Imperial College London

DrDariusArmstrong-James

Faculty of MedicineDepartment of Infectious Disease

Reader in Infectious Diseases and Medical Mycology
 
 
 
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d.armstrong

 
 
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Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

85 results found

Shah A, Armstrong-James D, Chotirmall SH, 2021, Respiratory mycoses: a call to action to recognize, educate and invest., Mycopathologia, ISSN: 0301-486X

Journal article

Di Paolo M, Hewitt L, Nwankwo E, Ni M, Vidal-Diaz A, Fisher MC, Armstrong-James D, Shah Aet al., 2021, Erratum to: A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis., JAC Antimicrob Resist, Vol: 3

[This corrects the article DOI: 10.1093/jacamr/dlab026.].

Journal article

Arastehfar A, Carvalho A, Houbraken J, Lombardi L, Garcia-Rubio R, Jenks JD, Rivero-Menendez O, Aljohani R, Jacobsen ID, Berman J, Osherov N, Hedayati MT, Ilkit M, Armstrong-James D, Gabaldón T, Meletiadis J, Kostrzewa M, Pan W, Lass-Flörl C, Perlin DS, Hoenigl Met al., 2021, Aspergillus fumigatus and aspergillosis: From basics to clinics., Stud Mycol, Vol: 100, ISSN: 0166-0616

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP 51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP 51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them.

Journal article

Thompson GR, Le T, Chindamporn A, Kauffman CA, Alastruey-Izquierdo A, Ampel NM, Andes DR, Armstrong-James D, Ayanlowo O, Baddley JW, Barker BM, Lopes Bezerra L, Buitrago MJ, Chamani-Tabriz L, Chan JFW, Chayakulkeeree M, Cornely OA, Cunwei C, Gangneux J-P, Govender NP, Hagen F, Hedayati MT, Hohl TM, Jouvion G, Kenyon C, Kibbler CC, Klimko N, Kong DCM, Krause R, Lee Lee L, Meintjes G, Miceli MH, Rath P-M, Spec A, Queiroz-Telles F, Variava E, Verweij PE, Schwartz IS, Pasqualotto ACet al., 2021, Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology., Lancet Infect Dis

The global burden of the endemic mycoses (blastomycosis, coccidioidomycosis, emergomycosis, histoplasmosis, paracoccidioidomycosis, sporotrichosis, and talaromycosis) continues to rise yearly and these infectious diseases remain a leading cause of patient morbidity and mortality worldwide. Management of the associated pathogens requires a thorough understanding of the epidemiology, risk factors, diagnostic methods and performance characteristics in different patient populations, and treatment options unique to each infection. Guidance on the management of these infections has the potential to improve prognosis. The recommendations outlined in this Review are part of the "One World, One Guideline" initiative of the European Confederation of Medical Mycology. Experts from 23 countries contributed to the development of these guidelines. The aim of this Review is to provide an up-to-date consensus and practical guidance in clinical decision making, by engaging physicians and scientists involved in various aspects of clinical management.

Journal article

Denny S, Abdolrasouli A, Elamin T, Gonzalo X, Pallett S, Charani E, Patel A, Donaldson H, Hughes S, Armstrong-James D, Moore LS, Mughal Net al., 2021, A retrospective multicenter analysis of candidaemia among COVID-19 patients during the first UK pandemic wave, Journal of Infection, Vol: 82, Pages: 276-316, ISSN: 0163-4453

Journal article

Hughes DA, Archangelidi O, Coates M, Armstrong-James D, Elborn SJ, Carr SB, Davies JCet al., 2021, Clinical characteristics of Pseudomonas and Aspergillus co-infected cystic fibrosis patients: A UK registry study., J Cyst Fibros

BACKGROUND: Pseudomonas aeruginosa (Pa) and Aspergillus species (Asp) are the most common bacterial and fungal organisms respectively in CF airways. Our aim was to examine impacts of Asp infection and Pa/Asp co-infection. METHODS: Patients on the UK CF Registry in 2016 were grouped into: absent (Pa-), intermittent (Pai) or chronic Pa (Pac), each with Asp positive (Asp+) or negative (Asp-). Primary outcome was best percentage predicted FEV1 (ppFEV1) that year. Secondary outcomes were intravenous (IV) antibiotic courses, growth (height, weight, BMI) and additional disease complications. Associations between outcomes and infection-status were assessed using regression models adjusting for significant confounders (age, sex, Phe508del homozygosity and CF-related diabetes (CFRD)). RESULTS: 9,270 patients were included (median age 19 [IQR 9-30] years, 54% male, 50% Phe508del/F508del). 4,142 patients (45%) isolated Pa, 1,460 (16%) Asp. Pa-/Asp+ subjects had an adjusted ppFEV1 that was 5.9% lower than Pa-/Asp- (p < 0.0001). In patients with Pai or Pac, there was no additional impact of Asp on ppFEV1. However, there was a higher probability that Pac/Asp+ patients had required IV antibiotics than Pac/Asp- group (OR 1.23 [1.03-1.48]). Low BMI, ABPA, CF-liver disease and CFRD were all more frequent with Asp alone than Pa-/Asp-, though not more common in Pac/Asp+ than Pac/Asp-. CONCLUSIONS: Co-infection with Pa and Asp was not associated with reduced lung function compared with Pa alone, but was associated with additional use of IV antibiotics. Asp infection itself is associated with several important indicators of disease severity. Longitudinal analyses should explore the impact of co-infection on disease progression.

