Treatment of invasive Candida and invasive Aspergillus infections in adult haematological patients☆

3.1.1. Epidemiological trends 

A shift towards non-albicans Candida species such as C. glabrata and C. krusei with decreased susceptibility or resistance to azoles has been observed in North America and Europe.[4], [5], [6] The increasing use of azoles has been reported as cause for this epidemiological shift but remains controversial.7 C. glabrata, the most frequent non-albicans species, is susceptible to AmB and to the echinocandins, but shows reduced susceptibility to azoles.[8], [9] C. krusei is susceptible to AmB, voriconazole and the echinocandins, but intrinsically resistant to fluconazole and itraconazole.8

3.1.2. Lipid formulations of amphotericin B 

There is no large randomised study comparing AmB deoxycholate and its lipid formulations in neutropenic hosts with candidaemia. The disadvantages of AmB deoxycholate are the infusion-related side effects (e.g. chills, fever, hypoxaemia and hypotension), nephrotoxicity and hypokalemia.10 Although four studies have shown that administration of AmB deoxycholate as a continuous infusion over 24h with saline loading reduced infusion-related reactions and renal impairment, alternative therapy may be more appropriate in patients with renal insufficiency or concomitant nephrotoxic drugs.[11], [12], [13], [14] Lipid formulations of AmB (colloidal dispersion, lipid-complex and liposomal) are better tolerated than AmB deoxycholate and have been used mainly in patients intolerant to AmB deoxycholate or with altered renal function. However, few studies with a limited number of patients have compared the efficacy of AmB deoxycholate with that of lipid formulations in the treatment of neutropenic patients with invasive candidiasis.

In an open randomised study of invasive fungal infections in neutropenic patients, liposomal AmB, 5mg/kg, was compared with AmB deoxycholate, 1mg/kg.15 A mycological response of documented yeast infection was seen in 3/5 patients treated with liposomal AmB versus 0/2 treated with AmB deoxycholate.

A retrospective review of five phase I–II trials investigated safety and efficacy of AmB colloidal dispersion (ABCD).16 Neutrophil status was not known for all patients. The overall response defined as clinical response with negative blood cultures was 39% (7 of 18 patients) for neutropenic compared to 79% (26 of 33) for non-neutropenic patients. Twenty three of 49 (47%) bone marrow transplant recipients responded successfully as compared to 24 of 39 (62%) non-transplanted patients.

A registry allowed collection of data on 124 patients treated in first and second lines with AmB lipid complex for an invasive candidiasis in the setting of a haematological malignancy or a HSCT.17 Sixty-one (49%) of the patients responded favourably to the therapy with similar response rates in C. albicans and in non-albicans Candida infections. Neutropenic status was not stated.

3.1.3. Fluconazole 

For decades, AmB deoxycholate had been the treatment of choice for invasive candidiasis. In three randomised studies, an observational study, a matched cohort study and in a retrospective study, fluconazole demonstrated similar effectiveness as AmB deoxycholate in patients with candidaemia (Table 1).[18], [19], [20], [21], [22] However, only the retrospective analysis included 217 (46%) neutropenic episodes of a total of 476 episodes (Table 2).20 The patient population of this study formed the basis of a randomised trial and a matched cohort study.[18], [19] A success rate of 53% was observed with AmB deoxycholate and 76% with fluconazole. Initial therapy, AmB deoxycholate or fluconazole, was not associated with outcome in a multivariate analysis. A successful outcome, defined as complete resolution of all clinical and laboratory signs of Candida infection, was observed in 96 (44%) neutropenic and in 186 (72%) non-neutropenic episodes. Unfortunately, number of neutropenic patients belonging to fluconazole or AmB deoxycholate group is not stated. Overall 3-month mortality was 52%, higher in neutropenic (63%) than in non-neutropenic patients (43%).

