Itraconazole oral solution for primary prophylaxis of fungal infections in patients with hematological malignancy and profound neutropenia: a randomized, double-blind, double-placebo, multicenter trial comparing itraconazole and amphotericin B

Systemic and superficial fungal infections are a major problem among immunocompromised patients with hematological malignancy. A double-blind, double-placebo, randomized, multicenter trial was performed to compare the efficacy and safety of itraconazole oral solution (2.5 mg/kg of body weight twice a day) with amphotericin B capsules (500 mg orally four times a day) for prophylaxis of systemic and superficial fungal infection. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (>0.5 x 10(9) neutrophils/liter) or up to a maximum of 3 days following the end of neutropenia, unless a systemic fungal infection was documented or suspected. The maximum treatment duration was 56 days. In the intent-to-treat population, invasive aspergillosis was noted in 5 (1.8%) of the 281 patients assigned to itraconazole oral solution and in 9 (3.3%) of the 276 patients assigned to oral amphotericin B; of these, 1 and 4 patients died, respectively. Proven systemic fungal infection (including invasive aspergillosis) occurred in 8 patients (2.8%) who received itraconazole, compared with 13 (4.7%) who received oral amphotericin B. Itraconazole significantly reduced the incidence of superficial fungal infections as compared to oral amphotericin B (2 [1%] versus 13 [5%]; P = 0.004). Although the incidences of suspected fungal infection (including fever of unknown origin) were not different between the groups, fewer patients were administered intravenous systemic antifungals (mainly intravenous amphotericin B) in the group receiving itraconazole than in the group receiving oral amphotericin B (114 [41%] versus 132 [48%]; P = 0.066). Adequate plasma itraconazole levels were achieved in about 80% of the patients from 1 week after the start of treatment. In both groups, the trial medication was safe and well tolerated. Prophylactic administration of itraconazole oral solution significantly reduces superficial fungal infection in patients with hematological malignancies and neutropenia. The incidence of proven systemic fungal infections, the number of deaths due to deep fungal infections, and the use of systemic antifungals tended to be lower in the itraconazole-treated group than in the amphotericin B-treated group, without statistical significance. Itraconazole oral solution is a broad-spectrum systemic antifungal agent with prophylactic activity in neutropenic patients, especially for those at high risk of prolonged neutropenia.     

Itraconazole is not effective for the prophylaxis of fungal infections in patients with neutropenia

 Fungal infections are a major problem among patients with hematological malignancies. To evaluate the efficacy of itraconazole (200 mg twice daily) in the prophylaxis of fungal infections in neutropenic patients, we conducted a prospective trial. A total of 61 patients with acute leukemia (113 cytotoxic chemotherapy episodes) were enrolled in the study. One patient in the itraconazole group was excluded because itraconazole was not taken due to gastrointestinal hemorrhage. Because the duration of neutropenia (neutrophil count, <0.5 × 10⁹/l) did not reach 7 days, 3 (1 patient) and 13 (4 patients) cytotoxic chemotherapy episodes in the itraconazole and control groups, respectively, were excluded. After these exclusions, the study population consisted of 31 patients (54 cytotoxic chemotherapy episodes) who had taken itraconazole and 24 patients (43 cytotoxic chemotherapy episodes) who had not taken itraconazole. Prophylactic treatment was initiated on the first day of chemotherapy and was continued until the end of the neutropenic period (absolute neutrophil count, >1 × 10⁹/l) unless a systemic fungal infection was documented or suspected. Thirteen episodes (24%) in the itraconazole group and 7 episodes (16%) in the control group proceeded to intravenous amphotericin B (P > 0.05). Fungal infections occurred in 9 episodes (17%) in the itraconazole group and in 5 episodes (12%) in the control group (P > 0.05). Overall mortality was five deaths in the itraconazole group and two in the control group. These deaths were not due to clinically documented fungal infection. In our study, efficacy of itraconazole in the prophylaxis of fungal infections in neutropenic patients was not detected. Received: March 25, 2002 / Accepted: October 1, 2002     

Itraconazole versus amphotericin B plus nystatin in the prophylaxis of fungal infections in neutropenic cancer patients.