Journal article

Arkell P, Mahboobani S, Wilson R, Fatania N, Coleman M, Borman AM, Johnson EM, Armstrong-James DPH, Abdolrasouli Aet al., 2021, Bronchoalveolar lavage fluid IMMY Sona Aspergillus lateral-flow assay for the diagnosis of invasive pulmonary aspergillosis: a prospective, real life evaluation, MEDICAL MYCOLOGY, Vol: 59, Pages: 404-408, ISSN: 1369-3786

Journal article

Williams TJ, Gonzales-Huerta LE, Armstrong-James D, 2021, Fungal-induced programmed cell death, Journal of Fungi, Vol: 7, Pages: 1-15, ISSN: 2309-608X

Fungal infections are a cause of morbidity in humans, and despite the availability of a range of antifungal treatments, the mortality rate remains unacceptably high. Although our knowledge of the interactions between pathogenic fungi and the host continues to grow, further research is still required to fully understand the mechanism underpinning fungal pathogenicity, which may provide new insights for the treatment of fungal disease. There is great interest regarding how microbes induce programmed cell death and what this means in terms of the immune response and resolution of infection as well as microbe-specific mechanisms that influence cell death pathways to aid in their survival and continued infection. Here, we discuss how programmed cell death is induced by fungi that commonly cause opportunistic infections, including Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans, the role of programmed cell death in fungal immunity, and how fungi manipulate these pathways.

Journal article

Di Paolo M, Hewitt L, Nwanko E, Ni M, Vidal-Diaz A, Fisher MC, Armstrong-James D, Shah Aet al., 2021, A retrospective 'real-world' cohort study of azole therapeutic drug monitoring and evolution of antifungal resistance in cystic fibrosis., JAC Antimicrob Resist, Vol: 3

Background: Individuals with cystic fibrosis (CF) have an increased susceptibility to fungal infection/allergy, with triazoles often used as first-line therapy. Therapeutic drug monitoring (TDM) is essential due to significant pharmacokinetic variability and the recent emergence of triazole resistance worldwide. Objectives: In this retrospective study we analysed the 'real-world' TDM of azole therapy in a large CF cohort, risk factors for subtherapeutic dosing, and the emergence of azole resistance. Methods: All adults with CF on azole therapy in a large single UK centre were included. Clinical demographics, TDM and microbiology were analysed over a 2 year study period (2015-17) with multivariate logistic regression used to identify risk factors for subtherapeutic dosing. Results: 91 adults were treated with azole medication during the study period. A high prevalence of chronic subtherapeutic azole dosing was seen with voriconazole (60.8%) and itraconazole capsule (59.6%) use, representing significant risk factors for subtherapeutic levels. Rapid emergence of azole resistance was additionally seen over the follow-up period with a 21.4% probability of CF patients developing a resistant fungal isolate after 2 years. No significant relationship was found however between subtherapeutic azole dosing and azole resistance emergence. Conclusions: Our study demonstrates a high prevalence of subtherapeutic azole levels in CF adults with increased risk using itraconazole capsules and voriconazole therapy. We show rapid emergence of azole resistance highlighting the need for effective antifungal stewardship. Further large longitudinal studies are needed to understand the effects of antifungal resistance on outcome in CF and the implications of subtherapeutic dosing on resistance evolution.

Journal article

Periselneris J, Schelenz S, Loebinger M, Macedo P, Adhya Z, Armstrong-James D, Kelleher WPet al., 2021, Bronchiectasis severity correlates with outcome in patients with primary antibody deficiency., Thorax

Bronchiectasis is a well-recognised complication of primary antibody deficiency (PAD) syndromes. Previous data suggest that mortality in common variable immune deficiency (CVID) is not associated with isolated bronchiectasis. A retrospective analysis of patients with CVID and specific antibody deficiency in two tertiary referral centres with lung disease was conducted. Severity of bronchiectasis at presentation was associated with mortality. Lower FEV1, colonisation with Pseudomonas aeruginosa and a diagnosis of COPD were also associated with mortality. Bronchiectasis is an important driver of mortality in patients with PAD syndromes.

