Oral antifungals as prophylaxis in haematological malignancy

Oral antifungals in haematological malignancy

Oral antifungals as prophylaxis in haematological malignancy A. G. Prentice,1 P. Donnelly2 1

Clinical Haematology Unit, Derriford Hospital, Plymouth, UK

2

Department of Haematology, University Hospital Nijmegen, PO Box 9101, 6500

HB Nijmegen,The Netherlands

Abstract In the standard treatment of patients with haematological malignancy, immunosuppressive therapy produces prolonged periods of neutropenia and mucositis, which increase the risk of systemic fungal infection. In allogeneic bone marrow transplantation, this risk extends well beyond the period of neutropenia when graft-versus-host disease, and its treatment, result in prolonged lymphocytopenia.Various agents are used for antifungal prophylaxis and treatment but all have limitations: amphotericin B is restricted by the need for intravenous infusion and the occurrence of adverse events, fluconazole by its narrow spectrum of activity and the emergence of fluconazoleresistant fungi and itraconazole capsules by erratic absorption. Oral administration of antifungals has clear advantages in prophylaxis and an important current strategy is to maximize the extent and reliability of the oral bioavailability of antifungal agents. Mucositis is the main obstacle for success of strategies based on oral delivery. In this review, the ability of these new oral formulations to deliver sufficient antifungal prophylaxis is evaluated. © 2001 Harcourt Publishers Ltd

INTRODUCTION n the past 30 years, the increased intensity of treatment of haematological malignancies has led to profound immunosuppression and a variable, sometimes extended time required for reconstitution of the immune system. Prolonged periods of neutropenia are associated with an increased susceptibility to systemic fungal infection particularly after bone marrow transplantation (BMT).1 Other risk factors for systemic fungal infections include gut mucositis, poor hand washing, construction work, contaminated water supply and the use of oral and intravenous (IV) broadspectrum antibiotics, steroids and central venous catheters. BMT recipients, particularly those transplanted for myelodysplastic syndrome, those given matched unrelated donor grafts and those who develop acute or chronic graft-versushost disease (GvHD), are at increased risk of systemic aspergillosis well beyond the period of neutropenia. These infections may be community acquired and can occur more than 1 year after transplantation.

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INCIDENCE OF INVASIVE FUNGAL INFECTIONS The incidence of systemic fungal infection is difficult to determine. Up to 50% of patients with haematological

malignancies have evidence of fungal infection at autopsy and overall mortality related to proven infection is high.2 In one retrospective study, mortality was 73% for BMT recipients with Candida infections and 84% for those with Aspergillus infections.3 Mortality was even higher in patients with mixed Aspergillus and Candida infections or with candidal tissue infection. The incidences of proven and suspected Aspergillus and Candida infections in the control arms of recent randomized controlled prophylaxis trials are lower (between 15% and 30%)4–6 than incidences determined by autopsy, reflecting the limitations of current diagnostic techniques.7 Until the introduction of effective prophylaxis, most opportunistic fungal infections in BMT recipients were due to Candida albicans; in one report, C. albicans was isolated from 67% of BMT recipients.8 Increasingly, non-albicans Candida species are being isolated9 and infections with Aspergillus species are being detected with greater frequency (incidence rates varying from 0 to 20%).10 In some BMT units, aspergillosis is now the most frequent systemic fungal infection. Other fungi are emerging as pathogens including Fusarium, Scedosporium and Trichosporon species, but infections remain rare.11,12 RECOGNITION OF FUNGAL DISEASE A single positive blood culture is diagnostic for systemic candidosis. Persistent isolation of Candida species from the urine of a febrile patient is also virtually diagnostic, and isolation from stools is highly suggestive. Blood cultures are seldom positive for Aspergillus, except in endocarditis. In suspected pulmonary aspergillosis, typical changes may be seen on computed tomography but plain radiology may be misleading and is unreliable. Bronchoalveolar lavage and transbronchial biopsy are not sufficiently sensitive or specific to detect systemic fungal infection reliably and serological tests for both Candida species and Aspergillus species are of unproven value. New diagnostic techniques, such as polymerase chain reaction (with a potentially high negative predictor value), the galactomannan assay and D-arabinitol: L-arabinitol ratios, may lead to more informed use of antifungal agents in treatment and prophylaxis. EMPIRICAL THERAPY The high mortality related to established infection and the poor yield of diagnostic techniques means that antifungal empirical therapy and prophylaxis are necessary in the management of high-risk patients with haematological malignancy. However, the evidence supporting empirical treatment originates in two small clinical trials using an inadequate dose of amphotericin B desoxycholate to treat refractory fever of unknown origin in patients after chemotherapy.13,14 A numerical improvement was seen in terms of resolution of fever, but not in deaths due to fungal infection. More recent trials of empirical therapy compared lipid-associated amphotericin B or IV itraconazole with conventional amphotericin B,15–17 but no placebo group was included in these trials to provide evidence that the incidence of proven deep fungal infections was reduced. This further emphasizes the need for effective antifungal prophylaxis.  2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 1–8 doi: 10.1054/blre.2001.0145, available online at http://www.idealibrary.com on

