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لعلاج مضاعفات مرض سرطان الدم pdf


Annals of Hematology© Springer-Verlag 200410.1007/s00277-004-0986-0

Review Article

Recent developments in the management of invasive fungal infections in patients with hematological malignancies
Meinolf Karthaus1

لعلاج مضاعفات سرطان الدم and Oliver A. Cornely2

(1) Medizinische Klinik II* Evangelisches Johannes-Krankenhaus* Schildescher Straße 99* 33611 Bielefeld* Germany(2) Klinik I für Innere Medizin* Universität zu Köln* Cologne* Germany



لعلاج مضاعفات سرطان الدمMeinolf Karthaus
Email:

Meinolf-Karthaus@johanneswerk.de
Fax: +49-521-8014307

Received: 6 September 2004 Accepted: 9 November 2004 Published online: 22 December 2004

Abstract Despite recent advances in the last decade* invasive fungal infections are still associated with a high morbidity and mortality. Invasive fungal infections constitute severe infectious complications in patients with hematological malignancies receiving myelosuppressive chemotherapy or sustained immunosuppression after allogeneic transplant regimens. Following a long period of stagnation* considerable progress has been made during the last 5 years in non-culture-based diagnostics and in the treatment of invasive fungal infections. This review highlights recent developments in the epidemiology* diagnosis* and treatment in the context of state-of-the-art management of invasive fungal infections in cancer patients.
Keywords Invasive fungal infection - Aspergillosis - Antigen assay - Antifungals - Azoles - Echinocandins - Candida - Infection

Introduction
Fungal infections have very serious implications and are most likely to affect patients with a hematological malignancy and disease- or treatment-related neutropenia. Approximately 5–10% of episodes of febrile neutropenia are caused by proven yeasts or mold infections [

50*

51*

53]. A higher incidence is observed if probable and/or possible infections are considered as well. The risk of fungal infection with organ involvement* i.e.* invasive fungal infection (IFI)* is particularly high after allogeneic transplantation. Of documented fungal infections* 50–60% are caused by Candida species: 30–40% are caused by Aspergillus spp. [

19*

20]. Infections due to other organisms such as non-fumigatus Aspergillus [

45]* Pseudallescheria boydii* Fusarium spp.* and Mucorales are rarer* but of increasing differential therapeutic significance [

35]. The authors performed a search of abstracts from hematology and infectious disease meetings held between January 2001 and May 2004 to provide the most recent developments. In addition* medical databases were checked for IFIs in hematology patients* diagnostic procedures* epidemiology* prophylaxis* and clinical trials involving hematology patients with fungal infections.


Recent epidemiological observations
Yeast infections are detected in an earlier phase following allogeneic transplantation (median 2 weeks post-transplantation) than infections by molds* which are more likely to be detected at a later stage after transplantation* i.e.* around day +100. The incidence of invasive aspergillosis (IA) was recently stated to be 7.1%. Risk factors for early occurrence of IA were conditioning regimens with melphalan/fludarabine/anti-CD52 antibody (alemtuzumab). Survival at day +180 was 28.6% for early IA vs 33% for late-onset IA. Risk factors for late-onset IA were severe graft-versus-host disease (GVHD) and treatment with steroids or alemtuzumab. Due to the fact that effective immunosuppressants are increasingly used to treat GVHD* the incidence of IA is likely to rise [

1].

Nonmyeloablative allogeneic stem cell transplantation (SCT) was introduced as a new therapeutic option in the late 1990s. Initial observations indicated that this type of transplantation* which is commonly implemented in the elderly and patients with multiple morbidities* is associated with a substantial risk of IFI. Invasive fungal infections have been observed at a prevalence of up to 23%* whereby 69% of the episodes were attributed to Aspergillus spp. and 31% to Candida spp. All IFIs were detected in the postengraftment period only (median: day +105). In addition to severe GVHD* the main risk factors were intestinal GVHD (p=0.017)* but not GVHD limited to the liver (p=0.18) or skin (p=0.50). Invasive fungal infection was detected more frequently in subjects receiving continuous steroid treatment with doses greater than 10 mg/kg (p=0.0021). The concomitant presence of a respiratory viral infection also seems to be associated with a higher risk of invasive fungal disease [

50].

These recent data emphasize the postengraftment timing of IA and confirm previously recognized risk factors (GVHD* receipt of corticosteroids* and neutropenia) and uncover the roles of lymphopenia and viral infections in further increasing the incidence of postengraftment IA since the 1990s [

26].


Candidemia epidemiology
The incidence of candidemia continues to rise in the United States. Candidemia was associated with a higher mortality than bacteremia (39 vs 26%). Bischoff et al. presented a 6-year review of North American candidemia data at the 2003 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)* which disclosed an annual incidence of candidemia of 4.0–5.4 per 10*000 hospital admissions [

3].

Species differentiation of 1596 Candida isolates showed 52.8% Candida albicans* 19.0% C. glabrata* 11.8% C. parapsilosis* 11.3% C. tropicalis* and 2.1% C. krusei. Candidemia was associated with a 1.8-fold infection-related mortality rate compared to bacteremia. Significant risk factors were the presence of indwelling central venous and arterial catheters* total parenteral nutrition* and mechanical ventilation. Interestingly* neutropenia played a less important role [

3]. The main source of infection in hematological cancer patients with mucositis was the gastrointestinal tract* as recently demonstrated by a DNA karyotype analysis in allogeneic SCT recipients with oral mucositis who developed candidemia [

39].

Pappas et al. [

36] conducted a prospective surveillance study in the United States at 25 transplantation centers in the period from March 2001 to December 2002. Of the 487 fungal infections documented* 46% were attributable to IA and other hyphomycetes; 43% were attributable to Candida spp. The mean time to onset of infection in transplant recipients was 84 days for invasive Candida infection and 146 days for invasive aspergillosis. Overall mortality was 46%* with a significantly higher mortality rate in PBSC recipients vs solid organ transplantation (68 vs 29%).