Journal article

Klionsky DJ, Abdel-Aziz AK, Abdelfatah S, Abdellatif M, Abdoli A, Abel S, Abeliovich H, Abildgaard MH, Abudu YP, Acevedo-Arozena A, Adamopoulos IE, Adeli K, Adolph TE, Adornetto A, Aflaki E, Agam G, Agarwal A, Aggarwal BB, Agnello M, Agostinis P, Agrewala JN, Agrotis A, Aguilar P, Ahmad ST, Ahmed ZM, Ahumada-Castro U, Aits S, Aizawa S, Akkoc Y, Akoumianaki T, Akpinar HA, Al-Abd AM, Al-Akra L, Al-Gharaibeh A, Alaoui-Jamali MA, Alberti S, Alcocer-Gomez E, Alessandri C, Ali M, Al-Bari MAA, Aliwaini S, Alizadeh J, Almacellas E, Almasan A, Alonso A, Alonso GD, Altan-Bonnet N, Altieri DC, Alves S, da Costa CA, Alzaharna MM, Amadio M, Amantini C, Amaral C, Ambrosio S, Amer AO, Ammanathan V, An Z, Andersen SU, Andrabi SA, Andrade-Silva M, Andres AM, Angelini S, Ann D, Anozie UC, Ansari MY, Antas P, Antebi A, Anton Z, Anwar T, Apetoh L, Apostolova N, Araki T, Araki Y, Arasaki K, Araujo WL, Araya J, Arden C, Arevalo M-A, Arguelles S, Arias E, Arikkath J, Arimoto H, Ariosa AR, Armstrong-James D, Arnaune-Pelloquin L, Aroca A, Arroyo DS, Arsov I, Artero R, Asaro DML, Aschner M, Ashrafizadeh M, Ashur-Fabian O, Atanasov AG, Au AK, Auberger P, Auner HW, Aurelian L, Autelli R, Avagliano L, Avalos Y, Aveic S, Aveleira CA, AvinWittenberg T, Aydin Y, Ayton S, Ayyadevara S, Azzopardi M, Baba M, Backer JM, Backues SK, Bae D-H, Bae O-N, Bae SH, Baehrecke EH, Baek A, Baek S-H, Baek SH, Bagetta G, Bagniewska-Zadworna A, Bai H, Bai J, Bai X, Bai Y, Bairagi N, Baksi S, Balbi T, Baldari CT, Balduini W, Ballabio A, Ballester M, Balazadeh S, Balzan R, Bandopadhyay R, Banerjee S, Banerjee S, Bao Y, Baptista MS, Baracca A, Barbati C, Bargiela A, Barila D, Barlow PG, Barmada SJ, Barreiro E, Barreto GE, Bartek J, Bartel B, Bartolome A, Barve GR, Basagoudanavar SH, Bassham DC, Jr RCB, Basu A, Batoko H, Batten I, Baulieu EE, Baumgarner BL, Bayry J, Beale R, Beau I, Beaumatin F, Bechara LRG, Beck GR, Beers MF, Begun J, Behrends C, Behrens GMN, Bei R, Bejarano E, Bel S, Behl C, Belaid A, Belgareh-Touzeet al., 2021, Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition), Autophagy, Vol: 17, Pages: 1-382, ISSN: 1554-8627

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Journal article

Murray A, Cass L, Ito K, Pagani N, Armstrong-James D, Dalal P, Reed A, Strong Pet al., 2020, PC945, a Novel Inhaled Antifungal Agent, for the Treatment of Respiratory Fungal Infections, JOURNAL OF FUNGI, Vol: 6

Journal article

Williams TJ, Harvey S, Armstrong-James D, 2020, Immunotherapeutic approaches for fungal infections, CURRENT OPINION IN MICROBIOLOGY, Vol: 58, Pages: 130-137, ISSN: 1369-5274

Journal article

Pagani N, Armstrong-James D, Reed A, 2020, Successful salvage therapy for fungal bronchial anastomotic infection after -lung transplantation with an inhaled triazole anti-fungal PC945., J Heart Lung Transplant, Vol: 39, Pages: 1505-1506

Journal article

Nuh A, Ramadan N, Schelenz S, Armstrong-James Det al., 2020, Comparative Evaluation of MIRONAUT-AM and CLSI broth microdilution method for antifungal susceptibility testing of Aspergillus species against four commonly used antifungals, MEDICAL MYCOLOGY, Vol: 58, Pages: 1085-1090, ISSN: 1369-3786

