Antifungal prophylaxis in neutropenia and HSCT

teaser

Yasmine Nivoix
Pharmacist Resident
Pharmacy
Hôpitaux
Universitaires de Strasbourg

Raoul Herbrecht
MD
Senior Consultant
Department of Hematology and Oncology
Hôpitaux
Universitaires de Strasbourg
Strasbourg, France
E:[email protected]

Fungal infections affect 10–50% of neutropenic patients and haematopoietic stem cell transplantation (HSCT) recipients. Mortality associated with fungal infections is high and is now the leading cause of infection mortality in many haematology units. Although profound and prolonged neutropenia following chemotherapy is the major risk factor for systemic fungal infections, other conditions such as the presence of a central venous line, colonisation with Candida spp, steroid therapy or chemotherapy- induced mucosal damage increase this risk.

Candidiasis and aspergillosis are the two most frequent fungal infections in cancer patients, but less common pathogens, such as Scedosporium spp, Fusarium spp, Trichosporon spp or Mucorales, are emerging as new challenges. Difficulty in establishing an accurate and early diagnosis may delay the initiation of appropriate treatment, reducing the likelihood of a successful outcome. The high case fatality rate of systemic fungal infections occurring in
severely immunosuppressed patients is the rationale for prophylactic approaches.

General prophylactic measures
Candida spp are usually acquired from the host’s own gastrointestinal and skin reservoir. The most important prophylaxis against candidiasis is to minimise the use of invasive procedures, prolonged neutropenia, the administration of broad-spectrum antibiotics and colonisation by Candida spp. Careful handwashing is also essential to limit nosocomial transmission.

Invasive aspergillosis is mainly an airborne disease caused by the inhalation of spores. The primary site of infection is predominantly the lower respiratory tract and to a lesser extent the upper respiratory tract. Specialised air-handling systems capable of excluding Aspergillus spores, such as high-efficiency particulate air filters with or without laminar airflow, reduce the incidence of aspergillosis. Endogenous Aspergillus spp acquired before hospitalisation in protective environments can also be responsible for the disease. Ideally, invasive aspergillosis prevention should involve action at two different levels: environmental control to avoid acquisition; and chemoprophylaxis for patients already colonised or at risk after discharge.

Haematopoietic growth factors certainly play an important role in the reduction of incidence of invasive fungal infection. They significantly reduce the duration of neutropenia, which is one of the most important risk factors for haematological patients. Although no clinical trial has demonstrated the beneficial role of growth factors in preventing invasive fungal infections, they are now routinely administered in patients at risk from prolonged neutropenia.

Antifungal agents
Over the past 20 years, a series of studies have evaluated the usefulness of antifungal agents in prophylaxis against fungal infections in neutropenic patients and HSCT recipients. Agents studied have included fluconazole, itraconazole, clotrimazole, oral and intravenous nystatin, and oral and aerosolised amphotericin B.

Fluconazole
There have been many prospective, randomised studies evaluating the prophylactic efficacy of fluconazole. Table 1 summarises the results of the largest randomised studies comparing fluconazole with a placebo, a polyene and itraconazole.(1–21)

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Invasive fungal infection rates and the empirical use of intravenous amphotericin B have been reduced in several studies comparing fluconazole with placebo.(2–4) The most convincing data have been reported in HSCT patients receiving fluconazole 400mg/day: fluconazole effectively prevents fungal colonisation, superficial fungal infections, invasive fungal infections and, in one of these studies, fungal-related deaths.(4) Results are more controversial in leukaemic patients, with no difference in invasive fungal infections and fungal-related death in a meta-analysis of 16 randomised studies.(22)

Fluconazole offers no protection against Aspergillus spp, and pathogenic Candida spp may be resistant (Candida krusei) or less sensitive (Candida glabrata) to this compound. Wingard et al first reported a shift toward C glabrata and C krusei infections in patients receiving fluconazole.(23,24) However, the epidemiology of nonalbicans Candida strains is variable. Some centres using fluconazole have reported no increase in infections due to such spp, while others had observed this emergence before the use of fluconazole.

