Download Diagnosis and treatment of invasive fungal infections

Diagnosis and treatment of invasive
fungal infections
Wouter Meersseman, University Hospital Leuven General Internal Medicine –Medical Intensive Care
Ostersund, Sweden 26 05 2015
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
> 50% developing
world
600,000
CDC estimate
Invasive
aspergillosis
50% in developed
world if treated
> 100,000
Many missed
diagnoses globally
Chronic
pulmonary
aspergillosis
15% in developed
world
> 450,000
Underdiagnosed
and mistaken for TB
Candida
bloodstream
infection
40% if treated
> 120,000
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
Mucormycosis
10-25% cutaneous
95% disseminated
20,000
No exact figures
Total
> 1,350,000
Probably a
significant
underestimate
Cryptococcal disease
Cryptococcal disease
• 67-year old man
• Heart transplant recipient 6 yrs earlier
• Presents with 3-month history of fever and
fatigue
• Was on mycophenolate and cyclosporin
• Gradually apathetic and mild memory
problems
Lumbar puncture: 102 cells, 47% lymphocytes,
protein 990 mg/lit and glucose 42 mg/dl,
cryptococcal antigen negative, india ink staining
negative
Culture CSF after three days growth of Cryptococcus neoformans
var. grubii
Complete resolution of fever after 1 week of ampho B and 5flucytosine
Cryptococcal disease: diagnosis
• Symptoms begin indolently over a period of 1-2 weeks: fever,
malaise, headache. Prolonged symptoms more frequent in
HIV-negative patients (cancer, steroids, transplant recipients)
• Mass lesions in the brain rarely occur in HIV-infected patients,
and in 10% of HIV-negative patients
• India ink staining positive > 75% of HIV-infected patients, in
only 50% of HIV-negative patients
• Cryptococcal antigen testing very sensitive in HIV-infected
patients (95%)
• Measure opening pressures in CSF !!!
42% of suspected cases had confirmed cryptococcal meningitis
Amphotericin B + 5FC superior !!
- Crypto-meningitis, 299 patients
- Ampho B 1 mg/kg
5-FC
100 mg/kg/day
Fluconazole 800 mg/day
Treatment strategy
- combo: 2 weeks→fluco 400 mg 8 wks
- mono: 4 weeks→ fluco 400 mg 6 wks
• Randomization after 7-11 days of combination therapy with amphotericin B
0,7-1,0 mg/kg and fluconazole 800 mg per day
• Consolidation and maintenance phase with fluconazole
• Therapeutic lumbar punctures on the day of diagnosis and day 7 and 14 of
treatment
• Primary end-point 26 week mortality
Cryptococcal disease: still substantial mortality
Cryptococcus gattii infections: this is another
disease than neoformans infections !!!
•
•
•
•
•
•
Originally most cases come from Papua New Guinea
and other subtropical areas (Brazil, India,…)
Linked to eucalyptus tree
Animals serve as sentinels
Can also cause meningo-encefalitis, but to a lesser
extent
Occurs nowadays also in more northern regions
(climate change)
Does occur more often in less immunocompromised
patients (smokers, COPD, marihuana)
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Cryptococcal
meninigitis
Invasive
aspergillosis
Chronic
pulmonary
aspergillosis
Case fatality rate
15-20% USA
600,000
> 50% developing
world Cryptococcal disease:
50% in developedIFI >
100,000
deaths/year
world if treated
Comments
CDC estimate
40-50% of the 1,350,000
Many missed
diagnoses globally
15% in developed
> 450,000 and cost Underdiagnosed
Drug availability
challenges
world
and mistaken for TB
Rapid bed-test available
Candida
bloodstream
infection
40% if treated
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
Mucormycosis
10-25% cutaneous
95% disseminated
Total
Estimated deaths
> 120,000
Huge potential to save lifes
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
20,000
No exact figures
> 1,350,000
Probably a
significant
underestimate
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
> 50% developing
world
600,000
CDC estimate
Invasive
aspergillosis
50% in developed
world if treated
> 100,000
Many missed
diagnoses globally
Chronic
pulmonary
aspergillosis
15% in developed
world
> 450,000
Underdiagnosed
and mistaken for TB
Candida
bloodstream
infection
40% if treated
> 120,000
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
Mucormycosis
10-25% cutaneous
95% disseminated
20,000
No exact figures
Total
> 1,350,000
Probably a
significant
underestimate
Invasive aspergillosis
Invasive aspergillosis
• Is it a frequent disease?
• In what kind of patients do we see invasive aspergillosis?
