Over the years, the spectrum of patients at risk for invasive fungal disease (IFDs) has expanded. This is a result of the aging of the general population, progress in supportive care allowing clinicians to perform a higher number of aggressive and curative treatments, the introduction of new drugs in clinical practice (i.e. monoclonal antibodies, TNF-inhibitors), and the increasing number of transplant procedures.1–3 However, hematologic patients, and in particular those suffering from acute myeloid leukemia (AML) and those treated with allogeneic stem cell transplant (allo-HSCT), still make up the biggest proportion of cases. Given the high mortality rate for IFDs, the use of mold active prophylaxis has increased in recent years, particularly in AML patients.
It is well known that a hypothetical ideal prophylactic agent should combine favorable profiles in terms of efficacy, spectrum, toxicity, cost, interactions and resistance generation. Two randomized clinical trials (RCT) demonstrated that fluconazole reduced the incidence of candidiasis in allo-HSCT when compared to placebo.4,5 However, its lack of activity against molds significantly limits the benefit of its use. Itraconazole covers a wider range of fungi, but the use of this drug was limited by poor absorption of the capsules and side effects from the oral solution.6,7
Posaconazole appears to be a valid alternative to old triazoles as it offers both a wide spectrum of activity and an acceptable toxicity profile. Two RCTs showed posaconazole to be more efficacious and to have an excellent safety profile in high-risk patients; both studies reported a significant reduction in breakthrough IFDs in a high-risk population8,9 and in antifungal use. Interestingly, among AML patients, posaconazole prophylaxis was shown also to have a significant impact on overall survival.8 However, it is worth noting that the impact of posaconazole on overall survival has never been proved by multivariate analysis. This is important given that both the phase and extent of the hematologic malignancy play a crucial role in determining patient outcome.10
Consequently, the use of posaconazole in hematology departments is on the increase. In this context, real life experiences may be of help in assessing whether good results from RCTs can be translated into clinical practice.14–21 All these experiences mainly focus on acute myeloid leukemia patients. As shown in Table 1, all reported experiences agree on the advantages of posaconazole in terms of proven/probable IFD incidence.
However, impressive results with posaconazole from RCTs should not lead physicians to the dangerous belief that IFDs are no longer a problem. It is worth noting that, despite the higher efficacy and the wider spectrum of this prophylactic agent, breakthrough infections may still occur, even if these are more rare. This is particularly true in clinical contexts other than clinical trials in which unselected, high-risk patients are treated and analyzed (Table 1). The physician must identify IFD cases as soon as possible in order to guarantee early and adequate treatment to patients.22
Physicians are now, therefore, faced with the question of how to manage febrile neutropenia in patients receiving posaconazole prophylaxis.
Given that clinical success depends on the achievement of adequate serum levels of the drug, controling compliance with oral drug intake is expected to be the first step in a management algorithm; signs and symptoms of diarrhea and gastrointestinal graft-versus-host disease (GVHD) should also be investigated. Determining serum posaconazole concentration would probably be the best and most direct way to answer these questions but most centers do not make this routine practice.23 However, it is worth noting that in vitro experiments have demonstrated that the concentration of posaconazole in mammalian host cell membranes may represent a new mechanism to mediate drug efficacy. This may help reinterpret the discrepancies between serum antifungal levels and efficacy.24
Maertens and colleagues first showed that the incorporation of new techniques into a diagnostic algorithm led to anti-fungal treatments being halved.25 Since then, there has been much debate about whether an empirical or a pre-emptive approach should be first choice in hematologic patients.26–31 All proposed pre-emptive approaches strictly rely on newer diagnostic procedures approved for clinical use (galactomannan, CT-scan, (1–3)β-D-glucan) and on polymerase chain reaction (PCR)-based techniques which are still under clinical investigation. However, many doubts have been raised about the reliability of diagnostic tools in the new and unexplored context of highly active anti-mold prophylaxis.
In particular, sensitivity of the galactomannan assay has been reported to be highly variable.32 It is well-known that galactomannan is released from the cell wall during hyphae growth and that antigen serum levels strongly correlate with fungal burden. It has been demonstrated in an animal model that posaconazole prophylaxis decreases circulating galactomannan indices.33 Marr and colleagues confirmed this in a clinical context, reporting that prior administration of mold-active antifungal drug decreases galactomannan test sensitivity by 30%.34 Its reduced accuracy in hematologic patients receiving itraconazole, posaconazole or voriconazole prophylaxis could be a significant limitation to the use of galactomannan quantification as a screening technique. Timing of antifungal therapy has been shown to have a major impact on hospital mortality and reduced sensitivity, and a lower negative predictive value could lead to treatment being delayed.
