Antifungal Prophylaxis In Neutropenic Patients Research Articles

Medical cost analysis for antifungal prophylaxis in neutropenic patients with hematological malignancies: a systematic simulation analysis

We assessed the medical costs of different antifungal agents for prophylaxis of invasive fungal infections in neutropenic patients in Japan with a cost simulation model designed for the study. We used probabilities of prophylaxis failure, possible cases for empiric therapy, probable proportions of infections caused by fungus species among prophylaxis failure patients, and incidence of adverse events caused by any reason, based on systematic analysis of previously reported randomized trials identified by a computerized search of the PubMed database. Antifungal agents were limited to oral fluconazole, oral itraconazole, micafungin, and liposomal amphotericin B. The range of the expected medical cost was simulated as a sensitivity analysis using 95% of confidence interval of a mean. Fifteen studies were identified for our analysis. The prophylactic efficacy was comparable between the four agents. The simulated expected cost for invasive fungal infection prophylaxis and treatment of the infection was $1,035.74 when oral itraconazole was used for prophylaxis, $1,552.81 with oral fluconazole, $2,245.96 with micafungin, and $3,028.10 with liposomal amphotericin B. The total cost including treatment cost for adverse events related to each drug was $2,742.14, $3,547.91, $3,034.57, and $3,028.10, respectively. This result was confirmed in a sensitivity analysis in which IFI incidence and therapy duration were tested as parameters. Our analysis results suggest that oral itraconazole is the most cost-effective prophylactic antifungal agent for invasive fungal infections in neutropenic patients with hematological malignancies, and this result was robust by sensitivity analysis.

Use of micafungin versus fluconazole for antifungal prophylaxis in neutropenic patients receiving hematopoietic stem cell transplantation

A prospective randomized clinical trial assessed the efficacy and tolerance of micafungin compared with that of standard fluconazole treatment in patients undergoing hematopoietic stem cell transplantation (HSCT). Adult patients (n = 106) were randomly assigned to receive prophylaxis with either micafungin 150 mg (n = 52), or fluconazole 400 mg (n = 52). Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and the absence of proven or probable IFI through the end of the 4-week period following treatment. The overall efficacy of micafungin was comparable to that of fluconazole (94 vs. 88%; difference 6.0%; 95% confidence interval, -5.4 to +17.4%; P = 0.295). A total of 2 (4.0%) of 50 patients in the micafungin arm and 6 (12.0%) of 50 patients in the fluconazole arm received empirical antifungal therapy (P = 0.06). Micafungin treatment did not result in increasing adverse effects and had a safe profile as fluconazole in neutropenic patients. This randomized trial indicates that the efficacy and tolerance of micafungin 150 mg was comparable to that of fluconazole 400 mg, suggesting that micafungin at 150 mg daily represents a valuable new treatment option for antifungal prophylaxis in HSCT recipients.

Medical Costs Analysis for Antifungal Prophylaxis in Neutropenic Patients with Hematological Malignancies: A Systematic Review Analysis.