Peripheral blood stem cell transplantation (PBSCT)
The incidence of postengraftment infections in hematopoietic stem cell transplant (HSCT) recipients increased during the 1990s. Recent epidemiological data were reported by Eser et al. [

12] on 117 microbiologically documented episodes of infection in 114 peripheral—84 autologous and 30 allogeneic—blood stem cell transplant recipients in the period from 1997 to 2003. Infectious complications occurred up to 1 year after conditioning: 59% of the infectious episodes occurred before engraftment and 41% were documented in the period after successful engraftment.

Microbiologically confirmed fungal infections were identified in only 14 of the 117 episodes (12% microbiologically documented infections)* of which 12 were attributable to Candida albicans and 2 to Aspergillus fumigatus.


Pediatric hematology
Rosen et al. [

57] investigated the incidence of fungal infections in 213 pediatric patients in a retrospective monocentric study. Forty-one episodes were identified in 29 patients [13.6% incidence in bone marrow transplantation (BMT)]. The underlying disease was acute lymphatic leukemia (ALL) in 38% and acute myeloid leukemia (AML) in 36% of the patients. The primary disease itself had no effect on the development of a fungal infection. Attributable organisms were Candida spp. (58%)* Aspergillus spp. (16%) and other* in some cases rarer species (26%). The incidence of infections caused by molds and non-albicans yeasts had increased significantly over the past half decade. The main sites of infection were the lungs (45%) followed by blood and urine (15%* respectively). Mortality was 83% in patients with BMT and fungal infection. The fungal infection was the major cause of death in 51.7% of the fatalities. The incidence of fungal infection in BMT patients was 2.7 times higher than in other childhood cancer populations* as a comparison with 1052 non-BMT patients elucidated.


Non-culture-based diagnostic techniques
Diagnostic criteria for defining opportunistic IFI have been published by Ascioglu et al. from a consensus conference of the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG). A definitive diagnosis is based on direct detection in or cultures of primarily sterile body fluids or tissue* or on histological identification of the organism in tissue [

2]. EORTC/MSG diagnostic criteria are designed for clinical trials. Also* having been established in controlled trials* their clinical use might result in underdiagnosis of IFIs. This gap remains an open discussion.

Non-culture-based diagnostic techniques [serology* imaging studies* polymerase chain reaction (PCR)] had been associated with the drawbacks of unsatisfying sensitivity and/or specificity until the mid 1990s. Nowadays* these have been greatly improved with the introduction of sandwich enzyme-linked immunosorbent assay (ELISA) [

16].

Non-culture-based techniques for diagnosing IA have improved steadily in recent years. The development of galactomannan (GM) antigen ELISA (Platelia Aspergillus* Bio-Rad Laboratories* Marnes-La-Coquette* France) significantly improved the quality of noninvasive diagnostics. The latter technique has a high specificity (>90%)* and the testلعلاج مضاعفات سرطان الدمs sensitivity can be raised by applying lower cutoffs than currently used in Europe* i.e.* 1.0. In the United States the test was licensed by the Food and Drug Administration (FDA) with a cutoff of 0.5 [

27]. Maertens et al. [

24] investigated this issue as the manufacturer initially recommended a higher cutoff of 1.5 in Europe. Interpretation of the test outcome has implications for the diagnosis and treatment administered for IA: Maertens et al. analyzed 1642 sequential serum samples on a twice-weekly basis during 124 consecutive episodes (16 proven IA* 13 probable IA* 21 possible IFI* 74 control episodes) in a prospective study in neutropenic subjects with a high risk of developing IA. The effects of using modified diagnostic cutoffs in adults are shown in Table

1. Table 1 Implications of modified cutoffs for Aspergillus GM ELISA [

24]. NPV negative predictive value* PPV positive predictive value


Cutoffs

1.5

1.0

0.9

0.8

0.7

0.6

0.5

Sensitivity (%)

82.7

93.1

96.5

96.5

96.5

96.5

96.5

Specificity (%)

100

100

98.6

97.3

93.2

86.4

85.1

PPV (%)

100

100

96.5

93.3

84.8

73.7

71.8

NPV (%)

93.7

97.4

98.6

98.6

98.6

98.5

98.4

Efficiency (%)

95.1

98

98

97

94.2

89.3

88.3



Only 2.1% of all serum samples in the control group were لعلاج مضاعفات سرطان الدم0.5 (similar to the 1.4% figure in the FDA document [

42]). The 85.1% specificity for a single positive serum sample is much lower than with the higher cutoffs used to date. On the basis of their results* Maertens et al. proposed two cutoff points which are lower than those accepted to date: (1) a لعلاج مضاعفات سرطان الدمstaticلعلاج مضاعفات سرطان الدم cutoff at 0.8 and (2) a لعلاج مضاعفات سرطان الدمdynamicلعلاج مضاعفات سرطان الدم cutoff at 0.5. A single sample with an index لعلاج مضاعفات سرطان الدم0.8 justifies initiating anti-Aspergillus treatment in an at-risk patient receiving prophylaxis for aspergillosis* even if the diagnosis is not confirmed in retrospect. The high mortality associated with genuine cases by far overrides the low risk of false-positive outcomes* especially given that well-tolerated antifungals are now available. A لعلاج مضاعفات سرطان الدمdynamicلعلاج مضاعفات سرطان الدم cutoff of >0.5 in two sequential samples is likewise diagnostic in the presence of increased specificity and a positive predictive value (PPV) of 98.6% and clinical efficacy of 98%. The use of GM ELISA with the modified dynamic and static cutoffs described above should permit earlier diagnosis of IA* as described by Maertens et al.