Table 2. Summary of main trials for first line therapy of candidaemia in neutropenic patients

	Ref.	Infection	Study design	Antifungal	Total patients	Neutropenic patients with candidiasis		Definition of success
						No. of patients	No. of successes (%)
	20	Candidaemia	Retrospective	Fluconazole or amphotericin B deoxycholate	476a	217a	96 (44%)a	Clinical and microbial response
	10	Febrile neutropenia	Randomised	Amphotericin deoxycholate	344	11	8 (73)	Composite criteria
				Liposomal amphotericin B	343	11	9 (82)
	25	Candidaemia	Randomised	Caspofungin	109	14	7 (50)	Clinical and microbial response
				Amphotericin B deoxycholate	115	10	4 (40)
	24	Febrile neutropenia	Randomised	Voriconazole	415	13b	6 (46)b	Composite criteria
				Liposomal amphotericin B	422	6b	4 (67)b
	26	Febrile neutropenia	Randomised	Caspofungin	556	12	8 (67)	Composite criteria
				Liposomal amphotericin B	539	12	5 (42)

a Number of neutropenic patients belonging to fluconazole or amphotericin deoxycholate group is not stated. b Voriconazole group : 13 patients with fungal infection at baseline including 10 candidiasis, 2 aspergillosis and 1 zygomycosis. Liposomal amphotericin B group: 6 patients with fungal infections at baseline including 3 candidiasis, 2 aspergillosis and 1 Trichoderma fungemia.

3.1.4. Voriconazole 

A large randomised study investigated the efficacy of voriconazole versus AmB deoxycholate followed by fluconazole after species identification and antifungal susceptibility testing in non-neutropenic patients with candidaemia and showed an equal efficacy of both treatment regimens (Table 1).2 Success rate defined as clinical cure and mycological eradication was equal in both treatment regimens (41%) with significantly less serious adverse events in the voriconazole group (46% versus 57%).

The compassionate use programme of voriconazole as salvage therapy for invasive candidiasis included 13 neutropenic patients with a favourable response in 6 (46%) of them.23 A similar number of neutropenic patients have been treated for a baseline fungal infection in trial for persistent febrile neutropenia.24

3.1.5. Caspofungin 

Two randomised studies compared caspofungin to AmB deoxycholate or to liposomal AmB in invasive candidiasis and in empiric therapy of febrile neutropenia, respectively (Table 1).[25], [26] Overall only 48 neutropenic patients with invasive candidiasis were treated in these two trials (Table 2). A post hoc analysis of the candidaemia study25 including only cancer patients showed response rates of 70% in caspofungin-treated and 56% in AmB deoxycholate-treated patients, with the lowest rates for both treatment groups in neutropenic leukaemic patients.27

3.1.6. Micafungin 

Results of a large randomised, double-blind trial compared micafungin and liposomal AmB for the treatment of invasive candidiasis. The results were available in an abstract form after the meeting was held.28 Success rates were similar in both arms: 89.6% (n=202) and 89.5% (n=190), respectively, with similar efficacy rates for C. albicans, C. parapsilosis, C. tropicalis or C. glabrata infections. Responses according to the neutrophil status have not yet been presented.

3.1.7. Anidulafungin 

Results of a randomised trial comparing anidulafungin and fluconazole in invasive candidiasis have been presented orally after the meeting was held.29 Success rates were 75.6% for anidulafungin treated-patients (n=127) and 60.2% for fluconazole treated-patients (n=118) at the end of intravenous therapy (p=0.01). Anidulafungin remained significantly superior to fluconazole after adjusting for the following baseline characteristics: immunosuppressive therapy, diabetes mellitus, prior azole therapy, baseline C. glabrata and catheter removal. At 6 weeks follow-up, the success rates were 55.9% and 44.1%, respectively. Only 3 and 4 four neutropenic patients have been included in the anidulafungin and fluconazole arm, respectively (Pfizer data on file).

3.1.8. Catheter removal 

The consensus opinion in the general population of patients with candidaemia is that the existing central venous lines should be removed, when feasible.30 Fungemia with C. parapsilosis has been shown to be more frequently associated with use of catheter than infection with other species.20 In neutropenic patients, the gastrointestinal tract is a frequent source of candidaemia and it appears difficult, on an individual basis, to determine the relative contributions of the catheter as the source of the candidaemia.[31], [32] Previous chemotherapy or corticosteroid therapy and dissemination of the infection have been associated with a non-catheter source for the candidaemia in cancer patients.32 Catheter removal within 72h after the onset of candidaemia improved response to antifungal treatment exclusively in patients with catheter-related candidaemia.