Purpose Invasive fungal infection (IFI) is one of the leading causes of mortality and morbidity in neutropenic patients with hematological malignancies (HM). Randomized studies and followed by metanalysis suggest the prophylactic effects of antifungal agents for chemotherapy-induced neutropenia. The purpose of this study is to estimate the medical costs on each antifungal agent for prophylaxis of antifungal infection in neutropenic patients in Japan.Method PubMed was searched for articles, which reported antifungal prophylaxis in neutropenic patients with HM, published after 1999, using 3 keywords; 'prophylaxis ', 'hematological malignancy' and 'fungal infection'. Fifteen articles that met the criteria were selected;1.randomized controlled trial,2.more than 100 cases overall,3.prospective study, and4.single agent used in each study arm.Antifungal agents were limited to the 4 drugs; fluconazole (FLCZ) capsules or tablets, itraconazole (ITCZ) capsules or oral solution, micafungin (MCFG), and liposomal amphotericin B (L-AMB). We assumed 3-week-prophylaxis after chemotherapy and 2-week-target therapy for the occurrence of the breakthrough infection, and designed the decision tree models in which a breakthrough fungal infection occurred in certain incidence of proven and probable IFI. The incidences of IFI from the 15 studies were applied to our model. MCFG, voriconazole (VRCZ) and L-AMB were applied as target therapies to the assumed Candida spp., Aspergillus spp., and other fungal infections, respectively. An average expected cost for prophylaxis on each antifungal agent was calculated and compared. Sensitive analysis was performed for the parameter of the incidence of breakthrough IFI.Results In each prophylaxis agent, the collected study population was 1061 cases in FLCZ, 1510 in ITCZ, 425 in MCFG, and 219 in L-AMB. The incidence of proven and probable IFI was 4.3% (46/1061) in FLCZ, 2.7% (41/1510) in ITCZ, 1.6% (7/425) in MCFG, and 3.7% (8/219) in L-AMB. Causative fungi were revealed in table 1 below. The mean duration to the breakthrough fungal infection was 20 days (95CI, 13–26) after chemotherapy. The average expected cost for prophylaxis in each drug was $1,098 for FLCZ, $532 for ITCZ, $1,313 for MCFG, and $2297 for L-AMB.Conclusion In our review, the prophylactic failure seems be comparable in the 4 antifungal agents. However, cost-effectiveness was the superior in the prophylaxis by ITCZ than the other agents in neutropenic patients with HM in Japan.The incidence of proven and probable IFI and its causes.Agents for prophylaxisProven and probable IFIProphylactic success (%) (95% CI)Candida spp. (%)Aspergillus spp. (%)Other fungus (%)FLCZ4.3% (46/1061)95.7 (94.3–96.7)23.763.213.2ITCZ2.7% (41/1510)97.3 (96.3–98.0)23.558.817.6MCFG1.6% (7/425)98.4 (96.6–99.2)57.114.328.6L-AMB3.7% (8/219)96.3 (93.0–98.1)75.025.00.0Number of the causative fungus is indicated as the proportion among prophylactic failure cases.

Population Pharmacokinetics (PK) of Oral Posaconazole (POS) for Antifungal Prophylaxis in Neutropenic Patients with Hematologic Malignancies.

In a recent large, randomized, multicenter study in neutropenic patients undergoing remission-induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome, prophylaxis with POS resulted in significantly fewer invasive fungal infections (IFIs) (2% vs 8%, P<0.001) and longer survival (P=0.04) vs fluconazole or itraconazole (Cornely et al New Engl J Med 2007; 356:348–59). Using data from this study, the relationship between demographic/baseline covariates and apparent volume of distribution (V/F) of POS was evaluated in a population modeling approach. In the full study, 304 patients were administered POS (200 mg tid) and 298 patients received fluconazole (400 mg qd) or itraconazole (200 mg bid) for up to 12 weeks. For the population PK analysis, data from 215 POS patients were analyzed using nonlinear mixed-effect modeling. The effect on POS V/F of IFI occurrence, demographic characteristics, and baseline variables (occurring at or before day 7) including mucositis, neutropenia, vomiting, diarrhea, proton pump inhibitor (PPI) or H2-receptor antagonist usage, bilirubin ≥2 × upper limit of normal (ULN) and gamma-glutamyl transferase (GGT) ≥2 × ULN was examined. A 2-stage “stepwise forward addition” followed by a “stepwise backward elimination” approach was used to build the covariate model. The model was validated by bootstrapping data with 85% and 50% partial sampling. POS V/F, and thus exposure, was statistically associated with diarrhea, PPI intake, bilirubin ≥2 × ULN, GGT ≥2 × ULN, and race (white vs nonwhite). None of these covariates predominated in patients with proven or probable IFI (n=7). Validation demonstrated the robustness of this model. A significant relationship was found between POS V/F (or exposure) and the following covariates: diarrhea, PPI intake, bilirubin ≥2 × ULN, GGT ≥2 × ULN, and race. However, the influence of these covariates on POS exposure is unlikely to be clinically relevant as none of the covariates predominated in the patients who developed IFI, and plasma POS levels were attained that were adequate for successful prophylaxis against IFIs. Thus, no dosage adjustments are recommended based on these covariates.

Comment on: Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies

Comment on: Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies

Itraconazole for Antifungal Prophylaxis in Neutropenic Patients: An Update of a Meta-Analysis with Now 3846 Patients.