Twice-weekly GM antigen monitoring was also investigated in Italy by Mattei et al. [

31] in a monocentric study in 109 subjects undergoing 162 hematological treatments* SCT* BMT or immunosuppressive therapy* e.g.* antithymocyte globulin (ATG) for aplastic anemia/myelodysplastic syndrome (MDS) or treatment with the nucleoside analogue 2-CDA. With a cutoff of >1.0* sensitivity was 53% and specificity was 99%. The negative predictive value (NPV) was 90% and the PPV was 73%. Lowering the cutoff to 0.7 increased the sensitivity to 76% while specificity moderately declined to 95%* the NPV rose to 94% and the PPV declined to 65%. An obvious correlation between the GM ELISA result and the clinical response to antifungal therapy was identified. GM antigen levels declined in all patients who responded to treatment* while values >1 persisted in patients with refractory disease. The time to the decrease of GM levels below 0.7 was 7 days.

The authors concluded that serial GM ELISA screening enables early diagnosis of invasive aspergillosis. Both groups concluded that the GM test cutoff point can be lowered (to 0.7 or 0.8) to raise the test sensitivity whilst retaining an acceptable level of specificity. Sequential GM ELISA monitoring during antifungal therapy in subjects with levels >0.7 after 7 days is an early way of identifying patients with resistant IA who require modification of their therapeutic regimen. The test is nonsensitive despite a lower cutoff in allogeneic SCT recipients receiving anti-Aspergillus antifungals as prophylaxis or treatment in response to fever of unknown origin (FUO).


Aspergillus PCR
Aspergillus PCR is described as a sensitive and early indicator of aspergillosis [

6

15]. However* international standardization is lacking [

18]. Serial two-step PCR was investigated in a prospective and blinded fashion in children receiving chemotherapy and SCT. Yadav et al. [

56] studied 38 patients during 84 episodes of fever (64 episodes of febrile neutropenia) during a 1-year study period. The sensitivity of PCR was 10 CFU/ml of Aspergillus DNA. Overall* 126 (17%) of 741 samples were positive* corresponding to 33 of 38 patients. PCR was sequentially positive in 13 of 84 febrile episodes (16%). PCR was positive on one occasion (31%) or intermittently (17/84* 20%) in 43 of 84 febrile episodes. PCR remained negative in 28 of 84 febrile episodes (33%). There were three proven* one probable* and two possible fungal infections (EORTC/MSG criteria) among 13 episodes with sequentially positive PCR outcomes. PCR was positive 5–35 days before clinical documentation of Aspergillus infection in three of these six episodes.

All four episodes with proven IA produced a positive PCR assay* but only three resulted in sequentially positive PCR assays. One of two probable IA episodes was sequentially positive and the other was intermittently positive. IA was identified in only 6 of 43 (14%) episodes with one-time or intermittently positive PCR (one proven* one probable* four possible). In the 28 febrile episodes where PCR was negative* there were no proven or probable* but two possible IAs. The authors concluded that serial PCR assay is a highly predictive and early marker for indicating the development of proven and probable IA (100%). By the same token* IA is unlikely to develop in subjects with consistently negative PCR assay results (negative predictive value of 92%).

Aspergillus PCR still has the drawback of a specificity problem and a lack of generally applicable standards [

18]. PCR assays yield a high workload* require standardization* and the sensitivity still needs to be confirmed* especially in adult allogeneic transplant recipients [

18].

In terms of its sensitivity in detecting disease* nested PCR was shown to be more sensitive (95 vs 89%) than GM ELISA at a cutoff of 0.5 [

34]. Incontestably* consistently negative PCR seems to virtually rule out invasive aspergillosis. In Yadav et al.لعلاج مضاعفات سرطان الدمs paper* PCR was not serially positive in one proven and one probable case of aspergillosis. It is still not clear whether and when positive PCR results (once* twice* serially* intermittent) justify the initiation of antifungal therapy* but this is the key issue in determining the value and role of PCR. It remains an open question whether standard PCR procedures can be established for diagnosing IA. Nor is it clear how to interpret negative PCR results following a preceding positive PCR* or whether and when de-escalation of antifungal treatment is justified solely on the basis of negative PCR assay results. A very innovative trial that has just been launched by the German Society of Hematology and Oncology investigates whether early empirical anti-Aspergillus treatment in the presence of a recent positive PCR and febrile neutropenia is more effective than delayed administration of antifungals (IDEA trial* Fig.

1). لعلاج مضاعفات سرطان الدم
Fig. 1 Immediate vs deferred antifungal therapy with voriconazole in febrile neutropenia and positive fungal PCR (IDEA trial)



Antifungal prophylaxis
Ideally* primary prophylaxis is the best means of combating infection. Prophylaxis of fungal infection has been the subject of a number of trials since the 1980s. Oral prophylaxis with topical polyenes may reduce the colonization of the gastrointestinal tract by yeasts* but up to now has not been proven to be effective in preventing IFIs in most patient populations. The effectiveness of systemic prophylaxis (fungal infections and overall survival) has been conclusively confirmed to date only in the area of allogeneic stem cell transplantation (fluconazole 400 mg/day). The readers further interested are referred to recent reviews on this topic [

5*

8].

Harousseau et al. [

14] studied amphotericin B lipid complex (ABLC) in a randomized open-label study in 288 patients. Two different prophylaxis concepts were compared: short-term prophylaxis with ABLC (1 mg/kg per day) until engraftment (arm A) and ABLC 2.5 mg/kg per day twice weekly until day +100 after transplantation (arm B). Study endpoints were safety and the absence of signs and symptoms of fungal infection until day +100 after SCT. At day 100* 185 patients were assessable in terms of the occurrence of IFI. Of these patients* 17.5% in arm A and 13.3% in arm B had proven or probable fungal infection (p=0.56). Overall survival at the end of the trial was significantly better among patients on long-term prophylaxis than in patients with prophylaxis until engraftment only (55.2 vs 43.4%* p=0.045). Median time to death was 181 days in arm B vs 134 days in arm A (p=0.01). Tolerability was similar in the two treatment arms* but a significantly higher incidence of creatinine levels above 220 لعلاج مضاعفات سرطان الدمmol/l was observed under short-term prophylaxis (33.1 vs 21.7%* p=0.03). Harousseau et al.لعلاج مضاعفات سرطان الدمs paper highlights the importance of prophylaxis after engraftment for this high-risk group* both in terms of invasive fungal disease and overall survival. However* ABLC vs the current standard of daily fluconazole 400 mg remains to be studied. A three-arm design incorporating a fluconazole arm would have been able to answer this question.

