1. ASIA-PACIFIC HEMATOLOGY CONSORTIUM
Fungal infections in hematology patients: advances in prophylaxis and treatment
Good afternoon, lady and gentleman, it is my pleasure to attend this conference, and share with you the advances in prophylaxis and treatment of fungal infections in hematology patients
Vincent CC Cheng
MBBS (HK), MD (HK), PDipID (HK), MCRP (UK), FRCPath (UK), FHKCPath, FHKAM (Path)
Department of Microbiology
Queen Mary Hospital

2. Mortality from invasive fungal infection in patients with acute leukemia and HSCT
As you know, the mortality from invasive fungal infections in patients with hematological malignancy and transplantation is high.
It ranges from 40-50% in patients with invasive candidasis, and over 70% in patients with invasive aspergillosis.
(40-50%)
(>70%)

3. Phases of opportunistic infections among allogeneic HCT recipients
Among the blood and marrow transplant recipient, the spectrum of invasive fungal infection depends on the day after transplantation.
Biol Blood Marrow Transplant Oct;15(10):

4. Standard dose 1 mg / kg / day (BW 50 kg)
Concentrations of Amphotericin B deoxycholate in tissues of 13 cancer patients
Standard dose 1 mg / kg / day (BW 50 kg)
50 mg per day
Liver
Spleen
In the past, there was only one available antifungal agents – ampho B deoxycholate, which takes a long time to achieve a therapeutic concentration in the tissue. Patient may have to stop the drug for nephrotoxicity before it becomes effective.
Antimicrob Agents Chemother Mar;33(3): Links
Tissue concentrations and bioactivity of amphotericin B in cancer patients treated with amphotericin B-deoxycholate.
Collette N, van der Auwera P, Lopez AP, Heymans C, Meunier F.
Laboratoire d'Investigation Clinique Henri Tagnon, Institut Jules Bordet, Centre des Tumeurs de l'Université Libre de Bruxelles, Belgium.
We have studied amphotericin B concentrations in tissues of 13 cancer patients who died after having received 75 to 1,110 mg (total dose) of amphotericin B-deoxycholate for suspected or proven disseminated fungal infection. Amphotericin B concentrations were measured by high-pressure liquid chromatography (HPLC) and by bioassay, the latter being done on tissue homogenates as well as on tissue methanolic extracts. The fungistatic and fungicidal titers of the tissue homogenates were also tested against three strains of Candida albicans and one strain of Aspergillus fumigatus. Tissue concentrations of amphotericin B measured by HPLC varied with the tested tissues as well as with the total dose of amphotericin B-deoxycholate administered and ranged from 0.4 to micrograms/g. A mean of 38.3% (range, 23.0 to 51.3%) of the total dose was recovered by HPLC from all of the tested organs. Bioassay of tissue methanolic extracts reached 58 to 81% of the concentration measured by HPLC, whereas only 15 to 41% was recovered from the homogenates. Overall, 27.5% of the total dose was recovered from the liver, 5.2% was recovered from the spleen, 3.2% was recovered from the lungs, and 1.5% was recovered from the kidneys. The median concentration in bile was 7.3 micrograms/ml, suggesting that biliary excretion could contribute to amphotericin B elimination to an estimated range of 0.8 to 14.6% of the daily dose. Fungicidal titers were seldom measured in tissues, but fungistatic titers were observed and were linearly correlated with amphotericin B concentration measured by HPLC. In conclusion, only a small proportion of the amphotericin B administered as amphotericin B-deoxycholate to patients seems diffusible and bioactive.
PMID: [PubMed - indexed for MEDLINE]
Kidney
Lung
20 days
MIC level
10 days
Antimicrob Agents Chemother Mar;33(3):362-8.

