Side effects of long-term azole therapy

Azole antifungals are the first-line of treatment or prophylaxis for many fungal infections. They are often administered long-term (weeks to months), which can be associated with a number of adverse effects. In patients receiving several medications, it can be difficult to identify whether antifungals are contributing to, or causing particular symptoms; recognition of common side effects, leading to treatment discontinuation or management, is therefore key to reducing symptoms and reversing toxicity.  A recent review by Dr Lydia Benitez and Dr Peggy Carver summarises these effects and their frequency:


Key points the authors highlight:

  • Liver toxicity, generally reversible, is common with all azoles.
  • Hormone-related adverse effects are observed with select azoles; these include hair loss, breast enlargement, decreased libido, impotence, and (rarely) adrenal insufficiency (beware drug interactions with inhaled and oral steroids).
  • Patients with fair skin on voriconazole should use liberal amounts of broad spectrum UV protectants and wear sun protective clothing, avoid excess sunlight, and undergo frequent monitoring of skin as phototoxic reactions progressing to development of skin cancer has been associated with long-term use.
  • Therapeutic drug monitoring may be utilized to minimise neuropathies in specific patient populations on voriconazole, as neuropathies are more common with higher concentrations and doses. Its role in preventing other long-term toxicities is less clear.

Azoles are a valuable resource in the treatment and prophylaxis for fungal infections. Despite being associated with a number of adverse effects, they are safer and more active than alternatives. Thorough knowledge of the side effects they may cause is therefore important, so that they can be recognised and managed promptly.

Read the paper here: Benitez, L.L. & Carver, P.L. Drugs (2019) 79: 833

Vitamin D deficiency may increase the risk of Amphotericin B-related kidney toxicity

Amphotericin B (AmB) is the drug of choice for the treatment of many fungal infections.  Despite this, the drug can cause several serious side effects, one of which being nephrotoxicity (toxicity to the kidneys). Conventional AmB can be adapted into a lipid emulsion preparation, which can reduce the risk of nephrotoxicity, while preserving its efficacy and remaining a lower cost option. Unfortunately this does not solve the problem, and nephrotoxicity remains an issue for many patients.

Vitamin D deficiency has been found to be a major problem worldwide, and can increase the risk of kidney-related disease, including drug-induced nephrotoxicity. A recent study by Daniela Ferreira and colleagues at the University of Sao Paulo looked at standard and vitamin D-deficient rats and found that the deficient rats treated with AmB presented with impaired renal function. This suggests that vitamin D deficiency may play a key role in the development of AmB-induced nephrotoxicity. Therefore, the authors state that it is essential to monitor levels of vitamin D in patients treated with both conventional and lipid formulations of AmB, in order to reduce the development of kidney disease.

Read the full paper here

New diagnostic tool paves the way for faster and earlier diagnosis of chronic pulmonary aspergillosis

A new screening test kit will speed up diagnosis of chronic pulmonary aspergillosis (CPA) say researchers from the University of Manchester. The test, available commercially from LDBio diagnostics, is very simple and needs no power source or equipment and therefore is likely to be very useful in resource poor settings.

CPA is a fungal disease associated with lung damage caused by other conditions including TB which is prevalent in low to middle income countries. CPA can get progressively worse over time and so early diagnosis is crucial to improve patient outcomes.

The team from the University of Manchester and the NHS Mycology Reference Centre, based at Wythenshawe Hospital, tested the LDBio Aspergillus ICT kit on blood samples collected from 154 CPA patients identified at the National Aspergillosis Centre in Manchester and 150 healthy volunteers. They found that the test had improved sensitivity (91.6%) and specificity (98.0%) for diagnosis of CPA in UK patients compared to existing diagnostic tests.

Limitations of current diagnostic procedures include high cost, long turn-around times, poor reproducibility and variations in performance. The new test is cheap, fast, reproducible and reliable. Therefore it is particularly useful in low to middle income countries where CPA diagnostics are a necessity for early recognition of CPA complicating TB, and to distinguish between these similarly presenting conditions.

Professor David Denning, Professor of Infectious Diseases in Global Health at the University of Manchester and Director of the National Aspergillosis Centre at the Manchester University NHS Foundation Trust said:

“With over 7 million people suffering TB in the lungs each year and 5-10% of them later getting the fungal infection aspergillosis in the lungs, a simple cost-effective test for aspergillosis is sorely needed. This new test fulfils these basic requirements and we are delighted to report that its diagnostic performance surpasses all the older tests as well. A real win-win for early diagnosis and reducing lung scarring and death.” 

The findings were published this month in the Journal of Clinical Microbiology.

Citation:

Evaluation of LD Bio Aspergillus ICT lateral flow assay for IgG and IgM antibody detection in chronic pulmonary aspergillosis. Elizabeth Stucky Hunter, Malcolm D. Richardson, David W. Denning. Journal of Clinical Microbiology Jun 2019, JCM.00538-19; DOI: 10.1128/JCM.00538-19

Read the paper!