A randomized study in allogeneic transplant recipients suggested that antifungal prophylaxis with itraconazole following SCT was more effective than fluconazole in this population [

54]* but a long-term survival benefit for itraconazole prophylaxis has yet to be proven [

21]. Similar results on itraconazole prophylaxis have been reported by Marr et al. [

28]. Due to devastating drug–drug interactions concomitant cyclophosphamide should be avoided [

29].

Winston et al. [

54] reported their long-term experience with itraconazole at the American Society of Hematology (ASH) 2003 for routine prophylaxis of Aspergillus infections from day +1 to day +100. Prophylaxis is begun with 200 mg i.v. twice daily for 2 days followed by 200 mg i.v. once daily until engraftment* followed by 200 mg p.o. twice daily. Prophylaxis was continued beyond day +100 in patients continuing to require systemic steroids because of GVHD* but without regular monitoring of itraconazole levels. Fifty-three allogeneic transplant recipients at high risk of developing Aspergillus infection (median age: 41 years* advanced disease: 79%* prior HSCT: 21%* unrelated donor: 38%* high-dose steroids for GVHD: 89%* grade 2–4 GVHD: 47%) received long-term prophylaxis in the period from December 2001 to July 2003. None of the 53 patients developed an Aspergillus infection* which was unexpected given the rates observed on the fluconazole regimens administered until December 2001 (0 vs 13%). Overall survival in the observation group was 51%* but there were no documented deaths attributable to fungal infection. Itraconazole was well tolerated apart from nausea and vomiting (n=11* 20%). The monocentric results reported by Winston et al. need to be verified in an externally validated controlled multicenter trial. Studies on the incidence of invasive aspergillosis should be interpreted with caution due to the methodological limitations contingent upon the use of a historical control population.

An early study comparing itraconazole i.v. (200 mg/day) with caspofungin (50 mg/day) for antifungal prophylaxis in 200 chemotherapy patients with AML or MDS revealed no difference in terms of incidence of fungal infections (five vs six)* FUO* pneumonia* or survival [

32].


Secondary prophylaxis after allogeneic SCT
There are few studies investigating secondary prevention after proven or probable fungal infection and resumption of myelosuppressive chemotherapy. Stute et al. [

46] used caspofungin 50 mg i.v./day for secondary prevention in a prospective phase I/II study in 26 allogeneic SCT recipients (24 probable and 2 proven infections/modified EORTC criteria). Fungal infections had been documented by chest CT (25/26) or in liver or spleen (8 cases). Secondary prevention took place from conditioning until stable engraftment. Six patients died on secondary caspofungin prevention (by day +100)* including five with infections (four fungal infections). Modification of antifungal treatment was necessary in only 4 of 26 patients. Of 12 patients with active fungal infection who received secondary prevention with caspofungin at the time of transplantation* 10 responded to caspofungin [4 complete remission (CR) and 6 partial remission (PR)]. One patient died of Scedosporium prolificans infection after being taken off treatment because of side effects.

The authors showed that secondary prevention with caspofungin is a well-tolerated option. Controlled studies are urgently necessary to demonstrate the efficacy of secondary prevention vs placebo and other antifungals* stratified by risk group. Combination of caspofungin and cyclosporin A (CsA) in allogeneic SCT requires special observation. In addition caspofungin is not licensed for prophylaxis at present.

A global study of the Infectious Disease Working Party of the German Society for Hematology and Oncology is currently following up secondary prevention data from patients with proven or probable IFI receiving secondary antifungal prevention as part of a myelosuppressive chemotherapy regimen [

9].


New insights in the treatment of antibiotic-refractory febrile neutropenia (FUO)
Mortality rates of 50 and 90% have been documented for proven IFI with Candida and Aspergillus spp.* respectively. For that reason* antifungal treatment is mostly initiated لعلاج مضاعفات سرطان الدمempirically.لعلاج مضاعفات سرطان الدم Antifungal therapy is started in the absence of a specific pathogen or clinically documented infection after 72–120 h in antibiotic-refractory febrile neutropenia. Empirical antifungal therapy was introduced in the 1980s and is now regarded as the standard of care in the management of antibiotic-refractory FUO (for 3–5 days) [

19]. The only antifungal available in the 1980s was amphotericin B (AmB) with its high toxicity. Lipid-based AmB* itraconazole* and fluconazole became available later (Table

2). Table 2 Empirical antifungal therapy for persistent febrile neutropenia (Walsh trials). L-AmB liposomal amphotericin B


L-AmB vs AmB [

49]

Voriconazole vs L-AmB [

51]

Caspofungin vs L-AmB [

53]

Patients

343

344

415

422

556

539

Success (%)

50

49

26

30.6

33.9

33.7

Defervescence (%)

58

58

33

37

41

41

Response (n)

9

8

6/13

4/6

14/27

7/27

Baseline IFI (%)

81.8

72.7

46.2

66.7

41.4

51.9

Breakthrough IFI (n)

11

27

8

21

29

24

No early discontinuation (%)

86

81

90

93

90

86

Survival (%)

92.7

89.5

92

94

93

89



Four studies published during the last 5 years contributed significantly to the knowledge on antifungal use in FUO. The first study by Walsh et al. [

49] demonstrated similar effectiveness of liposomal AmB and AmB deoxycholate. As far as side effects were concerned* liposomal AmB was superior in the highly clinically relevant issues of nephrotoxicity and infusion-related adverse events. In a second study* voriconazole did not prove to be non-inferior to liposomal AmB [

51]. However* significantly fewer breakthrough infections were observed on voriconazole. Caspofungin* the first echinocandin to receive market approval in 2002 for second-line treatment of invasive aspergillosis* was compared with liposomal AmB (3 mg/kg per day) in a third study of very similar design [

53]. Caspofungin was not inferior to liposomal AmB in this randomized double-blind study. In terms of defervescence and breakthrough infections* the two study arms were identical. In terms of treatment-related side effects* caspofungin displayed advantages vs liposomal AmB (nephrotoxicity* infusion-related side effects) [

53].