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Prentice and Donnelly PROPHYLAXIS Several classes of antifungal agent are available for prophylaxis (Table 1), such as the polyene macrolides (amphotericin B, nystatin) the imidazoles (ketoconazole, miconazole, clotrimazole), the triazoles (fluconazole, itraconazole), allylamines (such as terbinafine) and other agents (such as flucytosine). Many of these agents can be administered in different formulations by different routes. However, clotrimazole, miconazole and terbinafine have had limited use in haematology and will not be discussed further. Intravenous administration is the route of choice for patients with severely impaired swallowing, patients with achlorhydria, patients with a tendency to vomit, patients who are unconscious or intubated, and when a high steadystate plasma concentration of the antifungal drug is required. However, complicated infusion schedules are required and many of the drugs given by the IV route are expensive (such as lipid formulations of amphotericin B) or are associated

with treatment-limiting, infusion-related adverse events such as fever, hypotension, rigor and nephrotoxicity (such as amphotericin B).11,18 The IV route is important in culturedirected therapy but prophylaxis or empirical therapy often require long-term drug administration. The ease of use of oral antifungal agents makes them an attractive alternative to IV treatment, and their introduction has led to routine outpatient therapy for endemic mycoses. Nevertheless, the oral route also poses certain challenges, especially that of poor bioavailability relative to IV delivery. In addition, some of the agents that are suitable for oral delivery suffer from intrinsic deficiencies in efficacy and safety. The oral antifungal agents that are currently available are reviewed here.The importance of effective absorption to the systemic action of these agents is also considered, especially the contribution of reformulation to better delivery of agents for which poor delivery has previously been the limiting factor.

Table 1 Selected properties of oral antifungal agents used for treating systemic fungal infections Drug Polyene macrolides Amphotericin B

Nystatin

Azoles Imidazoles Ketoconazole

Miconazole Triazoles Fluconazole

Itraconazole

Others Flucytosine

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Spectrum of activity

Properties/formulations

Candida, Aspergillus and other filamentous fungi, life-threatening infections with the endemic fungi Coccidioides immitis, Histoplasma capsulatum and Blastomyces dermatitidis Reports of resistance in non-albicans Candida spp.

Delivered topically or systemically, most frequently used in IV form; oral tablets and suspension used mainly to treat thrush and gastrointestinal candidosis

Candida spp. and Aspergillus spp.

Oral formulation used for topical treatment of oropharyngeal candidosis. Main role is as prophylactic agent or in the treatment of thrush.

C. albicans and other Candida spp., all dematophytes, Malassezia furfur, B. dermatitidis, C. immitis, H. capsulatum, Paracoccidioides brasiliensis and Phialophora spp. NOT Aspergillus spp.

Topical and oral formulations available. Use in haematology largely supplanted by other azole antifungals

C. albicans, M. furfur and all common dermatophytes

Available as topical cream, oral gel and IV formulation. Parenteral form rarely used because of high toxicity

Many Candida spp. including C. albicans NOT Aspergillus spp., or some non-albicans Candida spp., e.g. C. glabrata and C. krusei

Water-soluble oral capsules, suspension or IV formulation.Treatment of choice for mucocutaneous candidosis in neutropenic patients. Used extensively in prophylaxis

C. albicans and non-albicans spp., A. flavus and A. fumigatus, B. dermatitidis and H. capsulatum

Drug of choice for some uncommon fungal infections. Indicated for prophylaxis of fungal infections expected to be sensitive to itraconazole. Oral capsules taken with food. Oral solution (taken before food) and IV formulation have improved bioavailability