Journal article

Armstrong-James D, Youngs J, Bicanic T, Abdolrasouli A, Denning DW, Johnson E, Mehra V, Pagliuca T, Patel B, Rhodes J, Schelenz S, Shah A, van de Veerdonk FL, Verweij PE, White PL, Fisher MCet al., 2020, Confronting and mitigating the risk of COVID-19 Associated Pulmonary Aspergillosis (CAPA), European Respiratory Journal, Vol: 56, Pages: 1-10, ISSN: 0903-1936

Cases of COVID-19 associated pulmonary aspergillosis (CAPA) are being increasingly reported and physicians treating patients with COVID-19-related lung disease need to actively consider these fungal co-infections.The SARS-CoV-2 (COVID-19) virus causes a wide spectrum of disease in healthy individuals as well as those with common comorbidities [1]. Severe COVID-19 is characterised acute respiratory distress syndrome (ARDS) secondary to viral pneumonitis, treatment of which may require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) [2]. Clinicians are alert to the possibility of bacterial co-infection as a complication of lower respiratory tract viral infection; for example a recent review found that 72% of patients with COVID-19 received antimicrobial therapy [3]. However, the risk of fungal co-infection, in particular COVID-19 associated pulmonary aspergillosis (CAPA), remains underappreciated.Fungal disease consistent with invasive aspergillosis (IA) has been observed with other severe Coronaviruses such as Severe Acute Respiratory Syndrome (SARS-CoV-2003) [4, 5] and Middle East Respiratory Syndrome (MERS-CoV) [6]. From the outset of the COVID-19 pandemic, there were warning signs of secondary invasive fungal infection; Aspergillus flavus was isolated from the respiratory tract from one of 99 patients in the first COVID-19 cohort from Wuhan to be reported in any detail [2] and Aspergillus spp. were isolated from 2/52 (3.8%) of a subsequent cohort of critically unwell patients from this region [7]. More recently, retrospective case series from Belgium [8], France [9], The Netherlands [10] and Germany [11] have reported evidence of CAPA in an alarming 20–35% of mechanically ventilated patients.

Journal article

Armstrong-James D, Koh M, Ostermann M, Cockwell Pet al., 2020, Optimal management of acute kidney injury in critically ill patients with invasive fungal infections being treated with liposomal amphotericin B., BMJ Case Rep, Vol: 13

Critically ill patients are at risk of developing both acute kidney injury (AKI) and invasive fungal infections (IFIs). Prompt and efficient treatment of the IFI is essential for the survival of the patient. This article examines three distinct clinical situations where liposomal amphotericin B, a broad-spectrum antifungal agent, was successfully used in the setting of AKI. The first was Aspergillus infection in a 63-year-old man with bleeding oesophageal varices related to advanced liver disease. The second was gastrointestinal mucormycosis in a 74-year-old man who developed a small bowel obstruction following an autologous stem cell transplant for mantle cell lymphoma. The third was a Fusarium infection in a 32-year-old woman on immunosuppression for a bilateral lung transplant for cystic fibrosis. In all three cases, liposomal amphotericin B was required for urgent management of the patient's IFI. We discuss the rationale for treatment with a potentially nephrotoxic agent in this setting.

Journal article

Chua F, Armstrong-James D, Desai SR, Barnett J, Kouranos V, Kon OM, Jose R, Vancheeswaran R, Loebinger MR, Wong J, Cutino-Moguel MT, Morgan C, Ledot S, Lams B, Yip WH, Li L, Lee YC, Draper A, Kho SS, Renzoni E, Ward K, Periselneris J, Grubnic S, Lipman M, Wells AU, Devaraj Aet al., 2020, The role of CT in case ascertainment and management of COVID-19 pneumonia in the UK: insights from high-incidence regions, The Lancet Respiratory Medicine, Vol: 8, Pages: 438-440, ISSN: 2213-2600

Journal article

Vakili M, Aliyali M, Mortezaee V, Mahdaviani SA, Poorabdollah M, Mirenayat MS, Fakharian A, Hassanzad M, Abastabar M, Yazdani Charati J, Haghani I, Tavakoli M, Maleki M, Armstrong-James D, Hedayati MTet al., 2020, Relationship between spirometry results and colonisation of Aspergillus species in allergic asthma., Clin Respir J