The study design of the three cited studies seems similar at first glance (composite endpoint). However* detailed analysis discloses differences in important areas (double-blind design vs open-label* percentage of transplant recipients* definition of defervescence for success)* precluding direct comparisons of the results from the three studies.

Boogaerts et al. [

4] studied itraconazole in 394 patients with febrile neutropenia (200 mg i.v. itraconazole b.i.d. for 2 days followed by 200 mg i.v. qd for a maximum of 12 days* followed by a 200 mg b.i.d. oral itraconazole suspension for up to 14 days) vs AmB i.v. (0.7–1 mg/kg per day for up to 28 days). The response rates for itraconazole were 48 vs 38% on AmB. Infusion-related side effects* nephrotoxicity* and treatment-limiting toxicity rates were significantly lower in the itraconazole arm in the presence of similar rates of breakthrough infection and mortality [

4]. Hence* phase III studies have identified effective alternatives to amphotericin B deoxycholate (cAmB)* all of which are superior in terms of drug safety (Table

3). Table 3 Unresolved questions for empirical antifungal therapy in febrile neutropenia
Unresolved questions

Commencement of empirical antifungal therapy: 120 h? 96 h? 72 h? earlier?

Sensitivity and specificity of non-culture-based diagnostic procedures for the commencement of empirical antifungal therapy (HRCT* PCR* AG)?

Gold standard of empirical therapy?

Duration of empirical antifungal therapy?

Dosage of empirical antifungal therapy?

Reimbursement of antifungal therapy?




Treatment of invasive candidiasis
Candida infections are mainly caused by C. albicans (50–60%)* but recent reports state a rising incidence of non-albicans Candida infections that may be resistant to fluconazole. Fluconazole remains a safe and effective alternative to amphotericin B deoxycholate (cAmB) in clinically stable patients who have not received azole prophylaxis [

40]. An initial daily dose of 800 mg is recommended in place of the widely studied 400 mg [

7*

11*

37]. Improved efficacy was demonstrated by an initial combination of cAmB plus fluconazole [

41]. This trial is particularly important* since no antagonism between AmB and fluconazole combination was proven [

41]. Fluconazole is not a safe choice for treating non-albicans candidemia* especially in cases where C. krusei (primary resistance) and C. glabrata (dose-dependent sensitivity) have been identified as the causative organisms. Treatment in these cases should be initiated with cAmB or* alternatively* with a new azole or caspofungin.

Caspofungin was compared with cAmB (50 mg/kg vs 0.6 mg/kg AmB) in a phase III trial in subjects with invasive Candida infections. The study involved patients with (n=24) and without neutropenia (n=200). Caspofungin achieved the study endpoint (non-inferiority). Response to treatment was documented in 73.4% of patients on caspofungin and 61.7% of subjects on cAmB. Incidences of drug-related toxicity (29 vs 54%) and nephrotoxicity (4 vs 23%) were much lower on caspofungin [

33]. Caspofungin was licensed for the first-line therapy of candidemia in nonneutropenic subjects.

Anidulafungin was investigated in a three-arm study (50/75/100 mg/day) in subjects with candidemia [

44]. This study demonstrated dose-dependent efficacy in favor of the higher doses (83.3 vs 92.9 vs 92.3%)* but there are no randomized phase III trials incorporating other antifungals.

Data on voriconazole in first-line treatment of candidemia were reported at the European Congress for Clinical Microbiologyand Infectious Diseases (ECCMID) in May 2004. According to data presented by Kullberg et al. [

22]* voriconazole will extend the therapeutic armamentarium for invasive Candida infections. Available data of the randomized phase III candidemia trials are presented in Table

4. Approval of voriconazole for the treatment of candidemia is expected in January 2005. Table 4 Randomized trials in candidemia (study endpoints and success)
Study (n)

Response rate (cured + improved)

Effectivity endpoint/duration

Overall mortality

Rex 1994 [

40] (n=20)6

70–79% (DRC) Fluconazole vs AmB

Variable: up to 12-week follow-up

33–40%

Rex 2003 [

41] (n=219)

56–69% (DRC) fluconazole vs AmB+fluconazole

1=time to failure* 2=variable up to 12 weeks

39–40%

Mora-Duarte 2002 [

33] (n=224)

73–62% (investigator) caspofungin vs AmB

Fixed: end of i.v. therapy

30–34%

Kullberg 2004 [

22] (n=370)

40–40% (DRC)a voriconazole vs AmB/fluconazole

Fixed: 12-week follow-up

36–42%

aSecondary analysis success rate=65% voriconazole vs 71% AmB/fluconazole* end of i.v. therapy

DRC data review committe




Clinically unstable patients should receive first-line treatment with cAmB (0.7–1 mg/kg per day)* lipid-based AmB (3 mg/kg)* voriconazole* or caspofungin. These agents may also be chosen in subjects unresponsive to fluconazole. Data from controlled trials confirming anecdotal experience are lacking in neutropenic patients* however. The efficacy of itraconazole for candidemia has not been reported from trials in hematological patients to date.


