Transcript Trends in fungal diseases

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
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
+600%
+300%
+300%
Martin et al, NEJM 2003;348:1546
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 2001:33 177-86
Candida bloodstream infections
in the UK
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
Kibbler CC et al, J Hosp Infect 2003;54:18
Prevalence of invasive
aspergillosis at autopsy
8
All other
Prevalence at Autopsy [%]
Candida spp.
Aspergillus spp.
6
In 1992 60% of
the IA patients
were
diagnosed at
autopsy and had
no treatment
4
2
0
78 79 80 81 82 83 84 85 86 87 88 89 90 91 92
Groll et al, J Infect 1996;33:23-32.
Rate per 100,000 population
0.0
0.2
0.4
0.6
0.8
Changing incidence of fatal invasive
mycoses in non-HIV patients in USA
Candidiasis
Aspergillosis
1981
1986
1991
1996
McNeil et al, Clin Infect Dis 2001;33:641
Predicted numbers of Candida and
Aspergillus infections in the UK
Patient group
No.
(2002)
% Candida
No Candida
% Aspergillus
No.
Aspergillus
793
4
32
10
79
2953
5
148
1.9
56
Leukaemia
16269
3
488
6
976
Solid tumour
(neutropenic)
28955
869
2
579
AlloBMTx
Solid organ Tx
Advanced
cancer
ICU
Burns
Renal dialysis
AIDS
Total
3
131678
1
1316
1.5
1975
210130
1
2101
0.2
420
378
5.6
21
1.9
7
24536
0.2
490
0.02
5
661
0.2
1
4
26
5466
4120
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 aspergillosis
Cerebral aspergillosis
50-75%
95%
Candidiasis
Candidaemia
40%
Case fatality rate with amphotericin B
Lin et al Clin Infect Dis 2001;32:258
Trends in fungal diseases
• Increasing cases of invasive fungal infections
• Poor diagnostic tools
Prevalence of invasive
aspergillosis at autopsy
8
All other
Prevalence at Autopsy [%]
Candida spp.
Aspergillus spp.
6
In 1992, 60%
In
of 1992
the 60% of
the IA patients
patients
were
were
diagnosed at
undiagnosed
autopsy
and had
and
no
treatment
untreated
4
2
0
78 79 80 81 82 83 84 85 86 87 88 89 90 91 92
Groll et al, J Infect 1996;33:23-32.
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
Fluconazole
C. albicans
C. parapsilosis
All others
Amphotericin B
C. albicans
C. tropicalis
C. parapsilosis
Caspofungin
C. albicans
C. tropicalis
C. glabrata
C. krusei
Less susceptible
Resistant
C. tropicalis
C. glabrata
C. krusei
C. lusitaniae
C. krusei
C. glabrata
C. parapsilosis
C. guilliermondii
C. lusitaniae
Candida glabrata and Candida krusei
• Fluconazole intermediate or resistant
• Respond poorly to amphotericin B treatment
• Increasingly common
Candida krusei
Candida glabrata
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
Candida bloodstream infections in
European cancer patients
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)
Viscoli C et al, Clin Infect Dis 1999;28:1071
Aspergillus –
38 species have caused disease
Common in the environment
A. nidulans – may be amphotericin B resistant
resistant
Lowamphotericin
frequency
resistance
A. terreusSometimes
– resistant
to AmB ofBazole
www.aspergillus.man.ac.uk
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;233:542-548,
NEMIS study
Antifungal drugs protective (Relative risk 0.3)
Blumberg HM et al, Clin Infect Dis 2001:33 177-86
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
Invasive aspergillosis
Allergic aspergillosis
Chronic pulmonary
Immune dysfunction
Immune hyperactivity
.
Frequency of aspergillosis
Frequency of aspergillosis
A unique microbial-host interaction
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.
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
Allergen
Asthma, no admission (n=82)
Asthma, 2+ admission (n=46)
House dust mite
56 %
67 %
Grass pollen
46 %
63 %
Cat
37 %
59 %
Dog
18 %
48 %
Any non fungal allergen
70%
74%
O’Driscoll et al, BioMed Central, 2004
Hospital admission with asthmatic attacks
and mould allergy
Allergen
Asthma, no admission (n=82)
Asthma, 2+ admission (n=46)
Aspergillus
7%
37 %
Alternaria
5%
26 %
Cladosporium
1%
41 %
Penicillium
2%
30 %
Candida
10 %
33 %
Any fungal allergen
16%
76%
O’Driscoll et al, BioMed Central, 2004
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 2002;325:411
Asthma severity, house dust mites,
cats and moulds
Allergen
(RAST test)
No asthma
n= 111
Mild asthma
FEV1 >75%
<90%
n= 67
House dust
mite
61%
71%
45%
77%
Cats*
49%
51%
38%
35%
Moulds#
17%
19%
36%
31%
* p = 0.05
# p = 0.01
Moderate Severe asthma
asthma FEV1 FEV1 <60%
>60% <75%
n= 42
n= 42
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)
IV Antifungal treatments - $700M
Treatments for
invasive
candidiasis
Treatments for
oesophageal
candidiasis
Treatments for
invasive
aspergillosis
76% of fungal
infections
5% of fungal
infections
19% of fungal
infections
49% of market
dollars
2% of market
dollars
49% of market
dollars
Current drug costs in the UK
(per typical course)
Indication
Candida in hospital (fluconazole)
£820
Candida in hospital (caspofungin) £4,676
Aspergillus in hospital (AmBisome) £5,538
Aspergillus in hospital (Voriconazole)
Toenail infections (terbinafine)
Vaginal thrush suppression (fluconazole)
Chronic pulmonary aspergillosis (voriconazole)
IV
Oral
£1,688
£536
£850
£20,506
UK antifungal expenditure
Annual expenditure (£M)
100
80
GP / community sales
Hospital sales
80% increase
20% per year
Total sales
60
40
20
1999
2003
Department of Health Prescription Cost Analysis, IMS
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)
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