Trends in fungal diseases Dr David W. Denning FRCP FRCPath Scientific Advisor to the Fungal Research Trust Clinician, Wythenshawe Hospital Head, Antifungal Testing Laboratory Faculty, University of Manchester

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools Replacement of sensitive species by resistant ones Increasing use of prophylaxis and empirical therapy Continuing high frequency of skin infection Increasing awareness of the role of fungi in allergy Increasing drug and hospitalisation costs

Trends in fungal diseases Increasing cases of invasive fungal infections

Increasing rate of candidiasis in the US Martin et al, NEJM 2003;348: % +600%

Invasive Candida infections in the USA The NEMIS study 6 Surgical Intensive Care Units in USA Overall rate 9.82/1000 admissions or 0.98/1000 patient days (range ) 48% C. albicans Mortality of Candida bloodstream infections 41% vs 8% in those without Blumberg HM et al, Clin Infect Dis 2001:

2 year prospective study in 6 UK hospitals 18.7 candidaemias /100,000 FTE’s, or 3 per 100,000 bed days 45% in ICU C. albicans in 65% Majority of isolates susceptible to fluconazole Outcome improved by removal of catheter Candida bloodstream infections in the UK Kibbler CC et al, J Hosp Infect 2003;54:18

Aspergillus spp. Candida spp. All other Prevalence at Autopsy [%] Prevalence of invasive aspergillosis at autopsy In % of the IA patients were diagnosed at autopsy and had no treatment Groll et al, J Infect 1996;33:23-32.

Changing incidence of fatal invasive mycoses in non-HIV patients in USA Rate per 100,000 population Candidiasis Aspergillosis McNeil et al, Clin Infect Dis 2001;33:641

Predicted numbers of Candida and Aspergillus infections in the UK Patient groupNo. (2002) % CandidaNo Candida% AspergillusNo. Aspergillus AlloBMTx Solid organ Tx Leukaemia Solid tumour (neutropenic) Advanced cancer ICU Burns Renal dialysis AIDS Total

Comparative frequencies of other medical conditions in the UK Number New HIV infections (2001) 4,731 Deaths due to hospital acquired infection (estimate) 5,000 New cases of TB (2003) 6,300 Meningitis (2002) 3,000

Invasive fungal infection – current mortality rates Mortality Aspergillosis Pulmonary aspergillosis50-75% Cerebral aspergillosis 95% Candidiasis Candidaemia 40%

Lin et al Clin Infect Dis 2001;32:258 Case fatality rate with amphotericin B

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools

Aspergillus spp. Candida spp. All other Prevalence at Autopsy [%] In % of the IA patients were diagnosed at autopsy and had no treatment Groll et al, J Infect 1996;33: In 1992, 60% of the patients were undiagnosed and untreated Prevalence of invasive aspergillosis at autopsy

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools Replacement of sensitive species by resistant ones

Antifungal susceptibility in Candida spp. Usually susceptible Less susceptibleResistant Fluconazole C. albicans C. tropicalis C. glabrata C. parapsilosis C. krusei All others Amphotericin B C. albicans C. lusitaniae C. krusei C. tropicalisC. glabrata C. parapsilosis Caspofungin C. albicans C. parapsilosis C. tropicalis C. guilliermondii C. glabrata C. lusitaniae C. krusei

Candida glabrata and Candida krusei Fluconazole intermediate or resistant Respond poorly to amphotericin B treatment Increasingly common Candida kruseiCandida glabrata

Biofilms and Candida parapsilosis 2 nd most common species in blood, related to catheters and glucose solutions Causes biofilms which usually require removal of catheters etc, as antifungal drugs are ineffective in eradicating biofilms Infected pacemaker and heart valve, after death

Prospective study of candidaemia in European cancer centres 289 episodes C. albicans in 70% of cancer and 36% of leukaemia patients Other species – C. parapsilosis (27) - C. tropicalis (23) - C. glabrata (21) - C. krusei (21) - C. guilliermondii (11) - other Candida spp. (7) Candida bloodstream infections in European cancer patients Viscoli C et al, Clin Infect Dis 1999;28:1071

A. nidulans – may be amphotericin B resistant A. terreus – resistant to AmB Aspergillus – 38 species have caused disease Common in the environment Sometimes amphotericin B resistant Low frequency of azole resistance

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools Replacement of sensitive species by resistant ones Increasing use of prophylaxis and empirical therapy

Prophylaxis in the surgical intensive care unit –Fluconazole vs. placebo in extremely high risk surgical intensive care patients –Placebo: 16% rate of invasive candidiasis –Fluconazole: 8% rate Pelz et al, Ann Surg 2001;233: ,

NEMIS study Antifungal drugs protective (Relative risk 0.3) Blumberg HM et al, Clin Infect Dis 2001:

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools Replacement of sensitive species by resistant ones Increasing use of prophylaxis and empirical therapy Continuing high frequency of skin infection

Scalp ringworm in children Increase in reported cases from: 27 in 1980 to 1227 in 2000 Reported carriage rate 12-47% in London primary school children Fuller Br Med J 2003;326:539

Toenail infections Reported frequency 2.8% of adults (1992). More recent European surveys suggest 5-25%, especially in the elderly If 5%, then >2,500,000 cases in the UK 60% treatment (3-6 months) prescribed by GPs without laboratory confirmation 20% failure rate Roberts, Br J Dermatol 1992;126 (Suppl 39):23-7 Pierard, Dermatology 2001;202:220-4.

