Comparison of micafungin and voriconazole in the treatment of invasive fungal infections in kidney transplant recipients

What is known and Objective: Invasive fungal infections are a major threat to renal transplant recipients. Micafungin and voriconazole are two useful antifungal agents for treating such infections. Our objective is to evaluate the comparative efficacy and safety of micafungin and voriconazole in the initial treatment of such infections. Methods: In this prospective, multicentre, open‐labelled, randomized, controlled trial, renal transplant recipients with invasive fungal infections were assigned to receive either micafungin or voriconazole. The enrolled subjects received a kidney transplant between March 2008 and March 2010 at one of the two transplant centres in Henan Province, China. The efficacy and adverse effects of the two treatments were compared. Results and Discussion: The clinical trial enrolled 65 patients, of whom 31 were treated with micafungin, and 34 with voriconazole. The rates of microbiological evidence of infection in the micafungin and voriconazole groups were 64·5% and 70·5%, respectively, whereas the rates of Candida as the major cultured fungus were 80·0% and 75·0%, respectively. Complicated bacterial infection rates in the two treatment groups were 38·7% and 32·4%, respectively, whereas complicated CMV viral infection occurred at a rate of 19·2% and 23·5%, respectively. Fungal infection within one to 3 months after transplant was 83·6% (26/31) and 85·3% (29/34) in the micafungin and voriconazole groups, respectively. There was no significant difference between the two groups in terms of efficacy, survival beyond 10 days and discontinuation of treatment because of lack of efficacy (P > 0·05). Mortality rates in the micafungin and voriconazole groups were 9·7% (3/31) and 12·1% (4/33), respectively. Rates of adverse effects in the two groups were 41·9% and 51·6% (P > 0·05), respectively. What is new and Conclusions: This is the first comparison of micafungin and voriconazole in renal transplant patients. Our study shows that the effectiveness of micafungin was similar to that of voriconazole in such patients.     

Uptake and efflux kinetics,and intracellular activity of voriconazole against Aspergillus fumigatus in human pulmonary epithelial cells: a new application for the prophylaxis and early treatment of invasive pulmonary aspergillosis

Invasive pulmonary aspergillosis (IPA), most caused by Aspergillus fumigatus, is a serious life‐threatening infection in immunocompromised patients. Voriconazole is used to prevent and treat IPA. However, little is known about the pharmacological characteristics of voriconazole in pulmonary epithelial cells, which are the target site for the prophylaxis and early treatment of IPA. The aim of the study was to evaluate the kinetics and activity of voriconazole against A. fumigatus in A549 cells. High‐performance liquid chromatography/tandem mass spectrometry and time‐kill method were used to study the cellular pharmacokinetic and pharmacodynamics of voriconazole. Voriconazole exerted a concentration‐dependent toxic effect on A549 cells and could penetrate into cells, reaching plateau concentrations of 1.14 ± 0.64, 3.72 ± 1.38 and 6.36 ± 0.95 ng/mg protein after A549 cells were exposed to voriconazole at extracellular concentrations of 2, 8 and 16 mg/L for 2 h, respectively. The efflux of voriconazole was rapid, with a half‐life of 10.2 min. Voriconazole can decrease the A. fumigatus conidia invade cells, and the number of viable A. fumigatus conidia in cells can be decreased 2.1‐ to 20.6‐fold when A549 cells were cultured in medium containing voriconazole. After 24‐h incubation, 75.6% and 80.5% of intracellular A. fumigatus were killed when extracellular voriconazole concentration was 8 and 16 mg/L, respectively. This study illustrated a new application for the prophylaxis and early treatment of IPA from the cellular pharmacokinetics and pharmacodynamics and emphasized the importance of monitoring concentrations of voriconazole in epithelial lining fluid in immunocompromised patients receiving voriconazole therapy.     

Invasive pulmonary aspergillosis in patients with solid tumours: risk factors and predictors of clinical outcomes

Abstract

Background: The characteristics and management of invasive pulmonary aspergillosis (IPA) in patients with hematologic malignancies are well known, but IPA in patients with solid tumours is not well described.

Methods: We retrospectively reviewed all Aspergillus-positive cultures at a tertiary cancer center during 2004–2017. We identified 101 patients with IPA and solid tumours. We analyzed the association between clinical features and treatment and 12-week mortality and response to antifungal therapy.