Antifungal combination therapy
Initial treatment with AmB (0.7 mg/kg) in combination with fluconazole (800 mg/day) for the first 5–6 days is superior to fluconazole alone in terms of time to eradication* but this regimen is also associated with a significantly higher incidence of side effects. The overall response rate was superior for the combination regimen (69 vs 56%* p=0.043) [

41].

Combinations of antifungals are being studied with great interest* especially those combining antifungals with different target sites (ergosterol synthesis-fungus cell wall) as therapeutic partners (e.g.* azole-echinocandin or polyene-echinocandin). Clinical trials are underway or in preparation. At present* combination treatment should only take place under clinical trial conditions.


Invasive Aspergillus infections
Infections by Aspergillus spp. are mainly observed in patients with neutropenia* neutrophil/macrophage dysfunction* cytotoxic chemotherapy* long-term steroid treatment* bone marrow/stem cell/or solid organ transplant recipients* and subjects with congenital or acquired immunodeficiency.

IA is associated with very high mortality (up to >90%) [

26]. Early treatment is crucial for a superior response. Reported response rates for invasive aspergillosis range from 30 to 60%* but the results of the various studies are not directly comparable because of a long-term lack of uniform diagnostic assessment criteria [

2]* different patient populations* and the use of historical controls [

25*

38].

However* the currently poor outcomes in treating proven cases of aspergillosis justify the application of intensive invasive diagnostic procedures and the earliest possible initiation of treatment.


Treatment of invasive aspergillosis
Treatment should be initiated immediately using the maximum tolerated doses of effective antifungals. Amphotericin B deoxycholate was a cornerstone for 30 years* a situation which has changed since the approval of voriconazole for first-line treatment of invasive aspergillosis.

Voriconazole* a second-generation azole* is considered to be the new gold standard. The starting dose is 6 mg/kg twice daily on day 1 followed by 4 mg/kg twice daily on subsequent days. Voriconazole administered in an intravenous/oral sequence is superior to AmB (1.0 mg/kg) in terms of response rates (52.8 vs 31.6%) and overall 12-week survival (70.8 vs 57.9%). This superiority to AmB was demonstrated both for isolated pulmonary involvement and for extrapulmonary involvement* in patients with and without neutropenia* and in allogeneic stem cell transplant recipients [

17]. Responses ranging from 16 to 54% have even been shown in subjects with cerebral involvement* which is otherwise associated with a very poor prognosis (see Table

5) [

47]. Transient disturbed vision is the most common side effect of voriconazole (observed in approximately 30%) [

10]. Table 5 Voriconazole for CNS aspergillosis [

47]
Treatment/primary disease

Number

Median duration of treatment* days (range)

Response rate (%)

Bone marrow transplantation

32

20 (3–390)

16

Hematological neoplasia

13

96 (5–522)

54

Solid organ transplantation

11

39 (7–285)

36

Chronic immunosuppression

11

122 (9–1128)

45

Others

14

82 (1–946)

50

Total

81

51 (1–1128)

35



Ullmann et al. presented data of an open-label phase II trial of micafungin (FK-463) in 283 patients with proven or probable invasive aspergillosis (alone or in combination with other antifungals). The trial included 81 patients (29%) with neutropenia. Observed response rates ranged from 22% for allogeneic transplant recipients (n=49) to 49% for leukemia patients (n=45) [

48].

Posaconazole is another broad-spectrum azole currently in late clinical development. Walsh et al. [

52] presented the results of a multicenter study investigating posaconazole as second-line therapy (refractory or intolerant to AmB or itraconazole) at the ASH 2003 meeting. The posaconazole arm contained individual patients who had already received voriconazole or caspofungin. The comparison was a historical control arm. Overall response at the end of treatment was 42% in the posaconazole arm (including 36% PR) and 26% in the control group (including 16% PR) [odds ratio: 4.06* 95% confidence interval (CI): 1.50* 11.04* p=0.006]. Response was 39% in subjects with pulmonary aspergillosis (25% in the control group) and 53% in subjects with primary extrapulmonary involvement (45% in the control group). Of 21 neutropenic subjects (24%) in the posaconazole group* 5 responded to treatment vs 2 of 26 neutropenic subjects in the control arm (8%). Response rates for posaconazole were also better in the subgroup of allogeneic transplant recipients [15/48 cases (31%) for posaconazole vs 7/34 cases in the control group (21%)].

Of 107 patients in the posaconazole group* 39 were rated nonresponders vs 52 of 86 patients (60%) in the control group. The study presented by Walsh et al. at the ASH 2003 is a case-control study* albeit with a complex design* and the study cannot replace a prospective controlled trial such as the one investigating voriconazole vs cAMB in IA.

After these preliminary results* caspofungin remains a standard in second-line treatment of invasive aspergillosis [

23].


New antifungals
Zygomycoses although rare* continue to represent a major therapeutic problem with a high rate of infection-related mortality. Whether or not the incidence of zygomycosis is increasing is still a matter of debate [

30]. High-dose AmB is the only treatment of proven efficacy. Posaconazole now seems to be effective against zygomycoses with response rates as high as 70%. It is the first azole active against Zygomycetes (Table

6). However* data were not obtained in prospective comparative studies. In addition* all survivors also underwent surgical debridement [

13]. Table 6 Posaconzole for zygomycosis [

13]
Treatment with posaconzole

Retrospective study including 23 patients:

Rhizopus (n=9)* Mucoraceae (n=3)* Cunninghamella (n=5)* Rhizomucor (n=2)* zygomycosis without further specification (n=4)

Most patients were pretreated with AmB

Posaconazole 800 mg p.o./day (4×200 or 2×400 mg) as salvage therapy

Response in 16/23 patients (70%)

Mean treatment duration with posaconazole: 137 days



Anidulafungin is currently in the late phase of clinical development. Other azoles—Ravuconazole* BAL4815* BAL8557 (targeting yeasts)—are still in the early stages of development [

43].