Athlete’s foot and cellulitis Athlete’s foot leads to skin breaks between the toes Bacteria may enter, leading to cellulitis 3% of UK general medical admissions are due to cellulitis

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools Replacement of sensitive species by resistant ones Increasing use of prophylaxis and empirical therapy Continuing high frequency of skin infection Increasing awareness of the role of fungi in allergy

Interaction of Aspergillus with people A unique microbial-host interaction Immune dysfunction Frequency of aspergillosis Immune hyperactivity Frequency of aspergillosis Invasive aspergillosis Chronic pulmonary Allergic aspergillosis.

Spore counts and asthma attacks and admission to hospital All circumstantial evidence Thunderstorm asthma – linked to Alternaria Asthma deaths (Chicago) linked to high ambient spores counts and season (summer autumn) when spore counts highest Asthma hospital admission linked to high ambient spore counts (Derby, New Orleans, Ottawa) Asthma hospital attendance linked to high spore counts, but not pollen counts (Canada) Asthma symptoms increased on days of high spore counts (California, Pennsylvania) O'Hollaren, N Engl J Med 1991; 324: 359; Newson, Occup Environ Med 2000; 57:

Fungus at home Environmental data Mouldy housing associated with worse asthma, with a correlation between asthma severity and degree of dampness in the home and separately with visible mould growth In Germany bronchial reactivity in children was associated with damp housing Mouldy and damp school associated with asthma symptoms and emergency room visits Highest concentration of Aspergillus fumigatus is at home Williamson, Thorax 1997;52:229. Taskinen, Acta Paediatr 1999; 88:1373.

Hospital admission with asthmatic attacks and mould allergy AllergenAsthma, no admission (n=82) Asthma, 2+ admission (n=46) House dust mite56 % 67 % Grass pollen46 % 63 % Cat37 % 59 % Dog18 % 48 % Any non fungal allergen70% 74% O’Driscoll et al, BioMed Central, 2004

AllergenAsthma, no admission (n=82) Asthma, 2+ admission (n=46) Aspergillus 7 % 37 % Alternaria 5 % 26 % Cladosporium 1 % 41 % Penicillium 2 % 30 % Candida10 % 33 % Any fungal allergen16% 76% O’Driscoll et al, BioMed Central, 2004 Hospital admission with asthmatic attacks and mould allergy

Severe asthma and moulds Severe asthma – 235 (21%) of all asthmatics Zureik et al, Br Med J 2002;325:411 Increasing frequency of fungal skin test positivity in severe asthma Odds ratio

Asthma severity, house dust mites, cats and moulds Allergen (RAST test) No asthma n= 111 Mild asthma FEV 1 >75% <90% n= 67 Moderate asthma FEV 1 >60% <75% n= 42 Severe asthma FEV 1 <60% n= 42 House dust mite 61%71%45%77% Cats*49%51%38%35% Moulds # 17%19%36%31% * p = 0.05 # p = 0.01 Langley, ATS 2004

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools Replacement of sensitive species by resistant ones Increasing use of prophylaxis and empirical therapy Continuing high frequency of skin infection Increasing awareness of the role of fungi in allergy Increasing drug and hospitalisation costs

Total addressable worldwide market for antifungal drugs Current estimate $5.2 billion Growing 20% annually

Current US antifungal market for injectables (2003) Treatments for oesophageal candidiasis 5% of fungal infections 2% of market dollars Treatments for invasive candidiasis 76% of fungal infections 49% of market dollars Treatments for invasive aspergillosis 19% of fungal infections 49% of market dollars IV Antifungal treatments - $700M

Current drug costs in the UK (per typical course) Indication IV Oral Candida in hospital (fluconazole) £820 Candida in hospital (caspofungin)£4,676 Aspergillus in hospital (AmBisome)£5,538 Aspergillus in hospital (Voriconazole)£1,688 Toenail infections (terbinafine) £536 Vaginal thrush suppression (fluconazole) £850 Chronic pulmonary aspergillosis (voriconazole)£20,506

UK antifungal expenditure Annual expenditure (£M) GP / community sales Hospital sales Total sales 80% increase 20% per year Department of Health Prescription Cost Analysis, IMS

Indirect costs Additional length of hospital stay (candidaemia) days Extra costs of each patient with aspergillosis $62,500 (£35,000) (1999 in US)

Trends in fungal diseases Increasing cases of invasive fungal infections Poor diagnostic tools Replacement of sensitive species by resistant ones Increasing use of prophylaxis and empirical therapy Continuing high frequency of skin infection Increasing awareness of the role of fungi in allergy Increasing drug and hospitalisation costs