INTRODUCTION AND OBJECTIVES: Exposure to fungi in patients with asthma leads to the release of various fungal antigens, which can increase the severity of asthma. Regarding this, the present study was conducted to evaluate the relationship between the colonisation of Aspergillus species and spirometry results in allergic asthma. MATERIALS AND METHODS: Two hundred sixteen patients with mild to severe asthma and 30 healthy controls were included. All participants underwent pulmonary function tests. Furthermore, sputum samples were collected from each subject. Each sputum sample was subjected to direct microscopic examination and fungal culture. All cultured Aspergillus colonies were identified at species level by molecular methods. Finally, all available data from sputum culture and spirometry test were analysed. RESULTS: Out of 216 sputum samples, 145 (67.1%) were positive for fungal growth. Furthermore, out of 264 grown fungal colonies, 137 (51.9%) were Aspergillus species. Among the Aspergillus isolates, A. flavus (29.2%) was the most prevalent species, followed by A. fumigatus (27.7%). The mean forced expiratory volume in one second (FEV1) in the mild, moderate and severe asthmatic patients with a positive sputum culture for fungi were obtained as 90.0 ± 11.1, 71.1 ± 15.9 and 54.9 ± 16.4, respectively. In general, Aspergillus species colonisation had no statistically significant effect on spirometry results of study patients. CONCLUSION: Our results showed that there is no difference in the FEV1 and forced vital capacity between Aspergillus positive and negative patients in any asthma severity group.

Journal article

Currie AJ, Main ET, Wilson HM, Armstrong-James D, Warris Aet al., 2020, CFTR Modulators Dampen Aspergillus-Induced Reactive Oxygen Species Production by Cystic Fibrosis Phagocytes., Front Cell Infect Microbiol, Vol: 10

Excessive inflammation by phagocytes during Aspergillus fumigatus infection is thought to promote lung function decline in CF patients. CFTR modulators have been shown to reduce A. fumigatus colonization in vivo, however, their antifungal and anti-inflammatory mechanisms are unclear. Other treatments including azithromycin and acebilustat may dampen Aspergillus-induced inflammation due to their immunomodulatory properties. Therefore, we set out in this study to determine the effects of current CF therapies on ROS production and fungal killing, either direct or indirect by enhancing antifungal immune mechanisms in peripheral blood immune cells from CF patients upon A. fumigatus infection. Isolated peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from CF patients and healthy volunteers were challenged with A. fumigatus following pre-treatment with CFTR modulators, azithromycin or acebilustat. Ivacaftor/lumacaftor treated CF and control subject PMNs resulted in a significant reduction (p < 0.05) in Aspergillus-induced ROS. For CF PBMC, Aspergillus-induced ROS was significantly reduced when pre-treated with ivacaftor alone (p < 0.01) or in combination with lumacaftor (p < 0.01), with a comparable significant reduction in control subject PBMC (p < 0.05). Azithromycin and acebilustat had no effect on ROS production by CF or control subject phagocytes. None of the treatments showed an indirect or direct antifungal activity. In summary, CFTR modulators have potential for additional immunomodulatory benefits to prevent or treat Aspergillus-induced inflammation in CF. The comparable effects of CFTR modulators observed in phagocytes from control subjects questions their exact mechanism of action.

Journal article

Rudramurthy SM, Colley T, Abdolrasouli A, Ashman J, Dhaliwal M, Kaur H, Armstrong-James D, Strong P, Rapeport G, Schelenz S, Ito K, Chakrabarti Aet al., 2019, In vitro antifungal activity of a novel topical triazole PC945 against emerging yeast Candida auris, Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 2943-2949, ISSN: 0305-7453

ObjectivesManagement of Candida auris infection is difficult as this yeast exhibits resistance to different classes of antifungals, necessitating the development of new antifungals. The aim of this study was to investigate the susceptibility of C. auris to a novel antifungal triazole, PC945, optimized for topical delivery.MethodsA collection of 50 clinical isolates was obtained from a tertiary care hospital in North India. Nine isolates from the UK, 10 from a CDC panel (USA) and 3 from the CBS-KNAW culture collection (Japanese and South Korean isolates) were also obtained. MICs (azole endpoint) of PC945 and other triazoles were determined in accordance with CLSI M27 (third edition). Quality control strains were included [Candida parapsilosis (ATCC 22019) and Candida krusei (ATCC 6258)].ResultsSeventy-four percent of isolates tested showed reduced susceptibility to fluconazole (≥64 mg/L). PC945 (geometric mean MIC = 0.058 mg/L) was 7.4-fold and 1.5-fold more potent than voriconazole and posaconazole, respectively (both P < 0.01). PC945 MIC values correlated with those of voriconazole or posaconazole, and only three isolates were found to be cross-resistant between PC945 and other azoles. ERG11 sequence analysis revealed several mutations, but no correlation could be established with the MIC of PC945. Tentative epidemiological cut-off values (ECOFFs) evaluated by CLSI’s ECOFF Finder (at 99%) with 24 h reading of MICs were 1, 4 and 1 mg/L for PC945, voriconazole and posaconazole, respectively. MIC values for quality control strains of all triazoles were in the normal ranges.ConclusionsPC945 was found to be a more potent inhibitor than posaconazole, voriconazole and fluconazole of C. auris isolates collected globally, warranting further laboratory and clinical evaluations.