It is also worth noting that the performance of a diagnostic test is largely influenced by the baseline prevalence of infections in the target population. Consequently, since posaconazole seems to reduce the incidence of IFDs, the positive predictive value of diagnostic tools is also expected to decrease. Notably, current ECIL guidelines suggest the use of monitoring for galactomannan in neutropenic patients who have a relatively high a priori probability (5–10%) of developing IA.35
Other authors have recently used an animal model to explore the possible influence of antifungal drugs on both galactomannan and quantitative PCR-based assays. It was found that the use of posaconazole in either prophylaxis or treatment may reduce the value of a negative PCR result in the early phase of aspergillosis, resulting in the need for daily PCR-based determinations for the first week.36 In the same experience, posaconazole treatment also resulted in a delay in galactomannan positivity. In this context, frequent and early testing appears to be needed to optimize diagnostic procedures, with the burden of additional costs in terms of economical and human resources.
Therefore, the optimal management of febrile neutropenia after posaconazole remains an unanswered question. A pre-emptive approach should be used with caution in this new clinical context. Despite the risk of overtreatment, empirical therapy still appears to be a valid and safe antifungal approach, particularly in the context of a wide spectrum anti-mold prophylaxis. Newer diagnostic tools have been shown to be reliable and accurate methods for the early detection of fungal diseases when serial determinations are performed in high-risk hematologic patients but the influence of mold-active prophylaxis on their accuracy should be noted. Further confirmation of the validity of diagnostic procedures is needed in this clinical setting to understand how best to use them. In addition, use of new detection techniques, such as quantification of fungal components in respiratory samples, should also be the subject of further analysis.
- Livio Pagano is Associated Professor of Hematology at the Catholic University of Sacred Heart, Rome, Italy. He is past-president of Federazione Italiana di Micologia Medica ed Animale (FIMUA) and executive member of EORTC Infectious Diseases Group. His main areas of interest are diagnosis and treatment of hematologic malignancies, clinical and epidemiology of secondary leukemias, and the management of infectious complications in neutropenic patients.
- Morena Caira is a post-doctorate reserch fellow in hematology at the Catholic University in Rome, Italy. Her major research interests include the epidemiology, diagnosis and treatment of infections in immunocompromised patients.
- Manuel Cuenca Estrella is the Director of the Spanish National Center for Microbiology and the Scientific Director of the Spanish Reference Laboratory of Medical Mycology where he runs a variety of research projects and scientific activities focused on fungal infections in man. He is the former Chairman of the European Fungal Infections Study Group of the European Society of Clinical Microbiology and Infectious Diseases (EFISG-ESCMID), a member of the Steering Committee of the Antifungal Subcommittee of Antifungal Susceptibility Testing of the European Committee of Antimicrobial Susceptibility Testing (AFST-EUCAST), and a member of other international societies and study groups.
- Financial and other disclosures provided by the author using the ICMJE (www.icmje.org) Uniform Format for Disclosure of Competing Interests are available with the full text of this paper at www.haematologica.org.
- Caira M, Mancinelli M, Leone G, Pagano L. Invasive aspergillosis in acute leukemias: old and new risk factors and epidemiological trends. Med Mycol. 2011; 49(Suppl 1):S13-6. PubMedhttps://doi.org/10.3109/13693786.2010.509138Google Scholar
- Pagano L, Caira M, Picardi M, Candoni A, Melillo L, Fianchi L. Invasive aspergillosis in patients with acute leukemia: update on morbidity and mortality—SEIFEM-C Report. Clin Infect Dis. 2007; 44(11):1524-5. PubMedhttps://doi.org/10.1086/517849Google Scholar
