Economic evaluation of voriconazole in the treatment of invasive aspergillosis in the Netherlands

OBJECTIVE: To asses the cost-effectiveness of voriconazole in comparison to conventional amphotericin B and itraconazole for the treatment of invasive aspergillosis in the Netherlands. METHODS: The cost-effectiveness of voriconazole in comparison to conventional amphotericin B or itraconazole was evaluated with a decision tree model followed by a life-time Markov model, focusing on long-term survival of patients treated for invasive aspergillosis. Efficacy after 12 weeks of treatment from clinical trials was used to estimate long-term effectiveness by extrapolating these short-term results over time. Information on medical resource consumption, treatment pathways and switch proportions were obtained from both the literature and Experts. Probabilistic analysis was used to compare the cost-effectiveness among the regimens. RESULTS: With voriconazole, the mean cost for treating invasive aspergillosis per patient was E32 651 (2.5th percentile and 97.5th of uncertainty distribution: E30 037; E36 859), compared to E33 616 (E30 920; E39 633) for conventional amphotericin B and E29 115 (E23 537; E61 414) for itraconazole. The mean survival of patients treated with voriconazole was 174.0 life weeks (160.1; 188.8), compared to 116.1 life weeks (104.8; 128.0) for conventional amphotericin B and 150.4 life weeks (109.1; 194.4) for itraconazole. The beneficial effects of voriconazole on both cost and effectiveness compared with conventional amphotericin B resulted in a probability of 69.8% that voriconazole was a dominant treatment (i.e. less costs and longer survival). The incremental cost-effectiveness ratio of voriconazole versus itraconazole was E150 per life week (i.e. 7800 euros per life-year gained). Depending on the willingness to pay (WTP) the probability of being cost-effective vs. itraconazole increased to a maximum probability of 70%. CONCLUSION: In the treatment of invasive aspergillosis, voriconazole is dominant over amphotericin B and cost-effective in comparison to itraconazole.     

Economic evaluation of voriconazole in the treatment of invasive aspergillosis in the Netherlands

ABSTRACT

Objective: To asses the cost-effectiveness of voriconazole in comparison to conventional amphotericin B and itraconazole for the treatment of invasive aspergillosis in the Netherlands.

Methods: The cost-effectiveness of voriconazole in comparison to conventional amphotericin B or itraconazole was evaluated with a decision tree model followed by a life-time Markov model, focusing on long-term survival of patients treated for invasive aspergillosis. Efficacy after 12 weeks of treatment from clinical trials was used to estimate long-term effectiveness by extrapolating these short-term results over time. Information on medical resource consumption, treatment pathways and switch proportions were obtained from both the literature and Experts. Probabilistic analysis was used to compare the cost-effectiveness among the regimens.

Results: With voriconazole, the mean cost for treating invasive aspergillosis per patient was €32?651 (2.5th percentile and 97.5th of uncertainty distribution: €30?037; €36?859), compared to €33?616 (€30?920; €39?633) for conventional amphotericin B and €29?115 (€23?537; €61?414) for itraconazole. The mean survival of patients treated with voriconazole was 174.0 life weeks (160.1; 188.8), compared to 116.1 life weeks (104.8; 128.0) for conventional amphotericin B and 150.4 life weeks (109.1; 194.4) for itraconazole. The beneficial effects of voriconazole on both cost and effectiveness compared with conventional amphotericin B resulted in a probability of 69.8% that voriconazole was a dominant treatment (i.e. less costs and longer survival). The incremental cost-effectiveness ratio of voriconazole versus itraconazole was €150 per life week (i.e. 7800 euros per life-year gained). Depending on the willingness to pay (WTP) the probability of being cost-effective vs. itraconazole increased to a maximum probability of 70%.

Conclusion: In the treatment of invasive aspergillosis, voriconazole is dominant over amphotericin B and cost-effective in comparison to itraconazole.     