Journal article

Budden KF, Shukla SD, Rehman SF, Bowerman KL, Keely S, Hugenholtz P, Armstrong-James DPH, Adcock IM, Chotirmall SH, Chung KF, Hansbro PMet al., 2019, Functional effects of the microbiota in chronic respiratory disease, Lancet Respiratory Medicine, Vol: 7, Pages: 907-920, ISSN: 2213-2600

The composition of the lung microbiome is increasingly well characterised, with changes in microbial diversity or abundance observed in association with several chronic respiratory diseases such as asthma, cystic fibrosis, bronchiectasis, and chronic obstructive pulmonary disease. However, the precise effects of the microbiome on pulmonary health and the functional mechanisms by which it regulates host immunity are only now beginning to be elucidated. Bacteria, viruses, and fungi from both the upper and lower respiratory tract produce structural ligands and metabolites that interact with the host and alter the development and progression of chronic respiratory diseases. Here, we review recent advances in our understanding of the composition of the lung microbiome, including the virome and mycobiome, the mechanisms by which these microbes interact with host immunity, and their functional effects on the pathogenesis, exacerbations, and comorbidities of chronic respiratory diseases. We also describe the present understanding of how respiratory microbiota can influence the efficacy of common therapies for chronic respiratory disease, and the potential of manipulation of the microbiome as a therapeutic strategy. Finally, we highlight some of the limitations in the field and propose how these could be addressed in future research.

Journal article

Periselneris J, Nwankwo L, Schelenz S, Shah A, Armstrong-James Det al., 2019, Posaconazole for the treatment of allergic bronchopulmonary aspergillosis in patients with cystic fibrosis., Journal of Antimicrobial Chemotherapy, Vol: 74, Pages: 1701-1703, ISSN: 0305-7453

OBJECTIVES: Allergic bronchopulmonary aspergillosis (ABPA) can accelerate lung function decline in patients with cystic fibrosis (CF). Antifungal medication can be used in addition to systemic corticosteroid treatment. PATIENTS AND METHODS: We evaluated Aspergillus-specific IgE and the use of therapeutic drug monitoring of triazoles in a retrospective analysis of 32 patients. RESULTS: There was a significant reduction in Aspergillus IgE with posaconazole but not with other triazoles (P = 0.026). Aspergillus IgE levels were inversely correlated with the therapeutic drug level of posaconazole. CONCLUSIONS: These data suggest that posaconazole is better than comparator azoles at decreasing serological response to Aspergillus and that this response was better with therapeutic levels of posaconazole.

Journal article

Eades CP, Armstrong-James DPH, 2019, Invasive fungal infections in the immunocompromised host: Mechanistic insights in an era of changing immunotherapeutics, Medical Mycology, Vol: 57, Pages: S307-S317, ISSN: 1369-3786

The use of cytotoxic chemotherapy in the treatment of malignant and inflammatory disorders is beset by considerable adverse effects related to nonspecific cytotoxicity. Accordingly, a mechanistic approach to therapeutics has evolved in recent times with small molecular inhibitors of intracellular signaling pathways involved in disease pathogenesis being developed for clinical use, some with unparalleled efficacy and tolerability. Nevertheless, there are emerging concerns regarding an association with certain small molecular inhibitors and opportunistic infections, including invasive fungal diseases. This is perhaps unsurprising, given that the molecular targets of such agents play fundamental and multifaceted roles in orchestrating innate and adaptive immune responses. Nevertheless, some small molecular inhibitors appear to possess intrinsic antifungal activity and may therefore represent novel therapeutic options in future. This is particularly important given that antifungal resistance is a significant, emerging concern. This paper is a comprehensive review of the state-of-the-art in the molecular immunology to fungal pathogens as applied to existing and emerging small molecular inhibitors.

