Biology of Blood and Marrow Transplantation
Volume 11, Issue 2 , Pages 77-84, February 2005

Riches usher dilemmas: Antifungal therapy in invasive aspergillosis

  • Pranatharthi Chandrasekar

      Affiliations

    • Department of Internal Medicine, Wayne State University, Detroit, MI
    • Corresponding Author InformationCorrespondence and reprint requests: Pranatharthi Chandrasekar, MD, Harper University Hospital, S Hudson Building, 3990 John R, Detroit, Michigan 48201

Received 3 August 2004; accepted 17 November 2004.

Article Outline

Key words:  Invasive aspergillosis , Antifungal drugs

 

Back to Article Outline

Introduction 

Despite the availability of potent new antifungal agents, systemic fungal infections are on the rise and are associated with significant mortality. Candida and Aspergillus species are the major fungal pathogens; although deaths from candidiasis have declined since the late 1980s, those due to invasive aspergillosis (IA) are increasing [1, 2, 3]. Fifty to ninety percent of patients with IA die despite therapy. Susceptible populations are hospitalized patients and immunocompromised hosts, such as cancer patients and transplant recipients.

The clinical outcome of patients with IA is largely dictated by the host immune status [4]. Two lines of host defense against aspergillus are resident macrophages and phagocytes [5, 6]. Impaired monocyte/macrophage function and neutropenia lasting 3 weeks or longer adversely affect the prognosis, despite appropriate antifungal therapy. In recent years, in the setting of stem cell transplantation, IA has become infrequent during pre-engraftment because peripheral blood as the stem cell source and the use of growth factors have reduced the duration of neutropenia. IA is now seen most commonly during postengraftment in the setting of graft-versus-host disease (GVHD) in allogeneic recipients; both GVHD and its treatment (eg, steroids) contribute to a delay in immune reconstitution, and the prognosis in this cohort with IA is poor [7, 8]. At present, regardless of the antifungal drug(s) used, a considerable number of transplant recipients with IA succumb to the infection in view of their persistently compromised immune status.

Successful management of IA consists of a decrease in immunosuppression, optimal antifungal therapy, and immune restoration (eg, correction of neutropenia with growth factors). The antifungal drugs available for therapy of IA are listed in Table 1.

Table 1. Drugs for Invasive Aspergillosis
Polyenes
Amphotericin B deoxycholate
Amphotericin B lipid forms
Amphotericin B lipid complex; Abelcet
Liposomal amphotericin B; Ambisome
Amphotericin B colloidal dispension; Amphocil
Azoles
Voriconazole; V-fend
Itraconazole; Sporanox
Posaconazole (not FDA licensed)
Ravuconazole (not FDA licensed)
Echinocandins
Caspofungin; Cancidas
Micafungin (not FDA licensed)
Anidulafungin (not FDA licensed)

FDA indicates Food and Drug Administration.

Amphotericin B, the mainstay of treatment of IA for many decades, is associated with disappointing outcomes (approximately one third survive) and considerable toxicity [9, 10]. There has been a recent surge in the development of new antifungal drugs, including new formulations of older drugs, new drugs in the older azole class, and entirely new classes of drugs with novel targets. In the polyene class, lipid forms of amphotericin B (LipAmB) are clearly less nephrotoxic than conventional amphotericin B deoxycholate (AmBD). Head-to-head comparative studies of AmBD and LipAmB are scarce. In the only comparative study of amphotericin B colloidal dispersion (ABCD) versus AmBD for treatment of IA, in a limited number of patients (n = 174), nephrotoxicity was less with ABCD (25% versus 49%), but efficacies were similar (52% and 51%) [11]. Reviewing several open-label studies, Ostrosky-Zeichner et al. [12] found better treatment response rates with LipAmB. The aggregate efficacy estimates for LipAmB and AmBD were 49% and 32%, respectively. They concluded that the superior safety profile of LipAmB and at least equivalent efficacy make these drugs preferable to AmBD for therapy of IA. Modestly sized open-label trials and databases from compassionate use with amphotericin B lipid complex or liposomal amphotericin B against IA in different populations suggest a 40% to 50% clinical response rate [13, 14, 15, 16]. Among LipAmB, ABCD has fallen out of favor in view of its high rate of infusional toxicities [11]. An open-label study with ABCD for the prevention of fungal infection in neutropenic patients had to be stopped prematurely after severe infusion-related side effects [17]. Data suggest that liposomal amphotericin B may have reduced nephrotoxicity and better tolerability during infusion, and dose escalations of the drug are feasible in serious infections [18, 19]; however, it is difficult to choose between the 2 lipid forms in the absence of data from direct comparative trials for therapy of IA. Because newer agents are becoming available, it is unlikely that a prospective trial comparing the 2 drugs will ever be conducted.