The efficacy and safety of itraconazole oral solution and a combination of amphotericin B capsules plus nystatin oral suspension were compared in the prophylaxis of fungal infections in neutropenic patients. In an open, randomized, multicentre trial, 144 patients received itraconazole oral solution 100 mg bd, and 133 patients received amphotericin B 500 mg tds plus nystatin 2 MU qds. Overall, 65% of itraconazole-treated patients were considered to have had successful prophylaxis, compared with 53% in the polyene group. Proven deep fungal infections occurred in 5% of patients in each group. Fewer patients receiving itraconazole than amphotericin plus nystatin had superficial infections (3 versus 8%; P = 0.066). This trend in favour of itraconazole was seen in patients with profound neutropenia (neutrophil count <0.1 x 10(9) cells/L at least once) or prolonged neutropenia (neutrophil count <1.0 x 10(9) cells/L for >14 days). The median time to prophylactic failure was longer in the itraconazole group (37 days) than in the polyene group (34 days). The number of patients with fungal colonization (nose, sputum, stool) changed more favourably from baseline to endpoint in the itraconazole group than in the polyene group. Both treatments were safe and well tolerated; however, patients receiving amphotericin plus nystatin had a higher incidence of nausea and rash. In conclusion, itraconazole oral solution at doses of 100 mg bd and oral amphotericin B plus nystatin have similar prophylactic efficacy against fungal infections in neutropenic patients. On the basis of reduced incidence of superficial fungal infections, fungal colonization and specific adverse events, itraconazole may be the preferred treatment.     

Impact of fluconazole prophylaxis on fungal colonization and infection rates in neutropenic patients. The Canadian Fluconazole Study

Fungal colonization profiles from four different anatomical sites were evaluated in 266 neutropenic cancer patients receiving intensive cytotoxic therapy for acute leukaemia or for autologous marrow transplantation. At the beginning of chemotherapy patients were allocated randomly to receive oral fluconazole 400 mg daily or an identical placebo until prophylaxis failure or marrow recovery. Candida albicans colonization was reduced from 30 to 10% in the fluconazole recipients while it increased from 32 to 57% in the placebo patients (P<0.001). By the end of prophylaxis, colonization with non-albicans Candida species increased from 7 to 21% and 8 to 18% in the fluconazole and placebo patients, respectively (P = 0.396). Although Candida glabrata was isolated more frequently at the end of the prophylactic period in the fluconazole patients than in the placebo patients (16 versus 7%), only one definite invasive C. glabrata infection was noted. Overall, definite invasive fungal infections were documented in 26 patients [four fluconazole versus 22 placebo patients (P< or =0.001)]. In 23 (92%) patients the infections were caused by persistently colonizing or newly acquired organisms. While probable invasive fungal infections were noted in five fluconazole patients, 10 placebo patients were also affected (P = 0.19). An end-of-prophylaxis colonization index >0.25 was 76% sensitive but only 69% specific for invasive fungal infection. However, a colonization index < or =0.25 at baseline had a negative predictive value of 88% for development of invasive fungal infection. Fluconazole prophylaxis decreased colonization by fungi and subsequent invasive fungal infections in neutropenic cancer patients.     

伊曲康唑治疗血液系统恶性肿瘤伴发真菌感染临床观察

目的观察伊曲康唑治疗血液系统恶性肿瘤患者伴发真菌感染的效果。方法选择我院2004年2月至2009年6月收治的恶性血液病合并侵袭性真菌感染患者(IFI)31例并分为两组,A组17例,予伊曲康唑注射液静脉注射2 d后改口服液续贯治疗,B组14例,予伊曲康唑注射液静脉注射14 d后改口服液续贯治疗。结果A组与B组IFI患者有效率分别为64.7%和64.3%。结论恶性血液病合并侵袭性真菌感染者应用改良伊曲康唑方案治疗有效,节约了医疗费用,其抗感染疗效与免疫力恢复速度密切相关。     

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 among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents

Invasive candidiasis and invasive mold infections cause significant morbidity and mortality in the hematopoietic stem cell transplant population, in particular in recipients of allografts. The introduction of a variety of new antifungal compounds over the past decade has focused attention on prophylactic strategies as a means to decrease the burden of invasive fungal infections (IFIs). Until recently, fluconazole has been the standard agent for prophylaxis before and after engraftment. In 2005, the echinocandin micafungin received US FDA approval for prophylaxis against IFIs in stem cell transplant recipients during the neutropenic period prior to engraftment. In patients with substantial risk for invasive mold infection, many centers now use a mold-active antifungal agent (e.g., a triazole such as itraconazole, voriconazole or posaconazole, or an echinocandin) as prophylaxis after engraftment. Several recent studies have highlighted the efficacy of these newer agents in preventing IFIs in these highly immunocompromised patients. This review will discuss current issues in IFI and new agents available for prophylaxis in allogeneic hematopoietic stem cell transplant recipients.     

Antifungal prophylaxis among allogeneic hematopoietic stem cell transplant recipients: current issues and new agents

Invasive candidiasis and invasive mold infections cause significant morbidity and mortality in the hematopoietic stem cell transplant population, in particular in recipients of allografts. The introduction of a variety of new antifungal compounds over the past decade has focused attention on prophylactic strategies as a means to decrease the burden of invasive fungal infections (IFIs). Until recently, fluconazole has been the standard agent for prophylaxis before and after engraftment. In 2005, the echinocandin micafungin received US FDA approval for prophylaxis against IFIs in stem cell transplant recipients during the neutropenic period prior to engraftment. In patients with substantial risk for invasive mold infection, many centers now use a mold-active antifungal agent (e.g., a triazole such as itraconazole, voriconazole or posaconazole, or an echinocandin) as prophylaxis after engraftment. Several recent studies have highlighted the efficacy of these newer agents in preventing IFIs in these highly immunocompromised patients. This review will discuss current issues in IFI and new agents available for prophylaxis in allogeneic hematopoietic stem cell transplant recipients.     

伊曲康唑联合重组人粒细胞集落刺激因子治疗中性粒细胞减少的血液病患者侵袭性真菌感染的疗效及安全性评价

目的 评价伊曲康唑联合重组人粒细胞集落刺激因子（rhG-CSF）治疗中性粒细胞减少的血液病患者合并侵袭性真菌感染的临床疗效及安全性.方法 回顾性分析2007年1月至2011年12月收治的103例血液病合并真菌感染的患者,治疗期间72例患者出现粒细胞缺乏,其中44例患者应用伊曲康唑联合rhG-CSF治疗（治疗组）,28例患者单独应用伊曲康唑治疗（对照组）.结果 治疗组患者有效率为72.73％,对照组为46.43％（P＜0.05）;中性粒细胞≤500/mm3且≥100/mm3的患者抗真菌治疗有效率明显高于中性粒细胞≤100/mm3的患者（P＜0.05）;粒缺持续时间≤10 d的抗真菌治疗有效率明显低于粒缺持续时间＜10 d的患者（P ＜0.05）;72例患者中确诊9例、临床诊断33例、拟诊30例;确诊组有效率低于临床诊断与拟诊组（P＜0.05）,抢先性治疗组（87.50％）和经验性治疗组（64.00％）的有效率均明显高于目标性治疗组（34.78％）,差异有统计学意义（P均＜0.05）.结论 伊曲康唑联合rhG-CSF治疗中性粒细胞减少的血液病患者真菌感染是有效安全的;中性粒细胞减少的程度和时间是影响真菌治疗效果的重要因素.     