Journal article

Warris A, Bercusson A, Armstrong-James D, 2019, Aspergillus colonization and antifungal immunity in cystic fibrosis patients., Med Mycol, Vol: 57, Pages: S118-S126

Cystic fibrosis (CF), caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, is the most common inherited life-limiting disease in North European people affecting 90,000 people worldwide. Progressive lung damage caused by recurrent infection and chronic airway inflammation is the major determinant of survival with a median age at death of 29 years. Approximately 60% of CF patients are infected with Aspergillus fumigatus, a ubiquitous environmental fungus, and its presence has been associated with accelerated lung function decline. Half of the patients infected with Aspergillus are <18 years of age. Yet time of acquisition of this fungus and determinants of CF-related Aspergillus disease severity and progression are not known. CFTR expression has been demonstrated in cells of the innate and adaptive immune system and has shown to be critical for normal function. Research delineating the role of CFTR-deficient phagocytes in Aspergillus persistence and infection in the CF lung, has only recently received attention. In this concise review we aim to present the current understanding with respect to when people with CF acquire infection with A. fumigatus and antifungal immune responses by CF immune cells.

Journal article

Yu L-S, Rodriguez-Manzano J, Malpartida-Cardenas K, Sewell T, Bader O, Armstrong-James D, Fisher MC, Georgiou Pet al., 2019, Rapid and sensitive detection of azole-resistant Aspergillus fumigatus by tandem-repeat loop-mediated isothermal amplification, Journal of Molecular Diagnostics, Vol: 21, Pages: 286-295, ISSN: 1525-1578

Invasive human fungal infections caused by multi-azole resistant Aspergillus fumigatus are associated with increasing rates of mortality in susceptible patients. Current methods of diagnosing infections caused by multi-azole resistant A. fumigatus are, however, not well suited for use in clinical point-of-care testing or in the field. Loop-mediated isothermal amplification (LAMP) is a widely used method of nucleic acid amplification with rapid and easy-to-use features, making it suitable for use in different resource settings. Here, we developed a LAMP assay to detect a 34 bp tandem repeat, named TR34-LAMP. TR34 is a high-prevalence allele that, in conjunction with the L98H single nucleotide polymorphism, is associated with the occurrence of multi-azole resistance in A. fumigatus in the environment and in patients. This process was validated with both synthetic double stranded DNA and genomic DNA prepared from azole-resistant isolates of A. fumigatus. Use of our assay resulted in rapid and specific identification of the TR34 allele with high sensitivity, detecting down to 10 genomic copies per reaction within 25 minutes. Fluorescent and colorimetric detections were used for the analysis of 11 clinical isolates as cross validation. These results show that the TR34-LAMP assay has the potential to accelerate the screening of clinical and environmental A. fumigatus to provide a rapid and accurate diagnosis of azole resistance, which current methods struggle to achieve.

Journal article

Abdolrasouli A, Scourfield A, Rhodes J, Shah A, Elborn JS, Fisher MC, Schelenz S, Armstrong-James Det al., 2018, High prevalence of triazole resistance in clinical Aspergillus fumigatus isolates in a specialist cardiothoracic centre, International Journal of Antimicrobial Agents, Vol: 52, Pages: 637-642, ISSN: 0924-8579

OBJECTIVES: To evaluate the prevalence of triazole-resistant Aspergillus fumigatus and common molecular cyp51A polymorphisms amongst clinical isolates in a specialised cardiothoracic centre in London, UK. METHODS: All A. fumigatus isolates were prospectively analysed from April 2014 to March 2016. Isolates were screened with a four-well VIPcheck™ plate to assess triazole susceptibility. Resistance was confirmed with a standard microbroth dilution method according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines. Triazole-resistant A. fumigatus isolates were subjected to a mixed-format real time polymerase chain reaction (RT-PCR) assay (AsperGenius®) to detect common cyp51A alterations. RESULTS: We identified 167 clinical A. fumigatus isolates from 135 patients. Resistance to at least one azole antifungal drug was confirmed in 22/167 (13.2%) of isolates from 18/135 (13.3%) patients, including 12/74 (16.2%) patients with cystic fibrosis (CF). The highest detection rate of azole-resistant A. fumigatus was among the 11- to 20-y age group. All triazole-resistant isolates (n = 22) were resistant to itraconazole, 18 showed cross-resistance to posaconazole and 10 displayed reduced susceptibility to voriconazole. No pan-azole-resistant A. fumigatus was identified. TR34/L98H was identified in 6/22 (27.3%) of azole-resistant isolates and detectable in 5/12 (42%) patients with CF. CONCLUSIONS: In our specialist cardiothoracic centre, the prevalence of triazole-resistant A. fumigatus is alarmingly high (13.2%). The majority of azole-resistant isolates were from patients with CF. We found a higher prevalence of the environmentally driven mutation TR34/L98H in our A. fumigatus isolates than in published UK data from other specialist respiratory centres, which may reflect differing patient populations managed at these institutions.

