Infections In Neutropenic Patients Research Articles

EFFICACY OF LL-37 AND GRANULOCYTE COLONY-STIMULATING FACTOR IN A NEUTROPENIC MURINE SEPSIS DUE TO PSEUDOMONAS AERUGINOSA

A promising therapeutic strategy for the management of severe Pseudomonas infection in neutropenic patients may result from the coadministration of colony-stimulating factors (CSFs) that help maintain immune competence and antimicrobial peptides, a novel generation of adjunctive therapeutic agents with antimicrobial and anti-inflammatory properties. A promising peptide with these properties is LL-37, the only member of the cathelicidin family of antimicrobial peptides found in humans. BALB/c male mice were rendered neutropenic by intraperitoneal administration of cyclophosphamide on days -4 and -2 preinfection. Septic shock was induced at time 0 by intraperitoneal injection of 2x10 colony-forming units of P. aeruginosa American Type Culture Collection (ATCC) 27853. All animals were randomized to receive intravenously isotonic sodium chloride solution, 1 mg/kg of LL-37, 20 mg/kg of imipenem, 0.1 mg/kg of granulocyte CSF (G-CSF), 1 mg/kg of LL-37+0.1 mg/kg of G-CSF, or 20 mg/kg of imipenem+0.1 mg/kg of G-CSF. Lethality and bacterial growth in blood, peritoneum, spleen, liver, and kidney were evaluated. All regimens were significantly superior to controls at reducing the mouse lethality rate and bacterial burden in organs. Particularly, the combination between LL-37 and G-CSF was the most effective in protecting neutropenic mice from the onset of sepsis and in vitro significantly reduced the apoptosis of neutrophils. Combination therapy between LL-37 and G-CSF is a promising therapeutic strategy for the management of severe Pseudomonas infection complicated by neutropenia.

Granulocyte Transfusion: Best Practice Collection & Transfusion

Serious and repeated infections with bacteria, yeast, and fungus continue to be a consequence of severe neutropenia. Previous attempts to prevent and/or treat these infections in severely neutropenic patients through use of neutrophil (PMN) transfusions achieved only modest success – largely due to the collection and transfusion of relatively small numbers of PMNs. Granulocyte colony-stimulating factor (G-CSF) has revolutionized the collection of PMNs for transfusion because stimulation of donors with G-CSF plus corticosteroids before leukapheresis permits collection of 6–8 × 10 to the 10 PMNs per each transfusion. Although questions and concerns have been raised about the biology and potential toxicity of giving G-CSF + steroids to normal allogeneic donors, these issues have questionable clinical significance. Properly controlled, clinical trials have not been performed to evaluate the efficacy and toxicity of PMN transfusions collected from donors stimulated with G-CSF + steroids. Therefore, despite the somewhat compelling ‘logic’ that transfusing very high numbers of PMNs should be helpful in treating serious infections in neutropenic patients, this practice can not be justified at this time. Indeed, published reports of individual patients and small series of patients have given mixed results (i.e., successes and failures). Hence, the need for properly-designed clinical trails.

Pilot Study on Septifast PCR for the Early Diagnosis of Invasive Fungal Infections in Neutropenic Patients with Acute Leukemia

Pilot Study on Septifast PCR for the Early Diagnosis of Invasive Fungal Infections in Neutropenic Patients with Acute Leukemia

1,3- -D-Glucan Antigenemia for Early Diagnosis of Invasive Fungal Infections in Neutropenic Patients with Acute Leukemia