Results: Fifty-one patients had lung cancer, 77 had underlying lung disease, 47 received chest radiation and 33 had chronic obstructive pulmonary disease. Aspergillus fumigatus was the most common type isolated (71%); 68 patients (70%) were treated with voriconazole monotherapy. Independent risk factors for 12-week mortality included receiving steroids within 30 days of diagnosis (hazard ratio 2.2, 95% confidence interval [CI]: 1.1–4.6; p?=?.03) and chest radiotherapy (hazard ratio 2.6, 95% CI: 1.2–5.5; p?=?.01). In multivariate analysis, a positive fungal stain was associated with lower odds of a successful response (odds ratio 0.2; 95% CI: 0.05–0.75; p?=?.02), whereas voriconazole treatment was associated with higher odds (odds ratio 10.1; 95% CI: 2.1–48.5; p?<?.01).

Conclusions: IPA should be considered in patients with solid tumours, particularly those with underlying lung disease.

• Key messages

• Invasive pulmonary aspergillosis should be considered in patients with solid tumours, particularly those with underlying lung disease, lung cancer and those who received chest radiotherapy.

• Most of the patients with invasive pulmonary aspergillosis and solid tumours presented with nonspecific symptoms and signs as well as nonspecific CT findings. Unlike patients with hematologic malignancies, fever and hemoptysis were not predominant symptoms and the classical halo sign and the air-crescent sign were not described.

• Independent risk factors for 12-week mortality included receiving steroids within 30 days of diagnosis and chest radiotherapy. In multivariate analysis, a positive fungal stain was associated with lower odds of a successful response to antifungal therapy, whereas voriconazole treatment was associated with higher odds.

     

Management of invasive pulmonary aspergillosis in non-neutropenic critically ill patients

During recent years, a rising incidence of invasive pulmonary aspergillosis (IPA) in non-neutropenic critically ill patients has been reported. Critically ill patients are prone to develop disturbances in immunoregulation during their stay in the ICU, which render them more vulnerable for fungal infections. Risk factors such as chronic obstructive pulmonary disease (COPD), prolonged use of steroids, advanced liver disease, chronic renal replacement therapy, near-drowning and diabetes mellitus have been described. Diagnosis of IPA may be difficult and obtaining histo- or cytopathological demonstration of the fungus in order to meet the gold standard for IPA is not always feasible in these patients. Laboratory markers used as a non-invasive diagnostic tool, such as the galactomannan antigen test (GM), 1,3-β-glucan, and Aspergillus PCR, show varying results. Antifungal therapy might be considered in patients with persistent pulmonary infection who exhibit risk factors together with positive cultures or sequentially positive GM and Aspergillus PCR in serum, in whom voriconazole is the drug of choice. The benefit of combination antifungal therapy lacks sufficient evidence so far, but this treatment might be considered in patients with breakthrough infections or refractory disease. This article is discussed in the editorial available at: .     

Economic evaluation of targeted treatments of invasive aspergillosis in adult haematopoietic stem cell transplant recipients in the Netherlands: a modelling approach

OBJECTIVES: The aim of this study was to assess the cost-effectiveness of a targeted treatment model of antifungal treatment strategies for adult haematopoietic stem cell transplant (HSCT) recipients in the Netherlands from a hospital perspective, using a decision analytic modelling approach. METHODS: The economic evaluation of desoxycholate amphotericin B, liposomal amphotericin B, voriconazole and caspofungin was undertaken. These drugs could be used alone, in various combinations or sequentially. In our model, first-line therapy consisted of either voriconazole or liposomal amphotericin B. If necessary, treatment was switched to a second-line treatment, including combination antifungal therapy. The theoretical population in this model consisted of adult HSCT recipients with proven or probable invasive aspergillosis (IA). Long-term survival was extrapolated from survival after 12 weeks of treatment and life expectancy. RESULTS: First-line antifungal treatment strategies with voriconazole were both more effective and less costly over first-line strategies employing liposomal amphotericin B at a dosage of 4 mg/kg/day. The strategy of voriconazole followed by caspofungin (voriconazole/caspofungin) was dominant over the strategies of voriconazole followed by liposomal amphotericin B (voriconazole/liposomal amphotericin B) or desoxycholate amphotericin B (voriconazole/desoxycholate amphotericin B). However, the voriconazole followed by the combination of liposomal amphotericin B and caspofungin strategy (voriconazole/liposomal amphotericin B+caspofungin) was more effective though more expensive than the voriconazole/caspofungin strategy resulting in an incremental cost-effectiveness ratio (ICER) of about euro107,000 for a life-year saved. At a dosage of 1 mg/kg/day of liposomal amphotericin B, the voriconazole/caspofungin strategy was more effective but more costly than the voriconazole/desoxycholate amphotericin B strategy with an ICER of euro10,000 for each extra life-year saved. Between the voriconazole/liposomal amphotericin B+caspofungin and the voriconazole/caspofungin strategies, the ICER was euro40,000. CONCLUSIONS: Probabilistic analyses on net monetary benefit showed that the voriconazole/caspofungin strategy had the highest probability of being the most cost-effective strategy.     