Voriconazole has fared significantly better than AmBD in the treatment of IA. Herbrecht et al. [20] demonstrated the safety and superiority of voriconazole over AmBD as primary therapy of IA in a randomized, unblinded trial. At week 12, good clinical response was noted in 53% of voriconazole recipients and 32% of AmBD recipients. Also, improved survival (71% versus 58%) occurred in the voriconazole-treated group. With this prospectively collected large database, voriconazole is now considered the drug of choice for initial therapy of IA. It should be noted that voriconazole was compared with AmBD and not LipAmB. In the same study, clinical responses with voriconazole and AmBD among allogeneic stem cell recipients were 32% and 13%, respectively, thus underscoring the significance of host immune status for a good outcome.

Itraconazole, with good activity against aspergillus, is available as a capsule, an oral suspension, and an intravenous formulation. The capsule formulation has suboptimal bioavailability and is hence not recommended for serious fungal infections. Although available for treatment of aspergillosis since 1990, the drug has not undergone rigorous evaluation. A retrospective survey of clinical practice showed 58% complete or partial responses with itraconazole capsule as primary therapy of IA in 58 patients, most of whom were not severely immunocompromised [9]. Previous open-label studies have shown comparable response rates with itraconazole capsules and AmBD [21, 22]. A regimen of intravenous itraconazole for 2 weeks followed by the oral formulation for 12 weeks was evaluated in 31 patients with pulmonary IA [23]. Forty-eight percent (15 of 31 patients) had a complete or partial response. Because large, randomized studies with itraconazole for therapy of IA are not available, this drug is not recommended as initial therapy.

Caspofungin does not have cidal activity against aspergillus and has not been evaluated for initial therapy of IA. It is approved for use in IA in patients intolerant of or who have infections refractory to other antiaspergillus drugs. When caspofungin was used as salvage therapy, 40 (45%) of 90 patients had a complete or partial response [24, 25].

Hence, at present, voriconazole is the drug of choice for initial therapy of IA. LipAmB has not been evaluated as well as voriconazole, and on the basis of several open-label studies, LipAmB may be considered as a secondary option for initial therapy when voriconazole cannot be used. Caspofungin is not a drug for initial therapy of IA. Investigational drug classes include allylamines, nikkomycins, sordarins, and pradimicins.

Expansion in the antifungal armamentarium has ushered in several management issues for which evidence-based answers are lacking. Table 2 lists several relevant questions; some of the critical questions are discussed.

Table 2. Clinical Questions Regarding Antifungal Therapy of IA
1. What is the best drug for initial therapy for IA under different circumstances?
2. What is the role of combination of antifungal agents?
Which drugs to combine?
When to use a combination?
3. How to monitor therapy?
4. In patients showing improvement,
What is the role of step-down therapy?
What is the duration of therapy?
5. In patients not showing improvement, what is the role of
Changing therapy to a different regimen?
Adding other agents to an existing regimen?
Increasing the dose of existing drugs?
6. What is the role of adjunct therapy?
Immunomodulation-interleukins, colony-stimulating factors, interferons, granulocyte transfusions, or vaccines
Surgery
7. What should be the antifungal strategy for those with a history of IA who are about to become immunosuppressed (eg, awaiting transplantation or cancer chemotherapy)?

Back to Article Outline

Voriconazole versus LipAmB for proven or suspected IA 

If IA is proven or probable, therapy with voriconazole is preferred. In certain clinical situations, however, voriconazole may not be the optimal choice. Table 3 provides guidelines for choosing between voriconazole and LipAmB in different clinical scenarios. As antimold azole prophylaxis (itraconazole or voriconazole) becomes commonplace, breakthrough aspergillosis with potential azole resistance or breakthrough zygomycosis may occur [26, 27, 28, 29]. Several institutions have reported breakthrough zygomycosis and other fungal infections in stem cell recipients receiving voriconazole as empiric therapy or prophylaxis. Thus, in the setting of mold-active azole prophylaxis, treatment of IA or other mold infections with an azole is not optimal; in such patients, LipAmB would be appropriate.

Table 3. Therapy of Suspected or Proven Aspergillosis: Choosing between Voriconazole and LipAmB
VariableVoriconazoleLipAmB
Breakthrough fungal infection (while receiving antimold azole prophylaxis)NoYes
Hyphae on histopathology
ZygomycesNoYes*
FusariumYesYes*
ScedosporiumYesNo
Culture*
Aspergillus terreusYesNo
Non-terreus Aspergillus sp.YesYes
Invasive aspergillosis with:
Normal renal statusYesYes
Renal insufficiencyYes†No
Concomitant nephrotoxinsYesNo

* High-dose LipAmB.

† Oral voriconazole.