C. albicans and C. neoformans

IV and oral formulations effective against some candidal infections but only when used in combination with amphotericin B

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Oral antifungals in haematological malignancy ORAL FORMULATIONS Polyene macrolides The polyene macrolides amphotericin B and nystatin posses broad spectrum activity (Table 1).18 The drugs act by binding to ergosterol in cell membranes, increasing membrane permeability and causing cell death. Poor absorption of amphotericin B and nystatin from the gut results in bioavailability of less than 5%,18 limiting the use of oral formulations of these agents for systemic fungal infections. The oral formulation of nystatin is used at high doses (4–6 mU/day) to treat oropharyngeal candidosis topically (Table 1). Nystatin is mainly used as a prophylactic agent, particularly in preventing the spread of C. albicans from the gut.19 The efficacy of nystatin suspension for antifungal prophylaxis in patients with haematological malignancy has been evaluated in several studies, but only one retrospective study using historical controls showed prevention of candidosis (in children with acute leukaemia)20,21 and there have been no randomized clinical trials of sufficient power to evaluate the drug. Suppression of Candida species in the gut may result in the reduced risk of candidaemia, which means oral polyene prophylaxis may be of value when used in combination with orally absorbed antifungal agents. In Europe, amphotericin B suspension has been given in high doses (1–2 g/day) to patients with haematological malignancies, but there have been no satisfactory randomized trials and hence there is no conclusive proof that the drug is effective. Flucytosine Flucytosine acts by disrupting DNA and RNA synthesis in the target organism. It can be used in the treatment of C. albicans and Cryptococcus neoformans infections, but only in combination with amphotericin B; the development of drug resistance is too great a problem if flucytosine is used alone. Flucytosine may also be associated with dose-related bone marrow aplasia or slow regeneration of neutrophils and other toxic effects such as nausea and diarrhoea. Insufficient data are available from patients with haematological malignancy to evaluate the efficacy of this drug as a prophylactic agent. Imidazoles The imidazole antifungal agents are synthetic compounds that inhibit fungal cytochrome P450 14α-demethylase, an enzyme that is involved in the synthesis of ergosterol, which is essential for the maintenance of the fungal membrane integrity and activity.The imidazole drugs ketoconazole and miconazole have poor safety profiles (Table 1). Ketoconazole Ketoconazole has low activity against Aspergillus species and non-albicans species of Candida. In a study of two sequential cohorts of neutropenic patients, those given ketoconazole had a significantly higher rate of fatal Aspergillus infection than those given itraconazole.22 In addition, ketoconazole causes dose-related gastrointestinal and endocrine side-effects.

Ketoconazole is a weak base, requiring an acid environment for optimum solubilization and absorption. In addition to elevated gastric pH, severe GvHD in BMT and food ingestion result in variable absorption.23,24 In healthy volunteers, the mean oral bioavailability is approximately 75% and a maximum plasma concentration of approximately 3.1 µg/ml is achieved 1–4 h after administration of ketoconazole 200 mg.25 Moreover, ketoconazole has a short elimination half-life (7–10 h).26 In patients with HIV or haematological malignancy, the erratic absorption of ketoconazole leads to inconsistent and lower oral bioavailability.24,27 In addition, ketoconazole inhibits cyclosporin absorption and causes more liver adverse events than other azole antifungals.28,29 For these reasons, ketoconazole has been largely supplanted by other azole antifungal agents. Triazoles The triazole antifungals (fluconazole and itraconazole) have the same mechanism of action as the imidazoles, but have a broader spectrum of activity and a longer half-life. They are associated with fewer adverse effects than the imidazoles because they have a greater specificity for fungal cytochrome P450 14α-demethylase than for mammalian cytochrome P450 enzymes.30 Despite the superficial chemical similarities of fluconazole and itraconazole, these agents have different efficacies as antifungal prophylactics because of differences in their spectrum of activity, pharmacokinetics and bioavailability. Fluconazole The use of fluconazole is limited by its lack of activity against moulds, which is an important deficiency because prophylaxis should cover these as well as yeasts. Oral fluconazole is useful for the treatment of mucocutaneous candidosis in neutropenic patients, oropharyngeal, vaginal and urinary candidosis, systemic candidal infections and cryptococcal infections. However, fluconazole is ineffective against Aspergillus species and Candida krusei and has variable activity against Candida glabrata (Table 1). Fluconazole has high oral bioavailability (more than 90%) because it is soluble in water.31 Neither food nor gastric pH affect its absorption, and there is no evidence that the bioavailability is impaired by the mucositis associated with allogeneic BMT. Fluconazole has a half-life of approximately 24 h and therapeutically effective peak plasma concentrations are achieved 2–4 h after a single oral dose. The peak plasma concentration is approximately two-fold higher after 6–10 days of treatment. Although a 7-day IV loading dose of fluconazole is recommended to achieve the maximum steady-state plasma concentration from day 1, which can be maintained by subsequent oral administration, this is unnecessary in the prophylactic setting. After 5–7 days of treatment, equivalent steady-state plasma concentrations are achieved with the IV and the oral preparation of fluconazole (200 mg/day).These concentrations can be achieved in most patients well before the onset of significant neutropenia. Whether the high water solubility and low protein binding characteristics of fluconazole influence the drug’s capacity to saturate tissue is not clear. Clinical trial results showing effective reduction by fluconazole of oropharyngeal infections by  2001 Harcourt Publishers Ltd Blood Reviews (2001) 15, 1–8