Invasive fungal infections (IFIs) are life-threatening complications in neutropenic patients with hematological malignancies. Because early diagnosis of IFI is difficult, new noninvasive, culture-independent diagnostic tools are needed to improve clinical management. Recent studies have reported that detection of 1,3-beta-D-glucan (BG) antigenemia may be useful for diagnosis of IFI. The aim of the present prospective study was to evaluate the usefulness of monitoring BG in patients undergoing chemotherapy for acute leukemia. BG antigenemia was measured by a colorimetric assay twice weekly in the absence of fever and daily in the presence of fever. IFIs were classified according to the criteria of the European Organization for Research and Treatment of Cancer/Mycoses Study Group. During 190 consecutive neutropenic episodes (median duration, 22 days; range, 7-113 days) in 95 patients, 30 proven or probable IFIs (13 aspergillosis, 15 candidiasis, and 2 mixed IFIs) were diagnosed. Sensitivity, specificity, positive predictive value, negative predictive value, and efficiency of 2 consecutive BG values > or =7 pg/mL for diagnosis of proven or probable IFI was 0.63 (95% confidence interval, 0.44-0.79), 0.96 (95% confidence interval, 0.89-0.98), 0.79 (95% confidence interval, 0.57-0.92), 0.91 (95% confidence interval, 0.84-0.95), and 0.89, respectively. The time interval between onset of fever as first sign of IFI and BG antigenemia was significantly shorter than the time to diagnosis of IFI by clinical, microbiological, radiological, and/or histopathological criteria (P < .001). BG values >50 pg/mL were observed in only 2 patients, both of whom experienced failure of antifungal therapy. Monitoring of BG antigenemia is a useful noninvasive method for early diagnosis of IFI in patients with acute leukemia.

Decreasing the incidence and impact of infections in neutropenic patients: evidence from meta-analyses of randomized controlled trials

Backgound: Neutropenia is a common complication of intensive chemotherapy in patients with solid organ or hematologic malignancies that is associated with a high risk for life-threatening infections. Many interventions have been employed in order to limit the incidence of these infections or to treat them when the prophylactic measures fail.Scope: The commonest characteristic of the randomized controlled trials (RCTs) conducted on this issue was the small sample size. In addition, if RCTs studying the prophylactic interventions were excluded, the aim of most of the rest of relevant RCTs was to prove the equal effectiveness of the tested interventions in terms of treatment success. We searched PubMed and Cochrane database to identify meta-analyses of RCTs in the field of febrile neutropenia.Results: The most prominent findings of these meta-analyses were the promising effect, although based on open label RCTs, of antimicrobial prophylaxis with fluoroquinolones on the mortality of all neutropenic patients and the beneficial effect of antifungal prophylaxis on mortality of neutropenic patients with allogeneic hematopoetic stem cell transplantation. Another noteworthy finding was the higher mortality associated with empiric cefepime treatment when compared with other β-lactams. In other cases, the findings of the published meta-analyses either confirmed or consolidated the results of individual RCTs.Conclusion: Meta-analyses are very useful for obtaining a better overview and to provide some general qualitative and quantitative conclusions, but are not always a substitute for appropriately powered, well-designed RCTs. In addition, the reported findings should be interpreted with caution taking into account the limitations of various methodological aspects of meta-analysis in general, as well as the limitations of the individual meta-analyses in this field.

Cost Effectiveness of Itraconazole in the Prophylaxis of Invasive Fungal Infections

Invasive fungal infections in neutropenic patients treated for haematological malignancies are associated with a high mortality rate and, therefore, require early treatment. As the diagnosis of invasive fungal infections is difficult, effective antifungal prophylaxis is desirable. So far, fluconazole has been the most commonly used. To assess the cost effectiveness of itraconazole compared with both fluconazole and no prophylaxis for the prevention of invasive fungal infections in haematological patients, mean age 51 years, in Germany and The Netherlands. We designed a probabilistic decision model to fully incorporate the uncertainty associated with the risk estimates of acquiring an invasive fungal infection. These risk estimates were extracted from two meta-analyses, evaluating the effectiveness of fluconazole and itraconazole and no prophylaxis. The perspective of the analysis was that of the healthcare sector; only medical costs were taken into account. All costs were reported in euro, year 2004 values.Cost effectiveness was expressed as net costs per invasive fungal infection averted. No discounting was performed, as the model followed patients during their neutropenic period, which was assumed to be less than 1 year. According to our probabilistic decision model, the monetary benefits of averted healthcare exceed the costs of itraconazole prophylaxis under baseline assumptions (95% CI: from cost-saving to euro 5000 per invasive fungal infection averted). Compared with fluconazole, itraconazole is estimated to be both more effective and more economically favourable, with a probability of almost 98%. In specific groups of neutropenic patients treated for haematological malignancies, itraconazole prophylaxis could potentially reduce overall healthcare expenditure, without harming effectiveness, in settings where fluconazole is common practice in the prophylaxis of invasive fungal infections.