3.1.9. Optimal duration of therapy of invasive candidiasis 

Duration of treatment should be long enough to avoid recurrence of infection and eradicate occult sites of haematogenous dissemination. However, shortening the treatment duration is often advocated to reduce costs, toxicity and the emergence of resistant organisms. Recent guidelines suggest that non-neutropenic patients with candidaemia should be treated for 2 weeks after the last positive blood culture and resolution of signs and symptoms of infection.[30], [33] Duration of therapy should be prolonged in case of organ dissemination.[34], [35]

International guidelines propose that in the setting of neutropenia, antifungal treatment be continued for 14 days after the last positive blood culture, resolution of signs and symptoms and recovery from the neutropenia.30 Following neutrophil recovery, ophthalmic examination, ultrasonography, CT-scan or MRI should investigate the possibility of ocular and hepatosplenic candidiasis. If hepatosplenic candidiasis is confirmed, antifungal therapy should be given for at least 6 weeks and up to 1 year,34 or until resolution or calcification of the lesions.30

3.1.10. Role of susceptibility testing in invasive candidiasis 

The increasing frequency of Candida isolates resistant to one or several antifungal agents has propelled interest in antifungal susceptibility testing and its correlation with response to therapy. Like antimicrobial susceptibility testing, the main goal of such testing should be to provide help to the physician by predicting clinical response, or at least forecasting failure.36

The possibility of microbiological resistance must always be considered when a patient has previously been treated with an azole or when C. krusei or C. glabrata are identified. The identification of the species already guides the physician in the choice of antifungal therapy. The existing guidelines remind us that antifungal susceptibility testing is not yet standard of care unlike for antibacterials.30 The authors consider antifungal susceptibility testing to be most helpful in infections with non-albicans Candida, and to support the switch to an oral azole for long-term therapy.

Studies attempting to correlate in vitro antifungal susceptibility testing results and outcome were conflicting.[37], [38], [39], [40], [41], [42], [43] More convincing results were obtained with fluconazole and voriconazole. Two studies suggested that the dose of the fluconazole be taken into account together with the MIC.[37], [44] In a homogeneous population of cancer patients, strictly defined inadequate antifungal therapy appeared to correlate with poor outcome.37 A recent study on the 249 patients infected with Candida sp. and treated with voriconazole in various phase III trials showed a correlation between high MIC (>4μg/mL) and low response rate (<60%).45

3.3.1. Candidaemia in haematologic patients before species identification (Table 3) 

Few data are available in haematological and/or neutropenic patients, making strong recommendations for this specific population much more difficult. Fluconazole may not be appropriate in neutropenic patients because of prior exposure to fluconazole as prophylaxis and to the reported shift to non-albicans strains in this population.[46], [47], [48] The quality of evidence to support the use of lipid AmB, caspofungin or voriconazole in neutropenic patients is based on limited clinical data and on expert opinions.

3.3.2. Candidaemia in haematologic patients when C. glabrata or C. krusei is identified (Table 4) 

Fluconazole is not recommended for C. krusei infection and generally not recommended for C. glabrata infection. Caspofungin is the agent of choice for these Candida infections. Although AmB is active against C. glabrata and C. krusei, AmB deoxycholate is only considered as an option for first line therapy because of its nephrotoxicity and infusion-related side-effects. Voriconazole may be considered an alternative for C. krusei infection and C. glabrata. When the patient is clinically stable and is able to take oral medication, a switch to oral voriconazole can be considered if the isolate is susceptible (CIII).

3.3.3. Catheter removal 

Removal of the central venous line is a consensus recommendation for the non-haematological patients with candidaemia (AII). In neutropenic or leukaemia patients, the quality of evidence is looser but in our opinion the existing catheters should be removed (BIII). Removal is always strongly recommended when C. parapsilosis is isolated (AII).

3.3.4. Optimal duration of therapy of invasive candidiasis 

In the absence of a study specifically addressing the question of duration of therapy of candidaemia in leukaemic patients, our recommendations are

3.3.5. Role of susceptibility testing in invasive candidiasis 

Our recommendation is to perform susceptibility testing in haematological patients on isolates from blood or normally sterile sites, in order to

4.1.1. Amphotericin B formulations 

AmB deoxycholate has been considered as the gold standard of the therapy of invasive aspergillosis for more than three decades. However, clinical data demonstrate efficacy in approximately one third of the patients.[52], [53], [54], [55] AmB deoxycholate is associated with significant side effects and renal toxicity.