Invasive fungal infections, esp. from Aspergillus spp., still are a major cause of mortality and morbidity in neutropenic patients with haematological malignancies. We have published a meta-analysis on the use of itraconazole for antifungal prophylaxis (Glasmacher et al., JCO 2003; 21: 4615) and now present updated results.Methods: In a continuous search of electronic databases and abstracts we identified randomized clinical trials in neutropenic patients that compared itraconazole with either nothing, oral polyenes or fluconazole. Again, analysis was restricted to proven invasive fungal infections according to EORTC/MSG criteria. Statistical analyses were performed with the Cochrane Review Manager (Version 2.4.8), relative risk ratios (RR) with their 95% confidence intervals (95%CI) and appropriate P values were reported. Subgroups were defined by itraconazole preparation and the comparator. A RR below 1 indicates better results for itraconazole.Results - New Trials: Two new trials with 54 and 195 evaluable patients (pts) were identified and the data of one unpublished trials was updated. Both studies used itraconazole solution (400 mg/d) and compared it to 400 mg/d fluconazole. One study applied intravenous solutions of both drugs if necessary. No study was powered to detect a significant difference in proven invasive fungal infections between the two drugs. One study reported a reduction of fungal-related mortality in the itraconazole arm (fluconazole 9/12, 75%, vs. itraconazole 5/11, 45%; P=0.154).Results - Meta-Analysis: The incidence of proven invasive fungal infection from all studies and arms was 4.1% and 8.3% if suspected infections were included. The reduction in the incidence of proven breakthrough invasive mycosis was significant (Table 1). As in the original analysis, the relative risk is reduced only in the group provided with itraconazole solution and with a relative risk reduction of 46%.Results - Itraconazole vs. Fluconazole: Table 2 reports a comparison of itraconazole solution vs. fluconazole for different relevant outcomes. There is a significant superiority of itraconazole for the reduction of all proven invasive fungal infections and for invasive Aspergillus infections and reductions are in the same range but not significant for the other outcomes.Conclusions: Itraconazole is still and significantly superior to its comparators, including fluconazole, in reducing the rate of breakthrough invasive fungal infections. This effect is only seen with the itraconazole oral or intravenous solution (at least 400 mg/d) which also reduce the rate of proven invasive Aspergillus infections.Table 1:Incidence of proven invasive fungal infectionsSubgroupNo. Pts (Trials)Relative Risk95%CIPAll studies3846 (15)0.620.45–0.770.003Itraconazole capsules735 (5)0.930.51–1.690.81Itraconazole solution3111 (10)0.540.37–0.770.0008Table 2:Comparison of itraconazole solution vs fluconazole (proven only)OutcomeNo. of trialsItraconazole (n/N)Fluconazole (n/N)Relative Risk95%CIPInvasive fungal infections623/88343/8740.520.32–0.840.008Invasive yeast infections69/85116//8540.560.25–1.240.15Invasive Aspergillus infections512/85024/8530.500.26–0.980.04Fungal-related Mortality420/75431/7540.640.38–1.090.10Abbrev.: n= pts. with event; N=total pts.

Fluconazole versus itraconazole for antifungal prophylaxis in neutropenic patients with haematological malignancies: a meta‐analysis of randomised‐controlled trials

Fluconazole and itraconazole are used as antifungal prophylaxis in neutropenic patients with haematological malignancies. A meta-analysis of randomised-controlled trials (RCTs) was performed in order to compare their safety and effectiveness in this population. Data were obtained from PubMed, Current Contents, Cochrane Central Register for Controlled Trials and references from relevant articles. Five RCTs were included in the analysis. Publication bias and statistically significant heterogeneity was not observed among the analysed studies. Fewer patients were withdrawn due to the development of adverse effects associated with fluconazole when compared with itraconazole [odds ratio (OR) = 0.27, 95% confidence interval (CI): 0.18-0.41]. On the contrary, prophylactic use of fluconazole resulted in significantly more fungal infections (documented and suspected infections combined, OR = 1.62, 95% CI: 1.06-2.48). There were no statistically significant differences regarding documented fungal infections (OR = 1.51, 95% CI: 0.97-2.35), invasive fungal infections (OR = 1.44, 95% CI: 0.96-2.17), overall mortality (OR = 0.89, 95% CI: 0.63-1.24) and mortality attributed by the authors to fungal infections (OR = 1.30, 95% CI: 0.75-2.25) between the two medications. These data suggest that, even though itraconazole is more effective than fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies, the development of more adverse effects may limit its use.