5. Time line of development of antifungal agents
Caspofungin
Micafungin
Anidulafungin
Voriconazole
Posaconazole
L-AmB
ABCD
ABLC
Terbinafine
Itraconazole
Griseofulvin
Amphotericin B
Fluconazole
Ketoconazole
However, as time goes by, there are more and more antifungal agents in the market, especially the presence of echinocandin, and new azole group.
Miconazole
Nystatin
5-FC

6. Fluconazole or itraconzole
( )
Persistent neutropenic fever
Prophylaxis
Known pathogen therapy
Liposomal Ampho B vs
Ampho B deoxycholate
Posaconazole vs
Fluconazole
(GVHD)
Voriconazole vs
Ampho B deoxycholate
(Aspergillus)
Caspofungin vs
Liposomal Ampho B
And these agents have been tested in various randomized control studies with relative merits in the past 15 years, and we will discuss the detail later.
For known pathogen therapy, the 12-week response rate in voriconazole group was 53% vs 32% in Ampho B. The survival rate of voriconazole was 71% vs 58% in Ampho B.
For neutropenic fever (voriconazole vs ambisome), the results has been controversial. The voriconazole treatment group did not meet the predefined composite primary end point for inferiority. When the elements of 5-elements composite end points were evaluated, data for 4 of the 5 elements favored ambisome, but the differences were not statistically significant.
5-elements: Breakthrough fungal infection, survived for seven days beyond the end of therapy, did not discontinue therapy prematurely, had resolution of the neutropenic fever, and successfully treatment of baseline fungal infection
Posaconazole vs
Fluconazole or itraconzole
(AML / MDS)
Caspo vs
Ampho B
(Candida)
Anidula vs
Flucon
(Candida)
Voriconazole vs
Liposomal Ampho B

7. were the major criteria used for stratification
Risk group stratification for development of invasive fungal infections in patients with hematologic malignancies +/- hematopoietic cell transplant
High risk
Prolong neutropenia (<0.1x109/L for 3 wk and / or <0.5x109/L for 5 wk)
Allogeneic unrelated or mismatched BMT
GVHD
High dose Arabinose-C
Corticosteroids > 1/mg/kg with neutropenia <0.1x109/L over 1 wk
Corticosteroids > 2 mg/kg over 2 wk
Intermediate risk (high intermediate)
Fungal colonization at 1 site with neutropenia x109/L for 3-5 wk
Fungal colonization at > 1 site
AML
Total body irradiation
Allogeneic matched sibling donor BMT
Intermediate risk (low intermediate)
Neutropenia x109/L < 3 wk
Antibiotics + lymphopenia <0.5x109/L
Older age
Presence of a central venous catheter
Degree of neutropenia, diagnosis, type of transplant, exposure to corticosteroids, type of chemotherapy, and prior fungal colonization
were the major criteria used for stratification
With the availability of news drugs, it is useful to stratify patients into different groups for the development of invasive fungal infections.
Low risk
Autologous BMT
Lymphoma
Childhood AML
Transpl Infect Dis Dec;11(6):480-90; Br J Haematol Aug;110(2):

8. were the major criteria used for stratification
Risk Based approach in antifungal treatment
Risk group
Prophylaxis
Pre-emptive
Empirical
Targeted
High
Yes
Intermediate (high)
Intermediate (low) ?
Low
Basically, the risk stratification is depends on the degree of neutropenia, diagnosis, type of transplant, exposure to steroid, type of chemotherapy, and the presence of fungal colonization.
Therefore, antifungal prophylaxis and empirical therapy is recommended in high and intermediate high risk group, while pre-emptive treatment is given in low or intermediate low risk group.
Known pathogen therapy is always considered in all patient groups.
We will discuss the treatment regimen one by one.
Degree of neutropenia, diagnosis, type of transplant, exposure to corticosteroids, type of chemotherapy, and prior fungal colonization
were the major criteria used for stratification
Br J Haematol Aug;110(2):

9. FLU 400 mg qd po or 200 mg bd iv vs placebo
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant
Study
Patients
Design
Regimen
Outcome
Fluconazole
Goodman et al (1992)
356 (allo/
auto BMT)
RCT (double blinded)
FLU 400 mg qd po vs placebo
IFI: FLU ↓
Mortality: FLU ↓
Winston et al (1993)
257 acute leukemia
patients on chemo
FLU 400 mg qd po or 200 mg bd iv vs placebo
IFI: No diff (3 cases of Aspergillus in both arms)
Mortality: no diff
Slavin et al (1995)
300 (allo/
FLU 400mg qd po vs placebo
Rotstein et al
(1999)
304 (44% auto BMT)
Antifungal prophylaxis. It has been well documented in the BMT setting. This is the first study to demonstrate the usefullness of fluconzole vs placebo in reducing the number of invasive fungal infection, mainly candidasis, and resulting in lower mortality.
The findings can be reproduced in the subsequent studies a few years later.
But the result is not that promising in patient with acute leukemia on induction chemotherapy.
Goodman JL, et al. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med 1992; 326 (13):
Winston DJ, et al. Fluconazole prophylaxis of fungal infections in patients with acute leukemia: results of a randomized placebo-controlled, double-blind, multicenter
trial. Ann Intern Med 1993; 7 (118):
Slavin MA, et al. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation : a prospective, randomized, double-blind study. J Infect Dis 1995; 171 (6):
Rotstein C, et al. Randomized placebo controlled trial of fluconazole prophylaxis for neutropenic cancer patients: benefit based on purpose and intensity of cytotoxic therapy. Clin Infect Dis 1999; 28 (2):