When histopathology of the biopsy specimen reveals hyphal forms suggestive of mold infection, aspergillus and zygomyces are the primary considerations; according to morphology, the pathogen needs to be identified before the empiric drug choice is made because zygomyces are voriconazole resistant. Both aspergillosis and zygomycosis have similar clinical presentations, and, not infrequently, the histology cannot distinguish the 2 pathogens. Informing the pathologist about the possibility of zygomycosis is helpful because the growth in culture is improved if the tissue is not finely sliced during specimen processing. If zygomyces and aspergillus are strong possibilities, then LipAmB is appropriate as empiric therapy against both pathogens. Less commonly, fusariosis or scedosporiosis may be suspected, particularly with positive blood cultures or skin lesions. Voriconazole is effective and approved for use against both fusarium and scedosporium [30], whereas higher-than-usual doses of amphotericin B lipid complex may be an alternative for fusariosis [13]. LipAmB is not effective against scedosporiosis. Pathogen identification by culture is important. Although clinically common species of Aspergillus fumigatus and A. flavus are susceptible to voriconazole and amphotericin B, A. terreus is resistant to the latter drug [31, 32, 33]. Better clinical outcomes have been noted with voriconazole in A. terreus infections [34]. In aspergillus-infected patients with renal compromise or those receiving nephrotoxic drugs, LipAmB is best avoided. The cyclodextrin vehicle in the intravenous formulation of voriconazole may accumulate in patients with renal insufficiency, and, hence, the oral formulation is preferred in such situations.

Back to Article Outline

Combination therapy 

The fact that only about 55% patients with IA have a complete or partial response with voriconazole underscores the clear need for treatment approaches other than monotherapy. What about simultaneous use of 2 or more agents? Distinction needs to be made between sequential therapy (one drug replacing another) and combination therapy (use of 2 or more drugs). With the latter strategy, 2 or more drugs may be started at the same time as the initial therapy or an additional drug or drugs may be added in a serial fashion to a failing monotherapy regimen. Previous in vitro/animal model studies with amphotericin B/flucytosine, amphotericin B/rifampin, and azole/rifampin combinations have produced conflicting data [35, 36]. Results of in vitro studies or animal model data with the combination of amphotericin B plus azole have not been favorable [37, 38, 39, 40], although this combination has frequently been used in desperate situations. The combination is no longer considered antagonistic, but no clear advantage over therapy with single agent has been shown. However, when an echinocandin is combined with an azole or amphotericin B, synergy is consistently noted both in vitro and in animal models [41, 42, 43, 44]. Also, successfully treated cases with a combination of caspofungin and itraconazole or LipAmB have been reported [45, 46, 47, 48]. Marr et al. [49] showed a significant reduction in mortality with caspofungin plus voriconazole as compared with voriconazole alone in a limited retrospective study of patients with aspergillosis who experienced failure of initial therapy with amphotericin B formulations. Overall, although the data for combination of amphotericin B plus azole are not encouraging, echinocandin-based combinations with an azole or polyene seem more promising.

With supportive clinical data lacking, combination therapy should not be the initial approach for all patients with IA. Because combination therapy is expensive, requires close monitoring (liver function tests [LFTs], calcineurin levels, and so on), and may turn out to be detrimental, this aggressive approach consisting of an echinocandin-based regimen may be reserved for situations with an anticipated poor outcome, such as a persistent, profound neutropenic state, severe GVHD/high-dose corticosteroid use, and disseminated or cerebral aspergillosis. Controlled clinical trials evaluating the efficacy of combination therapy over monotherapy are urgently needed.

Back to Article Outline

Assessment of treatment efficacy 

Clinical and radiologic changes have been the main tools to assess therapy. Gradual resolution of clinical symptoms and signs is anticipated with eradication of infection. Radiograph appearance may worsen initially before improvement; later, the abnormalities may remain unchanged once tissue scarring occurs. Recently, a noninvasive test, the serum aspergillus galactomannan (GM) assay, has become available for diagnosis [50, 51]. The sensitivity and specificity of the test are 81% and 89%, respectively. Numerous factors influence the performance of this assay, including biological factors, site of infection, Aspergillus species, underlying condition/immunosuppression, prior exposure to antifungal drugs, and presence of GM antibodies [52]. Consequently, both false-positive and false-negative results are not uncommon. Notably, the antibiotic piperacillin/tazobactam (Zosyn; Lederle, Pearl River, NY) may contain GM antigen, and its concomitant use may produce a false-positive test [53]. Besides diagnosing IA, the GM assay has also been used to monitor disease progression [54]. Serial GM index measurements seem necessary in most studies, and an increase of the GM index >1.0 over baseline during the first week of therapy has predicted treatment failure. Increasing GM values suggest treatment failure, whereas decreasing GM corresponds with a complete or partial clinical response. At present, more clinical experience is needed with the aspergillus GM assay to reliably use the test for diagnostic or prognostic purposes. Also, the serum glucan assay was recently licensed for diagnosis, and the polymerase chain reaction assay is under intense scrutiny [55, 56]. Reliable data are not available for use of these tests during therapy of IA.

