Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03443336 |
| Other study ID # |
2017-00984; me17Khanna |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2017 |
| Est. completion date |
June 2, 2021 |
Study information
| Verified date |
June 2021 |
| Source |
University Hospital, Basel, Switzerland |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Prospective multi-center surveillance study on the prevalence of azole-resistant Aspergillus
spp. in clinical isolates of patients with pulmonary colonization or invasive infections in
Switzerland
Description:
Azole-resistance in Aspergillus (A.) fumigatus has emerged as a global health problem. Even
more, it has been associated with high mortality rates in patients with invasive
aspergillosis.
Generally, two routes of resistance development are distinguished either in patients with
chronic pulmonary aspergillosis under long-term azole therapy or in agriculture by the use of
azoles as fungicides.
The primary mechanisms of resistance that have been described in clinical strains include
different point mutations in the cyp51A gene, which encodes the enzyme responsible for
converting lanosterol to ergosterol via demethylation. Some resistant isolates also contain a
tandem repeat in the promoter region of this gene that causes increased expression. These
mutations, including TR34/L98H and TR46/Y121F/T289A have been identified in the environment
and have been demonstrated to cause resistance to azole fungicides used in agriculture. These
mutations were also recently identified in haematological patients suffering from invasive
aspergillosis and were associated with a mortality rate of 88%.
Studies on the frequency of azole resistance in Aspergillus culture collections report the
first resistant isolates up to 20 years earlier than clinical and environmental studies.
Since then, microbiological resistance to azoles and clinical failures associated with this
resistance have been reported in several countries in Europe and elsewhere. The United
Kingdom and the Netherlands have reported increases in azole-resistant A. fumigatus. In the
United Kingdom, a statistically significant increase in azole resistance was noted between
2004 and 2009, with rates of 5 to 7% in 2004 to 2006 increasing to up to 20% in 2009. These
isolates were collected primarily in patients who received long-term azole therapy for the
treatment of chronic pulmonary aspergillosis. The observation has increased the awareness of
azole resistance in this patient population. Surveillance studies and case series over the
last years suggest the global presence of azole resistance in A. fumigatus, including in
Europe, the Middle East, Asia, Africa, Australia and, most recently, North and South America.
Moreover, some cryptic species of Aspergillus section Fumigati (e.g. A. lentulus, A.
udagawae), which cannot be reliably distinguished from A. fumigatus by standard diagnostic
methods, account for 3-5% of all A. fumigatus sensu lato clinical isolates and exhibit some
level of intrinsic azole resistance. The proportion of these cryptic species in other
Aspergillus sections (e.g. Flavi, Nigri, Terrei) is relatively unexplored. In addition, some
rare Aspergillus species with intrinsic azole resistance, such as Aspergillus calidoustus
(section Usti) are emerging as opportunistic pathogens in patients receiving azole
prophylaxis. These cryptic or rare Aspergillus spp. are often misidentified because of the
lack of discrimination by standard microbiological methods. Thus, their actual clinical
relevance is unknown.
In Switzerland, comprehensive data on azole resistance in A. fumigatus are lacking. The major
reason for this is the lack of routine testing of in vitro susceptibility of A. fumigatus
isolates in most microbiology laboratories.
The Fungal Infections Network of Switzerland (FUNGINOS) offers an optimal platform to
comprehensively assess the epidemiology of azole-resistance in A. fumigates and other
Aspergillus spp. Only recently invasive Candida infections (candidemia) have been
prospectively monitored by FUNGINOS over ten years from 2004 to 2013 in all Swiss University
clinics and 20 University-affiliated hospitals.