• What is the significance of a positive culture result from a
respiratory specimen?
• How do you diagnose invasive aspergillosis?
• What is the treatment for invasive aspergillosis?
• Is there a problem of resistance?
Invasive aspergillosis
• Is it a frequent disease?
• In what kind of patients do we see invasive aspergillosis?
• What is the significance of a positive culture result from a
respiratory specimen?
• How do you diagnose invasive aspergillosis?
• What is the treatment for invasive aspergillosis?
• Is there a problem of resistance?
Estimated number of cases of
invasive fungal infection UK [2002] in several
groups of immunocompromised patients
Patient group
Number of
patients
Invasive candidosis/ Expected number
Invasive
candidaemia risk
invasive candidosis/
aspergillosis
estimates**
candidaemia
risk estimates@
Allo HSCTx
Expected number
invasive
aspergillosis
4%
32
10%
79
5%
148
1.9%
56
3%
488
6%
976
3%
869
2%
579
1%
1316
1.5%#
1975
1%
2101
0.2%
420
5.6%
21
1.9%
7
490
0.02%
5
1
4%
26
793
Solid organ Tx
2953
Leukaemia
16269
Solid tumour
(neutropenic)
Advanced cancer
28955
131678
ICU
210130
Burns
378
Renal dialysis
0.2%
24536
HIV/AIDS
Probably underestimated
0.2%
661
Totals
5466
** no estimate for surgical patients, but some are in ICU, or have advanced cancer
@ no inclusion of most chronic chest, steroid-treated patients, an increasing group
# the literature figure is 6%, but felt to be autopsy selection bias, so reduced by 75%.
http://www.hpa.org.uk/web/HPAwebFile/HPAweb_C/1196942156347
4120
Autopsy analysis of invasive fungal
infections
Data on 1200
autopsies over 20
years
31% had IFI
Only 50% was
diagnosed premortem
Parameter
Age, yrs, mean
Sex, male, n
Haematological patients, n
Nonhematological patients, n
 COPD, n
 Solid organ
transplants, n
 Systemic disease, n
 Cirrhosis, n
 Other, n
SAPS II, mean
Predicted mortality, %
Observed mortality, %
ICU length of stay, days
Hemodialysis in ICU, n
Mechanical ventilation, n
Neutropenia (<500/mm3), n
Autopsy, n
All
(n=1
27)
61
84
38
89
35
9
Proven
(n=56)
Probable
(n=49)
Possible
(n=2)
Colonization
(n=20)
59
39
26
30
12
4
63
35
12
37
21
5
61
2
0
2
2
0
64
8
0
20
0
0
17
6
22
54
53%
86%
20
54
123
19
76
6
3
5
57
58%
98%
14
27
56
12
52
8
0
3
0
0
3
3
0
14
52
43
54
49%
31%
51%
90%
0%
50%
23 6.9% of
32 all admissions
28
20
0
7
Retrospective
47
2
18
A lot of
6
0 autopsy data
1
19
0 admissions
5
1850
Meersseman W. Invasive aspergillosis in critically ill patients
without malignancy Am J Respir Crit Care Med 2004
40 critically ill patients with H1N1: 9 developed invasive aspergillosis
(23%)
Major risk factor: steroids for ARDS
Clinical epidemiology (US data)
Underlying disease (960 patients) (2004-2008)
1.
2.
3.
4.
5.
6.
Haematological malignancy 464
Solid organ transplant
280
Stem cell transplant
268
HIV/AIDS
14
Immunodeficiency
4
Other
22
48.3 %
29.2 %
27.9 %
1.5 %
0.4 %
2.3 %
Steinbach WJ et al. Clinical epidemiology of 960 patients with
invasive aspergillosis from the PATH Alliance registry. J Infect 2012,
65, 453-464
Increased time to onset of IA in SOT
A positive airway sample is in
line with colonisation in most cases
4 Danish hospitals (3 months) (Jan March
2007)
1. 11.368 airway samples
2. 151 patients
3. Proven (n=3), probable (n=11), ABPA
(n=4), colonised (n=133)
4. 55% cystic fibrosis, 13% COPD, 7%
hematological, 18% ICU
5. ? Incidence 0.9-1.1 per 100.000 inhabitants
Mortensen KL et al. A prospective survey of Aspergillus spp, in
respiratory tract samples. Eur J Clin Microb Infect Dis 2011, 30:1355
Risk of acquisition (and pace of progression)
Examples of at-risk patients and pace of
progression
25%
20%
15%
10%
5%
True incidence
invasive aspergillosis
dependent on level of
immunosuppression
0.1-15%
PPV of culture
depending on level of
Degree of immunocompromise
immunosuppression
Invasive aspergillosis
• Is it a frequent disease?