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.

Bloodstream infections in neutropenic patients: early detection of pathogens and directed antimicrobial therapy due to surveillance blood cultures

Bloodstream infections (BSIs) are frequent infectious complications in neutropenic patients. In order to determine the efficacy of surveillance blood cultures (BCs) to detect BSIs prior to clinical manifestation we performed a prospective trial. One hundred patients with haematological malignancies and long-term neutropenia following intensive cytotoxic therapies were recruited. BCs were taken thrice weekly during neutropenia. Forty-two patients were diagnosed with BSI. In 18 (43%) of those patients surveillance BC results were positive and identified microorganisms prior to onset of fever. In patients with positive surveillance BCs modification of the clinical management (specific antimicrobial therapy, CVC removal) resulted in a shorter time to defervescence (median 1.5 days) compared with patients with BCs positive after onset of fever (median 3.5 days, P = 0.004). In conclusion we detected causative microorganisms in more than one-third of BSIs prior to onset of clinical manifestation. The impact of surveillance BCs on the outcome has to be assessed in randomized studies.

Levofloxacin vs. ciprofloxacin plus phenethicillin for the prevention of bacterial infections in patients with haematological malignancies

An open-label randomised clinical trial was designed to compare the efficacy and tolerance of levofloxacin and ciprofloxacin plus phenethicillin for the prevention of bacterial infections in patients with high-risk neutropenia, and to monitor the emergence of antimicrobial resistance. Adult patients (n = 242) scheduled to receive intensive treatment for haematological malignancies were assigned randomly to receive oral prophylaxis with either levofloxacin 500 mg once-daily (n = 122), or ciprofloxacin 500 mg twice-daily plus phenethicillin 250 mg four-times-daily (n = 120). The primary endpoint was failure of prophylaxis, defined as the first occurrence of either the need to change the prophylactic regimen or the initiation of intravenous broad-spectrum antibiotics. This endpoint was observed in 89 (73.0%) of 122 levofloxacin recipients and in 85 (70.8%) of 120 ciprofloxacin plus phenethicillin recipients (RR 1.03, 95% CI 0.88-1.21, p 0.71). No differences were noted between the two groups with respect to secondary outcome measures, including time to endpoint, occurrence of fever, type and number of microbiologically documented infections, and administration of intravenous antibiotics. A questionnaire revealed that levofloxacin was tolerated significantly better than ciprofloxacin plus phenethicillin. Surveillance cultures indicated the emergence of viridans group (VG) streptococci resistant to levofloxacin in 17 (14%) of 122 levofloxacin recipients; in these cases, the prophylactic regimen was adjusted. No bacteraemia with VG streptococci occurred. It was concluded that levofloxacin and ciprofloxacin plus phenethicillin are equally effective in the prevention of bacterial infections in neutropenic patients, but that levofloxacin is tolerated better. Emergence of levofloxacin-resistant VG streptococci is of concern, but appears to be a manageable problem.

Genome of the Opportunistic Pathogen Streptococcus sanguinis

The genome of Streptococcus sanguinis is a circular DNA molecule consisting of 2,388,435 bp and is 177 to 590 kb larger than the other 21 streptococcal genomes that have been sequenced. The G+C content of the S. sanguinis genome is 43.4%, which is considerably higher than the G+C contents of other streptococci. The genome encodes 2,274 predicted proteins, 61 tRNAs, and four rRNA operons. A 70-kb region encoding pathways for vitamin B(12) biosynthesis and degradation of ethanolamine and propanediol was apparently acquired by horizontal gene transfer. The gene complement suggests new hypotheses for the pathogenesis and virulence of S. sanguinis and differs from the gene complements of other pathogenic and nonpathogenic streptococci. In particular, S. sanguinis possesses a remarkable abundance of putative surface proteins, which may permit it to be a primary colonizer of the oral cavity and agent of streptococcal endocarditis and infection in neutropenic patients.