10. autologous and BMT) & HM patients Open-label
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant
Study
Patients
Design
Regimen
Outcome
Itraconazole
Morgenstern et al (1999)
445 (includes
autologous and BMT) & HM patients
Open-label
ITR 2.5 mg/kg cyclodextrin solution bd po vs FLU 100 mg suspension qd po
IFI: No diff
Mortality: ITR ↓
Huijgen et al (1999)
213 patients (57% auto BMT; 31% HM on chemo
RCT (double blinded)
ITR 100 mg bd po vs FLU 50 mg bd po
Mortality: no diff
Harousseau et al (2000)
557 HM patients (5% BMT)
ITR 2.5 mg/kg solution bd po vs AMB 500 mg capsule qid po
Mortality: No diff
Marr et al (2004)
304 (allo BMT)
ITR 2.5 mg/kg solution td po or 200 mg iv qd vs FLU 400 mg po or iv qd
IFI: ITR ↓
Later on, itraconazole is used as antifungal prophylactic agent. It is supposed to have anti-aspergillus activity. But the results are not impressive.
Morgenstern GR, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological alignancies. Br J Haematol 1999; 105 (4):
Huijgens PC, et al. Fluconazole versus itraconazole for the prevention of fungal infections in haemato-oncology. J Clin Pathol 1999; 52 (5):
Harousseau JL, et al. Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B. Antimicrob Agents Chemother 2000; 44 (7):
Marr KA, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood 2004; 103 (4):

11. POS 200 mg suspension td po vs FLU 400 mg qd po IFI: POSA ↓
Selected antifungal prophylaxis trials with > 100 patients with hematologic malignancies and Hematopoietic cell transplant
Study
Patients
Design
Regimen
Outcome
Posaconazole
Ullmann et al (2007)
600 (allo BMT)
RCT (double blinded)
POS 200 mg suspension td po vs FLU 400 mg qd po
IFI: POSA ↓
Mortality: POS ↓
Cornely at al (2007)
602 AML or MDS
patients on
chemotherapy
RCT (evaluator blinded)
POS 200 mg suspension td po vs FLU 400 mg suspension qd po or ITR 200 mg solution bd po
Micafungin
van Burik et al (2004)
889 (46% auto BMT, 54%
Allo BMT)
MICA 50 mg iv qd vs FLU 400 mg iv qd
IFI: MICA↓
Mortality: No diff
However, a breakthrough in antifungal prophylaxis occurs when a new azole, posaconazole is introduced to market. It is a broad spectrum agent with anti-mold activity. In these two sutdies published togehter in NEJM, it was clearly shown that the use of posaconazole in both BMT patients and patients with AML or MDS on chemotherapy, reduced the number of invasive fungal infection and mortality.
Micafungin was tested with Fluconzaole in a randomized double blind control trail. The use of mucafungin reduced the number of invasive fungal infection but not the mortality.
Ullmann AJ, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007; 356 (4):
Cornely OA, et al. Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007; 356 (4):
van Burik JA, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39 (10):