No data demonstrate convincing superiority in efficacy of liposomal AmB over AmB deoxycholate for the primary treatment of aspergillosis. A pooled analysis of three trials[15], [50], [56] and a compassionate use, multicenter study was performed applying the EORTC-MSG diagnostic criteria for case selection.57 The response rate to liposomal AmB was 47% in 61 cases of proven/probable invasive aspergillosis. A randomised trial (whose results were presented after the meeting was held) demonstrated in 201 patients that a standard daily dose of 3mg/kg was as effective as and better tolerated than a high daily dose of 10mg/kg for primary therapy.51 Response rate at end of the randomised therapy was 50% and 12-week survival rate was 72% in the standard dose arm.

AmB colloidal dispersion (6mg/kg/d) was compared to AmB deoxycholate for primary therapy in a randomised double-blind trial, including 174 patients.49 Similar low response rates were noted in both arms. The objective response rates were 13% and 15%, respectively.

Data for AmB lipid complex come from open-labelled emergency use programmes for salvage therapy and from a registry for first line therapy.[58], [59], [60] These studies were not comparative and therefore were less useful. However, a large number of cases were collected for the registry and efficacy was documented in 47% of 139 cases as first-line therapy and 44% of 216 cases as salvage therapy.60 Survival data are not available.

Safety profiles of the various lipid-based AmB differ with respect to immediate tolerance. Liposomal AmB proved to be better tolerated than AmB lipid complex in a double-blind randomised comparison in empiric therapy of febrile neutropenia.61 AmB colloidal dispersion given at 6mg/kg/d was associated with a higher frequency of immediate adverse events than AmB deoxycholate.49 With respect to nephrotoxicity, all forms were safer than AmB deoxycholate but induced a doubling in serum creatinine in more than 10% of the patients[49], [51], [60], [61] (see Table 6, Table 7).

Table 6. Strength of recommendation and quality of evidence for antifungal agents in primary therapy of invasive aspergillosis

	Agent	Grading
	Voriconazole	AI
	Amphotericin B deoxycholate	DI
	Liposomal amphotericin B	BIa
	Amphotericin B lipid complex	BII
	Amphotericin B colloidal dispersion	DI
	Caspofungin	CIII
	Itraconazole	CIIIb
	Combination therapy	DIII

a Provisional grading based on studies presented up to 31st December 2005. b Start with intravenous formulation.

Table 7. Strength of recommendation and quality of evidence for antifungal agents for salvage therapy of invasive aspergillosis

	Agent	Grading
	Voriconazole	BIIa
	Liposomal amphotericin B	BIIIb
	Amphotericin B lipid complex	BIIIb
	Caspofungin	BIIb
	Posaconazole	BIIb
	Itraconazole	CIIIb
	Combination therapy
	Caspofungin+lipid amphotericin B	CIII
	Caspofungin+voriconazole	CIII
	Amphotericin B+voriconazole	No data

a If not used for primary therapy. b No data in failures of voriconazole.

4.1.2. Azoles 

Only limited data are available on itraconazole in invasive aspergillosis. Denning et al. reported the results of oral itraconazole in 76 patients with various underlying conditions.62 Overall objective response rate was 39%. A strategy using intravenous itraconazole followed by the oral formulation was assessed in 31 patients with a successful response rate of 48%.63

Voriconazole was assessed in two open-labelled studies and response rates of 44% and 48% were reported.[64], [65] Superiority of voriconazole over AmB deoxycholate was demonstrated for efficacy, safety and survival in a randomised trial.1 Voriconazole proved to be superior to AmB deoxycholate irrespective of the host group, site of lesion and neutropenic status. Analysis of a series of 81 cases of cerebral aspergillosis treated with voriconazole showed a 35% response rate with a 31% survival.66 This study underscored the critical role of surgical resection of the lesion. The role of voriconazole in bone or joint aspergillosis has also been investigated in retrospective analysis of 20 patients with a 55% response rate.67 Very limited data are available on other extra-pulmonary Aspergillus infections. A. terreus, poorly sensitive to AmB, is susceptible in vitro to voriconazole. A review of its interest in A. terreus confirmed an improved outcome as compared to patients who received another agent.68

Oral posaconazole has been assessed in salvage therapy of various invasive fungal infections, including a cohort of 107 patients with aspergillosis.69 Comparison with an external control group of 86 cases showed a 42% favourable response rate in posaconazole-treated patients and a significant improved survival as compared to the external control group.