Evidence-based review of antifungal prophylaxis in neutropenic patients with haematological malignancies

There is still no consensus on the efficacy of antifungal prophylaxis in neutropenic patients after more than 50 clinical trials. This review evaluates the current evidence from all available meta-analyses of the use of intravenous amphotericin B, fluconazole and itraconazole for this indication. Four systematic reviews with meta-analysis and one evidence-based review without meta-analysis were evaluated. Efficacy of fluconazole has been shown on short-term follow-up after allogeneic stem cell transplantation but only itraconazole was effective in neutropenic patients with haematological malignancies for prolonged prophylaxis after allogeneic stem cell transplantation. Direct comparison between fluconazole and itraconazole for this indication shows the superiority of itraconazole which was the only drug able to prevent invasive Aspergillus infections in our previously published meta-analysis of 13 trials and 3597 patients. Efficacy of itraconazole correlates closely with its dose; an effect was seen only in clinical trials using at least 400 mg/day oral solution or 200 mg/day intravenous solution. With this dose, invasive fungal infections were reduced by 53% and mortality from invasive fungal infections was reduced by 47% (P<0.05). Toxicity of itraconazole is rare and usually not severe and drug interactions are easily manageable. Itraconazole is recommended for antifungal prophylaxis in high-risk neutropenic patients with haematological malignancies or for prolonged prophylaxis after allogeneic stem cell transplantation based on unambiguous evidence of efficacy and low toxicity from clinical trials and systematic reviews.

Micafungin versus Fluconazole for Prophylaxis against Invasive Fungal Infections during Neutropenia in Patients Undergoing Hematopoietic Stem Cell Transplantation

We hypothesized that chemoprophylaxis with the echinocandin micafungin would be an effective agent for antifungal prophylaxis during neutropenia in patients undergoing hematopoietic stem cell transplantation (HSCT). We therefore conducted a randomized, double-blind, multi-institutional, comparative phase III trial, involving 882 adult and pediatric patients, of 50 mg of micafungin (1 mg/kg for patients weighing <50 kg) and 400 mg of fluconazole (8 mg/kg for patients weighing <50 kg) administered once per day. Success was defined as the absence of suspected, proven, or probable invasive fungal infection (IFI) through the end of therapy and as the absence of proven or probable IFI through the end of the 4-week period after treatment. The overall efficacy of micafungin was superior to that of fluconazole as antifungal prophylaxis during the neutropenic phase after HSCT (80.0% in the micafungin arm vs. 73.5% in the fluconazole arm [difference, 6.5%]; 95% confidence interval, 0.9%-12%; P=.03). This randomized trial demonstrates the efficacy of an echinocandin for antifungal prophylaxis in neutropenic patients.

Itraconazole prevents invasive fungal infections in neutropenic patients treated for hematologic malignancies: evidence from a meta-analysis of 3,597 patients.

Efficacy of antifungal prophylaxis has not yet been convincingly proven in numerous trials of various antifungals. New evidence and the anti-Aspergillus efficacy of itraconazole prompted a new look at the data for the prevention of invasive fungal infections. Randomized, controlled studies with itraconazole for antifungal prophylaxis in neutropenic patients with hematologic malignancies were identified from electronic databases and hand searching. Thirteen randomized trials included 3,597 patients who were assessable for invasive fungal infections. Itraconazole reduced the incidence of invasive fungal infection (mean relative risk reduction, 40% +/- 13%; P =.002), the incidence of invasive yeast infections (mean, 53% +/- 19%; P =.004) and the mortality from invasive fungal infections (mean, 35% +/- 17%; P =.04) significantly. The incidence of invasive Aspergillus infections was only reduced in trials using the itraconazole cyclodextrine solution (mean, 48% +/- 21%; P =.02) and not itraconazole capsules (mean, 75% +/- 73% increase; P =.3). The overall mortality was not changed. Adverse effects were rare, hypokalemia was noted in three studies, and a higher rate of drug discontinuation was found in trials that compared itraconazole cyclodextrine solution to a control without cyclodextrine. The effect of prophylaxis was clearly associated with a higher bioavailable dose of itraconazole. Antifungal prophylaxis with itraconazole effectively prevents proven invasive fungal infections and-shown for the first time for antifungal prophylaxis-reduces mortality from these infections and the rate of invasive Aspergillus infections in neutropenic patients with hematologic malignancies. Adequate doses of the oral cyclodextrine solution (at least 400 mg/d) or i.v. formulations (200 mg/d) of itraconazole are necessary for these effects.