12. A randomized, double-blind trial comparing
voriconazole (200 mg twice daily) vs fluconazole (400 mg daily)
in allograft recipients >2 years of age considered to be at standard risk of IFI
Prophylaxis:
at least 100 days
extended to 180 days if
receiving prednisone (>1 mg/kg daily) and/or CD4 cells <200/µL
Serum galactomannan levels & intensive diagnostic process
Fungal-free survival:
78% with voriconazole (6 mo)
75% with fluconazole (6 mo)
64% with voriconazole (12 mo)
65% with fluconazole (12 mo)
Recently, vorioconzole was tested in a randomized double blind trail. The drugs were given for at least 100 days in allograft recipients over 2 years of age and who were considered to be at standard risk of invasive fungal infection. Duration of prophylaxis would be extended to 180 days if they received steroid and with low CD4 count.
Non-invasvie diagnostic test such as serum galactomannan antigen was measured, and followed by imaging studies.
You can see that the fungal free survival was comparable between voriconzole and fluconazole in 6 and 12 mo times.
Wingard JR, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 2010; 116: 5111–5118.

13. A prospective, phase III, randomized, open label, multi-centre clinical trial
Eligible patients:
>12 years of age
allogeneic HCT for acute leukaemia, transformed CML, or failure of lymphoma therapy
Prophylaxis :
at least 100 days antifungal
continued until 80 days
if IFI risk factors persisted
Primary endpoint:
Success of antifungal prophylaxis at day 180
(defined as fungal-free survival to day 180 without having discontinued study treatment for >14 days in total before day 100)
Survival outcome at Day 100, 180, and 1 year (no difference)
In addition, voriconazole was tested against itraconazole in multi-center clinical trail. The study design is similar to the previous study. Although the survival outcome had no difference, the composite end point suggests voriconzaole was superior to itraconazole.
Marks DI, et al. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic stem cell transplanation. Br J Haematol 2011; 155: 318–327.

14. Patient risk stratification and treatment recommendations for primary antifungal prophylaxis in haematology patients as per the ECIL-3 (3rd European Conference on Infections in Leukemia) guidelines
Based on the previously mentioned clinical studies, the 3rd European Conference on infections in Leukemia comes up with a guideline on the use of antifungal prophylaxis. It is recommended that fluconazole is still first line agent for BMT patients with initial neutropenia, while posaconazole is to be used in patients with GVHD and during induction chemotherapy.
However, since there is no iv formulation of posaconazole and the oral absorption of posaconazole may be erratic. Serum concentration of psoaconazole should be monitored to ensure the therapeutic drug level.
Serum drug concentrations of posaconazole and itraconazole be monitored to ensure therapeutic levels of these agents
Maertens J, et al. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3 – 2009 update. Bone Marrow Transplant 2011; 46: 709–718.

15. Empirical antifungal therapy: fever-driven approach
Targets haematology patients that have prolonged neutropenia
Persistent or relapsing fever despite 4–7 days of adequate broad spectrum antibiotics
Absence of
other clinical symptoms/signs,
conventional radiological and laboratory findings
specific investigations aimed at documenting invasive fungal disease (e.g. CT scan, detection of circulating fungal markers)
Based on moderate evidence from clinical trials with small sample size and debatable methodology/design
May results in significant overtreatment, toxicity and expenditure
So much so for prophylaxis.
Empirical antifungal therapy or fever driven approach has been an established clinical practice.
When patient has persistent neutropenic fever not responding to broad spectrum antibiotic for 4 days (some studies suggest 3 days), without definitive infective diagnosis, empirical antifungal treatment would be given.
However, this approach was only based on moderate evidence from clinical trails with small sample size.
This approach may also result in over treatment, toxicity and expenditure.
Klastersky J. Antifungal therapy in patientswith fever and neutropenia—more rational and less empirical? N Engl J Med 2004; 351: 1445–7.

16. Measures of the Success of Empirical Antifungal Therapy with Conventional or Liposomal Amphotericin B, Voriconazole, or Caspofungin
In fact, overall rate of fever resolution are ranged from 40-60% according to three clinical trails (Lip Amp B vs conventional Amp B / Lip Ampho B vs Voriconzole / Caspofungin vs Lip Amp B) on the empirical antifungal therapy.
Liposomal Ampho B vs Ampho B deoxycholate Liposomal Ampho B vs Voriconazole Caspofungin vs Liposomal Ampho B
Walsh TJ, et al. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. N Engl J Med 1999;340:
Walsh TJ, et al. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med 2002; 346:
Walsh TJ, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med 2004;351:
N Engl J Med Sep 30;351(14):

17. ECIL 3 guidelines on empirical antifungal treatment in neutropenic patients with persistent or relapsing fever
And based on these three clinical trails published in NEJM, the European guideline recommends the use of Lip Amp B or Caspofungin as empirical antifungal therapy in patients with persistent or relapsing neutropenic fever.
Bone Marrow Transplant 2011; 46: 709–718.