Oral voriconazole for empiric antifungal treatment in patients with uncomplicated febrile neutropenia

STUDY OBJECTIVE: To determine the success rate and toxicity profile of oral voriconazole when used as empiric antifungal therapy in patients with uncomplicated persistent neutropenic fever. DESIGN: Retrospective medical record review. SETTING: University hospital. PATIENTS: Twenty-seven patients who received oral voriconazole as empiric antifungal treatment during 31 episodes of persistent neutropenic fever between August 1, 2003, and April 1, 2006. MEASUREMENTS AND MAIN RESULTS: Data were collected on patient demographics, diagnosis, cancer treatment plan, voriconazole regimen, dates of voriconazole treatment, other antibiotics administered during the episode of fever, and adverse events. Patient survival data from at least 3 months of follow-up were also collected. Treatment success, which was defined as survival to the resolution of fever without a need to change antibiotics and without new fungal infections, was also determined. Median duration of therapy was 11 days (range 2-54 days). No patient discontinued the drug because of toxicity. The success rate was 55% (95% confidence interval [CI] 36-73%). For all patients, 90-day survival from the start of voriconazole treatment was 81% (95% CI 63-93%). Neither treatment success nor 90-day survival rates differed significantly when they were compared by the route used for loading doses or by the presence of a possible invasive fungal infection at the start of voriconazole therapy. CONCLUSION: Oral voriconazole appears to be a safe empiric antifungal treatment with an encouraging rate of activity for patients with neutropenia and uncomplicated persistent fever. Further research, including randomized controlled trials comparing the efficacy of intravenous versus oral voriconazole, is needed.     

Cost-effectiveness analysis of treatment with liposomal amphotericin B versus conventional amphotericin B in organ or bone marrow transplant recipients with systemic mycoses

Economic appraisal of pharmaceuticals is becoming increasingly important. In a retrospective study of patient records from 58 organ or bone marrow-transplanted patients with systemic mycoses, the cost-effectiveness of treatment with a liposomal amphotericin B formulation was compared with that of conventional amphotericin B. Treatment with liposomal amphotericin B results in fewer adverse reactions, increased life expectancy and higher costs than treatment with conventional amphotericin B. Pricing liposomal amphotericin B at about SKE6000 per patient treatment day will result in an additional cost per life-year gained of about SEK150 000 relative to that using conventional amphotericin B for patients receiving kidney, kidney and pancreas, or pancreas transplants. For liver and bone marrow transplant (BMT) recipients the marginal cost-effectiveness ratio was about SEK195 000 and SEK150 000 per life-year gained. Compared with alternative use of resources in society and health care, use of liposomal amphotericin B rather than conventional amphotericin treatment can be considered cost-effective at the price assumed.     

Caspofungin: new indication. No progress in invasive candidiasis

(1) The reference treatment for invasive candidiasis in patients without neutropenia is standard amphotericin B. If this treatment fails or is too nephrotoxic, second-line alternatives are liposomal amphotericin B and fluconazole. Voriconazole is a third-line option. (2) Caspofungin, an antifungal drug belonging to the echinocandin class, is now approved for use in this indication in France. (3) The clinical evaluation dossier contains no data from comparative trials with fluconazole or voriconazole. It only gives the results of a double-blind trial in 239 patients, designed to show simply that caspofungin was not inferior to standard amphotericin B. Most of the patients did not have neutropenia. About one-third of the patients died. There was no difference in mortality between the two groups. No data are available from trials versus other forms of amphotericin B. (4) In this trial, caspofungin had fewer adverse effects (especially nephrotoxicity) than standard amphotericin B. However, in other trials in other indications, caspofungin had more adverse effects than fluconazole. (5) In France, caspofungin costs nearly 100 times more than standard amphotericin B. (6) In practice, caspofungin has no proven advantages over existing options for the treatment of invasive candidiasis in patients without neutropenia.     