• In what kind of patients do we see invasive aspergillosis?
• What is the significance of a positive culture result from a
respiratory specimen?
• How do you diagnose invasive aspergillosis?
• What is the treatment for invasive aspergillosis?
• Is there a problem of resistance?
EORTC-Strict Definitions
for Invasive Fungal Infections – in hemato/onco
patients
2002 criteria1
2008 criteria2
Proven
Proven
Positive culture from a tissue
biopsy or a usually sterile fluid
(excluding BAL)
Positive culture from a tissue
biopsy or a usually sterile fluid
(excluding BAL)
Probable
Probable
Mycology + 1 major
(nodule with halo or air crescent)
or 2 minor radio-clinical signs)
Mycology + presence of dense,
well-circumscribed lesion with/without
halo, or an air-crescent sign, or a cavity
Possible
Either radioclinical signs or mycology
1
2
Ascioglu S, et al. Clin Infect Dis. 2002; 34:7–14.
De Pauw B, et al. Clin Infect Dis. 2008; 46(12): 1813–1821.
Possible
Specific radiological signs
(as defined above)
‘halo sign’
Patients presenting with a halo sign had
significantly better responses to treatment and
greater survival to 84 days than did patients
who presented with other imaging findings.
Halo sign almost exclusively seen in
neutropenic patients (coagulation necrosis)
Greene RE et al, Clin Infect Dis, 2007, 44: 373-9.
41-year old lady with acute myeloid
leukemia
Neutropenic for 15 days
Fever for 4 days
CT-scan: reversed halo sign
DEVELOPMENT OF PULMONARY CAT-IMAGE
Caillot et al. J Clin Oncol 2001; 19:253-9
Neutropenia
Halo sign
D 0-5
Air-space consolidation
D 5-10
Air-crescent sign
D 10 -20
Nodules in a patient with more than 10 days
neutropenia and fever not responding to broadspectrum antibiotics
A patient who is over 10 days neutropenic, develops pulmonary and
brain lesions
• Halo sign: only applicable to
neutropenic patients
• Radiology in ICU “clouded” by
atelectasis, pleural effusions, ARDS
• Necrotizing, cavitating lesions: not
specific
Direct examination
and culture
• Rapid
• Useful to interpret
culture results
• PPV depends on the degree
of immunodeficiency
• Lacks sensitivity
• Gram stain not optimal
• Fluorescent dyes: Calcofluor White
• No species identification
– Yeast versus mold
– Aspergillus-like hyphae versus Zygomycetes
Sensitivity culture and microscopy
No. (%) of patients
Proven IA
Probable IA
Possible IA
Total
Result BAL
(n = 4)
(n = 43)
(n = 20)
(n = 67)
Positive result of DE
1 (25%)
24 (56%)
5 (25%)
30 (45)
Positive culture result
2 (50%)
32 (74%)
3 (15%)
37 (55)
Positive result of DE
and/or culture
2 (50%)
37 (86%)
7 (35%)
46 (69)
DE, direct examination
Cornillet A. Comparison of Epidemiological, Clinical and Biological Features of Invasive
Aspergillosis. CID 2006; 43: 577
Non-culture based methods
Mannan
Galactomannan
(1-3)β-D-glucan
Hope WW, et al. Laboratory diagnosis of invasive aspergillosis. Lancet Infect
Dis 2005; 5:609-22
Non-culture based methods in the diagnosis of
mould and yeast infections
A. fumigatus
Non-fumigatus aspergillus
Fusarium
Zygomycetes
Candida
Cryptococcus
Histoplasma
Penicillium marneffei
Trichosporon
GM
+
+
+
+
+
+
BetaG
+
+
+
+
+
+
+
Hope WW et al. Lancet Infect Dis 2005; 5: 609-22
PCR
+
+
+
+
+
+
Sources of variability: patient population
Corticosteroid-induced Chemotherapy-induced
cytopenia
immunosuppression
Galactomannan: low
Galactomannan: high
Balloy et al. Infect Immun 2005; 73: 494
Chamilos et al. Haematologica 2006; 91: 986
In non-neutropenics galactomannan is cleared by
circulating neutrophils
Verweij. Failure to detect circulating Aspergillus markers. J Clin
Microbiol 2000: 3900
Performance GM in serum and BAL
OD index cut-off:
1,5
1,0
0,7
0,5
BAL serum BAL serum BAL serum BAL
serum
Sensitivity (%)
81
23
81
27
85
31
88
42
Specificity (%)
96
100
93
98
92
98
87
96
PPV (%)
81
100
79
88
73
89
72
85
NPV (%)
89
68
89
69
93
70
93
74
Meersseman et al., Am J Respir Crit Care Med 2008,
177: 27-34.