Back to Article Outline

Therapy in patients showing improvement 

For optimal outcome, appropriate antifungal drugs combined with an improvement in host immune status are essential. Defervescence and abatement of symptoms within 1 week of initial therapy suggest clinical improvement. Radiographic changes may seem worsened during the first several days of therapy before showing improvement. High-resolution computed tomography is helpful to observe the gradual diminution or disappearance of nodular or cavitary lesions. For patients showing clinical improvement, therapy may be changed from intravenous voriconazole to the more convenient oral formulation of the drug. The route of administration may be switched from intravenous to oral within a few days of treatment initiation. In the study by Herbrecht et al. [20], the switch from the intravenous to oral route occurred early, after a median of 10 days. Oral voriconazole has excellent bioavailability and, in comparison with the intravenous form, is considerably less expensive. Initiating therapy with the oral formulation of voriconazole may be appropriate in less critically ill patients with intact gastrointestinal absorption. If therapy was begun with LipAmB, then treatment may be switched to oral itraconazole or voriconazole upon clinical improvement. Completion of therapy with an azole after initial treatment with a polyene has become routine and seems safe. Although there is a theoretical concern of polyene/azole antagonism due to the common target site of ergosterol, sequential therapy with amphotericin B followed by itraconazole or voriconazole has been found to be effective [9, 57]. Maintenance of adequate serum levels is a significant concern, particularly with oral itraconazole. For this reason, the capsule formulation of itraconazole is to be avoided in serious infections, and standard doses of intravenous itraconazole or oral suspensions are acceptable. The latter formulations in routine doses produce adequate serum levels [58]. Routine measurements of voriconazole levels with either oral or intravenous formulations are not necessary. Symptoms of nausea, vomiting, and diarrhea due to chemotherapy, radiation, or GVHD may preclude oral therapy. Laboratory tests for monitoring therapy include complete blood counts, renal status, and LFTs. LFT abnormalities may be due to the fungal infection, the antifungal drug or other drugs, other opportunistic viral infections, or GVHD. Identifying the exact etiology of abnormal LFTs may be difficult; thus, liver biopsy may occasionally be required.

The duration of therapy is determined by the clinical and radiologic response and the patient’s underlying immune status. In general, therapy is administered for at least 3 to 4 months.

Back to Article Outline

Therapy in patients showing deterioration 

Clinical deterioration, despite therapy, may be a result of impaired host factors, the pathogen, or the drug [59]. The importance of an intact immune status for a good outcome cannot be overemphasized. Aspergillus may be present in large numbers, overwhelming the antimicrobial agent, or may be drug resistant. Aspergillus terreus is inherently resistant to polyenes in vitro, and poor clinical response has been documented [31, 33]. Resistance (primary or acquired) to polyenes among non-terreus Aspergillus species has been extremely rare, whereas in vitro/in vivo resistance to triazoles, though uncommon, has been reported [60, 61, 62, 63, 64, 65, 66, 67]. The mechanism of resistance to voriconazole in a clinical isolate has been elucidated [66]. With increasing use of triazoles for prophylaxis or therapy, the emergence of azole-resistant aspergillus or breakthrough zygomyces infections needs close observation [26, 27, 28, 29]. Also, antifungal drugs may fail to cure the infection because of inappropriate dose, fungistatic activity, poor absorption/distribution and metabolism, or drug interactions. With more drugs available, clinicians may feel tempted to modify therapy sooner than before. All of this needs careful consideration before a therapeutic modification is made.

Treatment modifications in patients with progressive IA on monotherapy include switching from one drug to another (sequential therapy), adding 1 or more drugs to an existing drug, or increasing the dose of drug. As with combination therapy, there are no convincing clinical data to support the use of sequential therapy. Voriconazole has been used with reasonably good results (approximately 50% response) as salvage therapy in most patients initially treated with amphotericin B [57]. At present, however, because voriconazole is commonly used as initial therapy, progressive IA may occur despite the azole. In such cases, the patients could theoretically be at a higher risk for treatment failure with a polyene because the prior azole exposure may have depleted the common target (ie, ergosterol) [68]. No clinical study, thus far, has implicated prior azole exposure (as prophylaxis or therapy) as a cause for subsequent failure with a polyene, but such patients may need close observation. Echinocandins have been used in a sequential fashion with encouraging results. The response rate with caspofungin as salvage therapy in refractory IA was 40%. A 22% to 28% response rate was observed when micafungin was added to a failing regimen of LipAmB [69]. In a retrospective study of salvage therapy with voriconazole or voriconazole plus caspofungin, the survival rate was 35% and 65%, respectively [49].

