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Specialist BMT Pharmacist
UKCCSG Antifungal Pharmacist
Oncology Day Beds
Bristol Royal Children’s Hospital
The incidence of invasive fungal infection (IFI) has risen dramatically over the past two decades,(1,2) partly due to increasing numbers of immunocompromised patients and of invasive procedures. The main groups concerned are patients with haematological malignancies, patients undergoing stem cell transplantation (SCT), solid organ transplant recipients and HIV-positive patients. This article will concentrate on the management of fungal infections in this field, with focus on invasive aspergillosis.
Candida species (spp) and Aspergillis spp are the pathogens responsible for the majority of IFIs. Candida spp are present in the patient’s own microflora, whereas Aspergillis spp are acquired from the environment through the respiratory tract and are found in soil, water and decaying vegetation. In SCT patients, a 40% mortality is observed with invasive candidiasis, a percentage that rises up to 90% with invasive aspergillosis (IA).(3,4)
The management of IFIs, especially aspergillosis, has been influenced by the difficulty in making a definite diagnosis. Traditionally, aspergillosis has been more difficult to diagnose than candidiasis; clinically, the initial symptoms and signs are nonspecific. Definite diagnostic procedures are not always possible, with only 20–30% of diagnoses being firmly established while the patient is still alive.(5)
Current developments, such as high-resolution CT scanning, antigen detection and PCR-based detection methods, could facilitate more rapid and definitive diagnosis. The use of these tools may improve outcome by allowing early targeted intensive treatment, thus making empiric treatment redundant. Given the difficulty in diagnosis, identification of the risk factors is very important.
The optimal antifungal drug should present a wide spectrum of activity, a favourable pharmacokinetic profile, adequate in-vivo efficacy, low toxicity and low cost. No agent currently satisfies all these criteria, but there have been some exciting new developments in the last few years. Until 2002, IFIs were treated by amphotericin products or itraconazole. Two new agents have since been introduced, voriconazole and caspofungin. The characteristics of each new drug and their place in therapy will be discussed.
Caspofungin acetate (Cancidas(™)), which is the first drug of the enchinocandin class to be marketed, has a novel mode of action: inhibiting beta-1,3-d-glucan synthesis, thus compromising the integrity of the fungal cell wall. As synthesis of this glucan does not occur in human cells, caspofungin has a good safety profile. Although caspofungin is not licensed in children, many centres have used the drug in this patient group. The dose used at the Bristol Royal Hospital for Children (BRHC, UK) is 50mg/m(2) daily, up to a maximum of 50mg.
Therapeutic indications are treatment of invasive candidiasis in non-neutropenic adult patients and treatment of invasive aspergillosis in adult patients who are refractory to or intolerant of amphotericin products and/or itraconazole. However, new data demonstrate that caspofungin is comparable to liposomal amphotericin B for empiric antifungal therapy.(6) This randomised, double-blind, multicentre trial compared caspofungin with AmBisome (3mg/kg) in the empiric setting. The design was identical to that of the voriconazole versus AmBisome empiric trial.(7)
Caspofungin fulfilled the criteria for noninferiority over AmBisome, and fewer cases of nephrotoxicity were observed with caspofungin (3% vs 12%). Caspofungin could be considered for an empiric licence. Caspofungin is given once daily as an intravenous (IV) infusion; as it is a very large molecule, it is unlikely to ever be available as an oral preparation. The size may also limit the distribution of caspofungin across the blood–brain barrier (BBB) and may therefore have reduced relevance in cerebral fungal infection. However, the structure of the BBB may be altered in cerebral infection and may not adhere to normal pharmacodynamic expectations.
Caspofungin does not inhibit cytochrome P450 and currently displays minimal drug interactions; there is no known antagonistic interaction between caspofungin and azoles or amphotericin products. Caspofungin is largely hepatically metabolised with minimal renal clearance; no adjustment is required for renal insufficiency. In hepatic insufficiency, a reduced dose of 35mg daily may be required.(8) There is no published experience of use in severe hepatic insufficiency.
While voriconazole was licensed for UK use only in 2002, voriconazole (Vfend(™)) has previously been available under a compassionate use scheme, giving us several years of experience in using this agent. Voriconazole is a broad-spectrum triazole antifungal agent that inhibits the synthesis of ergosterol, an essential component of the fungal cell membrane. Therapeutic indications are the treatment of invasive aspergillosis, fluconazole-resistant serious invasive candida infection and serious FIs caused by Scedosporium spp and Fusarium spp.
Voriconazole, which is licensed for use in children aged two years and above, is available as both IV and oral formulations, and will soon be available in an oral liquid formulation. This flexibility may allow for the treatment of patients on an outpatient basis, thereby reducing inpatient stays attributed to ongoing antifungal therapy.
A large, randomised, multicentre trial of voriconazole versus amphotericin B as primary therapy of acute invasive aspergillosis showed that voriconazole had superior response (53% vs 32%).(9) The study also showed superior survival for the voriconazole group (71% vs 58%). A second large study comparing voriconazole with AmBisome for empirical antifungal (AF) therapy in neutropenic patients with persistent fever showed that voriconazole failed to meet the statistical definition of noninferiority over AmBisome.(7) The overall success rate for AmBisome was 30.6%, compared with 26% for voriconazole; however, there were fewer cases of nephrotoxicity in the voriconazole group. The same study reported superiority of voriconazole over AmBisome in reducing breakthrough fever. This, along with the oral bioavailability of the drug, may lead to voriconazole being considered as a prophylactic agent. However, a randomised, controlled trial comparing voriconazole with itraconazole as a prophylactic agent is required before such a change in established practice can be considered.
Voriconazole could interact with a number of drugs, as it is metabolised by cytochrome P450. Of interest in the SCT setting are the interactions with ciclosporin (ciclosporin dose to be halved) and tacrolimus (tacrolimus dose to be reduced to one-third). A potential, although unstudied, interaction with vincristine may lead to increased vincristine levels and therefore neurotoxicity. In renal impairment (RI), oral voriconazole is safe to use. However, in moderate-to-severe RI, a switch from the IV preparation to oral is advised (due to the toxicity of the cyclodextrin vehicle). In mild-to- moderate hepatic cirrhosis the maintenance dose should be halved, and in severe hepatic impairment careful monitoring for drug toxicity is required if the use of voriconazole is required.(10)
IFI has high mortality rates in certain groups of patients, and all new AF drugs and medical advances in the area are gladly welcomed. However, further investigation is warranted to determine the optimum use for all agents in clinical practice, both new and established.