■ REPORT

Tackling the growing problem of antifungal resistance

STEVE TITMARSH

Until relatively recently, resistance to antifungal drugs has gone largely unreported in mainstream media, unlike the extensive coverage of resistance to antibiotics. However, we are now being warned that the consequences of antifungal resistance for human health, as well as our food supplies, could be serious unless action is taken. Here, we look at the extent of the problem and what is being done to combat it.

Figure 1. Aspergillus . At least 1.4 million people worldwide die as a result of infection by Candida, Aspergillus, Pneumocystis and Cryptococcus species ntifungal resistance has not received in May 2018 via a BBC report2 on a review Athe same level of attention in recent published in Science,3 which proposed years that has been seen with resist- that the widespread use of azoles for ani- ance to antibiotics and yet the existence mal healthcare and crop protection, for of resistant fungal species, particularly example, as well as for human healthcare those affecting immunocompromised may have contributed to the emergence of patients, has been discussed in the resistant fungal species. medical literature for more than two dec- The review, authored by an inter- ades.1 national group of researchers, led by The risk of fungal infection has risen Professor Matthew Fisher from the over recent years, in part as a result of Medical Research Council Centre for increasingly complex medical procedures, Global Infectious Disease Analysis, in particularly transplant surgery, which the School of Public Health at Imperial usually require patients to be immuno- College, London, is less than optimistic suppressed; the elderly and people with about the prospects for a world where cancer or HIV are also at greater risk. food supplies and health are threatened The issue of antifungal resistance and by multidrug-resistant pathogenic fungi its potential implications was brought to and antibiotic-resistant bacteria. They say the attention of the wider public in the UK that “crop-destroying fungi account for

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perennial yield losses of approximately 20% worldwide, with a further 10% loss post-harvest. Fungal effects on human health are currently spiralling, and the global mortality rate for fungal diseases now exceeds that for malaria or breast cancer and is comparable to those for tuberculosis and HIV”.3 Worldwide it is estimated that at least 1.4 million people die as a result of infection by Candida, Aspergillus (see Figure 1), Pneumocystis and Cryptococcus species.4 Use of antifungals for prophylactic treatment of at-risk patients over long periods is thought to be another of the factors that have contributed to the development of antifungal resistance.

Pockets of resistance Until recently, monitoring of antifungal resistance has not been a priority. The Figure 2. The proportion of Candida albicans specimens showing reduced susceptibility to focus of attention in the first English fluconazole and echinocandins has been rising over the past few years Surveillance Programme for Antimicrobial Samples from Public Health (14/210) of samples showed reduced Utilisation and Resistance (ESPAUR) England’s National Mycology Reference susceptibility to fluconazole and 2.2% report in 2014, for example, was firmly Laboratory (MRL; tested using Clinical (2/91) showed reduced susceptibility to on antibiotics (although the report did and Laboratory Standards Institute echinocandins. Thus far, no sample has acknowledge that antimicrobials included [CLSI] methodology) showing reduced shown reduced susceptibility to ampho- antifungals).5 The 2015 report acknowl- susceptibility to itraconazole rose from tericin B. By contrast, 100% of MRCM edged the need “to identify gaps within 1.4% in 2012 to 8.5% in 2016. In 2012, Candida glabrata specimens have shown current antifungal surveillance and seek 1.7% of samples showed reduced sus- reduced susceptibility to fluconazole to explore and implement improvements ceptibility to in 2012 rising since 2012, although the proportion of to national surveillance programmes”.6 to 4.7% in 2016. The number of samples MRL isolates with reduced susceptibility In 2016, ESPAUR devoted a chapter of its showing reduced susceptibility to posa- was 31.3% (119/380).8 report to antifungal resistance, prescrib- conazole fell from 10.6% in 2012 to 6.9% Reports for most of the rarer fungi ing and stewardship. It noted the rising in 2016. The ESPAUR report comments relate to invasive infection. For example, number of reports of resistant species that “the difference in resistance levels 100% of Lomentospora prolificans and of pathogenic fungi and cross-resistance could be due to population bias, with Purpureocillium lilacinum isolates show to clinical azoles and broad-spectrum samples referred to the MRCM provided reduced susceptibility to , antifungals.7 by a cohort of patients with chronic pul- 100% of Rasamsonia argillacea isolates The 2017 ESPAUR report records monary aspergillosis”.8 had reduced susceptibility to voricona- that Aspergillus fumigatus is by far the Resistance to all azole antifungal zole and 100% of Mucoromycotina and most common mould isolated from drugs has been recorded in the UK but Lomentospora prolificans isolates showed clinical samples. The percentage of it is rare. However, 100% triazole resist- reduced susceptibility to caspofungin. samples with reduced susceptibility to ance was recorded for Aspergillus ther- The ESPAUR reports notes that many itraconazole (as measured using the momutatus in aggregated data for MRCM Fusarium spp. tested were from cases of European Committee on Antimicrobial samples 2012–15.8 fungal keratitis in contact lens wearers – Susceptibility Testing [EUCAST] meth- Only a small number of Candida the organism is commonly isolated from odology in samples from the Mycology albicans samples (the most frequently blood cultures from patients with dissem- Reference Centre in Manchester isolated Candida species; see Figure 2) inated infection. Of the samples tested by [MRCM]) has fallen from 20.1% in 2012 from superficial sites are routinely tested MRL, 34.3%, 62.4% and 96.3% of isolates to 16.6% in 2015, and reduced suscep- for antifungal susceptibility (around 3–7% showed reduced susceptibility to ampho- tibility to voriconazole has fallen from annually). Nevertheless, the percentage tericin B, voriconazole and caspofungin, 20.9% to 13.4% in the same period. By of all MRCM specimen types showing respectively over an eight-year period contrast, reduced susceptibility to posa- reduced susceptibility to fluconazole and to 2016. Also isolates from sputum conazole has risen from 16.5% to 19.8% echinocandins has been rising during samples of cystic fibrosis patients con- between 2012 and 2015. the period 2012 to 2016. In 2016, 6.7% taining apio­spermum and prescriber.co.uk Prescriber November 2018 ❚ 25 ■ REPORT l Antifungal resistance