Diagnosing Fungal Infections in Neutropenic Patients

Fungal infections are among the most serious complications in neutropenic patients. A major problem that has compromised management of fungal infections is healthcare professionals' inability to recognize the infections when they occur. No adequate diagnostic tools exist to detect many of the fungal infections. Early diagnosis of disseminated candidiasis is a challenge because only 35%-50% of neutropenic patients have positive blood cultures (Bodey, 1997), and radiologic tests have low specificity in that patient population. For example, a routine chest x-ray can be negative, yet a computed tomography (CT) scan of the chest can be positive for pneumonia the next day. Therefore, fungal infections often are advanced before diagnostic confirmation; thus, overall outcomes are poor. A great effort has been invested in developing serologic tests to detect circulating antigens of fungi.

Update on bacterial infections in immunosuppressed patients

A multidisciplinary group of physicians with expertise in infections in neutropenic and hemato-oncology patients met to discuss the state of the art and the most relevant publications in the field of bacterial infection in neutropenic patients during the last two years. The group agreed that most studies are favorably inclined toward the use of prophylaxis in this setting, although several areas have yet to be clarified, such as identification of the patients at greatest risk and the period of increased risk, and the emergence of resistant organisms. Several papers on vancomycin as empirical therapy in febrile patients with neutropenia were discussed. Currently available evidence does not support the need for empirical glycopeptides initially, nor for persistent fever. Withholding specific treatment against Gram-positive infections pending growth of a resistant Gram-positive organism was considered as safe. As for the management of bacterial infection in low-risk patients with neutropenia, current data indicate that, even in this group, empiric coverage with broad-spectrum antibiotics is necessary, at least until culture results become available. Finally, the role of Streptococcus pneumoniae as a bacterial agent of infection in hematology-oncology patients revealed the low incidence of the problem, the community origin of most episodes, the frequent association with pneumonia, and related mortality not superior to that of the non-neutropenic population.

Inhaled Amphotericin B for Prophylaxis Against Invasive Aspergillus Infections

To evaluate the available literature describing the use of inhaled amphotericin B for prophylaxis of invasive Aspergillus spp. infections. A MEDLINE search was conducted (1966-July 2006) using the key terms amphotericin B, inhaled amphotericin B, Aspergillus spp., invasive aspergillosis, solid-organ transplant, neutropenia, and inhalation. Review of the reference lists of the identified articles was also performed. Study selection included published trials, case reports, and case series of humans with hematologic disease and solid-organ transplant who used inhaled amphotericin B in the prevention of invasive Aspergillus infections. Inhaled amphotericin B has been evaluated for the prevention of invasive aspergillosis (IA) infections in neutropenic patients and certain solid-organ transplant recipients. Use of inhaled amphotericin B seems to reduce the incidence of IA in these patients; however, some of the clinical evidence was limited by factors such as small sample sizes, lack of statistical analyses, and lack of power to detect a difference between prophylaxis and control groups. Although the clinical evidence supporting the use of inhaled amphotericin B has some limitations, its use still may be beneficial for the prophylaxis of invasive Aspergillus infections, especially in solid-organ transplant recipients where the evidence is strongest. Invasive Aspergillus infections are becoming more prevalent in high-risk populations (eg, patients with malignancies, following bone marrow transplantation, or following solid-organ transplantation). The mortality rates associated with IA are great in these populations, making prophylaxis an important consideration. Inhaled amphotericin B has recently come into vogue as an option for prophylaxis against IA. Some of the data available supports the use of inhaled amphotericin B for the prevention of IA while providing evidence of fewer drug interactions and toxicities associated with other antifungal agents.