18. Pre-emptive antifungal therapy: diagnostics-driven approach
The time period between fungal replication, invasion and appearance of signs and symptoms represents a window of opportunity for earlier treatment.
However, there is as yet no consensus definition of preemptive antifungal therapy.
Such therapy should not be triggered by fever as a sole criterion, but should rest on:
a clear identification of those patients who are at risk of fungal disease
utilization of sensitive techniques that facilitate rapid and early diagnosis of invasive mould infections, e.g. galactomannan, b-D-glucan or PCR testing as well as computerized radiological imaging techniques
With the advance in laboratory diagnostic and imaging studies, a pre-emptive or diagnostic driven approach was evolved.
It is believed that the time period between ………..
And such therapy should not be triggered by neutropenic fever alone. In fact, if the diagnostic test such as galactomannan antigen and CT scan showed the evidence of aspergillosis, antifungal treatment would be started even in patient without fever.
However, there is no consensus definition of preemptive antifungal therapy at this stage.

19. Diagnostic tools Advantages Disadvantages
Advantages and disadvantages of major non-culture-based laboratory diagnostic methods for IFI
Diagnostic tools
Advantages
Disadvantages
Galactomannan assay
Noninvasive serum assay
Biweekly testing may allow earlier detection of IA
With the cutoff OD index reduced to 0.5 (from 1.5), greater overall sensitivity improved from 76% to 97%
High percentage of false positives; sensitivity 100%-33%
Exposure to mold-active antifungals considerably reduces sensitivity
Some serum reactivity in patients on beta-lactam antibiotics
(1, 3)-beta-Dglucan
antigen test
Detects Candida and Aspergillus species and other opportunistic fungal pathogens
False-positive and false-negative
Sensitivity lower in patients with localized Aspergillus infection
Does not usually detect Cryptococcus species or Zygomycetes
PCR assays
Highly specific and sensitive
Negative result can rule out IA and potentially limits empiric therapy need
No pan-fungal assay available to date
Lack of a standardized method
Eur J Haematol Oct;87(4):

20. Fever-driven approach: Antifungal Rx: 41 of 136 episodes
Pre-emptive approach:
Antifungal Rx <25% episodes
(but identified 10 episodes of fungal infection without fever or with the presence of confounding febrile conditions)
No patient received mould-active prophylaxis
(? improving the sensitivity of the assay and favoring the pre-emptive approach)
This was the first prospective study to look at the feasibility of preemptive antifungal thearpy.
Antifungal agents (lip Amp B) was given according to the protocol using galactomann antigen test and CT scan.
Based on this preemptive approach, you can see that less than 25% of patients received antifungal therapy, even for those who did not have fever.
One of the key point that we have to address is that no patient received mould active prophylaxis such as posaconazole during the study period, which may improve the sensitivity of galactomanna assay.
liposomal amphotericin B
Clin Infect Dis Nov 1;41(9):

21. 17 patients developed an IFI: 4 (2.7%) in empirical group
293 patients with haematological malignancies (duration of neutropenia ≥ 10 days)
17 patients developed an IFI:
4 (2.7%) in empirical group
13 (9%) in pre-emptive group (P<0.02)
Overall survival rates:
2 weeks after neutrophil recovery (95% vs 97%, P=0.12)
Duration of neutropenia < 15 days:
no difference
Prolonged neutropenia:
↑risk of fungal infection in the pre-emptive therapy arm
Antifungal prophylaxis was given according to each center’s protocol
Amphotericin B deoxycholate (1 mg/kg/day)
Liposomal amphotericin (3 mg/kg/day)
Pre-emptive approach significantly reduced the use of antifungal agents (39.2% vs 61.3%, P<0.001)
Recently, a randomized control trail was published in CID to look at the performance of two approaches in almost 300 patients with hematological malignancies.
These patients were allowed to use antifungal prophylaxis according to the their protocols.
Amph B were used if clinically indicated.
It is expected that pre-emptive approach significantly reduced the use of antifungal agents.
As for the clinical outcome, you can see that although the overall patient survival among two groups were similar, more patients in pre-emptive group developed invasive fungal infection, especially for those patient with prolonged neutropenia.
Clin Infect Dis Apr 15;48(8):