In vitro susceptibility testing of Candida and Aspergillus spp. to voriconazole and other antifungal agents using Etest: results of a French multicentre study

Minimum inhibitory concentrations (MICs) of the antifungal agent voriconazole were determined using the Etest and compared with those of amphotericin B, itraconazole and fluconazole using 1986 clinical isolates of Candida spp. Voriconazole MICs were also compared with those of amphotericin B and itraconazole using 391 clinical isolates of Aspergillus spp. Voriconazole was found to have more potent activity and lower MIC values than amphotericin B, itraconazole and fluconazole against C. albicans, C. tropicalis, C. parapsilosis and C. kefyr. Against C. glabrata and C. krusei, voriconazole was more active than either of the other two azole antifungals but had similar activity to amphotericin B. For species of Aspergillus, MIC values of voriconazole were lower than those of amphotericin B and itraconazole against A. fumigatus and A. flavus, and were similar to those of amphotericin B against A. niger. Against A. terreus, MIC values for voriconazole and itraconazole were similar. A. terreus is known to be resistant to amphotericin B, and this was reflected in higher MIC values compared with those of voriconazole and itraconazole. Voriconazole therefore compares very favourably with other antifungal agents against a large number of clinical isolates of Candida and Aspergillus spp.     

Voriconazole: in the treatment of invasive aspergillosis

Voriconazole, a broad-spectrum triazole antifungal agent, inhibits the cytochrome P450-dependent enzyme 14-alpha-sterol demethylase, thereby disrupting the fungal membrane and stopping fungal growth. The drug shows excellent in vitro activity against Aspergillus spp., including itraconazole- and amphotericin B-resistant A. fumigatus isolates. At 12 weeks, 52.8% of voriconazole recipients achieved a successful outcome (complete or partial response) versus 31.6% of amphotericin B recipients in a randomised, nonblind trial in 392 patients (aged > or =12 years) with invasive aspergillosis. Patients received intravenous voriconazole (6 mg/kg once every 12 hours on day 1, then 4 mg/kg once every 12 hours for > or =7 days; patients could then be switched to oral voriconazole 200mg once every 12 hours) or intravenous amphotericin B (1 to 1.5 mg/kg/day for > or=14 days). At the investigators' discretion, those who failed to respond to or experienced toxicity with the initial randomised drug could be switched to other licensed antifungal therapy. Voriconazole was generally well tolerated. The most common treatment-related adverse events were transient visual disturbances (approximately 30% of patients) and skin rashes (6%). Voriconazole was generally better tolerated than amphotericin B; voriconazole recipients experienced significantly (p < 0.02 both comparisons) fewer treatment-related adverse events or serious adverse events. The incidence of visual disturbances was significantly (p < 0.001) higher with voriconazole than amphotericin B treatment.     

symbol: see text]Caspofungin and [symbol: see text]voriconazole for fungal infections

Systemic fungal infections are difficult to treat and often fatal. Established treatment options include conventional amphotericin B or one of its lipid-based or liposomal formulations, or a triazole antifungal such as fluconazole or itraconazole. [symbol: see text]Caspofungin (Cancidas--Merck Sharp & Dohme) and [symbol: see text]voriconazole (Vfend--Pfizer) are two new antifungals for severe infections caused by Candida spp. (invasive candidiasis) and Aspergillus spp. (invasive aspergillosis). Caspofungin is the first licensed echinocandin antifungal, while voriconazole is a triazole. Promotional claims for caspofungin include that it "provides an effective, yet less toxic, alternative to amphotericin B" while voriconazole is claimed to offer "significantly improved survival in invasive aspergillosis compared with amphotericin B". Here we consider the place of caspofungin and voriconazole in managing patients with severe fungal infections.     

Intravenous voriconazole therapy in a preterm infant

A preterm infant younger than 3 months developed a disseminated fluconazole-resistant Candida albicans infection that was treated with liposomal amphotericin B for 52 days, followed by the combination of intravenous voriconazole and liposomal amphotericin B for an additional 19 days. The infant received concomitant phenobarbital throughout the hospital stay. The infection resolved after addition of voriconazole to the treatment regimen. Intravenous voriconazole was begun at a high dosage, 6 mg/kg every 12 hours, for anticipated developmental and drug-induced changes in volume of distribution and clearance. On day 4 of therapy, serum concentrations of voriconazole were 3.27 microg/ml immediately after infusion and 0.33 microg/ml 6 hours after infusion. These levels were significantly lower than those achieved in adult pharmacokinetic and safety studies. After the infant's dosage was increased to 6 mg/kg every 8 hours, serum concentrations were 5.33 microg/ml 30 minutes after infusion and 2.67 microg/ml 6 hours after infusion. These levels were similar to those observed in adults. Intravenous voriconazole 6 mg/kg every 8 hours was administered safely, with concomitant phenobarbital therapy, in this preterm infant with developmentally diminished renal function.     

