A sexual reproductive cycle is an important mechanism by which fungi to spread antifungal resistance genes, but it wasn't proven until 2009 that this could happen in Aspergillus fumigatus. However, mating took around 6-12 months in the lab for most strains ('supermater' strain could complete it in 4 weeks) and it was not known how common this process was among strains found in nature. Scientists from the University of Nottingham tested a collection of 131 isolates from around the world and found that 97% could mate successfully, although the number of fertile cleistothecia produced varied widely.
Opportunist Coinfections by Nontuberculous Mycobacteria and Fungi in Immunocompromised Patients (Joao et al, 2020)
Like Aspergillus, there is a group of bacteria called non-tuberculous mycobacteria (NTM, e.g. MAC) that are found commonly in the soil but can sometimes cause an opportunistic infection, mostly in immunocompromised people or those with damaged lungs (e.g. OPD, TB, bronchiectasis). NTM can cause coinfections with various fungi including Aspergillus, Candida, Cryptococcus and Histoplasma.
This new review summarises the evidence for coinfections between NTM and different species of fungi, and which treatments are effective in which cases. As this is a relatively new field, much of the currently available evidence is in the form of case studies. One of the main limitations is that it can be difficult to distinguish true NTM infections from colonisation, making it difficult to measure prevalence or recruit patients to studies.
Intestinal Aspergillosis:Systematic Review on Patterns of Clinical Presentation and Management (Yelika et al, 2020)
Invasive Aspergillus infections typically begin in the lungs, but can occasionally arise from within the digestive system in immunocompromised patients whose intestinal mucosa is damaged. Patients receiving both surgery and antifungals tend to have better outcomes but the overall mortality rate is high (around 40%), particularly if there is angioinvasion leading to rupture of the bowel. Many of the symptoms are non-specific (abdominal pain, diarrhoea, bleeding, distention) and blood cultures are generally negative, so diagnosis is often delayed (average ~9 days). The authors urge clinicians to keep a high index of suspicion for intestinal aspergillosis in immunocompromised patients, and suggest that the gold standard for diagnosis should be evidence of Aspergillus in histopathology samples or cultures taken from the affected site.
A new study from researchers at the University of Manchester has found that of 58 million COPD patients hospitalised each year around the world, around 2 million also develop invasive aspergillosis, which is almost always fatal if left untreated. The group estimated the prevalence of COPD (GOLD stages II-IV) as 7.4% of the global population (7.77% in Europe). They also found high rates of Aspergillus sensitisation (7-18%) but this did not appear to be related to a lower lung function (FEV1).
“Both IA and chronic pulmonary aspergillosis occur in COPD, but are really underdiagnosed. We hope that improved awareness of this problem will drive greater use of Aspergillus antigen and antibody testing as well as fungal culture of sputum.” - Professor Denning
New antifungals in clinical trials: olorofim
A new review in Journal of Fungi forms a handy guide to everything we know so far about the novel antifungal olorofim (formerly F901318, owned by F2G). Preclinical work showed that it is active against
Aspergillus (including azole-resistant strains) and many filamentous and endemic/dimorphic fungi, but not yeasts or Mucorales. An international Phase IIb trial (
FORMULA-OLS) is currently recruiting to measure its safety and efficacy for patients with invasive fungal infections who are lacking suitable alternative treatments.
This is a particularly exciting drug to follow because it comes from a new class of antifungals, the orotomides, which targets pyrimidine biosynthesis, unlike existing antifungals that target the fungal cell wall. To reflect the dire need for new antifungals, it is being accelerated through the approval process: last year it received breakthrough drug designation, and this year also received orphan drug designation (ODD) and qualified infectious disease product (QIDP), as well as $60.8 million in funding.