Economic evaluation of the prevention and management of systemic fungal infections in neutropenic patients

Systemic fungal infections in neutropenic patients remain a clinical problem that is associated with morbidity and mortality. Continuing efforts are being made to develop improved (i.e., more effective or safe) drugs, and several new treatments have recently become available. These have increased the therapeutic options available to clinicians to address the problem of systemic fungal infections. Therapeutic choices are difficult when taking into account aspects of efficacy, safety and costs that are associated with the available alternatives. This review summarises the present status of health economic knowledge of the standard therapies that have been available for many years, and also reports on the most recent health economic evidence available for the newly developed treatment alternatives.

Successful Treatment of Breakthrough Trichosporon asahii Fungemia with Voriconazole in a Patient with Acute Myeloid Leukemia

We describe a 55-year-old man with acute myelogenous leukemia who developed breakthrough Trichosporon asahii fungemia during 5 days of micafungin treatment. Although the patient's clinical condition improved considerably after the start of voriconazole treatment, blood culture results remained positive for T. asahii for 3 days, and fever persisted for 7 days thereafter. The patient achieved complete hematological remission, and he received successful consolidation chemotherapy without developing Trichosporon infection with the prophylactic use of voriconazole therapy. This case report illustrates that voriconazole may be useful in the treatment of disseminated T. asahii infection in neutropenic patients.

Efficacy and Safety of Linezolid Compared with Vancomycin in a Randomized, Double-Blind Study of Febrile Neutropenic Patients with Cancer

Gram-positive pathogens can cause serious infections in neutropenic patients with cancer, and vancomycin therapy is often initiated empirically. Linezolid may offer an option for these patients. To compare the safety and efficacy of linezolid and vancomycin in febrile, neutropenic patients with cancer, we conducted a double-blind, multicenter equivalence study. Eligible patients with proven or suspected infection due to a gram-positive pathogen were randomized to receive linezolid or vancomycin. Clinical success rates 7 days after completion of therapy (primary end point) were equivalent between groups in the intent-to-treat (ITT) analysis (linezolid, 219 [87.3%] of 251 patients; vancomycin, 202 [85.2%] of 237 patients; 95% CI, -4.1 to 8.1; P=.52), modified ITT analysis, clinically evaluable analysis, and microbiologically evaluable analysis, as well as between subsets analyzed by malignancy and infection type. Mean time to defervescence was shorter for linezolid than vancomycin in the modified ITT (6.6 vs. 8.5 days; P=.04) and microbiologically evaluable subsets (5.9 vs. 9.1 days; P=.01), although post hoc analyses revealed delayed recovery of absolute neutrophil counts for linezolid in these subsets (P<.05). There were no between-group differences in microbiologic success rates in the modified ITT subset (41 [57.7%] of 71 patients vs. 29 [50.0%] of 58 patients; P=.38) and microbiologically evaluable subsets, as well as in mortality rates in the ITT subset (17 [5.6%] of 304 patients vs. 23 [7.6%] of 301 patients; P=.31) and all subsets. Distribution of adverse events, including reported hematologic events, was similar between groups, except that linezolid was associated with fewer drug-related adverse events (52 [17.2%] of 303 patients vs. 72 [24.0%] of 300 patients; P=.04) and fewer cases of drug-related renal failure (1 [0.3%] of 303 patients vs. 7 [2.3%] of patients; P=.04). Linezolid demonstrated efficacy and similar safety outcomes equivalent to those for vancomycin in febrile neutropenic patients with cancer.