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Prentice and Donnelly C. albicans32–34 and of stool culture carriage do not necessarily mean effective tissue saturation. The transatlantic difference in fluconazole dosages in randomized clinical trials is of interest. Despite the pharmacokinetic evidence that a repeated oral dose of 200 mg/day or 2–3 mg/kg/day should achieve a trough plasma concentration above the minimum inhibitory concentration for C. albicans of 4 µg/ml in chemotherapy and in BMT patients,35–37 investigators in the USA have used 400 mg/day doses in some studies, presumably in the hope that, by giving more fluconazole, one might overcome the intrinsic resistance of Aspergillus to this drug.38 It is now clear that fluconazole is clinically ineffective against Aspergillus, even at a dose of 2 g/day. European randomized clinical trials using much lower prophylactic doses of fluconazole (50–150 mg/day) show low incidences of proven deep fungal infection in their active (fluconazole) arms.40–42 Excessive use of fluconazole can lead to drug resistance,43–46 which is a serious risk during empirical treatment and prophylaxis. The emergence of fluconazole-resistant strains and the narrow spectrum of activity limit the use of fluconazole in the prophylactic setting.6 An oral suspension of fluconazole (powdered fluconazole dissolved in water) has been developed for children and patients who have difficulty swallowing fluconazole capsules.The fluconazole suspension has a more rapid effect on oral and oesophageal candidosis than the capsule formulation, presumably because it increases the area under the curve of fluconazole in saliva.47 The new suspension is unlikely to be more effective in systemic fungal infections because similar plasma concentrations of fluconazole are achieved with the suspension and capsule formulations. In addition, the formulation of the suspension does not change fluconazole’s inherent limitations of fluconazole – resistance and lack of activity against Aspergillus and non-albicans species of Candida. Despite the reservations, fluconazole has clearly changed the pattern of deep fungal infection in haematological units and has substantially reduced the risk of fatal and non-fatal C. albicans infections. Fluconazole influences the metabolism of cyclosporin and coadministration of these agents necessitates cyclosporin dosage reduction. However, the required dosage reduction is less during co-administration with fluconazole (approximately 50%) than during coadministration with ketoconazole (approximately 85%).48,49 Monitoring of cyclosporin concentrations is necessary to avoid nephrotoxicity. Itraconazole Itraconazole has a wide spectrum of antifungal activity (Table 1) and is the only available azole antifungal that is active against Aspergillus species, with in vitro activity against A. fumigatus similar to that of amphotericin B.50,51 Itraconazole has a long elimination half-life (24 h) and is metabolized by the liver to another active form, hydroxy-itraconazole,which has equivalent in vitro antifungal activity to the parent compound.This metabolite reaches steady-state plasma concentrations twice those of itraconazole, thus pharmacokinetic studies that report only itraconazole levels underestimate the overall bioavailability of effective antifungal activity. 4