Performance GM in serum and BAL
Meersseman et al., Am J Respir
Crit Care Med 2008, 177: 27-34.
Important caveat: galactomannan less useful in patients on posa prophylaxis
Performance GM in patients on
posaconazole
Conclusion: diagnosis of IA
• Much easier nowadays
• Combination of culture, biomarker and
radiological signs
• Blood GM and CT scan: applicable
early in the diagnosis (in neutropenic
patients)
• BAL – GM: think of it in nonneutropenics (GVHD – ICU patients
with risk factors)
• 59-year old man
• One year ago diagnosis of myelodysplastic
syndrome with 5% circulating neutrophils
• Now receiving ara-C and idarubicine for AML
• Day 30 persistent fever and painful skin lesions
• Negative galactomannan, negative blood cultures
• Culture results of BAL negative
According to protocol: look for another site and etiology
Differential
diagnosis
-
Aspergillosis
Fusariosis
Scedosporiosis
(mucor)
hyalohypho…
Fungal culture of the skin biopsy: Fusarium solani
Invasive aspergillosis
• Is it a frequent disease?
• In what kind of patients do we see invasive aspergillosis?
• What is the significance of a positive culture result from a
respiratory specimen?
• How do you diagnose invasive aspergillosis?
• What is the treatment for invasive aspergillosis?
• Is there a problem of resistance?
Amfotericin B
Echinocandins
Azoles
Posaconazole: prophylaxis
– Prophylaxis of invasive fungal infections in high-risk patients (SCTx – GvHD,
AML-MDS)
• Until March 2014 – only available as Noxafil oral suspension
– Dosing:
• Prophylaxis: 3 x 200 mg/day
• Treatment: 2 x 400 mg/day or 4 x 200 mg/day
Posaconazole oral suspension - PK
•
Absorption
– 2.6-4-fold higher if taken with a meal
– High-fat meal enhances absorption
(Fresubin)
– Ranitidine & PPI: gastric pH: 40% decrease
in posaconazole AUC and Cmax
• Avoid concomitant use of histamine 2blockers or PPIs!
– Mucositis (HSCT recipients with GvHD?)
Schiller D et al. Clin Ther 2007; 29: 1862-1886
Goodwin M et al. JAC 2007.
NOXAFIL® (posaconazole) Gastro-resistant Tablets:
Product Characteristics1
• Designed to help prevent immediate drug release in
the stomach and delay the release of posaconazole
until the tablets reach the small intestine1
• 100 mg posaconazole dispersed in
hydroxypropylmethyl cellulose acetate succinate (4:1)
• NOXAFIL gastro-resistant tablets are packaged in a
blister in cartons of 24 (2x12) or 96 (8x12) tablets1
• No dose adjustments are required when used
concomitantly with antacids, H2-receptor
antagonists, and PPIs
• No (significant) impact of food
• Available & Reimbursed since March 2015
1. Krishna G et al. Antimicrob Agents Chemother. 2012;56;4196–4201.
2. SmPC NOXAFIL®(posaconazole), 09/2014.
*Tablets not actual size
NOXAFIL® Gastro-resistant
Tablet* (100 mg)
53
NOXAFIL® (posaconazole) IV Solution:
Composition and Nature1
•
Each vial contains 300 mg of posaconazole.
•
Each mL contains 18 mg of posaconazole.
•
Posaconazole IV solution was developed to ensure
adequate posaconazole exposure in patients unable
to tolerate/absorb oral posaconazole formulations; a
switch to oral administration is recommended as
soon as the patient’s condition allows
•
The intravenous formulation of posaconazole is an
aqueous solution containing the solubilizer
sulfobutyl ether-beta-cyclodextrin (SBECD)
•
Available and reimbursed Q4 2015?
.
1. SmPC NOXAFIL®(posaconazole), 09/2014.
* Vial not actual size
54
Dosing posaconazole
formulations
Dosing
Remarks
Oral suspension
Prophylaxis: 3 x 200 mg
Treatment: 2 x 400 mg or 4 x 200 mg
With a high-fat meal or
Fresubin
Without PPI or ranitidine, if not
possible: add cola
Dose fractionnation
Gastro-resistent
tablet
LD day 1: 2 x 300 mg (= 2 x3 tablets)
MD (day 2): 1 x 300 mg (= 1x3 tablets)
No food effect
No PPI effect
Do not crush or chew tablet!
