumed sepsis. Fungi are a cause of sepsis, albeit less common than bacterial pathogens.

Invasive fungal infections are medical emergencies with high mortality and antifungal treatment should be started on clinical suspicion for patients at risk.

Start Smart: In starting empirical antimicrobial therapy, we aim to make an informed choice. The following should be taken into account:

• The suspected diagnosis and therefore likely organisms: The most common fungal cause of sepsis on ICUs is Candida where as neutropenic (haematology oncology) patients are more at risk for invasive mould infections
• Previous microbiology results (acknowledge the potential need for additional tests)
• Local resistance patterns
• Local, national or international guidance on the treatment of each diagnosis

Then Focus: Following initial treatment, we review antimicrobial therapy (often at 48 hours when treating sepsis). The following should be taken into account:

• The patient’s clinical response
• Available microbiology results (including those that could be used to rule out invasive fungal infection)
• Other diagnostic results (e.g. therapeutic drug monitoring)

Right drug, right time, right dose, right route and right duration

The “Right drug, right time, right dose, right route and right duration” principle encourages the prescriber to consider each factor when starting antimicrobial therapy. This is to ensure that adverse drug effects and antimicrobial resistance are avoided while the patient receives adequate treatment for their infection.

• Right drug: Which antimicrobial will be the most appropriate? Will it cover the suspected or confirmed organism? Which drug will get to the site of infection best? Is the antimicrobial chosen the narrowest spectrum option? Is combination therapy indicated?
• Right time: When should the patient be started on antimicrobial therapy? Does the patient have suspected sepsis, requiring immediate treatment? Can we await diagnostic tests before starting treatment?
• Right dose: What is the minimum effective dose we can give the patient? What dose will minimise the risk of emerging resistance? Does the drug require therapeutic drug monitoring? What dose will minimise the risk of adverse effects or toxicity?
• Right route: Which route is the most appropriate for the patient?
• Right duration: What is the minimum course length that will treat the infection? Is there an appropriate time to de-escalate therapy (to a narrower spectrum, or IV to oral option)?

In order to treat patients in line with these principles, we gain information from:

• Local, national and international guidelines
• Expert opinion (Microbiologist, Infectious Diseases specialists, Mycologists, Pharmacists)
• Microbiology and mycology results (this is a continuous process)
• Drug literature, prescribing guidelines, national drug formularies, drug-drug interaction databases (e.g. the BNF, Aspergillus website)

Think beyond antifungals

When treating for a suspected or proven fungal infection, antifungals form an important part of treatment. However, addressing the underlying causes, sources of infection and contributing factors is essential. This will both prevent further infections and improve clinical response.

It is also important to remember that most fungi readily form biofilms highly resistant to antifungals and they cannot be treated without physical disruption or removal of the biofilms. In case of systemic fungal infections, line removal is highly important and surgical interventions may also be required.

Here are a few common and/or serious fungal infections, along with known risk factors:

Above is an image of dentures soaking in water. Water alone will not sterilise the dentures to prevent colonisation with yeast.

Oral candidosis

• Poor dental hygiene
• Poor dentition and dental prostheses
• Antibiotic use (especially broad-spectrum options)
• Smoking
• Diabetes mellitus
• Diet (high sugar, carbohydrate and dairy)
• Nutritional deficiencies, especially iron deficiency
• Immunosuppression (e.g. HIV, leukaemia, chemotherapy)

Invasive aspergillosis

• Hematopoietic stem cell transplant (HSCT) recipients
• Solid organ transplant recipients
• Prolonged neutropenia
• Immunosuppression (post-transplant, high-dose steroid treatment, anti TNF-a therapy)
• HIV patients with acquired immune deficiency syndrome (AIDS)
• Viral lower respiratory tract infections
• Environmental exposure (hospital construction)

Above, any intravenous catheter is a potential source of Candida infection.

Candidaemia (systemic candidosis)

• Total parenteral nutrition
• Central venous catheters
• Surgical procedures (especially affecting the gastrointestinal tract)
• Haemodialysis
• Prolong admission on an intensive care unit (ITU)
• Antibiotic use (especially broad spectrum options)
• Prior Candida colonisation
• Mechanical ventilation

The common theme for each of these conditions is the presence of healthcare-associated factors. The clinician should think carefully about which of these can be modified in each patient.

Next we will move on to a clinical case. An opportunity to put the principles of stewardship, and our new understanding of fungal pathology, into action.