Voriconazole: new preparation. Invasive aspergillosis: benefits to be confirmed

(1) Amphotericin B is the antifungal drug of choice for the treatment of invasive aspergillosis, severe candidiasis and Fusarium infection. Voriconazole is an antifungal azole sold in France for oral and intravenous treatment of these infections. (2) In 391 patients with established or probable invasive aspergillosis, combined analysis of two trials comparing voriconazole (intravenously then orally) with conventional amphotericin (intravenously) showed that the 12-week survival rate was significantly higher with voriconazole (70.8% versus 57.9%). Unfortunately, these results are undermined by methodological flaws such as the lack of blinding, the very different intravenous treatment periods in the two groups, and subsequent oral treatment with different antifungal drugs. Voriconazole has not been compared with liposomal amphotericin B. (3) In the treatment of severe candidiasis, and severe Scedosporium and Fusarium infections, we only have the (favourable) results of non comparative trials in small numbers of patients refractory to other antifungal drugs. (4) The main adverse effects were visual disturbances, elevated hepatic enzyme levels, acute renal failure, and sometimes serious cutaneous reactions. It lengthens the QT interval and can cause torsades de pointes. It inhibits the cytochrome P450 isoenzymes CY3A4, CYP2C9 and CYP2C19, hence a high risk of potentially serious drug interactions. (5) Voriconazole can be given by mouth or by IV infusion, whereas liposomal amphotericin B must be given intravenously. (6) In practice, another more rigorous trial is needed to confirm the favourable results obtained with voriconazole in invasive aspergillosis. Voriconazole is the first-line treatment for severe Scedosporium infections, despite limited experience. It is a last resort for severe candidiasis and severe Fusarium infection.     

Current antifungal treatment of fusariosis

Fungi of the genus Fusarium are well known as major plant pathogens and soil inhabitants, but also cause a broad spectrum of human infections. Fusariosis is the second most common mould infection after aspergillosis, and keratitis is the most encountered implantation infection in immunocompetent individuals. Natamycin is active against Fusarium species both in vitro and in vivo, and is used along with voriconazole as the mainstay of treatment for Fusarium keratitis. Onychomycosis is treated with terbinafine, voriconazole and sometimes itraconazole. Cure is possible despite high in vitro minimum inhibitory concentrations (MICs). Recently, disseminated infections have increased dramatically, mainly affecting severely immunocompromised patients. The remarkable intrinsic resistance of Fusarium species to most antifungal agents results in high mortality rates in this patient population. Recovery of neutropenia is essential for patient survival and treatment should include voriconazole or amphotericin B as first–line and posaconazole as salvage therapy.     

Voriconazole treatment of invasive aspergillosis: real-world versus health-economic model results

OBJECTIVE: The objective of this study was to assess, in a real-world setting, the predictive validity (in terms of clinical outcome and treatment cost) of the voriconazole arm of a health-economic model applied in the Belgian reimbursement submission for use of voriconazole in the treatment of invasive aspergillosis. METHODS: A non-interventional study was designed to prospectively collect clinical response and direct costs data related to the treatment of invasive aspergillosis with voriconazole (oral, intravenous) in real-world practice. The outcomes of this study were compared with the inputs and outputs of the health-economic model. For the analysis, unit costs of 2002 from the public payer's perspective, as used in the model, were applied. RESULTS: Data from 116 patients with invasive aspergillosis starting treatment with voriconazole were collected. At 12 weeks, there were similar rates of satisfactory clinical response for the observational study and the model, the latter based on the results of a clinical study (50% vs 53%, respectively). Overall mortality rates at 84 days were 42% in the observational study and 29% in the model. Average total healthcare cost associated with voriconazole treatment was lower in the observational study compared with the model for all patients. When the cost for all hospitalization days from the start until the end of the fungal infection was included in the analysis, the average total cost was euro19,674. When the cost for only those hospitalization days solely related to the fungal infection was included in the analysis, the average total cost was euro12,376. These costs are below the cost predicted by the model of euro21,298. CONCLUSIONS: This analysis demonstrates that the results provided in the voriconazole arm of the health-economic model were valid estimates with regard to real-world outcomes but with a slightly better survival rate and higher costs than in real life.     