IV formulation
LD day 1: 2 x 300 mg
MD (day 2): 1 x 300 mg
Central line: 90 min
Peripheral line (preferably only
one administration): 30 min
+16,7 mL WFI
Dilute in 150 mL Glu 5% or
NaCl 0,9%
Targeted therapy for invasive aspergillosis
392
Amphotericin B
Enrolled
3
8
Safety
196
185
Population
2
0
Voriconazole
No Treatment
Incorrect
Randomization
No Definite or
Probable
Aspergillosis
per
Blinded DRC
Success at 12 wk
Mortality
194
185
52 Intention to
Treat
133
Population
50
144
53%
29%
-21%
-13%
32%
42%
Herbrecht, N Engl J Med 2002
Isavuconazole or Cresemba
Intravenous solution does not contain cyclodextrin, once-day regimen is possible,
oral treatment is feasible, more predictable pharmacokinetics, some activity against
mucormycosis
Why TDM?
Wide intra-and interindividual variability
Correlation between efficacy/toxicity and drug levels
Proposed reference interval trough levels at steady state: 2-5.5 µg/mL
Pascual A et al. CID 2008; 46 (2): 201-11.
Inter- en intrapatient variability
in plasma exposure
1.
Non linear kinetics – increasing the dose gives
unproportional increase in exposure!
2.
Extensive CYP450 metabolisation
Drug-drug interactions – difficult to manage: in UZ
Leuven: CPOE alerting module
3.
Genetic polymorphism CYP2C19 – especially important
in Asian population (up to 20% vs. Caucasians: 2%)
4.
Influence of food (enteral feeding in ICU…) – should be
given without meal!
Interpatient variability
(correlation dose - level)
Intrapatient variability
(consecutive levels within
patient)
Trifilio S. Cancer 2007; 8: 1532-5.
Side effects
•
Cumulative dose – longterm treatment
– Phototoxicity – Squamous cell carcinoma
– Periosteal ossification (fluoride excess)
•
High levels
– Hepatotoxicity
– Visual disturbances
– Neurotoxicity
Luke DR. J Pharm Sci 2010; 99(8): 3291-301.
Wermers RA et al. CID 2011; 52:604-611.
Azole resistance frequency
in A. fumigatus 1997–2009
Bueid A et al. J. Antimicrob. Chemother. 2010;65:2116-2118
SCARE study
Overal resistance rate 3.2 % (pan-azole)
Combination study
voriconazole + anidulafungin or
placebo
•
•
Treatment with the combination of voriconazole and anidulafungin resulted in a lower
all-cause mortality rate at six weeks compared to voriconazole alone
This difference did not achieve the pre-specified threshold for statistical superiority
KM Survival to Week 12 (MITT)
•
•
•
•
Majority of MITT pts were diagnosed with
probable IA based on positive GM (serum
and/or BAL) (218/277 (78.7%)):
In a post-hoc analysis superiority
demonstrated in this subgroup.
Mortality in the GM-based group at week 6
was 17/108 (15.7%) for combination and
30/110 (27.3%) for monotherapy; p-value was
<0.05 (95% CI -22.69, -0.41)
The safety and tolerability of the combination
of voriconazole and anidulafungin in this study
was similar to that of voriconazole
monotherapy.
Marr K et al. Ann Intern Med 2015;162: 81-89,
P= 0.08
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Cryptococcal
meninigitis
Invasive
aspergillosis
Chronic
pulmonary
aspergillosis
Candida
bloodstream
infection
Pneumocystis
pneumonia
Case fatality rate
15-20% USA
> 50% developing
world
Estimated deaths
Comments
600,000
CDC estimate
Invasive
aspergillosis: 8-10%
of the 1,350,000
50% in developed
> 100,000
Many missed
world if treated IFI deaths/year
diagnoses globally
15% in developed > 450,000
Underdiagnosed
world Substantial progress in early
and diagnosis
mistaken for TB
(galactomannan, CT scan)
40% if treated
> 120,000
Substantial progress in treatment (voriconazole
TDM, posaconazole tablet and IV,
15% in AIDS isavuconazole)
> 80,000
Most cases in Africa
50% in non-AIDS
not diagnosed and
Potential danger of azole resistance
100% mortality
Mucormycosis
Total
10-25% cutaneous
No“things”
exact figures
No high20,000
potential for newer
to improve
95% disseminated
> 1,350,000
Probably a
significant
underestimate
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
> 50% developing
world
600,000
CDC estimate
Invasive
aspergillosis
50% in developed
world if treated
> 100,000
Many missed
diagnoses globally
Chronic
pulmonary
aspergillosis
15% in developed
world
> 450,000
Underdiagnosed
and mistaken for TB
Candida
bloodstream
infection
40% if treated
> 120,000
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
Mucormycosis
10-25% cutaneous
95% disseminated
20,000
No exact figures
Total
> 1,350,000
Probably a
significant
underestimate
Chronic aspergillosis
Think of it in people with longstanding cough and low-grade fever, previous history of
tuberculosis, COPD or sarcoidosis, No immunosuppression required.
