Avoiding fungal infections in vulnerable patients

Dr Cornelia Lass-Flörl

Division of Hygiene and Medical Microbiology, Innsbruck Medical University, Austria

Invasive fungal diseases (IFD) are a cause of morbidity and mortality in patients undergoing cancer chemotherapy, haematopoetic stem-cell transplantation, solid organ transplantation or aggressive surgical interventions.1 Difficulty in early diagnosis often results in delayed antifungal therapy, which adversely impacts patients’ outcome. Attributable mortality rates for invasive candidiasis (IC) and invasive aspergillosis (IA) are 33% and 42%, respectively.2

Candida species (spp.) and Aspergillus spp. have been the main cause if IFDs, but other opportunistic pathogens such as the zygomycetes have emerged. Prevention of IFDs is thus an important clinical effort. The triazoles, echinocandins, and polyenes constitute the three classes of antifungal drugs for prophylaxis.

When considering prophylaxis, the following factors needs to be taken into account:

1. Risk factors for IFDs
2. Local epidemiology
3. Choice of drug
4. Timing and duration of prophylaxis.

The introduction of antifungal agents for the prevention of infection has significantly reduced the incidence of IFDs by 50%, and antifungal prophylaxis decreases overall mortality by 21% and fungal-related deaths by 45%.2

Drugs

Azoles
Fluconazole is the most extensively studied triazole and its attractive features include ease of administration, tolerability, favorable safety profile and low cost. Fluconazole, as shown in many randomised trials, has decreased rates of fungal colonisation, superficial and IFDs.3

On the other hand, fluconazole has a limited spectrum of activity. It lacks activity against C. krusei and moulds and demonstrates variable sensitivity for C. glabrata. Breakthrough infections have been reported.4 A daily dose of 400mg is recommended in allogeneic transplant recipients from the day of transplantation until engraftment. Lower doses of 50 to 200mg have not been proven to be efficacious in the prevention of IFDs.3

Itraconazole has been a triazole of interest because of its expanded spectrum of activity inclusive of aspergillus spp. Capsule use has been limited because of its erratic bioavailability, but itraconazole oral solution is better absorbed. Adverse effects and drug interactions with itraconazole are major drawbacks. Data are not compelling to support widespread use in patients with hematologic malignancies.1,4

Voriconazole is a derivative of fluconazole and is a first-line treatment for IA.1,5 Voriconazole, available in both oral and parenteral formulations, exhibits a wide spectrum of activity against clinically important fungal pathogens. It is active against Candida spp., including C. krusei and C. glabrata and Aspergillus spp., but does not cover the zygomycetes.

Wingard et al6 compared voriconazole to standard fluconazole prophylaxis in a randomised, double-blind, multicentre study in allogeneic hematopoietic stem-cell transplantation (HSCT) recipients. Voriconazole did not meet superiority in the primary end-point – fungal-free survival – yet there was a trend for less proven Aspergillus infections. Overall survival and drug tolerability were similar in both study groups.

Posaconazole is the most recent azole with broad-spectrum activity against several fungi; it is unique in having activity against zygomycetes. This agent is available only as an oral solution and should be administered with food for optimal bioavailability. Its use will be limited in patients unable to tolerate oral intake.

Two key studies demonstrated that posaconazole was significantly more effective in preventing IA, reducing death related to fungal infections and reducing overall mortality than the comparators.7,8 Posaconazole is now fully incorporated into the Infectious Disease Society of America (IDSA) clinical practice guidelines, at the highest level of recommendation, for prevention of Aspergillus infections in patients at high risk.1

There has been increased concern about significant inter- and intrapatient variability in voriconazole and posaconazole plasma levels. Low levels have been associated with fungal breakthrough infections.

Patients receiving extended-spectrum azoles may receive agents which interact with the hepatic cytochrome P450 isoenzymes. Voriconazole has greatest affinity for the CYP2C19 and low affinity for the CYP3A4 isoenzyme, whereas posaconazole inhibits the CYPP3A4 isoenzyme. Such inhibitions may increase the levels of concomitantly administered drugs such as RNA polymerase inhibitors and calcineurin inhibitors.2

Echinocandins
Echinocandins (caspofungin, anidulafungin and micafungin) are active against candida spp. and Aspergillus spp. These agents have a favorable safety profile and fewer drug interactions than the azoles. Echinocandins only can be given intravenously and thus are only suitable for short periods of prophylaxis.