Another strategy during progressive IA is to increase the dose of drug. The dose of LipAmB may safely be increased from 5 mg/kg to higher doses [19, 70], and, likewise, the dose of caspofungin may safely be increased; whether higher doses are more effective is not clear.

Back to Article Outline

Adjunct therapy 

In the compromised host with IA, immune enhancement with interleukins, colony-stimulating factors, and γ-interferon are adjunct strategies [34]. Although supportive data from in vitro and murine model studies are available, clinical evidence for the use of such expensive agents is lacking. A European Organization for Research and Treatment of Cancer multicenter prospective survey involving 20 hospitals in 8 countries concluded that the use of growth factors did not influence outcome in patients with IA and underlying hemologic malignancies [71]. Thus, routine use of these agents is not recommended. Likewise, an absence of clinical evidence negates the routine use of white blood cell transfusion in patients with IA.

Surgical resection may play an important adjunct role in patients with hemoptysis or in those with lesions close to large blood vessels, threatening hemorrhage. Surgery is likely to be successful with solitary and easily accessible lesions in patients who are surgical candidates. Caillot et al. [72] documented an 84% cure rate with a combination of medical and surgical therapy in neutropenic patients with IA. However, surgical resection may not be feasible in many patients. At present, the role of surgery needs to be individualized. Surgery alone, however, is not adequate and must always be combined with medical therapy.

Back to Article Outline

Secondary prophylaxis 

Deep-seated foci of IA often remain after treatment, and reactivation of IA during a new neutropenic episode and during stem cell transplantation is estimated to be 30% to 50% [73]. In the past, prior IA was considered a major contraindication for stem cell transplantation; at present, this opinion is changing [74]. In a retrospective study of 48 stem cell recipients with prior IA, the risk of aspergillus relapse was 33%, and the death rate among those with relapsed IA was 88% [75]. The study showed that patients receiving secondary prophylaxis with absorbable or intravenous antifungal drugs had fewer relapses of IA than those who did not receive prophylaxis. There are no prospective studies of secondary prophylaxis in cancer patients or transplant recipients with prior IA. In a small study of 11 leukemic patients with previous aspergillosis (n = 10) or candidiasis (n = 2), voriconazole was administered as prophylaxis for 44 to 245 days during transplantation or consolidation chemotherapy; none had relapse of fungal infection [73]. Given the poor outcome in patients with IA, it is widely accepted to administer antifungal chemoprophylaxis to patients with prior IA who are about to become neutropenic for a prolonged period or who are about to undergo stem cell transplantation.

Back to Article Outline

Conclusion 

In summary, with the arrival of new drugs belonging to old and new classes, there is renewed optimism in the management of IA. Concomitantly, several questions have arisen. These issues are not just academic but are of increasing clinical importance, because more than half of patients with IA succumb to this infection. Appropriate clinical data in the management of aspergillosis are urgently needed to practice evidence-based medicine. However, relevant data are difficult to generate with rapidly changing practices in the management of both transplantation and infection. In the absence of such evidence, management practices will continue to vary widely among institutions, frequently at great economic cost and increased patient morbidity.

