The management of febrile neutropenia in the posaconazole era: a new challenge?

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, TNFinhibitors), and the increasing number of transplant procedures. 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 alloHSCT when compared to placebo. 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. 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 population and in antifungal use. Interestingly, among AML patients, posaconazole prophylaxis was shown also to have a significant impact on overall survival. 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. These recent data led to the approval of posaconazole prophylaxis in high-risk categories, and all current consensus guidelines recommend this approach with a high level of evidence. 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. 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. 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. 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. Maertens and colleagues first showed that the incorporation of new techniques into a diagnostic algorithm led to antifungal treatments being halved. Since then, there has been much debate about whether an empirical or a pre-emptive approach should be first choice in hematologic patients. 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