Strategies for managing systemic fungal infection and the place of itraconazole

Systemic fungal infections are an increasing cause of mortality and morbidity in patients with haematological malignancies and certain other conditions associated with profound immunosuppression. The majority of such infections are caused by Aspergillus and Candida species. In recent years, the number of available drugs effective in the therapy of these difficult infections has expanded. Large clinical trials have been performed in different settings such as prophylaxis, empirical and first-line therapy. For prophylaxis, the azoles fluconazole and itraconazole have been most widely studied. These azoles are available in both oral and intravenous formulations. Itraconazole has a wide spectrum of activity including Aspergillus, Candida albicans and non-albicans species. Two large studies comparing the use of itraconazole with fluconazole for primary prophylaxis in high-risk patients who were recipients of allogeneic stem cell transplants have recently been reported. These have confirmed that itraconazole is effective in this setting in reducing the rate of systemic fungal infections. However, there are concerns with regard to increased toxicity and the potential for drug interactions with itraconazole compared with fluconazole. In the empirical setting, large randomized studies support the use of caspofungin and liposomal amphotericin B. Voriconazole and lipid-associated amphotericin B have been shown to be effective in first-line therapy and caspofungin for salvage. New approaches to management include efforts at improving diagnosis, combination antifungal therapy and treatment strategies for emerging moulds.     

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.     

Network Meta-analysis and Pharmacoeconomic Evaluation of Fluconazole,Itraconazole, Posaconazole,and Voriconazole in Invasive Fungal Infection Prophylaxis

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting.     

Posaconazole versus fluconazole or itraconazole for prevention of invasive fungal infections in patients undergoing intensive cytotoxic therapy for acute myeloid leukemia or myelodysplasia: a cost effectiveness analysis

Introduction  

Invasive fungal infections (IFI) remain a clinical concern in hematological patients with prolonged neutropenia because they are a major cause of morbidity and mortality. In a recent randomized trial, prophylaxis with posaconazole was associated with fewer IFI and related deaths relative to a fluconazole or itraconazole (Flu/Itra) control group (p < 0.001). In the current study, a cost effectiveness analysis was conducted to estimate the economic value of posaconazole as an alternative to Flu/Itra when used to prevent IFI in this patient population.     

Efficacy of recombinant human granulocyte-colony stimulating factor alone and in combination with antifungal agents against disseminated trichosporonosis in neutropenic mice

The ability of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to protect and potentiate the activity of antifungal agents against a lethalTrichosporon beigelii infection in myelosuppressed mice was evaluated in this study. Mice were rendered neutropenic by 2 consecutive-day intraperitoneal injections of cyclophosphamide (200 mg/kg). Recombinant hG-CSF, given subcutaneously at daily doses of 15, 60, and 120 μg/kg for 6 days, shortened the period of neutropenia and increased the number of circulating neutrophils in a dose-dependent manner. When rhG-CSF was administered to neutropenic mice before challenge withT. beigelii (5×10⁶ CFU), it protected against the lethal infection, resulting in improved survival and decreased numbers of fungal cells in the lung, liver, spleen and kidney. However, when the inoculum size increased to 7×10⁶ CFU, a poorer result was obtained using a dose of 60 μg/kg of rhG-CSF, suggesting that the activity of rhG-CSF is dependent on the severity of theT. beigelii infection. Combined with fluconazole (10 mg/kg) or amphotericin B (1 mg/kg), rhG-CSF improved the median survival time from 16 days with fluconazole (59%) and 12 days with amphotericin B (41%) alone to 20 days (93%) and 16 days (55%) in neutropenic mice treated with rhG-CSF plus fluconazole or amphotericin B, respectively. However, the combination of rhG-CSF and itraconazole did not produce significant improvement in survival or clearance of fungal cells from the organs of neutropenic mice. These findings show that rhG-CSF may be a useful immunomodulator againstTrichosporon infections in neutropenic mice and the therapeutic outcome improves when used in combination with fluconazole or amphotericin B.     

Urine D-arabinitol/L-arabinitol ratio in diagnosing Candida infection in patients with haematological malignancy and HIV infection

Adult patients with hematologic malignancies along with HIV infected patients were prospectively studied to determine the performance of urine D-arabinitol/L-arabinitol (DA/LA) ratio in diagnosing invasive candidiasis. Ten evaluable febrile neutropenic patients had proven invasive candidiasis and elevated DA/LA ratios were found in 5. Invasive candidiasis with normal DA/LA ratios was most frequently due to Candida krusei infection. This Candida species is a non-producer of arabinitol. Only 4 of 81 febrile neutropenic patients given either antifungal prophylaxis or empiric antifungal treatment had elevated DA/LA ratios. Only 1 of 15 HIV positive patients with either oropharyngeal or esophageal candidiasis had elevated DA/LA ratios. Widespread use of fluconazole prophylaxis in bone marrow transplantation patients at the study hospital has led to an increased prevalence of C. krusei infection. This is the likely reason for the low sensitivity of the test in proven and suspected invasive Candida infections reported here.     