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The bioavailability of itraconazole capsules may be variable but absorption, and therefore bioavailability, is improved when the drug is taken with food.52 Poor and erratic absorption of the capsule form has been reported in pharmacokinetic studies in patients receiving conventional therapy for acute myeloid leukaemia (AML) and in allogeneic BMT recipients with severe mucositis or GvHD.53 Absorption of the capsule formulation is also reduced when gastric acidity is lowered by H2 antagonists.54,55 However, in healthy volunteers not taking any other medication, a maximum plasma concentration of 200–400 ng/ml is reached 5 h after a single oral dose of the itraconazole capsule 200 mg,49 and this rises 2–3-fold after 7–14 days of repeated daily dosing. The problems of absorption and bioavailability of itraconazole capsules may be overcome by increasing the dose in patients given conventional chemotherapy for AML; satisfactory and predictable levels were obtained in most patients in one pharmacokinetic study using itraconazole capsules at a dose of 600 mg/day.56 Unlike fluconazole, itraconazole binds strongly to protein, which may explain why itraconazole accumulates in high concentration in tissues and is highly effective against superficial fungal infections, particularly in keratinized tissue. If the problems of bioavailability of oral administration of the capsules were overcome, this property of tissue accumulation could be an advantage in prophylaxis of deep fungal infection in neutropenic patients. The itraconazole oral solution is a soluble complex containing hydroxypropyl-β-cyclodextrin, which has a bioavailability 35–37% greater than the capsules in healthy volunteers (when taken with food). In healthy volunteers, absorption of the itraconazole oral solution is almost complete when taken under fasting conditions57–58 and bioavailability is 60% greater than with the capsule formulation (Fig. 1). Other pharmacokinetic properties, such as the time to reach the maximum plasma concentration and the half-life, are the same with the itraconazole oral solution and capsule. In patients receiving conventional chemotherapy for AML or autologous BMT for a variety of haematological malignancies, the itraconazole oral solution provides high and consistent plasma concentrations of itraconazole (more than 350 ng/ml by day 8 and more than 750 ng/ml by day 15 of treatment with itraconazole 5 mg/kg/day) (Table 2).59–61 Tissue biopsy measurements of itraconazole in healthy volunteers and post-final dose washout measurements in AML patients suggest intense tissue saturation of itraconazole. In these patients receiving itraconazole oral solution, H2 antagonists had no significant impact on the pharmacokinetic profile of itraconazole.62 In adult allogeneic BMT recipients, in whom mucositis and GvHD might be expected to impair absorption and bioavailability, the same high plasma concentrations of itraconazole are achieved with the oral solution (more than 350 ng/ml by day 8 of treatment with itraconazole 400 mg/day).63 The trough plasma concentrations of itraconazole recorded in these studies imply that monitoring of plasma concentrations is probably unnecessary. Tentative minimum inhibitory concentrations of itraconazole have been established for Candida species as follows: susceptible, up to 215 ng/ml; susceptible dependent on dose, 250–500 ng/ml; resistant, at least 1000 ng/ml.37 For

Oral antifungals in haematological malignancy 180 Relative bioavailibility (%)

160 140 120 100 80 60 40 20 0

Capsules with food

Solution with food

Solution fasting

Fig. 1 Relative bioavailability of itraconazole capsules and itraconzole and solution after a single dose in healthy volunteers.

Aspergillus infections, data are less clear but one retrospective analysis suggests a significantly higher incidence of aspergillosis in patients whose plasma concentrations of itraconazole fall below 250 ng/ml.53 In pharmacokinetic studies the mean trough concentration of itraconazole is in excess of 500 ng/ml by day 15–22, which is well in excess of

Candida species’ minimum inhibitory concentrations and in excess of the concentration required to reduce the incidence of Aspergillus infection. The most significant problem with the itraconazole oral solution remains compliance, and gastrointestinal sideeffects frequently necessitate withdrawal.4, 41, 64 However, a recent pharmacokinetic study showed that the new intravenous formulation of itraconazole was suitable for continued prophylaxis in patients who cannot tolerate oral formulations.65 The improved pharmacokinetic profile and bioavailability of the itraconazole oral solution result in good antifungal efficacy in clinical studies.This solution is effective against fluconazole-resistant Candida infection66–68 and this property, combined with the activity of itraconazole against Aspergillus species, may make the new itraconazole oral solution the best prophylactic antifungal agent available.The oral solution (5 mg/kg/day) has been evaluated as prophylaxis in neutropenic patients in three major studies.4,41,69 The results are summarized in Table 3. In all three studies, itraconazole was associated with a lower overall incidence of fungal infections, a lower death rate from fungal infections and a lower requirement for IV amphotericin B in cases of suspected deep fungal infection than in the comparative arms of the studies. In a study in patients receiving chemotherapy for haematological malignancy, in which