Interaction of the Echinocandin Caspofungin with Amphotericin B or Voriconazole against Aspergillus Biofilms In Vitro

Aspergillus biofilms were prepared from 22 strains of Aspergillus spp. via a 96-well plate-based method. Using a broth microdilution checkerboard technique with the XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] colorimetric assay, we demonstrated a synergistic antifungal activity against 18 of 22 Aspergillus biofilm strains with a combination of caspofungin and amphotericin B and against 13 of 22 strains with a combination of caspofungin and voriconazole. We did not observe antagonism.     

Outcomes of mechanically ventilated hematology patients with invasive pulmonary aspergillosis

Background

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection documented in up to 15% of hematology patients who require intensive care for acute respiratory failure. We report outcomes in hematology patients given mechanical ventilation (MV) with IPA.

Methods

Retrospective study of all hematology patients given MV with IPA between January 1998 and March 2011 at a single center. Predictors of 6-month survival or mortality were identified using multivariable analysis.

Results

We studied 67 patients including 49 (73%) with neutropenia, 23 (34%) with long-term steroid therapy, and 14 (21%) with allogeneic bone marrow transplantation. Incidence of IPA in the ICU decreased between 1998 and 2011, and mortality in patients receiving mechanical ventilation did not change. IPA was confirmed in 6 patients by autopsy and was probable in 61 patients based on host factors, clinical and radiographic features, and either Aspergillus isolation (50 patients) or Aspergillus antigen detection alone (11 patients). Concomitant bacterial infections were documented in 24 (36%) patients. ICU and 6-month mortality rates were 67 and 82%, respectively. Mortality was stable throughout the study period. Concomitant bacterial infection was independently associated with higher mortality [HR, 2.1 (1.2?C3.8)]. Mortality was lower in patients given voriconazole [OR, 0.5 (0.3?C0.9)].

Conclusion

Hospital mortality remains high in hematology patients requiring MV with IPA, particularly when concommittant infection occurred. The use of voriconazole improved survival.     

Efficacy of the Investigational Echinocandin ASP9726 in a Guinea Pig Model of Invasive Pulmonary Aspergillosis

ASP9726 is an investigational echinocandin with in vitro activity against Aspergillus species. We evaluated the pharmacokinetics and efficacy of this agent in an established guinea pig model of invasive pulmonary aspergillosis. ASP9726 plasma concentrations were measured in guinea pigs administered either a single dose or multiple doses of this agent at 2.5, 5, and 10 mg/kg of body weight/day by subcutaneous injection. Immunosuppressed guinea pigs were inoculated with A. fumigatus AF293, and ASP9726 (2.5, 5, and 10 mg/kg/day), voriconazole (10 mg/kg by oral gavage twice daily), or caspofungin (3 mg/kg/day by intraperitoneal injection) was administered for 8 days. Changes in fungal burden were measured by enumerating CFU and by quantitative PCR of specimens from within the lungs, as well as by analysis of serum (1→3)-β-d-glucan and galactomannan. Lung histopathology was also evaluated. ASP9726 plasma concentrations increased in a dose-proportional manner, and the drug was well tolerated at each dose. Each dose of ASP9726, voriconazole, and caspofungin significantly reduced pulmonary fungal burden as measured by quantitative PCR and by determining (1→3)-β-d-glucan and galactomannan levels, but only voriconazole significantly reduced numbers of CFU. ASP9726 at 5 mg/kg also significantly improved survival. Histopathology demonstrated morphological changes in hyphae in animals exposed to ASP9726 and caspofungin, consistent with the activities of the echinocandins. These results suggest that ASP9726 may be efficacious for the treatment of invasive pulmonary aspergillosis.     