22. Known pathogen therapy (Targeted therapy) of mould infections
Voriconazole:
first-line therapy of invasive aspergillosis based on
the results of a prospective, randomized clinical trial with amphotericin B deoxycholate as comparative initial therapy in possible, probable or proven disease
149 (54%) of 277 patients were culture +ve for Aspergillosis
Finally, known pathogen therapy.
Voriconazole is now recommended as the first line therapy for invasive aspergillosis according the results of a prospective randomized trail with Amp B. The response rate at 12 weeks was significantly better in voriconazole group.
Among 277 patients recruited, about 54% if them had culture documentation of aspergillus.
However, the use of voriconazole may be affected by drug interaction, impariment of liver and renal function, as well as preexisting exposure to mould active azole.
Potential concern of using voriconazole:
prior exposure to mould-active azoles, the concomitant use of contraindicated medication (e.g. sirolimus), the risk of severe drug interactions, moderate to severe hepatic or renal impairment
Herbrecht R, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002; 347: 408–15.

23. Treatment of aspergillosis: clinical practice guidelines of IDSA
Condition
Primary Rx
Alternative Rx
Invasive pulmonary aspergillosis
Invasive sinus aspergillosis
Tracheobronchial aspergillosis
Chronic necrotizing pulmonary aspergillosis (subacute invasive
pulmonary aspergillosis)
Aspergillosis of the CNS
Voriconazole (6 mg/kg IV every 12 h for 1 day, followed by 4 mg/kg IV every 12 h; oral dosage is 200 mg every 12 h)
L-AMB (3–5 mg/kg/day IV), ABLC (5 mg/kg/day IV),
Caspofungin (70 mg day 1 IV
and 50 mg/day IV thereafter),
Micafungin (IV 100–150 mg/day; dose not established),
Posaconazole (200 mg QID
initially, then 400 mg BID PO after stabilization of diseased),
Itraconazole (dosage
depends upon formulation)
Anyway, based on this publication in NEJM, voriconzaole is recommended as primary treatment for almost all forms of invasive aspergillosis in IDSA guideline. Whereas the other antifungal agents are categorized as alternative treatment.
Surgical debridement may be indicated
Walsh TJ, Anaissie EJ, Denning DW et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008; 46: 327–60.

24. Known pathogen therapy (Targeted therapy) of mould infections
Echinocandins in the primary therapy of invasive aspergillosis: limited data
non-comparative Phase II study in two different cohorts:
N=61
Favorable response: 33%
N=24
Favorable response: 42%
Echinocandin has been tested in limited number of patients with invasive aspergillosis. The clinical response is ranged between 30-40%.
Viscoli C, et al. An EORTC Phase II study of caspofungin as first-line therapy of invasive aspergillosis in haematological patients. J Antimicrob Chemother 2009; 64: 1274–81.
Herbrecht R, et al. Caspofungin first-line therapy for invasive aspergillosis in allogeneic hematopoietic stem cell transplant patients: an European Organisation for Research and Treatment of Cancer study. Bone Marrow Transplant 2010; 45:
1227–33.

25. Choice of antifungal combination therapy
Caspofungin Micafungin Anidulafungin
Amphotericin B
How about the combination antifungal therapy?
Especially using the drugs on different target sites.
This the fungal cytoplasmic membrane which contain more ergosterol in fungus than cholesterol when compared with human cells. This is the target of polyenes antifungal such as amphotericin B and nystatin. And its synthesis is inhibited by fluconazole, itraconazole, voriconazole, posaconazole. The osmotic stability of the fungal cell is maintained by an outer cell wall which contains the mannan and protein on the surface beta glucan polyssacharides in the middle, its synthesis is inhibited by the echinocandins such as caspofungin, micafungin, and anidulafungin and the synthesis of chitin at the inner surface is inhibited by nikkomycins.
Fluconazole Itraconazole Voriconazole Posaconazole
Trends Microbiol 2003;11:272–279.