Efficacy of caspofungin against invasive Candida or invasive Aspergillus infections in neutropenic patients

Neutropenia is an indicator of poor prognosis in patients with fungal infections. All available clinical trial experience from the caspofungin development program was reviewed to ascertain the efficacy of caspofungin in neutropenic patients with documented invasive aspergillosis (IA) or invasive candidiasis (IC). The review was limited to neutropenic patients with proven IC or proven/probable IA at caspofungin onset. Data were available from four clinical trials. All patients had an absolute neutrophil count < 500/mm(3) at the initiation of caspofungin. In all cases caspofungin was administered as monotherapy at a dose of 50 mg/day, after a 70-mg loading dose. In all patients efficacy was assessed at the completion of caspofungin therapy. Success included complete and partial responses. Sixty-eight neutropenic patients were identified with documented invasive infection, including 27 with IC and 41 with IA. Most patients had acute or chronic leukemia. A favorable response was noted in 63% (17 of 27 patients) of patients with IC, including a 58% (14 of 24 patients) response as first-line therapy and a 100% (3 of 3 patients) response as salvage therapy. Success in candidemia was 68% (17 of 25 patients). Outcomes across the different Candida species were similar. Favorable responses were noted in 39% (16 of 41 patients) of patients with IA, including a 42% (5 of 12 patients) response as first-line therapy and 38% (11 of 29 patients) response as salvage therapy. Success by site of IA was 40% for pulmonary (12 of 30 patients), 43% for sinus (3 of 7 patients), and 25% for skin/disseminated site (1 of 4 patients). A review of the caspofungin database demonstrates that this echinocandin is effective in neutropenic patients with documented cases of IC or IA.

An open-label randomized trial comparing itraconazole oral solution with fluconazole oral solution for primary prophylaxis of fungal infections in patients with haematological malignancy and profound neutropenia

This trial studied the efficacy and safety of itraconazole and fluconazole in the prevention of invasive fungal infections in neutropenic patients with haematological malignancies. An 8 week, open-label, randomized, parallel-group, multicentre trial comparing itraconazole oral solution (2.5 mg/kg twice daily; N=248) with fluconazole oral solution or capsules (400 mg daily; N=246) in 494 patients with anticipated profound neutropenia (i.e. neutrophil count expected to be <500 cells/mm3 for at least 10 days) from tertiary care centres. Invasive fungal infections were reported for 4 out of 248 patients (1.6%) in the itraconazole group and 5 out of 246 patients (2.0%) in the fluconazole group. Invasive Aspergillus infections were proven for 2 out of 248 patients (0.8%) in the itraconazole group and 3 out of 246 patients (1.2%) in the fluconazole group. For both the ITT and profoundly neutropenic populations, no differences were detected between treatment groups in proven or suspected invasive fungal infections or other endpoints. The mortality rates owing to proven invasive fungal infections were 2 out of 248 patients (0.8%) for the itraconazole group and 3 out of 246 patients (1.2%) for the fluconazole group. There was also no difference between treatment groups in the number of patients who recovered from neutropenia or in the duration of neutropenia. More discontinuation of drug intake owing to nausea and more hypokalaemia occurred in the itraconazole group, other adverse events and the total number of adverse events were similar in both groups. In this study there were no differences in the efficacy and safety of itraconazole and fluconazole prophylaxis in neutropenic patients with haematological malignancies.

Antifungal Treatment with Caspofungin: A Single Centre Experience.