- Pagano L, Akova M, Dimopoulos G, Herbrecht R, Drgona L, Blijlevens N. Risk assessment and prognostic factors for mould-related diseases in immunocompromised patients. J Antimicrob Chemother. 2011; 66(Suppl 1):i5-14. PubMedhttps://doi.org/10.1093/jac/dkq437Google Scholar
- Slavin MA, Osborne B, Adams R, Levenstein MJ, Schoch HG, Feldman AR. Efficacy and safety of fluconazole prophylaxis for fungal infections after marrow transplantation--a prospective, randomized, double-blind study. J Infect Dis. 1995; 171(6):1545-52. PubMedhttps://doi.org/10.1093/infdis/171.6.1545Google Scholar
- Goodman JL, Winston DJ, Greenfield RA, Chandrasekar PH, Fox B, Kaizer H. A controlled trial of fluconazole to prevent fungal infections in patients undergoing bone marrow transplantation. N Engl J Med. 1992; 326(13):845-51. PubMedhttps://doi.org/10.1056/NEJM199203263261301Google Scholar
- Winston DJ, Maziarz RT, Chandrasekar PH, Lazarus HM, Goldman M, Blumer JL. 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(9):705-13. PubMedhttps://doi.org/10.7326/0003-4819-138-9-200305060-00006Google Scholar
- Marr KA, Crippa F, Leisenring W, Hoyle M, Boeckh M, Balajee SA. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem cell transplants. Blood. 2004; 103(4):1527-33. PubMedhttps://doi.org/10.1182/blood-2003-08-2644Google Scholar
- Cornely OA, Maertens J, Winston DJ, Perfect J, Ullmann AJ, Walsh TJ. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007; 356(4):348-59. PubMedhttps://doi.org/10.1056/NEJMoa061094Google Scholar
- Ullmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007; 356(4):335-47. PubMedhttps://doi.org/10.1056/NEJMoa061098Google Scholar
- Maertens JA, Nucci M, Donnelly JP. The role of antifungal treatment in hematology. Haematol. 2012; 97(3):325-7. https://doi.org/10.3324/haematol.2012.061952Google Scholar
- Walsh TJ, Anaissie EJ, Denning DW, Herbrecht R, Kontoyiannis DP, Marr KA. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008; 46(3):327-60. PubMedhttps://doi.org/10.1086/525258Google Scholar
- Maertens J, Marchetti O, Herbrecht R, Cornely OA, Flückiger U, Frêre P. European guidelines for antifungal management in leukemia and hematopoietic stem cell transplant recipients: summary of the ECIL 3--2009 update. Bone Marrow Transplant. 2011; 46(5):709-18. PubMedhttps://doi.org/10.1038/bmt.2010.175Google Scholar
- Cornely OA, Böhme A, Buchheidt D, Einsele H, Heinz WJ, Karthaus M. Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology. Haematol. 2009; 94(1):113-22. https://doi.org/10.3324/haematol.11665Google Scholar
- Ananda-Rajah MR, Grigg A, Downey MT, Bajel A, Spelman T, Cheng AC. Comparative clinical effectiveness of prophylactic voriconazole/posaconazole to fluconazole/itraconazole in patients with acute myeloid leukaemia/myelodysplastic syndrome undergoing cytotoxic chemotherapy over a 12-year period. Haematologica. 2012; 97(3):459-63. PubMedhttps://doi.org/10.3324/haematol.2011.051995Google Scholar
- Busca A, Frairia C, Marmont F, Audisio E, Pecoraro C, de Rosa FG.Paper presented at: ; Google Scholar
- Candoni A, Simeone E, Caira M, Mazzuzzo M, Fanin R, Pagano L.Paper presented at: ; Google Scholar
- Egerer G, Geist MJ. Posaconazole prophylaxis in patients with acute myelogenous leukaemia--results from an observational study. Mycoses. 2011; 54(Suppl 1):7-11. PubMedhttps://doi.org/10.1111/j.1439-0507.2010.01979.xGoogle Scholar
- Hahn J, Stifel F, Reichle A, Holler E, Andreesen R. Clinical experience with posaconazole prophylaxis--a retrospective analysis in a haematological unit. Mycoses. 2011; 54(Suppl 1):12-6. https://doi.org/10.1111/j.1439-0507.2010.01980.xGoogle Scholar
- Lerolle N, Lafaurie M, Touratier S, Tournoud M, Raffoux E, Ribaud P.Paper presented at: ; Google Scholar
- Michallet M, Sobh M, Morisset S, Kraghel S, Nicolini FE, Thomas X. Risk factors for invasive aspergillosis in acute myeloid leukemia patients prophylactically treated with posaconazole. Med Mycol. 2011; 49(7):681-7. PubMedGoogle Scholar