4.1.3. Echinocandins 

Caspofungin has mainly been assessed in salvage therapy. A non-comparative trial was conducted in 83 patients refractory or intolerant to standard therapy.70 The overall response rate was 45%, but only 26% in neutropenic patients and 14% in allogeneic HSCT recipients. Similar response rates (44%) were reported in 48 patients receiving caspofungin on a compassionate basis.71 Candoni et al. have treated 32 patients, including 8 HSCT recipients, with proven or probable invasive aspergillosis in first-line with caspofungin.72 A favourable response was seen in 56% of the patients. Safety profile of caspofungin is excellent with minimal drug-related toxicity.

4.1.4. Combination therapy 

Combination therapy has been proposed in the therapy of the most severe invasive fungal infection, including invasive aspergillosis. The most common rationales for combination therapy are an expected synergy with complementary targets within the fungal cells, an increase of the spectrum of action and complementary pharmacokinetic or pharmacodynamic characteristics.73 While most data demonstrated synergy or additive effects in both in vitro and in vivo experimental models, no prospective comparative clinical trial has so far been published on combination therapy in first-line or salvage therapy. Non-comparative studies provide controversial results. Success rates ranging from 21% to 60% have been reported.[74], [75], [76] A combination of voriconazole and caspofungin given as salvage therapy after failure of AmB provided a substantial improved 3-months survival in allogeneic HSCT recipients compared with voriconazole monotherapy in a historical control group.77

4.1.5. Susceptibility testing 

Filamentous fungi are not routinely tested for susceptibility. Despite controversial results, no correlation between in vitro susceptibility to AmB and in vivo outcome was convincingly demonstrated in murine models.[78], [79], [80] Correlation between in vitro and in vivo resistance of A. fumigatus to itraconazole needs careful selection and standardisation of test conditions to generate reproducible data.81 Lass-Florl et al. correlated susceptibility to AmB and survival in 6 patients.82 Twenty two of 23 patients with a resistant strain died. Correlation between failure to AmB and infection with A. terreus has been demonstrated.[82], [83], [84] Data are lacking for the new antifungal agents (see Fig. 2).

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Fig. 2. Survey on current practice: preferred therapy for invasive candidiasis after species identification (38 responses).

4.3.1. Primary therapy 

Voriconazole is strongly recommended for pulmonary invasive aspergillosis (Table 4). It can be assumed that voriconazole is also recommended for extra-pulmonary infections, including central nervous system aspergillosis. There are insufficient data for recommendations of when to initiate oral treatment. In addition, oral dosing not adapted to weight may lead to suboptimal therapy. Intravenous voriconazole administration is contra-indicated in renal insufficiency.

AmB lipid complex was given the score BII. Based on the data of Cornely et al. presented after the meeting,51 the committee decided to give a provisional grade BI to liposomal amphotericin B. Liposomal AmB and AmB lipid complex represent an alternative when voriconazole is contra-indicated.

AmB colloidal dispersion is generally not recommended due to poor general tolerance and low objective response rates in a randomised study. AmB deoxycholate is generally not recommended.

Caspofungin and itraconazole have been graded CIII for first-line therapy because of insufficient data in this setting. Combination therapy is generally not recommended in first line. Posaconazole has not been scored in the absence of data in first line therapy.

4.3.2. Salvage therapy 

Caspofungin and posaconazole were similarly graded. Liposomal AmB, AmB lipid complex and itraconazole were graded on the basis of expert opinions. No data are available for any of these agents in the event of voriconazole failure.

Voriconazole was graded for salvage therapy provided the patient had not received this agent in first-line. Combinations of caspofungin and voriconazole or caspofungin and a lipid-based AmB were scored as an option. In the absence of data, a combination of AmB and an azole was not scored.

4.3.3. Optimal duration of therapy 

Therapy must be long enough to achieve complete response and to allow recovery from immunocompromised conditions. No fixed duration can be proposed.

4.3.4. Susceptibility testing 

Aspergillus should not routinely be tested for susceptibility. They should be identified to the species level because this gives useful information for therapy, especially in A. terreus infections (CIII).

4.3.5. Surgery 

Surgery should be considered when a pulmonary lesion is contiguous with a large vessel, in case of haemoptysis from a single lesion and on a case by case basis in localised extra-pulmonary lesions, including central nervous system localisations (CIII).