Itraconazole
Itraconazole is an agent suitable for oral and intravenous administration. Its spectrum of action includes Candida and Aspergillus spp. Studies comparing itraconazole capsules with placebo or fluconazole failed to show any difference in colonisation or infections.(15,17)

More recently, itraconazole oral solution, a formulation providing higher serum levels, proved to be more effective than fluconazole in preventing invasive fungal infections in allogeneic HSCT recipients.(19) Itraconazole oral solution also reduced the rate of invasive fungal infection in patients with a haematological malignancy in a placebo-controlled study.(16) Itraconazole oral solution is mainly effective for prophylaxis of Candida infections, but the expected efficacy of itraconazole in preventing invasive aspergillosis has yet to be demonstrated. A metaanalysis of seven prophylaxis studies demonstrated a reduction in fungal-related mortality in patients receiving itraconazole oral solution.(25) Efficacy of itraconazole seems strongly correlated to its serum levels. Levels higher than 500ng/ml are necessary to reduce the rate of invasive infections.(26)

Other licensed antifungal agents
Oral administration of amphotericin B suspension is associated with poor compliance due to its bad taste, and, like amphotericin B capsules, it has never convincingly demonstrated any efficacy.(27)

Low-dose intravenous amphotericin B has been evaluated in HSCT recipients. In two historical comparisons, invasive fungal infection rates (including aspergillosis in one study) were decreased.(28,29) Perfect et al compared low-dose (0.1mg/kg/d) iv amphotericin B with placebo in the setting of HSCT.(30) Oropharyngeal colonisation was lower, and survival at six weeks post-transplantation was improved, but this improvement could not be associated with a reduction in invasive fungal infections. Infusionrelated adverse effects were higher in the amphotericin B group but with no significant organ toxicity. More recently, it was shown that iv amphotericin B (0.5mg/kg) given three times a week was no more effective but more toxic than fluconazole (400mg/ day).(31)

Intravenous low-dose liposomal amphotericin B (2mg/kg, three times a week) failed to reduce fungal infections and mortality in a double-blind study in bone marrow patients.(32)

The value of an intranasal spray or of aerosolisation of amphotericin B to prevent aspergillosis is still controversial.(33) Efficacy was not confirmed in a recent randomised trial.(34)

Oral nystatin and clotrimazole troches failed to prevent systemic fungal infection or to reduce death.(35,36)

New classes of antifungal agents
Voriconazole, posaconazole, caspofungin or other echinocandins appear to be promising for fungal infection prophylaxis due to their broad-spectrum activity, including against Aspergillus spp. Studies either have been conducted but with as yet unpublished results or are under consideration.

Who should receive chemoprophylaxis?
The risk of developing a fungal infection depends on the severity and the duration of the neutropenia.(37)

Allogeneic HSCT recipients run the highest risk of invasive fungal infections, not only during the neutropenic phase but also during the months following transplantation, especially when graftversus- host disease (GVHD) occurs.(38) Fluconazole at 400mg/day and itraconazole oral solution at 2.5mg/kg twice daily are currently the two available options.

Autologous HSCT recipients are at lower risk, as they have a short duration of neutropenia. No study has been specifically conducted in this patient population, and it is therefore difficult to conclude whether or not these patients benefit from chemoprophylaxis.

Whether or not leukaemic patients should receive prophylactic antifungal agents during induction and consolidation chemotherapy remains controversial. The usual practice is to administer fluconazole or itraconazole, especially when patients are colonised by yeasts at more than one site.

When antifungal prophylaxis is used, it should be started at the same time as chemotherapy is initiated and continued during neutropenia. Once the neutrophils recover (absolute neutrophil count, ANC >500/μl), prophylaxis can be discontinued in leukaemic patients.(33,37) In allograft recipients, prophylaxis must be continued regardless of the neutrophil count because of the risk of systemic fungal infection should the patient develop GVHD. Particular attention must be given to patients who need high-dose
steroids to counter GVHD and those with active cytomegalovirus infection. Although no optimal duration of antifungal prophylaxis has been defined in this population, a recent recommendation proposed a duration of three months post-transplantation.(39)

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