Infections are the main complication for patients with hematologic diseases and severe neutropenia and among them fungal infections are the most diffucult to treat and a major cause of mortality for these patients. Now we have a new antifungal class, Echinocandins which work with a new and different mechanism of action regarding azoles and amphotericin B, so we wanted to verify the tolerability and efficacy of Caspofungin (Caspo). From January 2004 until now we have treated 15 consecutive oncohemopatic and neutropenic patients admitted at our Institution. The schedule of treatment was: in case of persistent fever (at least 4 days) during broad spectrum antibiotic therapy a high-resolution CT-scan of the lungs, an abdomen US-scan, swabs from pharynx, nose and rectum and blood cultures were performed. In case of positivity of one or more of these findings suggesting for invasive fungal disease, Caspofungin was administered at the dosage of 70 mg i.v. on the first day and 50 mg i.v. from the second day; the infusion time was 1 hour. The patients were 10 males and 5 females, the mean age was 46 yrs (range 19–60 yrs). The diagnoses were: acute myeloid leukemia 8, acute lymphoblastic leukemia 3, lymphoma 4; the disease's phases were: onset 3, first remission 3, remission>I 2, partial remission 5, relapse 1, resistant 1. Two patients received an allogeneic BMT, 1 an autologous BMT, the other patients an induction or consolidation or rescue chemotherapy course. In four cases Caspo was administered as secondary prophylaxis of a previous invasive fungal infection while for the other patients Caspo was administered for persistent fever and at least one lesion of the lungs or other organs with no evidence of bacterial or viral infection. The mean time of treatment was 18 days (range 6–21 days); the treatment was not discontinued for anyone of them because of adverse events; the dosage of Caspo was not changed for anyone. For the 2 allogeneic BMT Cyclosporine A administration was not changed and we did not found any renal or liver alterations. All the patients received a concomitant broad spectrum antibiotic therapy (association of Tazobactam/Piperacilline, Amikacine and Vancomycin) and for none of them we registered any liver or renal disfunction. No adverse events during the infusion of Caspo were seen and it was not necessary to administer any drug before the infusion. We did not seen breakthrough fungal infections. In 2 patients a proven fungal infection (Aspergillus fumigatus and Aspergillus spp) was demonstrated so the other cases remained probable or possible infections. No progression of the infection was seen. All the infections, except one, resolved; one patient died after 6 days of antifungal treatment for leukemia progression. Five patients died: 4 for leukemia and 1 for bacterial infection (Pseudomonas aeruginosa) after the fungal infection. In conclusion now we have a new treatment option for fungal infections in neutropenic patients and this option is safe, it does not preclude any other treatment (such as CsA), it is well tolerated and the resolution rate of the infections is very high, probably because of the new mechanism of action of the drug. Moreover the cost of the drug is lower than other antifungal treatments. According to these preliminary data we have decided to continue this experience to verify them in a larger cohort of patients.

Cost-Effectiveness of Itraconazole for the Prophylaxis of Invasive Fungal Infections for Neutropenic Patients; a Study for 3 European Countries.

Background: Invasive fungal infections present a leading cause of mortality and morbidity in neutropenic patients treated for hematologic malignancies. As the diagnosis and management of invasive fungal infections is difficult, effective antifungal prophylaxis is desirable. Itraconazole is a broad spectrum antifungal agent with activity against Candida species as well as Aspergillus species, whereas fluconazole primarily targets Candida. There is no published data comparing cost-effectiveness of both antifungal agents.Objective: To asses the cost-effectiveness of itraconazole compared with (i) prophylactic fluconazole and with (ii) no prophylaxis in the prevention of invasive fungal infections in Germany, the Netherlands and the UK.Methods: A probabilistic decision model was designed to evaluate the incremental cost-effectiveness of itraconazole versus fluconazole and versus no prophylaxis (see Figure). Baseline risks for invasive fungal infections and risk reductions for itraconazole (>200mg/day) and fluconazole (400mg/day PO or 200mg/day IV) were taken from studies recently published in two meta-analyses. Costs were evaluated from the health care perspective. Drug acquisition costs for the two prophylactic regimens were calculated using 2003 prices. We estimated the increase in the length of stay as a result of an invasive infection using local or national databases and costed this using reference prices.Results: The meta-analysis revealed that itraconazole is effective in averting invasive fungal disease, in particular aspergillosis. The mean increase in the length of stay for invasive fungal infections was estimated at 9.3 days (rather similar for all 3 countries). As an illustration for our findings: in the Netherlands, itraconazole prophylaxis was expected to be cost-saving compared to fluconazole and provided limited extra costs compared to no prophylaxis at all. Cost-effectiveness was €470 per invasive infection averted for the itraconazole compared to no prophylaxis (95%-CI ranging from cost-saving to €5926 per infection averted). Other country-specific results will be presented at the conference.Discussion & Conclusions: Our study shows that itraconazole prophylaxis is effective and is clinically likely to result in cost-savings or provide an acceptable cost-effectiveness. Itraconazole should be the first choice in the prophylaxis of invasive fungal infections in neutropenic patients with hematologic malignancies, from the clinical and economic point of view. [Display omitted]