Exophiala spp. showed reduced suscepti- terreus, Scedosporium spp, Fusarium alternating treatment with different drugs bility to caspofungin (64.3% and 90.9% of spp, and members of the Mucorales. may be effective in slowing the develop- samples, respectively).8 C. auris and C. glabrata are emerging as ment of resistance. Another approach Candida auris is causing some con- multi-drug resistant. The most common being investigated is vaccination, par- cern as it is associated with fatality mechanism of resistance are mutations ticularly to protect high-risk groups from rates of between 30% and 70% in those that change the conformation of the drug invasive fungal infection.15 infected and it has caused prolonged target site. Another mechanism involves outbreaks of hospital-acquired infection upregulation of efflux pumps that prevent Conclusion in five continents. It is associated with drug accumulating inside cells, reducing The fact that resistance to antifungal invasive infections, such as candidaemia, their efficacy.3 drugs has received relatively little atten- pericarditis, urinary tract infections and tion until recently means that the true pneumonia and exhibits reduced suscepti- How to fight back? extent of the problem is probably not bility to fluconazole, and variable suscepti- Fisher et al. comment that a range of yet fully understood. Nevertheless, the bility to other antifungal agents. The good strategies are need to combat the threat implications of fungal infections, particu- news for England, according to the latest posed by antifungal resistance, includ- larly systemic disease, that are resist- (2018) ESPAUR report, is that up to the ing improved stewardship and the devel- ant to one or more antifungal drugs are end of September 2018 the number of opment of novel antifungals with new potentially serious, particularly for those cases of colonisation and infection with C. modes of action. Writing in The Lancet, patients whose immune systems are auris was lower than 2017. Since 2013, Perlin et al. add that rapid fungal diagnos- compromised. It seems prudent there- 225 cases have been reported in England, tics and therapeutic drug monitoring may fore for healthcare professionals to pay 61 of which were infections, including 31 also be needed.13 more attention to the potential threat candidaemias. So far, no deaths have It may take some time for anti- posed by drug-resistant organisms and been associated with the cases.9 fungal stewardship to be established do all they can to use antifungal drugs Public Health England guidance on widely in the health system. A survey of wisely, much as they are being encour- management, infection prevention and English acute Trusts published in 2017 aged to do with antibiotics. At the same control of C. auris was updated in August found that although 46 of the 47 that time, it must be hoped that researchers 2017 and a patient information leaflet as responded to the survey had an antimi- will be supported and encouraged to well as guidelines for care in community crobial stewardship programme, only five continue to look for new ways of treat- settings were made available.10 First-line had a dedicated antifungal stewardship ing fungal infections, and that they are therapy is an echinocandin and specific programme and overall just 20 included successful. susceptibility testing should be carried antifungal stewardship as part of their out as soon as possible. Resistance can antimicrobial stewardship programme. Of References evolve quite quickly. Dual therapy may be the Trusts that did not have an antifungal 1. Alexander BD, Perfect JR. Antifungal needed to treat urinary tract or central stewardship programme, 14 said it was resistance trends towards the year 2000. nervous system infection with C. auris.11 because of a lack of resources or staff Implications for therapy and new approaches. Drug resistance varies from organism time. Availability of rapid diagnostics and Drugs 1997;54(5):657–78. to organism and from country to coun- clinical support would enable them to 2. BBC News. Growing resistance to antifungal drugs ‘a global issue’. 18 May 2018. Available try. For example, in its global report on conduct antifungal stewardship activities, from: www.bbc.co.uk/news/health-44160730 surveillance of antimicrobial resistance 12 Trusts said.14 [accessed August 2018]. in 2014, the WHO showed that resist- The NHS Improving Value Antifungal 3. Fisher MC, et al. Worldwide emergence ance to fluconazole among all species of Stewardship Project, established in of resistance to antifungal drugs challenges Candida ranged from 33% in Denmark to February 2017, aims to develop guidance human health and food security. Science 0.9% in the Republic of Korea.12 for NHS England commissioning teams 2018;360(6390):739–42. focusing on the following key areas: 4. Sanglard D. Emerging threats in antifun- Resistance mechanisms • Optimisation of the use of empirical gal-resistant fungal pathogens. Front Med In their Science review, Fisher et al. note antifungal treatment 2016;3:11. that there are just four main classes of • Improvements in antifungal diagnostic 5. Public Health England. English surveillance antifungal drugs used to treat clinical testing to inform treatment and antifun- programme for antimicrobial utilisation and disease: polyenes (eg amphotericin B); gal stewardship activities resistance (ESPAUR). Report 2014. September 2014. azoles; a pyrimidine analogue (5-fluoro­ • Reduction of selective pressure and the 6. Public Health England (PHE). English sur- cytosine); and the newest class, the echi- impact of resistant fungal pathogens veillance programme for antimicrobial utilisa- nocandins (eg caspofungin). Resistance • Increased use of antifungals with lower tion and resistance (ESPAUR). Report 2015. has been documented to all licensed sys- acquisition costs. November 2015. temic antifungals, albeit at differing rates. 7. Public Health England (PHE). English Resistance to a broad range of antifun- Combination therapy, particularly using Surveillance Programme for Antimicrobial gals has been recorded for Aspergillus drugs with different modes of action, or Utilisation and Resistance (ESPAUR). Report