26. Choice of antifungal combination therapy
Cancer Feb 15;97(4):
These are the initial studies to test the combination of lip Amp B and Caspofungin in patients with refractory aspergillosis.
Cancer Jul 15;98(2): Links
Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies.
Kontoyiannis DP, Hachem R, Lewis RE, Rivero GA, Torres HA, Thornby J, Champlin R, Kantarjian H, Bodey GP, Raad II.
Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
BACKGROUND: Caspofungin (CAS) as salvage therapy for refractory invasive aspergillosis (IA) had a response rate of 45% among a heterogeneous group of patients. The use of CAS with other agents is appealing given its unique mechanism of action. Therefore, the authors retrospectively evaluated the efficacy and toxicity of CAS plus liposomal amphotericin B (LipoAMB) in patients with documented (definite or probable) or possible IA. METHODS: Patients were evaluable for outcome if they received CAS/LipoAMB for at least 7 days. Patients who received CAS and LipoAMB sequentially were excluded. All patients were evaluable for toxicity. Outcome was assessed weekly and at the end of therapy. Stable disease and progression were considered treatment failures. RESULTS: Forty-eight patients with documented (n=23) or possible (n=25) IA were identified between March 2001 and December The majority of the patients (65%) received CAS/LipoAMB as salvage therapy for progressive IA despite 7 or more days of previous LipoAMB monotherapy. The overall response rate was 42%. No significant toxic effects were seen. Factors associated with failure at the end of therapy were documented IA (P=0.03), significant steroid use before the study (P=0.02), and duration of combination therapy for less than 14 days (P=0.01). The response rate in patients with progressive documented IA was low (18%). CONCLUSIONS: The CAS/LipoAMB combination is a promising preemptive therapy for IA and was generally well tolerated. This combination might have limited benefit as salvage therapy for documented IA. Copyright 2003 American Cancer Society.
PMID: [PubMed - indexed for MEDLINE]
Cancer Feb 15;97(4): Links
Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin.
Aliff TB, Maslak PG, Jurcic JG, Heaney ML, Cathcart KN, Sepkowitz KA, Weiss MA.
Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
BACKGROUND: Pulmonary aspergillosis and other invasive fungal infections (IFIs) commonly complicate the management of patients with acute leukemia. Standard amphotericin-based therapies may be ineffective for many patients and the available salvage agents (itraconazole and caspofungin) are reported to possess only moderate activity against resistant infections. Laboratory evidence suggests a synergistic interaction between amphotericin and caspofungin. The authors treated a group of patients with amphotericin-refractory IFIs with the combination of caspofungin and amphotericin (or liposomal amphotericin). METHODS: A retrospective evaluation of patients with amphotericin-resistant IFIs was conducted. Diagnosis was based on clinical, radiographic, and when available, microbiologic data. Response to combination antifungal therapy was graded as either favorable or unfavorable. Favorable responses included improvement of both clinical and radiographic signs of fungal pneumonia. All other responses were graded as unfavorable. RESULTS: Thirty patients were included in this analysis. Twenty-six patients had acute leukemia. Based on recently published criteria, the IFIs were classified as proven in 6 patients, probable in 4 patients, and possible in 20 patients. The median duration and dose of amphotericin monotherapy were 12 days (range, 4-65 days) and 7.8 mg/kg (range, mg/kg), respectively. The median duration of combination therapy was 24 days (range, 3-74 days). Eighteen patients (60%) experienced a favorable antifungal response. Twenty patients with acute leukemia received combination therapy for fungal pneumonias arising during intensive chemotherapy treatments. Favorable responses were observed in 15 of these patients (75%), and antifungal response did not depend on the response of the underlying leukemia. Survival to hospital discharge was significantly better (P < 0.001) in patients having a favorable response. Mild to moderate nephrotoxicity was noted in 50% of patients, necessitating the substitution of liposomal amphotericin. Mild elevation of alkaline phosphatase levels occurred in 30% of patients. Caspofungin was temporarily withheld from one patient who developed moderate but reversible biochemical hepatotoxicity. CONCLUSIONS: The antifungal combination of caspofungin and amphotericin can be administered safely to high-risk patients with hematologic malignancies. Although an absolute assessment of efficacy is limited by the design of this study, encouraging outcomes were noted for many patients. The authors plan to evaluate this regimen further in a randomized clinical trial. Copyright 2003 American Cancer Society
PMID: [PubMed - indexed for MEDLINE]
Cancer Jul 15;98(2):292-9.