References

1.Almyroudis N* Jaffe D* Sepkowitz KA* Pamer EG* Meier EN* Papadopoulos E* Small TN* Papanicolaou GA (2003) Risk factors for late invasive aspergillosis (IA) after allogeneic stem cell transplantation. In: 43rd ICAAC abstracts* American Society for Microbiology* September 2003* p 457* M-1006 2.Ascioglu S* Rex JH* de Pauw B et al (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34:7–14


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لعلاج مضاعفات سرطان الدم

لعلاج مضاعفات سرطان الدم 3.Bischoff TR* Tallent S* Adera T* Wenzel RP* Edmond MB (2003) Epidemiology of nosocomial candidemia: a six-year national perspective. In: 43rd ICAAC abstracts* American Society for Microbiology* September 2003* p 348* K 452e 4.Boogaerts M* Winston DJ* Bow EJ* Garber G* Reboli AC* Schwarer AP* Novitzky N* Boehme A* Chwetzoff E* De Beule K (2001) Intravenous and oral itraconazole versus intravenous amphotericin B deoxycholate as empirical antifungal therapy for persistent fever in neutropenic patients with cancer who are receiving broad-spectrum antibacterial therapy. A randomized* controlled trial. Ann Intern Med 135:412–422 5.Bow EJ* Laverdière M* Lussier N* Rotstein C* Cheang MS* Ioannou S (2002) Antifungal prophylaxis for severely neutropenic chemotherapy recipients. A meta-analysis of randomized-controlled clinical trials. Cancer 94:3230–3246 6.Buchheidt D* Hummel M* Schleiermacher D* Spiess B* Skladny H* Schwerdtfeger R* Cornely OA* Wilhelm S* Reuter S* Kern WV* Suedhoff T* Moerz H* Hehlmann R* German Aspergillus PCR Study Group. Prospective multicenter clinical evaluation of a nested PCR assay* a lightcycler mediated PCR assay and a galactomannan ELISA for detection of invasive aspergillosis in neutropenic high risk patients. In: 43rd ICAAC Abstracts* American Society for Microbiology* September 2003* p 478* M-2057 7.Buechner T* Fegeler W* Berhardt H et al (2002) Treatment of severe candida infections in high-risk patients: an interdisciplinary consensus. Eur J Clin Microbiol Infect Dis 21:337–352 8.Cornely OA* Ullmann AJ* Karthaus M (2003) Evidence-based assessment of primary antifungal prophylaxis in patients with hematologic malignancies. Blood 101:3365–3372 9.Cornely OA* Bethe U* Böhme A Buchheidt D* Cesaro S* Karthaus M* Maertens J et al (2003) Detection of predictor variables for breakthrough invasive fungal infection (IFI) during secondary prophylaxis (SP). Results from a European registry. In: 43rd ICAAC Abstracts* American Society for Microbiology* September 2003* p 456* M-1001 10.Denning DW* Ribaud P* Milpied N et al (2002) Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 34:563–571


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لعلاج مضاعفات سرطان الدم 31.Mattei D* Mordini N* Lo Nigro C* Musso M* Gallamini A (2003) Galactomannan antigenemia for early diagnosis and treatment of invasive aspergillosis: three years single centre experience (abstract 3632). In: Proceedings 45th ASH 2003 32.Mattiuzzi GN* Kantarjian H* Alvarado G* Kontoyiannis D* Pierce S* Cortes J* Giles F* Raad I* Verstovsek S* Leitz G* Estey E (2003) Intravenous itraconazole (ITRA) vs caspofungin (CASPO) prophylaxis (P) in patients (PTS) with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) undergoing induction chemotherapy (IC). In: 43rd ICAAC abstracts* American Society for Microbiology* September 2003* p 451* M-984 33.Mora-Duarte J* Betts R* Rotstein C* Lopes-Colombo A* Thomson-Moya L* Smietana J et al (2002) Caspofungin (CAS) versus Amphotericin B deoxycholate (AmB) in the treatment (Rx) of invasive candidiasis (IC) in neutropenic (N) and non-neutropenic (NN) patients (Pts): a multicentre* randomized* double-blind study. N Engl J Med 347:2020–2029


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لعلاج مضاعفات سرطان الدم 34.Morrissey C.O.* Halliday C.* Chen S.* Slavin M.* Wesselingh S.* Sorrell T. Comparison of the Sensitivity and Specificity of Aspergillus galactomannan (GM) sandwich ELISA and a nested Aspergillus PCR assay for the diagnosis of invasive aspergillosis (IA). In: 43rd ICAAC abstracts* American Society for Microbiology* September 2003* p 460* M-1019 35.Nucci M* Marr KA* Queiroz-Telles F* Martins CA* Trabasso P* Costa S* Voltarelli JC* Colombo AL* Imhof A* Pasquini R* Maiolino A* Souza CA* Anaissie E (2004) Fusarium infection in hematopoietic stem cell transplant recipients. Clin Infect Dis 38:1237–1242 36.Pappas PG* Morgan J* Hajjeh RA* Transplant Associated Infection Surveillance Network (TRANSNET) (2003) Prospective surveillance for invasive fungal infections (IFIs) in hematopoietic stem cell (HSCTs) and solid organ transplant recipients (SOTs) in the United States. In: 43rd ICAAC abstracts* American Society for Microbiology* September 2003* p 458* M-1010 37.Pappas PG* Rex JH* Sobel JD* Filler SG* Dismukes WE* Walsh TJ* Edwards JE (2004) Infectious Diseases Society of America. Guidelines for treatment of candidiasis. Clin Infect Dis 38:161–189