Posaconazole: a new antifungal weapon

The last twenty years, the incidence of invasive fungal infections (IFI) has risen dramatically due to the prolongation of survival of patients with multiple risk factors for fungal infections. Amphotericin B was for more than 40 years the gold standard for almost all IFI, but toxicity and resistance, especially of new and emerging pathogens remained important issues. Fluconazole and itraconazole have also the same disadvantage of resistance. Voriconazole, a new triazole antifungal has offered an additional option, but the problem of resistant aspergillosis, and zygomycosis remains. Echinocandins (caspofungin, micafungin and anidulafungin) are active only against Candida and Aspergillus spp., but not against Fusarium, Scedosporium and Zygomycetes. Posaconazole is the most recently approved triazole with broad spectrum activity against Candida spp., Aspergillus spp., Cryptococcus neoformans, Zygomycetes, dermatiaceous, dimorphic, and other fungal pathogens. Interestingly, posaconazole is active against Candida spp., resistant to fluconazole and itraconazole, and Aspergillus fumigatus resistant to fluconazole itraconazole, amphotericin B, and voriconazole. The results from clinical trials of posaconazole as salvage treatment are encouraging. Multicenter clinical trials have also established its role in the prophylaxis of (IFI) in the severely immunocompromised patients such as those after hematopoietic stem cell transplantation (HSCT) who developed graft versus host disease (GVHD), as well as the neutropenic patients with an acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after myeloablative chemotherapy. Posaconazole has pharmacokinetic advantages and low side effect profile, which are very important, especially in the seriously ill population.     

氟康唑预防血液病患者真菌感染的疗效分析

目的评价接受大剂量化疗和自体造血干细胞移植（HSCT）患者氟康唑200~400 mg口服或静脉预防真菌感染的疗效。方法总结2008至2009年上海市瑞金医院骨髓移植病区35例血液恶性疾病患者42例次大剂量化疗和自体HSCT,采用氟康唑200-400 mg口服或静脉预防真菌感染直至粒细胞缺乏得以恢复,所有粒细胞缺乏伴发热的患者均接受广谱抗菌药物治疗,结合高分辨计算机断层扫描（CT）和真菌病原学检测即曲霉半乳甘露聚糖（GM）抗原和1-3-β-D葡聚糖（BDG）抗原的检测结果,调整、指导临床的抗真菌治疗。结果本试验入组患者的外周血白细胞（WBC）计数谷值的中位数为0.1×10^9/L[（0.1-0.5）×10^9/L]。粒细胞缺乏（中性粒细胞〈0.5×10^9/L）持续时间的中位数为9 d（2-21 d）,大剂量化疗组和自体HSCT组间差异无统计学意义（P=0.36）。6例次（14.3%）从未出现粒细胞缺乏伴发热事件,36例次（85.7%）出现了粒细胞缺乏伴发热事件,发热持续时间的中位数为4.5 d（1-13 d）,大剂量化疗组和自体HSCT组患者中粒细胞缺乏伴发热的发生率差异无统计学意义（P=0.38）。其中7例虽经广谱抗菌药物经验性治疗,但仍持续发热7 d以上,GM/BDG试验动态观察和胸部CT扫描,尚无1例达到侵袭性真菌感染（IFI）的临床诊断和确诊标准。总共只有3例接受经验性广谱抗真菌的治疗,占粒细胞缺乏伴发热患者的8.3%。结论对于接受阿糖胞苷为主的大剂量化疗和自体HSCT的血液恶性疾病患者,与接受异体HSCT治疗患者不同,其曲霉感染的风险相对比较低。因此应用氟康唑作预防治疗即可达到满意的预防真菌感染疗效,无需应用广谱抗真菌药物进行预防治疗。     