Important role for antibody testing (IgG against Aspergillus, precipitines)
No role for antigen markers such as galactomannan in blood
Role for long term treatment with voriconazole
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Cryptococcal
meninigitis
Invasive
aspergillosis
Chronic
pulmonary
aspergillosis
Candida
bloodstream
infection
Pneumocystis
pneumonia
Mucormycosis
Total
Case fatality rate
15-20% USA
> 50% developing
world
Estimated deaths
Comments
600,000
CDC estimate
Chronic
aspergillosis: important
entity under50% in developed
> 100,000
Many missed
diagnosed, especially of importance
in “poor”
world if treated
diagnoses globally
countries
15% in developed
> 450,000
world
Underdiagnosed
and mistaken for TB
Guidelines will be published in the near future
40% if treated
> 120,000
Think of it in people with underlying lung
diseases. Perform antibody testing
15% in AIDS
> 80,000
Most cases in Africa
50% in non-AIDS
notwith
diagnosed
and
Role for longterm treatment
voriconazole
100% mortality
10-25% cutaneous
95% disseminated
20,000
> 1,350,000
No exact figures
Probably a
significant
underestimate
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
> 50% developing
world
600,000
CDC estimate
Invasive
aspergillosis
50% in developed
world if treated
> 100,000
Many missed
diagnoses globally
Chronic
pulmonary
aspergillosis
15% in developed
world
> 450,000
Underdiagnosed
and mistaken for TB
Candida
bloodstream
infection
40% if treated
> 120,000
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
Mucormycosis
10-25% cutaneous
95% disseminated
20,000
No exact figures
Total
> 1,350,000
Probably a
significant
underestimate
Candida bloodstream infections
and invasive candidiasis:
diagnostic issues
Clinical scenario
A 62-year old man was admitted to the intensive care unit with a severe
pneumococcal pneumonia. On the sixth hospital day, he remained intubated
and received broad-spectrum antibiotics for his pneumonia when new fever
and hypotension developed, requiring volume resuscitation and
administration of vasopressors. The patient has bilateral infiltrates, requires
55% oxygen and has a creatinine level of 3.4 mg/dl. Two days later, you get
a phone call that yeasts grow from the blood cultures (taken on the day of
new onset fever). A decision is made to start antifungal treatment.
Relevant questions:
- Should antifungal treatment have been started earlier?
- Should your patient has been on prophylaxis?
- What are the treatment options?
Treatment
of proven/probable
invasive fungal infection
Pre-emptive therapy
in early diagnosis
Empiric therapy in (persistent)
fever
Prophylaxis in high/medium risk patients
Problems with the diagnosis of Candida infections
• Three types of diseases
Candidemia (CVC or bacterial
translocation from the gut)
Candidemia with deep-seated
infection
Deep-seated infection without
candidemia
• Gold standard of proven
disease performs poorly
Blood cultures require
-at least 1 CFU/ml
-equals 5.6 x 103 CFU in blood
volume (0.2% of systemic
circulation)
•6-yr autopsy study
•Autopsy rate 75%
•41 of 803 autopsies
(5.1%) disseminated
candidiasis at autopsy
•37 had blood
cultures; 16 had
fungaemia (43%)
Berenguer et al,Diagn Microbiol
Infect Dis 1993;17:103-109
If diagnosis performs bad, should we prophylaxe our
ICU patients?