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لعلاج مضاعفات سرطان الدم 38.Patterson TF* Kirkpatrick WR* White M et al (2000) Invasive aspergillosis. Disease spectrum* treatment practices* and outcomes. I3 Aspergillus Study Group. Medicine (Baltimore) 79:250–260 39.Redding SW* Kirkpatrick WR* Coco BJ* White WS* Patterson TF* Marr KA (2003) Oral colonization as a source of Candida glabrata candidemia with allogeneic bone marrow transplant. In: 43rd ICAAC abstracts* American Society for Microbiology* September 2003* p 458* M-1011 40.Rex JH* Bennett JE* Sugar AM* Pappas PG* van der Horst CM* Edwards JE* Washburn RG* Scheld WM* Karchmer AW* Dine AP et al (1994) A randomized trial comparing fluconazole with amphotericin B for the treatment of candidemia in patients without neutropenia. Candidemia Study Group and the National Institute. N Engl J Med 331:1325–1330


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لعلاج مضاعفات سرطان الدم

لعلاج مضاعفات سرطان الدم 42.Marr KA* Balajee SA* McLaughlin L* Tabouret M* Bentsen C* Walsh TJ (2004) Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis 190:641-649 43.Schmitt-Hoffmann AH* Roos B* Heep M* Weidekamm E* Beglinger C. Pharmacokinetics of BAL4815* a new azole antifungal* after administration of single ascending oral doses of its pro-drug BAL8557. In: 43rd ICAAC Abstracts* American Society for Microbiology* September 2003* p 30* A-1568 44.Schranz JA* Krause D* Goldstein BP* Henkel T (2003) Efficacy of Anidulafungin (ANID) for the treatment of candidemia. In: 43rd ICAAC abstracts* American Society for Microbiology* Sept 2003* p 448* M-971 45.Steinbach WJ* Benjamin DK* Kontoyiannis DP* Perfect JR* Lutsar I* Marr KA* Jafri HS* Walsh TJ (2003) Invasive aspergillosis (IA) caused by Aspergillus terreus: multicenter retrospective analysis of 87 cases. In: 43rd ICAAC Abstracts* American Society for Microbiology* September 2003* p 475* M-1753 46.Stute N* Kratochwille A* Zabelina T* Fehse N* Hassenpflug W* Panse J* Woltschke C* Ayuketang F* Schieder H* Renges H* von Hinüber R* Kabisch H* Zander AR* Kroge N (2003) Caspofungin is highly effective as secondary prophylaxis in allogeneic stem cell transplantation in patients with prior systemic or invasive fungal infections (abstract 3636). In: Proceedings 45th ASH 2003 47.Troke PF* Schwartz S* Ruhnke M* Ribaud P* Corey L* Driscoll T* Fätkenheuer G* Schuler U* Thiel E* Dodell B* Lutsar I (2003) Voriconazole (VRC) therapy (Rx) in 86 patients (pts) with CNS aspergillosis (CNSA): a retrospective analysis. In: 43rd ICAAC Abstracts* American Society for Microbiology* September 2003* p 476* M-1755 48.Ullmann A* Van Burik JA* McSweeney P* Ratanatharathorn V* Raymond J* de Morais VL* McGuirk J* Lau W* Facklam D* Koblinger S* Reusch M* Marr K* Patterson TF* Denning DW (2003) An open phase II study of the efficacy of micafungin (FK463) alone and in combination for the treatment of invasive aspergillosis (IA) in adults and children (abstract). In: 13th ECCMID 10–13 May 2003 49.Walsh TJ* Finberg RW* Arndt C et al (1999) Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med 340:764–771 50.Walsh TJ* Roden M* Nelson L* Knudsen T* Venzon D* Segal B* Barrett J* Childs R (2002) Invasive fungal infections complicating non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT). In: Proceedings 42nd ICAAC* San Diego* 27–30 September 2002* M-1233 51.Walsh TJ* Pappas P* Winston DJ et al (2002) Voriconazole versus liposomal amphotericin B for empirical antifungal therapy of persistently febrile neutropenic patients: a randomized* international* multicenter trial. N Engl J Med 340:764–771 52.Walsh TJ* Patterson T* Langston A* van Burik J* Louie A* Herbrecht R* Hadley S* Perfect J* Hsu C* Gogate J* Hardalo C* Patino H* Pedicone L* Corcoran G* Raad I (2003) Posaconazole for treatment of invasive aspergillosis in patients who are refractory to or intolerant of conventional therapy: an externally controlled blinded trial (abstract 682). In: Proceedings 45th ASH 2003 53.Walsh TJ* Teppler H* Donowitz GR* Maertens JA* Baden LR* Dmoszynska A* Cornely OA* Bourque MR* Lupinacci R* Sable C* De Pauw B (2004) Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in persistent febrile neutropenic patients. N Engl J Med 351:1391–1402 54.Winston DJ* Maziarz RT* Chandrasekar PH* Lazarus HM* Goldman M* Leitz G* Territo MC (2003) Long-term antifungal prophylaxis in allogeneic bone marrow transplant patients: a multicenter* randomized trial of intravenous/oral itraconazole versus intravenous/oral fluconazole. Ann Intern Med 138:705–713 55.Winston DJ* Emmanouilides C* Bartoni K* Schiller GJ* Paquette R* Territo MC (2003) Elimination of Aspergillus as a significant pathogen in an allogeneic hematopoietic stem cell transplant program after introduction of routine long-term itraconazole prophylaxis (abstract 685). In: Proceedings 45th ASH 2003 56.Yadav SP* Chen S* Halliday C* Shaw PJ (2003) Serial Aspergillus PCR assays for the early diagnosis of invasive aspergillosis in children with leukemia or undergoing stem cell transplantation (abstract 3621). In: Proceedings 45th ASH 2003 57.Rosen GP* Nielsen K* Pediatrics TM (2003) Fungal infections in pediatric bone marrow transplant recipients and non-transplant oncology patients (abstract 5535). In: Proceedings 45th ASH 2003





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للاسف معظم سرطانات الدم توثر تاثيرا كبيرا علي المناعه اما :بسبب :
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و لذلك علاج الامراض الفطريه قد يكون منقذا لحياه المريض في بعض الحالات العنيفه
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