Amphotericin B colloidal dispersion (Amphocil) vs fluconazole for the prevention of fungal infections in neutropenic patients: data of a prematurely stopped clinical trial

We conducted an open label, randomised clinical trial to compare amphotericin B colloidal dispersion (ABCD, Amphocil) 2 mg/kg/day intravenously with fluconazole 200 mg/day orally, for the prevention of fungal disease in neutropenic patients with haematological malignancies. In the event of unresolved fever after 4 days of empirical antibacterial therapy, patients in both treatment groups were to receive ABCD, 4 mg/kg/day. However, the study had to be stopped in an early phase, due to severe side-effects of ABCD. A total of 24 patients were enrolled, 12 patients were randomly assigned to receive prophylactic ABCD, which was administered for a mean of 13.9 days. Fluconazole prophylaxis was given to 12 patients for a mean of 21.2 days. Therapeutic ABCD, 4 mg/kg, was initiated in four patients because of suspected fungal infection, all of whom had initially received fluconazole. A high rate of infusion-related toxicity of ABCD was observed. Chills occurred in 15/16 ABCD recipients (94%), accompanied by a temperature rise of >/=2 degrees C in 4/16 patients and of >/=1 degrees C but <2 degrees C in 10/16 patients. Other ABCD-related adverse events were hypotension (4/16), nausea with vomiting (5/16), tachycardia (7/16), headache (3/16) and dyspnoea (3/16). For premedication patients received: antihistamines (12/16), hydrocortisone (9/16) and/or morphine (6/16). ABCD was discontinued in 8/16 patients (50%) due to side-effects, which ultimately dictated early termination of the study. We conclude that ABCD is not suitable for antifungal prophylaxis in neutropenic patients due to severe infusion-related side-effects. Subject numbers were too low for conclusions on variables of antifungal efficacy.

Antifungal Prophylaxis in Neutropenic Patients with Hematologic Malignancies: Is There a Real Benefit?

Invasive fungal infections have been reported with an increasing incidence over the last 20 years. Fungal infections are an important cause of morbidity and mortality in patients with hematological malignancies. Therefore, in neutropenic patients different regimens of antifungal prophylaxis have been performed for more than 20 years, but the effect of antifungal prophylaxis is controversial. A long duration of neutropenia, impaired cell-mediated immunity as well as continuous corticosteroid therapy and sustained immunosuppression for graft-versus-host disease in patients treated with allogeneic bone marrow transplantation are known risk factors for invasive mycosis. Since early diagnosis of invasive fungal infection is difficult, strategies to prevent fungal infections seem to be attractive. The introduction of triazoles have provided us with a better armamentarium to prevent fungal infections. In this review, the current strategies of antifungal prophylaxis are discussed. Antifungal prophylaxis has been effective in reducing candida infection, however, there has been no proven successful prevention of invasive aspergillosis. In addition, there is no clearly proven benefit of antifungal prophylaxis regarding the reduction in the overall mortality. Thus the best way to reduce invasive fungal-related mortality will be early diagnosis and preemptive therapeutic approaches.

Antifungal prophylaxis in neutropenic patients with hematologic malignancies.

Antifungal prophylaxis in neutropenic patients with hematologic malignancies.

Antifungal prophylaxis in neutropenic patients

Although a number of studies have been published on antifungal prophylaxis in neutropenic and bone marrow transplantation patients, there are a lot of conflicting data. Some of this may be due to a lack of consensus on the definition of fungal disease and the definition of end-points for treatment. The risk factors associated with fungal infection, the causative species and the antifungals currently used for prophylaxis are reviewed. Future trends in prophylaxis, such as the use of growth factors and peripheral blood stem cells are discussed.