Charité University Hospital, Campus Virchow-Klinikum, Department of Haematology and Oncology, Augustenburger Platz 1, D-13353 Berlin, Germany
During the past two decades, significant progress has been made in the management of infectious complications in patients with malignancies. The intensification of antineoplastic therapy and transplant procedures was enabled by stringent guidelines for the early diagnosis of infections and systematically escalated antimicrobial treatment, both based upon large prospective clinical studies. A broad spectrum of highly efficacious antibiotic and antiviral agents have helped to reduce the mortality from invasive bacterial or viral infections to <510% in these patients. At the same time, systemic and deep organ fungal infections have become the leading causes of death among patients with aggressive haematological malignancies and among transplant recipients.1 Sophisticated guidelines for the classification2 and treatment3,4 of Candida and Aspergillus infections published by expert committees are helping clinicians to use their limited armamentarium of conventional antifungal drugs in a clinically appropriate fashion, as well as to assess their efficacy more precisely. However, the best known standard first-line agent to be administered to almost all patients with serious fungal infections has been amphotericin B deoxycholate (D-AmB), despite its substantial toxic potential and possibly unsatisfactory clinical response rates. The widely available alternative, liposomal AmB (L-AmB), although at least as effective as D-AmB5,6 has missed the chance to be designated the worldwide first-line standard simply because of its extraordinarily high price. This constellation is indeed remarkable: the designation of D-AmB as first-line standard and the clinical prerequisites for the switch from D-AmB to L-AmB3 being defined as based purely upon economic rather than clinical considerations. Many experienced clinicians treating patients with invasive fungal infections are proud of their capability of maintaining the majority of their patients on D-AmB by means of a vigorous management of side effects and toxicity, thus preventing unacceptable rates of long-term renal failure.7 With a view towards the saving of their hospital budget, this is fair. From an ethical point of view, it is a profound dilemma.
At the same time, new broad-spectrum antifungal agents have entered the clinical stage. Among them, voriconazole, caspofungin and intravenous itraconazole have been demonstrated to be at least as effective as, yet significantly better tolerated than, D-AmB.
Voriconazole
The US Mycoses Study Group and the Invasive Fungal Infections Co-operative Group of the European Organisation for Research and Treatment of Cancer recently reported that in patients with proven or probable invasive aspergillosis, voriconazole is significantly superior to D-AmB with respect to response rates (53% versus 31%) and survival (71% versus 58%).8 This report will initiate a profound debate about the necessity of defining a new standard for the first-line antifungal treatment of choice in patients with proven or probable invasive aspergillosis. Remarkably, voriconazole is the first antifungal showing relevant response and survival rates in patients treated for aspergillosis with cerebral involvement.
Walsh et al.9 were able to show that voriconazole was as effective as L-AmB for empirical therapy in neutropenic patients with fever refractory to broad-spectrum antibiotics. The rate of breakthrough fungal infections was significantly lower in patients treated with voriconazole compared even with those receiving L-AmB (1.9% versus 5%). However, the response rates (defined at defervescence during neutropenia and absence of breakthrough fungal infections and no withdrawal due to adverse events and survival) were disappointing in both groups (26% versus 31%). Taking into account that in this study: (i) the preceding first-line antibacterial treatment had not been standardized; (ii) patients with clinically documented infections could be included; (iii) modification of antibacterial treatment was not standardized; and (iv) critical breakthrough fungal infections were not specified with respect to the interval between their manifestation and the start of antifungal treatment, one cannot accept this result as a representative clinical outcome in patients with persisting fever of unknown origin. Two major critical issues with voriconazole must be taken into account: the occurrence of (pathophysiologically still undetermined) transient visual disturbances in about 30% of patients, and the considerable number of drugs showing important interactions with voriconazole. For some of them, co-medication with voriconazole is contraindicated (e.g. rifampicin, carbamazepine, quinidine and sirolimus), while for others, dose adjustment of voriconazole and/or the other agent is required (e.g. omeprazole, ranitidine, phenytoin, rifabutin, vinca alkaloids, benzodiazepines and statins).
Intravenous itraconazole
Itraconazole, the only triazole presently licensed for the treatment of aspergillosis, has recently become available for intravenous administration. In neutropenic patients with haematological malignancies and refractory fever, intravenous itraconazole has shown at least equivalent efficacy (47% versus 38%) to D-AmB.10 Not surprisingly, it was significantly better tolerated (withdrawal due to toxicity 19% versus 38%) and showed less nephrotoxicity than D-AmB. Beyond that, about one-third of patients given intravenous itraconazole could be switched to the oral formulation after a median of 9 days of treatment. As with voriconazole, an important potential for interactions with a large number of other drugs must be considered for itraconazole.
Caspofungin
In mainly HIV-positive patients with oesophageal and oropharyngeal candidiasis, the new antifungal agent caspofungin in a dosage of 35 or 50 mg/day showed superior efficacy compared with low-dose D-AmB (0.5 mg/kg/day).11 Remarkably, this compound, representing the first clinically studied agent from a new class of antifungals inhibiting the synthesis of ß-(1,3)-d-glucan in the fungal cell wall, was extremely well tolerated. A dose-limiting toxicity has not yet been defined. Beyond that, resistance to this and other echinocandin antifungals has so far been experimentally induced in Candida species only at extremely low rates in vitro.12 Caspofungin has also shown significant efficacy as salvage antifungal in 63 patients with documented invasive aspergillosis refractory or intolerant to conventional antifungals.13 Based upon the clearly documented response to caspofungin in 41% of these patients, the drug was approved in early 2001 by the Food and Drug Administration (FDA) for the treatment of patients with aspergillosis refractory or intolerant to other licensed antifungals. However, the very small number of neutropenic patients recruited for this study precludes any clinical conclusion on the efficacy of caspofungin in this subgroup of patients. Critical aspects of caspofungin are the as yet undetermined interaction with cyclosporin, the absence of relevant penetration to the central nervous system and the lack of any oral formulation expected in the future. Most interestingly, there are experimental results from animal models indicating a remarkable activity of echinocandins in combination with other antifungal agents, such as triazoles. This observation may open new perspectives for the clinical management of severely immunocompromised patients with invasive aspergillosis.
Open questions
Apart from this exciting progress in the field of antifungal treatment options, a few critical considerations should be made. First, the results of clinical trials of voriconazole and caspofungin in patients with aspergillosis have not yet been published in peer-reviewed articles. Secondly, one must warn against designating patients as refractory to an established antifungal therapy after only 1 week of treatment. Caillot et al.14 have shown that the extent of lung infiltrates in patients with invasive pulmonary aspergillosis almost inevitably quadrupled during the first 2 weeks of effective antifungal treatment, before a regression of the infiltrates could be noted. Thirdly, a recently published paper by Eriksson et al.15 indicated that infusion-related side effects and nephrotoxicity of D-AmB may be reduced significantly by the prolongation of D-AmB application to 24 h, without compromising the response rates. Fourthly, none of the licensed or upcoming new antifungals has shown activity in all clinically relevant invasive fungal infections, and the new triazole compounds, although having been demonstrated to be effective in fluconazole-resistant Candida species, are not immune to cross-resistance. Hence, the selection of antifungal agents will always have to be made with caution and experience. Finally, the introduction of the new antifungal drugs into clinical practice would be much less difficult if their acquisition costs were less life-threatening to hospital budgets! One can express the hope that the new competition on the market will force the manufacturers of these drugs to listen to reason and help clinicians to escape from their ethical dilemma.
Notes
* Tel: +49-30-450-553-607; Fax: +49-30-450-553-971; E-mail: georg.maschmeyer{at}charite.de
References
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