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2016. November 2016. collections/candida-auris [accessed August antifungal resistance: prevalence, mecha- 8. Public Health England. English Surveillance 2018]. nisms, and management. Lancet Infect Dis Programme for Antimicrobial Utilisation and 11. Public Health England. Guidance for the 2017;17:e383–92. Resistance (ESPAUR). Report 2017. October laboratory investigation, management and 14. Micallef C, et al. An investigation of anti- 2017. infection prevention and control for cases of fungal stewardship programmes in England. J 9. Public Health England. English Surveillance Candida auris. June 2016 (updated August Med Microbiol 2017;66(11):1581–9. Programme for Antimicrobial Utilisation 2017). Available from: https://www.gov. 15. Scorzoni L, et al. Antifungal therapy: new and Resistance (ESPAUR). Report 2018. uk/government/publications/candida-auris- advances in the understanding and treatment October 2018. Available from: https://www. laboratory-investigation-management-and- of mycosis. Front Microbiol 2017;8:36. gov.uk/government/publications/english- infection-prevention-and-control surveillance-programme-antimicrobial- 12. World Health Organization. Antimicrobial Declaration of interests utilisation-and-resistance-espaur-report resistance: global report on surveillance. April None to declare 10. Public Health England. Collection. The 2014. Available from: http://www.who.int/ characteristics, diagnosis and management drugresistance/documents/surveillancereport/ of Candida auris. June 2016 (updated August en/ Steve Titmarsh is a freelance medical 2017). Available from: www.gov.uk/government/ 13. Perlin DS, et al. The global problem of writer

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