恶性血液病患儿继发侵袭性肺部真菌感染4例的诊断和治疗

目的提高临床医师对儿童恶性血液病、肿瘤疾病患儿合并侵袭性肺部真菌感染(IPFI)尤其是侵袭性肺曲霉菌感染(IPA)的认识,早期及时地诊断及治疗提高患儿生存率。方法对本院在2007年1月至2008年6月收治的4例血液病患儿合并IPA的临床诊治过程及预后进行回顾性分析。结果 4例患儿均符合IPFI的诊断标准,1例为临床诊断,另3例为拟诊;4例患儿存在化疗后中性粒细胞减少>10 d,造血干细胞移植后移植物抗宿主病,长期应用激素等宿主因素,典型肺CT空洞改变;1例痰培养示咽曲霉菌生长的诊断依据,同时应用伏立康唑、米卡芬净等抗真菌药物治疗。4例患儿均死亡。结论儿童恶性血液病、恶性肿瘤合并IPA进展快、病原学诊断困难、预后差,早期诊断及治疗对挽救患儿生命至关重要。     

Current strategies in the treatment of invasive Aspergillus infections in immunocompromised patients.

Aspergillus infections have a very high mortality rate. Their incidence is growing because of the increasing number of immunocompromised patients. Treatment of Aspergillus infection is difficult, and the agents used have numerous adverse effects and toxicities. Recently, new and less nephrotoxic formulations of amphotericin B have come onto the market and other new drugs, such as voriconazole and terbinafine, are under evaluation for this infection. Restoration of host immune defences by tapering of immunosuppressive therapy in transplant patients or correction of granulocytopenia in haematological disease is the cornerstone of modern treatment of aspergillosis in immunocompromised patients. In patients with invasive aspergillosis it is very important to achieve therapeutic concentrations of antimycotic drugs as quickly as possible. Patients at high risk of developing aspergillosis (e.g. those with granulocytopenia) should be treated on the basis of clinical or radiological criteria alone if microbiological or histological diagnosis would significantly delay treatment. Conventional amphotericin B is still the first-line treatment for patients with invasive aspergillosis. In transplant patients receiving other nephrotoxic drugs, particularly cyclosporin, first-line therapy with one of the new amphotericin B formulations should be considered. If the emergence of renal toxicity in any patient precludes aggressive treatment, the patient should be switched to one of the new formulations of amphotericin B. For patients cured with amphotericin B, secondary prophylaxis is needed at the end of the intravenous therapy. Amphotericin B by aerosol or itraconazole are possible solutions. In non-invasive forms of aspergillosis, such as suppurative bronchitis, patients could be treated either with amphotericin B or itraconazole as first-line therapy.     

An economic evaluation of Tomudex (raltitrexed) and 5-fluorouracil plus leucovorin in advanced colorectal cancer.

Our objective was to establish the balance between costs and effects of treatment with Tomudex (raltitrexed) as an alternative to treatment with 5-fluorouracil (5-FU) plus leucovorin (LV) in patients with advanced colorectal cancer. Data were used from an international, open label randomized clinical trial. Costs were calculated by multiplying resource utilization data with Dutch estimates of unit costs. Effects have been expressed in terms of 6 months and 1 year survival, and in terms of the number of patients without severe adverse events including WHO grade 3 and 4 leucopenia, mucositis, anemia and severe asthenia. Cost effectiveness is expressed in terms of costs per additional day of survival and costs per additional patient without any severe adverse event. The clinical results did not show significant survival differences implying great uncertainty about the cost-effectiveness of raltitrexed in terms of additional costs per additional life-year gained. However, 80% of the initially higher cost of raltitrexed ($3132 per patient) is compensated by savings due to a more convenient administration scheme leading to a net cost of $626 per patient treated. Weighed against the decrease in adverse events, a cost-effectiveness ratio results of $3936 per additional patient free of any severe adverse event. More favorable estimates result when the convenience of the administration scheme is valued in positive monetary terms.     