Journal article

Santiago V, Rezvani K, Sekine T, Stebbing J, Kelleher P, Armstrong-James Det al., 2018, Human NK cells develop an exhaustion phenotype during polar degranulation at the aspergillus fumigatus hyphal synapse, Frontiers in Immunology, Vol: 9, ISSN: 1664-3224

Pulmonary aspergillosis is an opportunistic fungal infection affecting immunocompromised individuals. Increasing understanding of natural killer (NK) cell immunobiology has aroused considerable interest around the role of NK cells in pulmonary aspergillosis in the immunocompromised host. Murine studies indicate that NK cells play a critical role in pulmonary clearance of A. fumigatus. We show that the in vitro interaction between NK cells and A. fumigatus induces partial activation of NK cell immune response, characterised by low-level production of IFN-γ, TNF-α, MIP-1α, MIP-1β, and RANTES, polarisation of lytic granules and release of fungal DNA. We observed a contact-dependent down-regulation of activatory receptors NKG2D and NKp46 on the NK cell surface, and a failure of full granule release. Furthermore, the NK cell cytokine-mediated response to leukaemic cells was impaired in the presence of A. fumigatus. These observations suggest that A. fumigatus-mediated NK cell immunoparesis may represent an important mechanism of immune evasion during pulmonary aspergillosis.

Journal article

Nwankwo L, Periselneris J, Cheong J, Thompson K, Darby P, Leaver N, Schelenz S, Armstrong-James Det al., 2018, Impact of an antifungal stewardship programme in a tertiary respiratory medicine setting: a prospective real-world study, Antimicrobial Agents and Chemotherapy, Vol: 62, ISSN: 0066-4804

There has been an increase in fungal infections in patients with chronic lung disease over the past decades, which is associated with rapidly increasing costs to healthcare systems.An antifungal stewardship team was introduced to a tertiary cardiopulmonary hospital, consisting of a medical mycologist and pharmacy support providing weekly stewardship ward rounds, twice monthly multidisciplinary team meetings and a dedicated weekly outpatient clinic. A database was set up to record the activity of the stewardship team.During the first eighteen months of implementation the antifungal stewardship team had reviewed 178 patients, with 285 recommendations made to inpatients, and 287 outpatient visits. The commonest diagnoses treated were allergic bronchopulmonary aspergillosis and chronic pulmonary aspergillosis. Cystic fibrosis was the largest patient group treated followed by asthma and interstitial lung disease. There was a significant, sustained reduction in monthly antifungal expenditure (p=0.005) by £130,000 per month. There was also a significant reduction in antifungal use measured as Defined Daily Dose/100 bed days (p=0.017). There were no significant changes in expenditure on diagnostic tests. There has been a trend toward more patients having therapeutic levels of voriconazole (p=0.086) and a significant increase in therapeutic levels of posaconazole (p<0.0001).This study shows that an effective antifungal stewardship programme can significantly reduce expenditure in a specialist respiratory service.

Journal article

Abdolrasouli A, Petrou MA, Park H, Rhodes J, Rawson T, Moore L, Donaldson H, Holmes A, Fisher M, Armstrong-James Det al., 2018, Surveillance for azole-resistant Aspergillus fumigatus in a centralized diagnostic mycology service, London, United Kingdom, 1998-2017, Frontiers in Microbiology, Vol: 9, ISSN: 1664-302X

Background/Objectives: Aspergillus fumigatus is the leading cause of invasive aspergillosis. Treatment is hindered by the emergence of resistance to triazole antimycotic agents. Here, we present the prevalence of triazole resistance among clinical isolates at a major centralized medical mycology laboratory in London, United Kingdom, in the period 1998–2017.Methods: A large number (n = 1469) of clinical A. fumigatus isolates from unselected clinical specimens were identified and their susceptibility against three triazoles, amphotericin B and three echinocandin agents was carried out. All isolates were identified phenotypically and antifungal susceptibility testing was carried out by using a standard broth microdilution method.Results: Retrospective surveillance (1998–2011) shows 5/1151 (0.43%) isolates were resistant to at least one of the clinically used triazole antifungal agents. Prospective surveillance (2015–2017) shows 7/356 (2.2%) isolates were resistant to at least one triazole antifungals demonstrating an increase in incidence of triazole-resistant A. fumigatus in our laboratory. Among five isolates collected from 2015 to 2017 and available for molecular testing, three harbored TR34/L98H alteration in the cyp51A gene that are associated with the acquisition of resistance in the non-patient environment.Conclusion: These data show that historically low prevalence of azole resistance may be increasing, warranting further surveillance of susceptible patients.

Journal article

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