- Vehreschild JJ, Rüping MJ, Wisplinghoff H, Farowski F, Steinbach A, Sims R. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia: a 6 year experience of the Cologne AML cohort. J Antimicrob Chemother. 2010; 65(7):1466-71. PubMedhttps://doi.org/10.1093/jac/dkq121Google Scholar
- Khalafallah A, Maiwald M, Hannan T, Abell S, Staker J, Supperamohan A. Early implementation of antifungal therapy in the management of febrile neutropenia is associated with favourable outcome during induction chemotherapy for acute leukaemias. Intern Med J. 2011. https://doi.org/10.1111/j.1445–5994.2011.02638.xGoogle Scholar
- Lipp HP. Posaconazole: clinical pharmacokinetics and drug interactions. Mycoses. 2011; 54(Suppl 1):32-8. PubMedhttps://doi.org/10.1111/j.1439-0507.2010.01984.xGoogle Scholar
- Campoli P, Al Abdallah Q, Robitaille R, Solis NV, Fielhaber JA, Kristof AS. Concentration of antifungal agents within host cell membranes: a new paradigm governing the efficacy of prophylaxis. Antimicrob Agents Chemother. 2011; 55(12):5732-9. PubMedhttps://doi.org/10.1128/AAC.00637-11Google Scholar
- Maertens J, Theunissen K, Verhoef G, Verschakelen J, Lagrou K, Verbeken E. Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis. 2005; 41(9):1242-50. PubMedhttps://doi.org/10.1086/496927Google Scholar
- Tan BH, Low JG, Chlebicka NL, Kurup A, Cheah FK, Lin RT. Galactomannan-guided preemptive vs. empirical antifungals in the persistently febrile neutropenic patient: a prospective randomized study. Int J Infect Dis. 2011; 15(5):e350-6. PubMedhttps://doi.org/10.1016/j.ijid.2011.01.011Google Scholar
- Girmenia C, Micozzi A, Gentile G, Santilli S, Arleo E, Cardarelli L. Clinically driven diagnostic antifungal approach in neutropenic patients: a prospective feasibility study. J Clin Oncol. 2010; 28(4):667-74. PubMedhttps://doi.org/10.1200/JCO.2009.21.8032Google Scholar
- Pagano L, Caira M, Nosari A, Cattaneo C, Fanci R, Bonini A. The use and efficacy of empirical versus pre-emptive therapy in the management of fungal infections: the HEMA e-Chart Project. Haematol. 2011; 96(9):1366-70. https://doi.org/10.3324/haematol.2011.042598Google Scholar
- Cordonnier C, Pautas C, Maury S, Vekhoff A, Farhat H, Suarez F. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized, controlled trial. Clin Infect Dis. 2009; 48(8):1042-51. PubMedhttps://doi.org/10.1086/597395Google Scholar
- Dignan FL, Evans SO, Ethell ME, Shaw BE, Davies FE, Dearden CE. An early CT-diagnosis-based treatment strategy for invasive fungal infection in allogeneic transplant recipients using caspofungin first line: an effective strategy with low mortality. Bone Marrow Transplant. 2009; 44(1):51-6. PubMedhttps://doi.org/10.1038/bmt.2008.427Google Scholar
- Oshima K, Kanda Y, Asano-Mori Y, Nishimoto N, Arai S, Nagai S. Presumptive treatment strategy for aspergillosis in allogeneic haematopoietic stem cell transplant recipients. J Antimicrob Chemother. 2007; 60(2):350-5. PubMedhttps://doi.org/10.1093/jac/dkm217Google Scholar
- Cuenca-Estrella M, Bassetti M, Lass-Flörl C, Rácil Z, Richardson M. Detection and investigation of invasive mould disease. J Antimicrob Chemother. 2011; 66(Suppl 1):i15-24. PubMedhttps://doi.org/10.1093/jac/dkq438Google Scholar
- Petraitiene R, Petraitis V, Groll AH, Sein T, Piscitelli S, Candelario M. Antifungal activity and pharmacokinetics of posaconazole (SCH 56592) in treatment and prevention of experimental invasive pulmonary aspergillosis: correlation with galactomannan antigenemia. Antimicrob Agents Chemother. 2001; 45(3):857-69. PubMedhttps://doi.org/10.1128/AAC.45.3.857-869.2001Google Scholar
- Marr KA, Laverdiere M, Gugel A, Leisenring W. Antifungal therapy decreases sensitivity of the Aspergillus galactomannan enzyme immunoassay. Clin Infect Dis. 2005; 40(12):1762-9. PubMedhttps://doi.org/10.1086/429921Google Scholar
- Marchetti O, Lamoth F, Mikulska M, Viscoli C, Verweij P, Bretagne S. ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients. Bone Marrow Transplant. 2011. https://doi.org/10.1038/bmt.2011.178.Google Scholar
- McCulloch E, Ramage G, Rajendran R, Lappin DF, Jones B, Warn P. Antifungal treatment affects the laboratory diagnosis of invasive aspergillosis. J Clin Pathol. 2011. PubMedhttps://doi.org/10.1136/jcp.2011.090464Google Scholar