27. Choice of antifungal combination therapy
Patients (HSCT or hemic malignancies) Pulmonary aspergillosis (proven or probable)
Failure with amphotericin B
Voriconazole
Caspofungin
P=0.048
* historical control
And this is the most recent study, using voriconazole and caspofungin as combination, in patients with refractory pulmonary aspergillosis not responding to amph B. The patient survival was just significantly better than using voriconazole alone.
Clin Infect Dis Sep 15;39(6): Epub 2004 Aug 27. Links
Comment in:
Clin Infect Dis Sep 15;39(6):803-5.
Clin Infect Dis Apr 1;40(7):1073-5; author reply
Combination antifungal therapy for invasive aspergillosis.
Marr KA, Boeckh M, Carter RA, Kim HW, Corey L.
Program in Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
BACKGROUND: Aspergillosis therapy with amphotericin, azoles, or echinocandins is associated with substantial mortality, ranging from 30% to 80%, depending on the stage of infection and the host's underlying disease. The results of in vitro studies and animal models suggest that combination therapy with azoles and echinocandins may have additive activity against Aspergillus species. METHODS: We evaluated the outcomes of patients with aspergillosis who experienced failure of initial therapy with amphotericin B formulations and received either voriconazole (n=31) or a combination of voriconazole and caspofungin (n=16) for salvage therapy. RESULTS: The combination of voriconazole and caspofungin was associated with improved 3-month survival rate, compared with voriconazole alone (hazard ratio [HR], 0.42; 95% confidence interval [CI], ; P=.048). In multivariable models, salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with therapy with voriconazole (HR, 0.28; 95% CI, ; P=.011), independent of other prognostic variables (e.g., receipt of transplant and type of conditioning therapy). The probability of death due to aspergillosis was lowest in patients who received the combination regimen. CONCLUSIONS: Randomized trials are warranted to determine whether this combination should be used as primary therapy for aspergillosis.
PMID: [PubMed - indexed for MEDLINE]
Observational study
of salvage therapy
Clin Infect Dis Sep 15;39(6):

28. Antifungal treatment of other invasive mould infections
Fusarium and Scedosporium spp:
Voriconazole and lipid formulations of amphotericin B
+/-surgical debridement of necrotic tissue
Posaconazole can be used as salvage therapy for these infections
Invasive mucormycosis:
Lipid-based formulation of amphotericin B as first-line therapy
As you can see, the data on known pathogen therapy is rather limited, especially on antifungal therapy at this stage. As for the other invasive mould infections, the recommendation is mostly based on case reports.
Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin Microbiol Rev 2007; 20: 695–704.
Troke P, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob
Agents Chemother 2008; 52: 1743–50.
Spellberg B, et al. Clinical practice: recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 2009; 48: 1743–51.

29. J Clin Microbiol. 2009 Sep;47(9):2834-43.
Sometimes, rare fungus can cause serious problem. I just want to cite a recent outbreak of infection infection due to Rhizopus microsporus among our hematology and bone marrow transplant patients in QMH. The first case was a 6-year-old boy with necrotic bowel. Within a few months time, we have encountered the second case. Extensive outbreak investigation was performed and finally tracked down the source of infection as a contaminated oral tablet alloupirinol.
J Clin Microbiol Sep;47(9): 29

30. Roll-plating of allopurinol
Once we know that this is contaminated, we also roll the tablet on the agar plate which also showed the rhizopus. This is the container of allopurinol at QMH. 30

31. Estimated number of preventable cases in HK (1 year period)54 36 18 12 18
If we can stop this outbreak by controlling food and allopurinol, we can save at least 16 lives every year.
Total cases from Nov to Feb = 18 cases / 4 months
No. of symptomatic cases (mucosal + invasive) = 6 / 18 (5 invasive & 1 mucosal) = 1/3
Total no. cases in 1 year = 18 x 3 = 54 per year
No. of symptomatic cases = 54 x 1/3 = 18 per year 6
*Attack rate = (mucosal + invasive) / total = 6 / 18 = 33.3%
**Lives saved = 16 (only 1 / 8 = 12.5% symptomatic patients survived) 31