Back to Article Outline

References 

  1. McNeil MM , Nash SL , Hajjeh RA , et al.   Trends in mortality due to invasive mycotic diseases in the United States, 1980–1997 . Clin Infect Dis. . 2001;33:641–647
  2. Baddley JW , Stroud TP , Salzman D , Pappas PG . Invasive mold infections in allogeneic bone marrow transplant recipients . Clin Infect Dis. . 2001;32:1319–1324
  3. Marr KA , Carter RA , Crippa F , Wald A , Corey L . Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients . Clin Infect Dis. . 2002;34:909–917
  4. Denning DW . Invasive aspergillosis in immunocompromised patients . Curr Opin Infect Dis. . 1994;7:456–462
  5. Schaffner A , Douglas H , Braude A . Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes . J Clin Invest. . 1982;69:617–631
  6. Schneemann M , Schaffner A . Host defense mechanism in Aspergillus fumigatus infections . Contrib Microbiol. . 1999;2:57–68
  7. Wingard JR . Antifungal chemoprophylaxis after blood and marrow transplantation . Clin Infect Dis. . 2002;34:1386–1390
  8. Palmer LB , Greenberg HE , Schiff MJ . Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease . Thorax . 1991;46:15–20
  9. Patterson TF , Kirkpatrick WR , White M , et al.   Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus Study Group . Medicine (Baltimore) . 2000;79:250–260
  10. Lin SJ , Schranz J , Teutsch SM . Aspergillosis case-fatality rate (systematic review of the literature) . Clin Infect Dis. . 2001;32:358–366
  11. Bowden R , Chandrasekar P , White MH , et al.   A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients . Clin Infect Dis. . 2002;35:359–366
  12. Ostrosky-Zeichner L , Marr KA , Rex JH , Cohen SH . Amphotericin B (time for a new “gold standard.”) . Clin Infect Dis. . 2003;37:415–425
  13. Mehta J , Kelsey S , Chu P , et al.   Amphotericin B lipid complex (ABLC) for the treatment of confirmed or presumed fungal infections in immunocompromised patients with hematologic malignancies . Bone Marrow Transplant. . 1997;20:39–43
  14. Walsh TJ , Hiemenz JW , Seibel NL , et al.   Amphotericin B lipid complex for invasive fungal infections (analysis of safety and efficacy in 556 cases) . Clin Infect Dis. . 1998;26:1383–1396
  15. Mills W , Chopra R , Linch DC , Goldstone AH . Liposomal amphotericin B in the treatment of fungal infections in neutropenic patients (a single-centre experience of 133 episodes in 116 patients) . Br J Haematol. . 1994;86:754–760
  16. Ng TT , Denning DW . Liposomal amphotericin B (AmBisome) therapy in invasive fungal infections. Evaluation of United Kingdom compassionate use data . Arch Intern Med. . 1995;155:1093–1098
  17. Timmers GJ , Zweegman S , Simoons-Smit AM , van Loenen AC , Touw D , Huijgens PC . Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients (data of a prematurely stopped clinical trial) . Bone Marrow Transplant. . 2000;25:879–884
  18. Wingard JR , White MH , Anaissie E , Raffalli J , Goodman J , Arrieta A  L Amph/ABLC Collaborative Study Group . A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia . Clin Infect Dis. . 2000;31:1155–1163
  19. Walsh TJ , Goodman JL , Pappas P , et al.   Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi (maximum tolerated dose study) . Antimicrob Agents Chemother. . 2001;45:3487–3496
  20. Herbrecht R , Denning DW , Patterson TF , et al.  Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer  Global Aspergillus Study Group   Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis . N Engl J Med. . 2002;347:408–415
  21. Denning DW , Lee JY , Hostetler JS , et al.   NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis . Am J Med. . 1994;97:135–144
  22. Stevens DA , Lee JY . Analysis of compassionate use itraconazole therapy for invasive aspergillosis by the NIAID Mycoses Study Group criteria . Arch Intern Med. . 1997;157:1857–1862
  23. Caillot D , Bassaris H , McGeer A , et al.   Intravenous itraconazole followed by oral itraconazole in the treatment of invasive pulmonary aspergillosis in patients with hematologic malignancies, chronic granulomatous disease, or AIDS . Clin Infect Dis. . 2001;33:83–90
  24. Maertens J , Raad I , Sable C , et al.   Multicenter, noncomparative study to evaluate safety and efficacy of caspofungin in adults with invasive aspergillosis refractory or intolerant to amphotericin, amphotericin B lipid formulations, or azoles . [abstract j-1103] Program and Abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (Toronto) . Washington, DC: American Society for Microbiology; 2000;
  25. Maertens J , Raad I , Petrikkos G , et al.   Update on the multicenter noncomparative study of caspofungin in adults with invasive aspergillosis refractory or intolerant to other antifungal agents (analysis of 90 patients) . [abstract N-868] Program and Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (San Diego) . Washington, DC: American Society for Microbiology; 2002;
  26. Warris A , Weemaes CM , Verweij PE . Multidrug resistance in Aspergillus fumigatus . N Engl J Med. . 2002;347:2173–2174