Author
Patients Setting
Therapy
Fungal infections
fluconazole
Pelz
Mortality
placebo
fluconazole
placebo
260
SICU
FLU 800 load
then 400mg po, od
until ICU discharge
8.5
15.4
10.7
12.3
43
SICU
FLU 400mg iv, od
8.7
35.0
30.4
50.0
Garbino
204
mixed
FLU 100mg iv, od
( + other agents)
3.8
9.9
38.8
40.6
Ables
119
SICU
FLU 800mg load
then 400mg po/iv, od
until ICU discharge
13.3
18.6
20.0
18.6
Eggimann
FLU = fluconazole; po =oral; iv = intravenous; SICU=surgical intensive care unit
Prophylactic Treatment with Fluconazole in ICU
Patients
→
Decreases incidence of invasive candidiasis
→ Has
no mortality benefit
OR 0.44 (CI 0.27-0.72)
OR 0.87 (CI 0.59-1.28)
Comments
• Widespread use of prophylaxis not warranted
- emergence of resistance in previously susceptible strains
- shift to less susceptible or resistant non-albicans spp. (e.g. C.glabrata)
- may lead to more adverse drug reactions + potential for interactions
• Should target only those patients at the highest risk
- major abdominal surgery with recurrent perforation and/or anastomotic leaks
- presumed risk of invasive candidiasis = 10-15%
Can we predict more accurately and
treat according to risk factors?
• Prospective cohort study in 933 surgical ICU patients
• 455 historical controls
• 478 patients treated with fluconazole, 800mg iv load, then 400mg
/day for 4 weeks, started when corrected colonization index (CCI)* >
0.4
CCI =
highly positive samples
total number of samples
Candida infections
3.8% vs. 7.0%; p=0.03
%7
6
> 100 CFUs for rectal & oropharyngeal swabs
> 105 CFUs/mL for urine, gastric & tracheal aspirate
5
Proven ICU-acquired candidiasis
0% vs. 2.2%; p< 0.001
4
3
2
1
0
Piarroux R, et al. Crit Care Med 2004; 32: 2443-9
fluconazole
placebo
Colonization from airway samples: no reason
to treat
1587 admissions
301 died (19
%)
232 autopsies
(autopsy rate 77%)
135 patients with evidence of
pneumonia (58 %)
77 patients
with respiratory sample
positive for Candida spp
(57 %)
Candida pneumonia
n=0
97 patiënts with no evidence of
pneumonia (42 %)
58 patients
without respiratory
sample positive for
Candida spp
(43 %)
Candida pneumonia
n=0
Meersseman W et al. Intens Care Med
2009; 35: 1526-31
Pre-emptive Therapy: Candida score
• Prospective cohort study in 1107 ICU patients
• Patients had to be in the ICU for at least 7 days
• Scoring system:
- surgery 1 point
- multifocal colonization 1 point
- total parenteral nutrition 1 point
- severe sepsis 2 points
•Hypothesis: Candida score > 3 is associated with prevalence of
Candidemia of 10-15% and as such the score could be used as a
valuable pre-emptive tool
•Drawback: diagnostic study, not a therapeutic study
Leon C, et al. Crit Care Med 2009;
32: 2443-9
Pre-emptive Therapy: biomarkers
(beta D-glucan)
• Potential advantages
- rapid turn-around time
- not dependent on viable organisms
- may be positive prior to cultures, and stay positive during treatment
- may offer quantitative data with prognostic significance
• Potential disadvantages
- do not recover organisms
- may not speciate Candida or distinguish between fungi
- may need to be run in batch by clinical microbiology laboratory due
limited number of samples
- may have low treshold for contamination
- financial costs
Time to abandon prophylaxis
and empiric therapy
Select those patients in which
you expect a 10-15%
incidence of yeast infection
- Candida score >3
- beta D-glucan or PCR
In order to decrease the 50%
“missed” diagnoses by picking
up deep seated candidiasis
Important caveat: false positive rate beta-Dglucan (high negative predictive value)
Candida bloodstream infections
and invasive candidiasis:
therapeutic issues
Candidemia treatment trials
• “A is non-inferior to B”
• Fungicidal anidulafungin (probably
candins) clear Candida quicker than the
fungistatic fluconazole (as does ampho
B!)
• Anidulafungin: only echinocandin that
was compared to fluconazole
What about increasing resistance to
echinocandins?