Table 2 Itraconazole pharmacokinetics in patients with acute myeloid leukaemia (AML) or recipients of autologous transplantation (AUTO) Variable

Cmax (ng/ml) Cmin (ng/ml) AUC (ng/ml/hours)

Day 1

Day 8

Day 15

AML

AUTO

AML

AUTO

AML

AUTO

149 ± 40 0 –

107 ± 48 19 ± 33 1479 ± 933

593 ± 319 409 ± 252 –

723 ± 217 394 ± 110 13 302 ± 5016

1160 ± 594 715 ± 385 22 055 ± 9775

1292 ± 357 845 ± 221 25 143 ± 6460

Data are means ± SD. Cmax = maximum plasma concentration. Cmin = minimum plasma concentration. AUC = area under the curve for 0–24 h, calculated using the trapezoidal rule. Adapted with permission.59 Table 3 Selected data from clinical trials assessing itraconazole oral solution in prophylaxis Patients [n (%)] Menichetti et al.4 itraconazole (n = 201) All fungal infections Deep aspergillosis Use of IV amphotericin B Death with proven deep fungal infection

48 (24)* 4 (2) 47 (23)† 1 (0)

Morgenstern et al.62

Harousseau et al.68

placebo (n = 204)

itraconazole (n = 288)

fluconazole (n = 293)

itraconazole (n = 281)

68 (33)* 1 (0) 64 (31)† 5 (2)

67 (23) 0 (0) 39 (14)* 0 (0)

82 (28) 4 (1) 58 (20)* 4 (1)

93 (33) 5 (2) 90 (32) 1 (0)

amphotericin B (n = 276) 103 (37) 9 (3) 102 (37) 5 (2)

*P ≤ 0.05 (statistical significance); †0.05 < P ≤ 0.1 (statistical trend).

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Prentice and Donnelly itraconazole was compared with cyclodextrin placebo plus standard antibiotics, an unexpected, but not significant, excess of Aspergillus infections was seen in the itraconazole arm.4 In the second study, in which itraconazole was compared with fluconazole (100 mg/day), a significant excess of Aspergillus infections and deaths was seen in the fluconazole arm.41 In the third study, in which itraconazole was compared with oral amphotericin B capsules (2 g/day), a non-significant excess of Aspergillus infections was seen in the amphotericin B arm.69 Further randomized, controlled studies of itraconazole oral solution in high-risk patients are needed. Interactions between itraconazole and other drugs have been reported anecdotally. Interaction with cyclosporin can result in an elevation of cyclosporin levels.70, 71 The required dosage reduction of cyclosporin is likely to be similar to that required during co-administration with fluconazole48 in a steady state, but in view of the greater problems of compliance and gut side-effects with itraconazole, close monitoring of levels and dose adjustments are required.72 Sporadic cases of interaction between itraconazole and vincristine, resulting in neurotoxicity, have also been reported.73

CONCLUSIONS Systemic fungal infections remain a major cause of death in BMT recipients. In the past 10 years, oral antifungal agents (e.g. azoles) have been developed, which are easier to use and less toxic than IV amphotericin B. These agents have increased the options for the treatment and prophylaxis of systemic fungal infections, but some are limited by toxicity or a narrow spectrum of activity. Other agents with better side-effect profiles and a broad spectrum of activity have low bioavailability. With the differences in absorption of some drugs in some patient populations, it is important to understand the pharmacokinetics of these agents in different patient groups. Erratic gastrointestinal absorption is a particular problem in BMT recipients and recent research has been concentrated on developing new drugs or new formulations with enhanced bioavailability. Encouraging results have been obtained with new formulations of itraconazole and the consistent plasma concentrations gained result in therapeutic benefits. These advances should provide clinicians with greater flexibility in the treatment and prophylaxis of systemic fungal infections in BMT recipients.

Correspondence to:Archibald G. Prentice, Clinical Haematology Unit, Plymouth Hospitals NHS Trust Derriford Hospital, Plymouth PL6 8DH, UK.Tel.: + 44 (0) 1752 792401; Fax: +44(0) 1752 792400; E-mail: [email protected]

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