High prevalence of non-albicans yeasts and detection of anti-fungal resistance in the oral flora of patients with advanced cancer

Oral fungal infections frequently develop in individuals with advanced cancer. This study examined the oral mycological flora of 207 patients receiving palliative care for advanced malignant disease. Demographic details and a clinical history were documented from each participant. A tongue swab was collected and cultured on CHROMAgar Candida (CHROMAgar Paris, France). All yeasts were identified by germ tube test, API ID 32C profiles and, for Candida dubliniensis, by species-specific PCR. Susceptibility to fluconazole and itraconazole was determined by a broth microdilution assay according to the National Committee for Clinical Laboratory Standards (NCCLS). At time of sampling, 54 (26%) of the 207 subjects had clinical evidence of a fungal infection and yeasts were isolated from 139 (67%) individuals. In total, 194 yeasts were isolated, of which 95 (49%) were Candida albicans. There was a high prevalence of Candidia glabrata (47 isolates) of which 34 (72%) were resistant to both fluconazole and itraconazole. All nine isolates of C. dubliniensis recovered were susceptible to both azoles. No relationship was established between anti-fungal usage in the preceding three months and the presence of azole resistant yeasts. This study of patients with advanced cancer has demonstrated a high incidence of oral colonization with non-C. albicans yeasts, many of which had reduced susceptibility to fluconazole and itraconazole. The role of improved oral care regimes and novel anti-fungal drugs merits further attention, to reduce the occurrence of fungal infection in these patients.     

Effects of fluconazole on viable cell count in experimental intraperitoneal Candida abscesses

We investigated the effects of fluconazole in experimental intraperitoneal Candida abscesses in neutropenic mice treated with cyclophosphamide to assess a clinically appropriate method for the application of fluconazole in fungal infections in patients with neutropenia. The efficacy of fluconazole in fungal infection was investigated in treatments started immediately after Candida albicans inoculation and before C. albicans inoculation (preventive use of fluconazole). In this intraabdominal fungal abscess model, it was confirmed that fungi in already formed abscess were not reduced in number by fluconazole, even when those fungi were susceptible to fluconazole. Fluconazole was effective with both administration methods. We conclude from this study that the effect of the preventive use of fluconazole was equivalent to the effect when treatment was started immediately after fungal inoculation. Received: May 6, 1999 / Accepted: April 26, 2000     

G-CSF mobilised granulocyte transfusions in 32 paediatric patients with neutropenic sepsis

Introduction In this retrospective, uncontrolled, observational study, the effect of granulocyte colony-stimulating factor (G-CSF)-stimulated granulocyte transfusions (GTX) in neutropenic paediatric patients with sepsis was evaluated.Patients and methods Granulocytes were collected from unrelated, ABO group-matched and cytomegalic-antibody compatible donors. For neutrophil mobilization, donors received a single subcutaneous dose of glycosylated G-CSF (Lenograstim, Chugai Pharma, Japan) plus oral dexamethasone (8 mg). In total, 168 (range 1–19 per patient) GTX were transfused in 32 children with a median age of 7.4 (0.25 to 16) years.Results The underlying diseases comprised predominantly haematooncological malignancies (31 children). In 15 of 32 patients, neutropenia was related to allogeneic stem cell transplantation. All children suffered from sepsis based on international criteria (fever, tachycardia, respiratory rate >2 SD above normal in the context of a suspected or proven infection). In ten children bacteria were isolated, in six children a fungal infection was diagnosed and four sepsis episodes were caused by viral infections. GTX contained a median neutrophil number of 6.3 (range 1.9–13.9)×10¹⁰ per transfusion and obtained a sustained haematological response after GTX. Nineteen out of 32 children survived the neutropenic sepsis, particularly nine out of 11 patients with bacterial sepsis.Discussion In contrast to the non-survivors, we observed a significant decrease in the C-reactive protein levels shortly after initiation of the GTX treatment in the surviving patients. A clear-cut benefit of GTX for children with neutropenic sepsis cannot be concluded from these data, but in children with (severe) bacterial sepsis refractory to antibiotic treatment, GTX were feasible, safe and could reduce mortality rates in this subgroup of patients.