Problem is most relevant with Candida glabrata
Increasing resistance of candida glabrata against
echinocandins
Echinocandin resistance against candida glabrata
Clinical failure especially in patients with longstanding echinocandin use
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
600,000
CDC estimate
> 50% developing
world Invasive candidiasis/candidemia
Invasive
aspergillosis
50% in developed
world if treated
Chronic
pulmonary
aspergillosis
15% in developed
> 450,000
Underdiagnosed
 100,000
deaths per year
world
and mistaken for TB
Candida
bloodstream
infection
Many missed
diagnoses globally
 Emerging echinocandin resistance is a
40% if treated significant
> 120,000
concern
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
Mucormycosis
10-25% cutaneous
95% disseminated
Total
> 100,000
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
20,000
No exact figures
> 1,350,000
Probably a
significant
underestimate
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
> 50% developing
world
600,000
CDC estimate
Invasive
aspergillosis
50% in developed
world if treated
> 100,000
Many missed
diagnoses globally
Chronic
pulmonary
aspergillosis
15% in developed
world
> 450,000
Underdiagnosed
and mistaken for TB
Candida
bloodstream
infection
40% if treated
> 120,000
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
Mucormycosis
10-25% cutaneous
95% disseminated
20,000
No exact figures
Total
> 1,350,000
Probably a
significant
underestimate
Pneumocystis jirovecii pneumonia
•
•
•
•
•
Cellullar immune deficiency (CD4)
Most studies done in HIV
High negative predictive value LDH
Problems with PCR: “too sensitive”??
Immunofluorescence: “not sensitive
enough”?
Very high beta-D-glucan levels in PJP
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
> 50% developing
world
600,000
CDC estimate
Invasive
aspergillosis
50% in developed
world if treated
> 100,000
Many missed
diagnoses globally
Chronic
pulmonary
aspergillosis
15% in developed
world
> 450,000
Underdiagnosed
and mistaken for TB
Candida
bloodstream
infection
40% if treated
> 120,000
Pneumocystis
pneumonia
15% in AIDS
50% in non-AIDS
> 80,000
Most cases in Africa
not diagnosed and
100% mortality
Mucormycosis
10-25% cutaneous
95% disseminated
20,000
No exact figures
Total
> 1,350,000
Probably a
significant
underestimate
Mucormycosis
Incidences of mucormycosis over
6 decades (1940–1999), by host
population, 929 cases
Roden M et al., CID, 2005;41(5):634-53.
Incidence of mucormycosis cases in
a Belgian hospital from 2000
through 2009
•
•
•
•
•
•
31 patients: 21 proven, 10 probable
M/F: 16/15
Mean age: 54 years (12-79 years)
61% haematological patients
45% co-infections with Aspergillus (halo-sign!)
Mortality rate = 65% (48%, directly related to
infection)
V. Saegeman et al., Emerg Infect Dis 2010, 16: 1456-1458.
Big increasing mass in a neutropenic patients with BAL galactomannan
negative: think of mucormycosis
Galactomannan negative !!
Mucormycosis
Global Action Fund for Fungal Infections
(www.gaffi.org)
Fungal infection
Case fatality rate
Estimated deaths
Comments
Cryptococcal
meninigitis
15-20% USA
600,000
> 50% developing
world Mucormycosis
CDC estimate
Invasive
aspergillosis
50% in developed
world if treated
Many missed
diagnoses globally
Chronic
pulmonary
aspergillosis
15% in developed
> 450,000 recognized
Underdiagnosed
 Increasingly
in the voriconazole
world
and mistaken for TB
era
Candida
bloodstream
infection
40% if treated
> 120,000
 Does
occur in immunocompetent patients
Pneumocystis
pneumonia
Mucormycosis
Total
> 100,000
mainly as a necrotizing skin infection
15% in AIDS
> 80,000
Most cases in Africa
 Liposomal
ampho B preferred
treatment
50% in non-AIDS
not diagnosed and
100% mortality
10-25% cutaneous
95% disseminated
20,000
> 1,350,000
No exact figures
Probably a
significant
underestimate
Some new kids on the horizon…
- In 2012 and 2013: 749 cases of infections with Exserophilum rostratum
- Linked to epidural injections with methylprednisolone acetate
- 61 deaths occurred
Young lady in UZ Leuven, Belgium. Kidney transplant at the age of 34
Ethiopian origin. 6 months posttransplant: painful lesion left lower limb
4 months later
Despite stopping
immunosuppressants,
transplantectomy
Administration of lipo
ampho B,
isavuconazole,
posaconazole
Thick walled brown pigment on hematox eosin staining
Cladophialophora bantiana
Prospective study 2012005
TRANSNET
-
Skin
Pulmonary
Disseminated
Brain (cladophialophora)
In conclusion
- High income countries
Invasive infections: diagnostic issues (candida), emerging resistance
(azole resistance in Aspergillus,
echinocandin resistance in
candida)
- Resource limited countries
Unacceptably high number of deaths in cryptococcal disease
Increase in candida, aspergillus and mucormycosis in some countries
No acces to drugs such as flucytosine