  27. Marty FM , Cosimi LA , Baden LR . Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants . N Engl J Med. . 2004;350:950–952
  28. Imhof A , Balajee SA , Fredricks DN , Englund JA , Marr KA . Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole . Clin Infect Dis. . 2004;39:743–746
  29. Siwek GT , Dodgson KJ , de Magalhaes-Silverman M , et al.   Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis . Clin Infect Dis. . 2004;39:584–587
  30. Perfect JR , Marr KA , Walsh TJ , et al.   Voriconazole treatment for less-common, emerging, or refractory fungal infections . Clin Infect Dis. . 2003;36:1122–1131
  31. Sutton DA , Sanche SE , Revankar SG , Fothergill AW , Rinaldi MG . In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole . J Clin Microbiol. . 1999;37:2343–2345
  32. Walsh TJ , Petraitis V , Petraitiene R , et al.   Experimental pulmonary aspergillosis due to Aspergillus terreus (pathogenesis and treatment of an emerging fungal pathogen resistant to amphotericin B) . J Infect Dis. . 2003;188:305–319
  33. Iwen PC , Rupp ME , Langnas AN , Reed EC , Hinrichs SH . Invasive pulmonary aspergillosis due to Aspergillus terreus (12-year experience and review of the literature) . Clin Infect Dis. . 1998;26:1092–1097
  34. Steinbach WJ , Benjamin DK , Kontoyiannis DP , et al.   Infections due to Aspergillus terreus (a multicenter retrospective analysis of 83 cases) . Clin Infect Dis. . 2004;39:192–198
  35. Johnson MD , MacDougall C , Ostrosky-Zeichner L , Perfect JR , Rex JH . Combination antifungal therapy . Antimicrob Agents Chemother. . 2004;48:693–715
  36. Steinbach WJ , Stevens DA , Denning DW . Combination and sequential antifungal therapy for invasive aspergillosis (review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001) . Clin Infect Dis. . 2003;37:S188–S224
  37. Sugar AM . Use of amphotericin B with azole antifungal drugs (what are we doing?) . Antimicrob Agents Chemother. . 1995;39:1907–1912
  38. Denning DW , Hanson LH , Perlman AM , Stevens DA . In vitro susceptibility and synergy studies of Aspergillus species to conventional and new agents . Diagn Microbiol Infect Dis. . 1992;15:21–34
  39. Hughes CE , Harris C , Moody JA , Peterson LR , Gerding DN . In vitro activities of amphotericin B in combination with four antifungal agents and rifampin against Aspergillus spp . Antimicrob Agents Chemother. . 1984;25:560–562
  40. Maesaki S , Kohno S , Kaku M , Koga H , Hara K . Effects of antifungal agent combinations administered simultaneously and sequentially against Aspergillus fumigatus . Antimicrob Agents Chemother. . 1994;38:2843–2845
  41. Arikan S , Lozano-Chiu M , Paetznick V , Rex JH . In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp . Antimicrob Agents Chemother. . 2002;46:245–247
  42. Perea S , Gonzalez G , Fothergill AW , Kirkpatrick WR , Rinaldi MG , Patterson TF . In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp . Antimicrob Agents Chemother. . 2002;46:3039–3041
  43. Kirkpatrick WR , Perea S , Coco BJ , Patterson TF . Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis . Antimicrob Agents Chemother. . 2002;46:2564–2568
  44. Petraitis V , Petraitiene R , Sarafandi AA , et al.   Combination therapy in treatment of experimental pulmonary aspergillosis (synergistic interaction between an antifungal triazole and an echinocandin) . J Infect Dis. . 2003;187:1834–1843
  45. Lum LR , Turco TF , Leone J . Combination therapy with caspofungin and amphotericin B lipid complex . Am J Health Syst Pharm. . 2002;59:80–81
  46. Rubin MA , Carroll KC , Cahill BC . Caspofungin in combination with itraconazole for the treatment of invasive aspergillosis in humans . Clin Infect Dis. . 2002;34:1160–1161
  47. Kontoyiannis DP , Hachem R , Lewis RE , et al.   Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary or salvage treatment of invasive aspergillosis in patients with hematologic malignancies . Cancer . 2003;98:292–299
  48. Aliff TB , Maslak PG , Jurcic JG , et al.   Refractory Aspergillus pneumonia in patients with acute leukemia (successful therapy with combination caspofungin and liposomal amphotericin) . Cancer . 2003;97:1025–1032
  49. Marr KA , Boeckh M , Carter RA , Kim HW , Corey L . Combination antifungal therapy for invasive aspergillosis . Clin Infect Dis. . 2004;39:797–802
  50. Maertens J , Van Eldere J , Verhaegen J , Verbeken E , Verschakelen J , Boogaerts M . Use of circulating galactomannan screening for early diagnosis of invasive aspergillosis in allogeneic stem cell transplant recipients . J Infect Dis. . 2002;186:1297–1306
  51. Maertens J , Verhaegen J , Lagrou K , Van Eldere J , Boogaerts M . Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients (a prospective validation) . Blood . 2001;97:1604–1610
  52. Mennink-Kersten MA , Donnelly JP , Verweij PE . Detection of circulating galactomannan for the diagnosis and management of invasive aspergillosis . Lancet Infect Dis. . 2004;4:349–357
