Trends in fungal diseases

1
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
• WWW.aspergillus.man.ac.uk

2
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

3
Trends in fungal diseases

• Increasing cases of invasive fungal infections

4
Increasing rate of candidiasis in the US
600
300
300
Martin et al, NEJM 20033481546
5
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 0.28-1.78)
• 48 C. albicans
• Mortality of Candida bloodstream infections 41
  vs 8 in those without

Blumberg HM et al, Clin Infect Dis 200133 177-86
6
2 year prospective study in 6 UK hospitals
18.7 candidaemias /100,000 FTEs, 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 20035418
7
Prevalence of invasive aspergillosis at autopsy
All other
Candida spp.
Aspergillus spp.
In 1992 60 of the IA patients were diagnosed at
autopsy and had no treatment
Prevalence at Autopsy
Groll et al, J Infect 19963323-32.
8
Changing incidence of fatal invasive mycoses in
non-HIV patients in USA
Rate per 100,000 population 0.0 0.2 0.4 0.6
0.8
Candidiasis Aspergillosis
1981 1986 1991 1996
McNeil et al, Clin Infect Dis 200133641
9
Predicted numbers of Candida and Aspergillus
infections in the UK
10
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
11
Invasive fungal infection current mortality
rates
Mortality Aspergillosis Pulmonary
aspergillosis 50-75 Cerebral
aspergillosis 95 Candidiasis
Candidaemia 40
12
Case fatality rate with amphotericin B
Lin et al Clin Infect Dis 200132258
13
Trends in fungal diseases

• Increasing cases of invasive fungal infections
• Poor diagnostic tools

14
Prevalence of invasive aspergillosis at autopsy
All other
Candida spp.
Aspergillus spp.
In 1992, 60 of the patients were undiagnosed and
untreated
In 1992 60 of the IA patients were diagnosed at
autopsy and had no treatment
Prevalence at Autopsy
Groll et al, J Infect 19963323-32.
15
Trends in fungal diseases

• Increasing cases of invasive fungal infections
• Poor diagnostic tools
• Replacement of sensitive species by resistant
  ones

16
Antifungal susceptibility in Candida spp.

• Usually susceptible Less susceptible Resistan
  t
• Fluconazole
• C. albicans C. tropicalis C. glabrata
  
• C. parapsilosis C. krusei
• All others
• Amphotericin B
• C. albicans C. lusitaniae C. krusei
• C. tropicalis C. glabrata
• C. parapsilosis

Caspofungin C. albicans C. parapsilosis C.
tropicalis C. guilliermondii C. glabrata C.
lusitaniae C. krusei
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Candida glabrata and Candida krusei

• Fluconazole intermediate or resistant
• Respond poorly to amphotericin B treatment
• Increasingly common

Candida krusei
Candida glabrata
18
Biofilms and Candida parapsilosis

• 2nd 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
19
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 1999281071
20
Aspergillus 38 species have caused disease
Common in the environment


www.aspergillus.man.ac.uk
21
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

22
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 2001233542-548,
23
NEMIS study

• Antifungal drugs protective (Relative risk 0.3)

Blumberg HM et al, Clin Infect Dis 200133 177-86
24
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

25
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 2003326539
26
Toenail infections

• Reported frequency 2.8 of adults (1992). More
  recent European surveys suggest 5-25,
  especially in the elderly
• If 5, then gt2,500,000 cases in the UK
• 60 treatment (3-6 months) prescribed by GPs
  without laboratory confirmation
• 20 failure rate

Roberts, Br J Dermatol 1992126 (Suppl
39)23-7 Pierard, Dermatology 2001202220-4.
27
Athletes foot and cellulitis

• Athletes foot leads to skin breaks between the
  toes
• Bacteria may enter, leading to cellulitis
• 3 of UK general medical admissions are due to
  cellulitis

28
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

29
Interaction of Aspergillus with peopleA unique
microbial-host interaction
Invasive aspergillosis
Allergic aspergillosis
Frequency of aspergillosis
Frequency of aspergillosis
Chronic pulmonary
Immune dysfunction
Immune hyperactivity
.
30
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 57 786-92.
31
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 199752229. Taskinen, Acta
Paediatr 1999 881373.
32
Hospital admission with asthmatic attacks and
mould allergy
Allergen Asthma, no admission (n82) Asthma,
2 admission (n46) House dust mite 56
67 Grass pollen 46 63 Cat 37
59 Dog 18 48 Any non fungal
allergen 70 74
ODriscoll et al, BioMed Central, 2004
33
Hospital admission with asthmatic attacks and
mould allergy
Allergen Asthma, no admission (n82)
Asthma, 2 admission (n46) Aspergillus 7
37 Alternaria 5 26
Cladosporium 1 41 Penicillium 2
30 Candida 10 33 Any fungal
allergen 16 76
ODriscoll et al, BioMed Central, 2004
34
Severe asthma and moulds
Severe asthma 235 (21) of all asthmatics
Odds ratio
Increasing frequency of fungal skin test
positivity in severe asthma
Zureik et al, Br Med J 2002325411
35
Asthma severity, house dust mites, cats and moulds
p 0.05 p 0.01
Langley, ATS 2004
36
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

37
Total addressable worldwide market for antifungal
drugs
Current estimate 5.2 billion Growing 20 annually
38
Current US antifungal market for injectables
(2003)
IV Antifungal treatments - 700M
Treatments for invasive candidiasis 76 of fungal
infections 49 of market dollars
Treatments for oesophageal candidiasis 5 of
fungal infections 2 of market dollars
Treatments for invasive aspergillosis 19 of
fungal infections 49 of market dollars
39
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

40
UK antifungal expenditure
GP / community sales
100
Hospital sales
80 increase 20 per year
Total sales
80
60
Annual expenditure (M)
40
20
2003
1999
Department of Health Prescription Cost Analysis,
IMS
41
Indirect costs

• Additional length of hospital stay (candidaemia)
  15-36 days
• Extra costs of each patient with aspergillosis
  62,500 (35,000) (1999 in US)

42
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