Only micafungin has been approved for prophylaxis of candida infections in patients undergoing HSCT.4 There are no data for use of echinocandin prophylaxis in patients with acute leukemia and other hematologic malignancies.

Polyenes
Amphotericin B (AMB), the oldest antifungal agent, has one of the broadest antifungal spectrums available, but its long-term use has been limited by renal and infusional toxicities.

There have been no adequately powered randomised controlled trials to establish the effectiveness of AMB or its lipid formulations for prophylaxis in either HSCT recipients or patients with hematologic malignancies. Published trials have inadequate numbers and/or study designs and are not convincing.2

Studies looking at high-dose weekly liposomal administration for outpatient convenience have shown poor tolerability.9,10 Because inhalation of conidiospores is the first step in the pathogenesis of IA, there has been interest in evaluating the efficacy and safety of aerosolised amphotericin B for antifungal prophylaxis to avoid systemic toxicity. No differences in rates of IFDs, attributable mortality or overall mortality were seen.

Risk factors
The event rates for IFDs in HSCT vary considerably depending on a number of risk factors.1,2,4 Recipient-related predictors include older age at the time of transplant, increased bone marrow iron stores at the time of transplant, APACHE II scores of greater than 11, and advanced underlying disease at the time of transplant (see Table 1 and 2).

Transplant procedure-related predictors include type of transplant (autologous vs allogeneic), recipient-donor relatedness (matched related, mismatched related, or unrelated), conditioning regimen (myeloablative vs nonmyeloablative or reduced intensity), conditioning regimen–related oral and intestinal mucositis, prolonged severe pre-engraftment neutropenia, monocytopenia at day 30 post-transplant, source of the stem cell product (bone marrow vs peripheral blood vs cord blood), stem cell dosing, and stem cell product manipulations – e.g. T-cell depletion and CD34 selection (see Table 1 and 2).

Transplant complication-related predictors include administration of corticosteroids as part of the graft-versus-host disease (GVHD) prophylaxis regimen, administration of corticosteroids for the treatment of GVHD, administration of tumour necrosis factor-α for the treatment of steroid-refractory GVHD, acquisition of respiratory virus infection, and cytomegalovirus (CMV) disease – see Table 1 and 2.

A similar situation applies for IFDs in solid organ transplantation (SOT) patients. Liver and pancreas recipients are at high risk for infection with Aspergillus spp or Candida spp; lung transplant recipients with Aspergillus spp in cultures, allograft rejection, and CMV infection may benefit from antifungal prophylaxis for at least four months or until the anastomosis has healed (see Table 1 and 2).  

Antifungal chemoprophylaxis in acute 
leukemia/myelodysplasia
In a meta-analysis of 16 prospective, randomised trials in patients with chemotherapy-induced neutropenia, fluconazole prophylaxis seemed to be effective when the incidence of fungal infections was expected to be greater than 15%.

A large multicentre trial comparing mould-active posaconazole with fluconazole or itraconazole demonstrated a 75% reduction in the risk for IFDs overall, and an 86% reduction in the risk for IA among posaconazole recipients with acute leukemia or myelodysplastic syndrome.7 There was a 27% reduction in all-cause mortality among the posaconazole recipients.

A multicentre, randomised, placebo-controlled study of antifungal prophylaxis with voriconazole11 was terminated early due to ethical concerns about the use of a placebo when the all-cause mortality results of the posaconazole trial became available.8 Proposed regimens are given in Table 3.

The IDSA1 has subsequently recommended (A-I recommendation) posaconazole-based anti-fungal prophylaxis for patients with acute myeloid leukemia or myelodysplastic syndrome for whom the receipt of intensive cytotoxic therapy places them at higher risk for IFDs caused by 
Aspergillus spp.

Antifungal chemoprophylaxis in hematopoietic stem cell transplantation
Prophylaxis with fluconazole has reduced the incidence of IC overall mortality in HSCT recipients,12 but the rates for invasive mould infections (IMI) remained unchanged.  