  53. Adam O , Auperin A , Wilquin F , Bourhis JH , Gachot B , Chachaty E . Treatment with piperacillin-tazobactam and false-positive Aspergillus galactomannan antigen test results for patients with hematological malignancies . Clin Infect Dis. . 2004;38:917–920
  54. Boutboul F , Alberti C , Leblanc T , et al.   Invasive aspergillosis in allogeneic stem cell transplant recipients (increasing antigenemia is associated with progressive disease) . Clin Infect Dis. . 2002;34:939–943
  55. Kawazu M , Kanda Y , Nannya Y , et al.   Prospective comparison of the diagnostic potential of real-time PCR, double-sandwich enzyme-linked immunosorbent assay for galactomannan, and a (1→3)-beta-D-glucan test in weekly screening for invasive aspergillosis in patients with hematological disorders . J Clin Microbiol. . 2004;42:2733–2741
  56. Buchheidt D , Hummel M , Schleiermacher D , Spiess B , Hehlmann R . Current molecular diagnostic approaches to systemic infections with aspergillus species in patients with hematological malignancies . Leuk Lymphoma. . 2004;45:463–468
  57. Denning DW , Ribaud P , Milpied N , et al.   Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis . Clin Infect Dis. . 2002;34:563–571
  58. Winston DJ , Maziarz RT , Chandrasekar PH , et al.   Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients (A multicenter, randomized trial) . Ann Intern Med. . 2003;138:705–713
  59. Masia Canuto M , Gutierrez Rodero F . Antifungal drug resistance to azoles and polyenes . Lancet Infect Dis. . 2002;2:550–563
  60. Loeffler J , Stevens DA . Antifungal drug resistance . Clin Infect Dis. . 2003;36:S31–S41
  61. Chandrasekar PH , Cutright JL , Manavathu EK . Correlation of in vitro and in vivo susceptibilities of laboratory-selected amphotericin B-resistant isolates of Aspergillus fumigatus . Programs and Abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September . 2002;
  62. Dannaoui E , Borel E , Monier MF , Piens MA , Picot S , Persat F . Acquired itraconazole resistance in Aspergillus fumigatus . J Antimicrob Chemother. . 2001;47:333–340
  63. Denning DW , Radford SA , Oakley KL , Hall L , Johnson EM , Warnock DW . Correlation between in-vitro susceptibility testing to itraconazole and in-vivo outcome of Aspergillus fumigatus infection . J Antimicrob Chemother. . 1997;40:401–414
  64. Moore CB , Sayers N , Mosquera J , Slaven J , Denning DW . Antifungal drug resistance in Aspergillus . J Infect. . 2000;41:203–220
  65. Warris A , Weemaes CM , Verweij PE . Multidrug resistance in Aspergillus fumigatus . N Engl J Med. . 2002;347:2173–2174
  66. Manavathu E , Espinel-Ingroff A , Alangaden G , Chandrasekar P . Molecular studies on voriconazole-resistance in a clinical isolate of Aspergillus fumigatus . Programs and Abstracts of the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, September . 2003;
  67. Balajee SA , Weaver M , Imhof A , Gribskov J , Marr KA . Aspergillus fumigatus variant with decreased susceptibility to multiple antifungals . Antimicrob Agents Chemother. . 2004;48:1197–1203
  68. Kontoyiannis DP , Lewis RE , Sagar N , May G , Prince RA , Rolston KV . Itraconazole-amphotericin B antagonism in Aspergillus fumigatus (an E-test-based strategy) . Antimicrob Agents Chemother. . 2000;44:2915–2918
  69. Ratanatharathorn R , Flynn P , VanBurik J , et al.   Micafungin in combination with systemic antifungal agents in the treatment of refractory aspergillosis in bone marrow transplant patients . Abstracts of the 44th Annual Meeting of the American Society of Hematology, Philadelphia, PA, December . 2002;
  70. Hooshmand-Raad R , Reed M , Chu A , et al.   Safety of high dose/long duration amphotericin B lipid complex therapy. Focus on fungal infections 14, New Orleans, LA, March . 2004;
  71. Denning DW , Marinus A , Cohen J , et al.  EORTC Invasive Fungal Infections Cooperative Group   An EORTC multicentre prospective survey of invasive aspergillosis in haematological patients (diagnosis and therapeutic outcome) . J Infect. . 1998;37:173–180
  72. Caillot D , Couaillier JF , Bernard A , et al.   Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia . J Clin Oncol. . 2001;19:253–259
  73. Cordonnier C , Maury S , Pautas C , et al.   Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients and stem cell transplant recipients . Bone Marrow Transplant. . 2004;33:943–948
  74. Cordonnier C , Beaune J , Offner F , Marinus A , Ljungman P , Meunier F  Infectious Diseases Working Party of the EBMT and the EORTC Invasive Fungal Infections Cooperative Group . Aspergillosis prior to bone marrow transplantation . Bone Marrow Transplant. . 1995;16:323–324
  75. Offner F , Cordonnier C , Ljungman P , et al.   Impact of previous aspergillosis on the outcome of bone marrow transplantation . Clin Infect Dis. . 1998;26:1098–1103

PII: S1083-8791(04)00624-X

doi:10.1016/j.bbmt.2004.11.021

Biology of Blood and Marrow Transplantation
Volume 11, Issue 2 , Pages 77-84, February 2005

Article Tools