Breathe journal June 2019 – ‘Living well with a Chronic Respiratory Disease’

The current issue of the European Respiratory Society’s journal, Breathe, focuses on living well with a chronic respiratory disease, and includes an article from an ABPA patient. Links to this patient voice article, and other pieces which may be of interest to aspergillosis patients are highlighted below.

Introduction: Living well with a chronic respiratory disease

Chief Editor, Claudia Dobler, introduces this issue in a short editorial. This covers a number of the burdens that lung disease patients can face, and the various ways in which they can achieve well-being and adjust to their circumstances in the face of chronic illness.

Living with allergic bronchopulmonary aspergillosis

Mike Chapman shares his experiences of living with ABPA and other respiratory problems. Many aspergillosis patients will identify with his experience of a lengthy and difficult journey to diagnosis, and trying to remain positive, despite debilitating health conditions.

Music and dance in chronic lung disease

This article covers the growing interest in using music and dance as part of a holistic approach to managing chronic lung disease. Several recent studies have focused on the benefits that music and dance have on the physical, mental and social health of those with chronic lung disease; this piece goes over some of this research, and the key gaps that are missing.

The role of cognitive behavioural therapy in living well with COPD

Anxiety and depression are common in people with chronic obstructive pulmonary disease and, as well as being major problems themselves, can interact with and worsen physical symptoms. This article again focuses on the holistic treatment of the patient, and suggests how we can incorporate CBT into routine care for those with COPD.

Where are the gaps in education in the field of rare lung disease? Perspectives from the ERN-LUNG educational programme survey

ERN-LUNG (the respiratory-focused European reference network) recently sent a survey out to healthcare professionals and patients to find out the gaps in rare lung disease education in Europe. From a patient’s perspective, a large majority thought that there was a need for patient education at a European level, but only just over a 3rd were aware of existing resources. 95% thought that patients had a role to play in the education of professionals. Read the article to see the key conclusions from the survey.

Click here to read the full journal

Aspergillus – Pseudomonas interactions; a match made in heaven or hell?

In the last years clinicians and researchers have realised that the interactions between microorganisms in polymicrobial infections (when a single patient is colonised/infected with two or more pathogens) are relevant for the progression of the disease. Contacts between pathogens can affect their fitness (how well they can grow inside us) and also impact on the response of our immune system. However, the research into this novel and extremely complex area is still in its infancy and we need to gain much more information before being able to understand what is going on in each specific condition. It is suspected that in some interactions the microorganisms may compete with each other, which is usually good for us. However, in other types of interactions the pathogens may help each other, which is of course detrimental for the patients. In the case of Aspergillus – Pseudomonas interaction it is still not completely clear which is taking place, a positive or a negative interaction.

Pseudomonas (mainly the species Pseudomonas aeruginosa) is a common bacterial pathogen and Aspergillus (mainly the species Aspergillus fumigatus) is the most common fungal pathogen of the human respiratory tract. Both organisms are able to grow in the lungs of immunosuppressed individuals and also of patients with certain underlying diseases, such as bronchiectasis, chronic obstructive pulmonary disease (COPD), hospital acquired pneumonia and cystic fibrosis. Since the awareness of the importance of polymicrobial infections is quite recent, there are not many reports of the incidence of co-infection with these two pathogens yet. One of the few, from the end of 2018, reported a prevalence of co-infection in cystic fibrosis patients of 15.8% (1). That means that almost sixteen percent of all cystic fibrosis patients may be co-infected with both Pseudomonas and Aspergillus… This is of course not trivial!

 Several studies carried out in various laboratories around the world would suggest that the interaction between Aspergillus and Pseudomonas is of competitive nature. That would indicate that they weaken each other during co-infection, which could mean good news for patients. However, there are also results, including some clinical evidence, that suggest the opposite, the pathogens could be helping each other in the human lungs. What seems clear is that having both pathogens is not good for the patients (2). Therefore, we need to understand how these microbes interact during co-infection to be able to decide which course of action is best, should we treat against both or only one? Which one first, or both at the same time?

To address these questions my research group, in the Manchester Fungal Infection Group, is trying to understand the specific interactions that take place between Aspergillus fumigatus and Pseudomonas aeruginosa under conditions that are similar to co-infection of the human lung.

We want to discover which interactions are the important ones. This will help us understand what is going on during co-infection and we can then use this knowledge to improve the management and treatment of patients.

Dr Jorge Amich | MRC Career Development Fellow

Manchester Fungal Infection Group (MFIG)

1. Zhao J, Cheng W, He X, Liu Y.2018. The co-colonization prevalence of Pseudomonas aeruginosa and Aspergillus fumigatus in cystic fibrosis: A systematic review and meta-analysis. Microb Pathog 125:122-128.

2. Reece E, Segurado R, Jackson A, McClean S, Renwick J, Greally P.2017. Co-colonisation with Aspergillus fumigatus and Pseudomonas aeruginosa is associated with poorer health in cystic fibrosis patients: an Irish registry analysis. BMC Pulm Med 17:70.

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