The IDSA has recommended (A-I recommendation) posaconazole-based antifungal prophylaxis for the subgroup of allogeneic HSCT recipients with GvHD.1 In contrast, antifungal prophylaxis is not recommended for autologous HSCT recipients, particularly where hematopoietic growth-factor support is being concomitantly prescribed. Proposed regimens are given in Table 3.

Antifungal chemoprophylaxis in organ transplantation
Lung transplantation is associated with a relatively high incidence of IFDs, which, in turn, directly affect the morbidity and mortality. Based on historical data, the prevalence of fungal infections in the lung transplant population not receiving antifungal prophylaxis is approximately 13%. Candida spp. and Aspergillus spp. are the top fungal pathogens responsible for IFDs in this population, historically accounting for up to 80% of fungal infections.13

For lung transplant recipients, infections of the lung, mediastinum, and pleural space account for 80% of all infections.14 The timeline for infections following transplantation has traditionally been divided into three phases: the first month, months two through to six, and more than six months after transplant. The risk of developing an invasive mycosis during each of these periods relates to the patient’s overall state of immunosuppression and exposure to fungal pathogens.15

There is no widely accepted consensus with regard to antifungal prophylaxis following SOT, but many transplant centres use targeted antifungal prophylaxis based on the presence of risk factors. Most lung transplant programmes use some type of antifungal preventive therapy immediately after transplant, with the duration of prophylaxis varying between one and three months (most are ≤6 months).

Aerosolised amphotericin B-based regimens alone or in combination with a systemic azole, such as fluconazole, or systemic therapy alone with a mould-active azole, such as itraconazole, are the regimens most often used. Small studies evaluating inhaled aerosolised amphotericin B deoxycholate and amphotericin B lipid complex (ABLC) have shown that these drugs are safe in the lung transplant population.

Although aerosolised ABLC tends to be better tolerated than aerosolised amphotericin B deoxycholate, studies have documented minimal systemic absorption for both and little systemic toxicity when amphotericin B-based drugs are administered via aerosolisation.

This, coupled with the ease of once-weekly treatments amenable to long-term and outpatient administration, make this an attractive approach to antifungal prophylaxis.13 Proposed regimens are given in Table 3.

Conclusion
Voriconazole and posaconazole are two second-generation triazole antifungals that are widely used for preventing and treating a variety of IFDs. On the basis of published literature and professional guidelines, the following points need to be taken into account:

• 
Antifungal prophylaxis is indicated in patients with haematological malignancies and at high risk for IFDs
• 
The best prophylactic antifungal agent should confer protection against either moulds or yeasts
• 
Currently, the best results have been provided by posaconazole prophylaxis in patients with haematological diseases
• 
There is no widely accepted consensus following solid organ transplantation. Prophylaxis depends on individual 
risk factors.  

Effective non-drug prevention measures require meticulous attention to cleanliness: hand washing, central line care, and good patient oral and personal hygiene. Patients should avoid situations in which they might be exposed to moulds, such as gardening, construction sites or exploring caves.

References

1. 
Walsh TJ et al. Clin Infect Dis 2008;46:327-60.
2. 
Robenshtok E et al. J Clin Oncol 2007;25(34):5471-89.
3. 
Bow EJ et al. Cancer 2009;94:3230-46.
4. 
Maertens J et al. Eur J Cancr Suppl 2007;5:43-8.
5. 
Herbrecht R et al. N Engl J Med 2002;347:408-15.
6. 
Wingard J et al. (Abstract 163) Blood 2010 [ahead of print].
7. 
Ullman AJ et al. N Engl J Med 2007;356:335-47.
8. 
Cornely OA et al. N Engl J Med 2007; 56:348-59.
9. 
El-Cheick J et al. Bone Marrow Transplant 2007;39:301-306.
10. 
Cordonnier C et al. Int J Antimicrob Agents 2008;31:135-41.
11. 
Vehreschild JJ et al. J Infect 2007;55:445-49.
12. 
Marr KA et al. Blood 2004;103:1527-33.
13. 
Zaas AK et al. Current Fungal Infection Reports 2008;2:103-11.
14. 
Frost AE. Transplant Proc 1999;31:175-77.
15. 
Fishman JA. N Engl J Med 2007;357:2601-14