Invasive aspergillosis: epidemiology, diagnosis and management in immunocompromised patients

Morbidity and mortality caused by invasive Aspergillus infections are increasing. This is because of the higher number of patients with malignancies treated with intensive immunosuppressive therapy regimens as well as their improved survival from formerly fatal bacterial infections, and the rising number of patients undergoing allogeneic haematopoietic stem cell or organ transplantation. Early initiation of effective systemic antifungal treatment is essential for a successful clinical outcome in these patients; however, clinical clues for diagnosis are sparse and early microbiological proof of invasive aspergillosis (IA) is rare. Clinical diagnosis is based on pulmonary CT scan findings and non-culture based diagnostic techniques such as galactomannan or DNA detection in blood or bronchoalveolar lavage samples. Most promising outcomes can be expected in patients at high risk for aspergillosis in whom antifungal treatment has been started pre-emptively, backed up by laboratory and imaging findings. The gold standard of systemic antifungal treatment is voriconazole, which has been proven to be significantly superior to conventional amphotericin B and has led to a profound improvement of survival rates in patients with cerebral aspergillosis. Liposomal amphotericin B at standard dosages appears to be a suitable alternative for primary treatment, while caspofungin, amphotericin B lipid complex or posaconazole have shown partial or complete response in patients who had been refractory to or intolerant of primary antifungal therapy. Combination therapy with two antifungal compounds may be a promising future strategy for first-line treatment. Lung resection helps to prevent fatal haemorrhage in single patients with pulmonary lesions located in close proximity to larger blood vessels, but is primarily considered for reducing the risk of relapse during subsequent periods of severe immunosuppression. Strict reverse isolation appears to reduce the incidence of aspergillosis in allogeneic stem cell transplant recipients and patients with acute myeloid leukaemia undergoing aggressive anticancer therapy. Well designed, prospective randomised studies on infection control measures effective to prevent aspergillosis are lacking. Prophylactic systemic antifungal treatment with posaconazole significantly improves survival and reduces IA in acute myeloid leukaemia patients and reduces aspergillosis incidence rates in patients with intermediate-to-severe graft-versus-host reaction emerging after allogeneic haematopoietic stem cell transplantation. Voriconazole prophylaxis may be suitable for prevention of IA as well; however, the results of large clinical trials are still awaited.     

Pharmacoeconomic analysis of caspofungin versus liposomal amphotericin B as empirical antifungal therapy for neutropenic fever.

PURPOSE: An analysis was conducted that evaluated and compared the cost differences between caspofungin and liposomal amphotericin B when the medications were used as empirical antifungal therapy for persistent fever during neutropenia. METHODS: Rates of drug use and impaired renal function (IRF) were based on data from published studies. IRF was defined as a doubling of the serum creatinine level or, if the creatinine level was elevated at enrollment, an increase of at least 1 mg/dL. The estimates of the costs for drug acquisition and treating IRF were derived using published data and applied to compare caspofungin with liposomal amphotericin B. Sensitivity analyses were performed by varying the IRF and relative acquisition costs to assess the effect of these factors on the cost differences. RESULTS: The acquisition costs per patient were 6942 dollars for liposomal amphotericin B and 3996 dollars for caspofungin. The estimated cost per patient from IRF was 3173 dollars for liposomal amphotericin B and 793 dollars for caspofungin. Combining drug acquisition and IRF costs, the overall treatment cost per patient for caspofungin was 5326 dollars less than for liposomal amphotericin B. In sensitivity analyses of drug costs, the price of liposomal amphotericin B would have to be 23.95 dollars per vial for the overall treatment costs to be equal. CONCLUSION: Comparison of cost estimates derived from published data revealed that a combined estimate of acquisition costs and costs related to the treatment of IRF was lower for caspofungin than for liposomal amphotericin B for empirically treating patients with neutropenic fever.     

Pharmacoeconomic analysis of amphotericin B lipid complex versus liposomal amphotericin B in the treatment of fungal infections

BACKGROUND: Potential differences in toxicity, potency and acquisition price among the liposomal amphotericin B formulations makes it unclear which agent is less costly when total resource consumption and treatment-associated costs are considered. DESIGN: A retrospective cost-minimisation analysis in 51 patients was performed to compare the cost of amphotericin B lipid complex (ABLC) and liposomal amphotericin B (L-AMB) from the hospital perspective. Costs ($US, 2001 values) were divided into level I (acquisition price only), level II (costs of all associated treatment, i.e. adverse events, failures, etc.) and level III (total fungal-related hospitalisation) costs. RESULTS: No significant differences in patient demographics or length of therapy were apparent among those receiving ABLC or L-AMB. The clinical success rate in this population was similar between ABLC and L-AMB (53% vs 60%, p = 0.68), thus justifying the use of a cost-minimisation analysis. Among patients with baseline elevations in serum creatinine, 47% receiving ABLC and 10% receiving L-AMB experienced further increases in serum creatinine (p = 0.025). No differences in total treatment costs (level I, II, or III) were evident between patients receiving ABLC or L-AMB. When adjusted for duration of therapy, however, costs were significantly lower for ABLC than for L-AMB (level I: ABLC $US340 versus L-AMB $US435, p = 0.002; level II: ABLC $US361 versus L-AMB $US454, p = 0.027). The costs attributable to the prevention or treatment of adverse events were not different between the two treatments, and the economic outcome in this analysis was highly sensitive to the acquisition price and dosage of the lipid antifungal formulation. Two-way sensitivity analysis revealed that as long as the milligram price of L-AMB was greater than 135% of the milligram price of ABLC, ABLC remained the less costly formulation. CONCLUSION: In this patient population, total hospitalisation costs were not different between lipid antifungal formulations. However, after controlling for duration of therapy, ABLC was less costly than L-AMB, when considering acquisition costs of the lipid antifungal agent and costs associated with concomitant antifungal therapy and the treatment of adverse events or lipid failures, indicating that the acquisition price of these agents should be predictive of their cost differences.     

New antifungal agents and preparations

In neutropenic patients amphotericin B remains the drug of choice for the treatment of systemic fungal infections. On the basis of a superior efficacy in combination with a lower toxicity, the triazoles have superseded the older azoles. Regularly, amphotericin B and a triazole are used simultaneously without any evidence from clinical trials that such a strategy is safe and efficacious. Liposomal preparation, lipid complex or colloidal dispersion of amphotericin B have been produced successfully to reduce toxicity. However, there is only one small randomised study that hints at the superiority of liposomal amphotericin B over amphotericin B deoxycholate. Promising new agents like candins, sordarins, high dose oral terbinafine, the third generation azoles, and liposomal nystatin are under development. The first phase II study on voriconazole in the treatment of pulmonary aspergillosis has produced encouraging results. The major promise of the new candins lies in the activity against Candida species, including those resistant to the azoles and polyenes, and in a mechanism of action totally different from the established antifungals. Cytokines and colony stimulating factors are theoretically very promising but there are no clinical studies that warrant routine use.     

Dose tolerability of chronically inhaled voriconazole solution in rodents

Invasive pulmonary aspergillosis (IPA) is a fungal disease of the lung associated with high mortality rates in immunosuppressed patients despite treatment. Targeted drug delivery of aqueous voriconazole solutions has been shown in previous studies to produce high tissue and plasma drug concentrations as well as improved survival in a murine model of IPA. In the present study, rats were exposed to 20 min nebulizations of normal saline (control group) or aerosolized aqueous solutions of voriconazole at 15.625 mg (low dose group) or 31.25 mg (high dose group). Peak voriconazole concentrations in rat lung tissue and plasma after 3 days of twice daily dosing in the high dose group were 0.85 ± 0.63 μg/g wet lung weight and 0.58 ± 0.30 μg/mL, with low dose group lung and plasma concentrations of 0.38 ± 0.01 μg/g wet lung weight and 0.09 ± 0.06 μg/mL, respectively. Trough plasma concentrations were low but demonstrated some drug accumulation over 21 days of inhaled voriconazole administered twice daily. Following multiple inhaled doses, statistically significant but clinically irrelevant abnormalities in laboratory values were observed. Histopathology also revealed an increase in the number of alveolar macrophages but without inflammation or ulceration of the airway, interstitial changes, or edema. Inhaled voriconazole was well tolerated in a rat model of drug inhalation.