Effect of plasma uric acid on pharmacokinetics of cyclosporine A in living‐related renal transplant recipients and pharmacokinetic study in rats with experimental hyperuricaemia

Objectives: Renal transplant recipients are thought to have an increased risk of hyperuricaemia (HU); therefore, the effects of plasma uric acid (UA) on the pharmacokinetics (PK) of cyclosporine A (CyA), an immunosuppressant, in renal transplant recipients and experimental animals were investigated. Methods: An open‐label, non‐randomized, retrospective study was performed in renal transplant recipients. Data from 76 subjects who received a renal transplantation with CyA medication were included. We compared the PK of CyA of recipients showing a high UA level with the other recipients. In addition, PK studies were performed using hyperuricaemic‐model rats (HU rats) prepared by subcutaneous injection of the uricase inhibitor, potassium oxonate and intraperitoneal injection of UA. Results: The area under the blood concentration vs. time curve (AUC) up to 9 h, the blood level at 2 h after dose and peak level in high UA recipients (UA > 7·0 mg/dL) was significantly lower (about 10–16%) than that in the other recipients, although there were no differences in dose, and the trough blood level. On the contrary, there were no differences in PK parameters after intravenous administration of CyA between HU and control rats; however, AUC, peak level and bioavailability in HU rats (2·01 ± 0·56 μg h/mL, 0·47 ± 0·26 μg/mL and 0·186 ± 0·05, respectively) after oral administration were significantly lower than in the control animals (6·13 ± 0·97 μg h/mL, 0·82 ± 0·17 μg/mL and 0·458 ± 0·07 μg/mL, respectively). In addition, the absorptions of CyA and midazolam, an ideal probe for CYP3A, from the intestinal loop in HU rats were significantly less (about 50% and 37%, respectively) than in the controls. Conclusions: The absorption of CyA was affected by plasma UA in transplant recipients and experimental rats. The contribution of intestinal metabolism by CYP3A to decreasing CyA absorption in HU rats was significant. These results suggest that transplant recipients with high UA may have poor absorption of CyA.     

Efficacy of caspofungin and voriconazole combinations in experimental aspergillosis

Guinea pigs were infected with Aspergillus fumigatus at two challenge doses and treated for 7 days with a placebo, intraperitoneal caspofungin (1 mg/kg daily), oral voriconazole (1 mg/kg twice a day), or a combination of the caspofungin and voriconazole treatments. The combination therapy statistically significantly prolonged survival over that with the control at both challenge doses and achieved a statistically significant reduction in kidney burdens as measured by quantitative PCR. The same was true for animals given caspofungin alone at both levels of challenge and for animals treated with voriconazole alone at the lower challenge dose. However, the effects of combination therapy on prolongation of survival were greater than those of either monotherapy at both challenge doses, and the reduction in kidney burdens with combination therapy was significantly greater than that with caspofungin alone in the animals given the lower challenge dose. No synergistic interactive effects were seen for the two agents in checkerboard titration experiments in vitro. We conclude that therapy of experimental aspergillosis with caspofungin and voriconazole combined offers slight additional improvements in efficacy rather than effects of a clearly synergistic nature.     

Invasive pulmonary aspergillosis due to Aspergillus lentulus in an adult patient: A case report and literature review

Aspergillus fumigatus is the commonest cause of pulmonary aspergillosis; however, a recently developed molecular genetic technique identified A. lentulus as a sibling species. Most of the isolates were found in solid organ recipients, often associated with a fatal outcome. Moreover, there is concern that A. lentulus has low susceptibility to multiple antifungal agents. Herein, we report an adult immunocompromised patient with proven invasive pulmonary aspergillosis (IPA) caused by A. lentulus, which was identified through molecular genetic analysis. The patient was diagnosed with IPA by bronchoscopy 3 weeks after initiating systemic corticosteroid therapy for anti-neutrophil cytoplasmic antibody-associated vasculitis. The clinical course of IPA due to A. lentulus showed improvement after treatment with the antifungal agent voriconazole. In summary, we report an adult immunocompromised patient without a history of transplantation who was diagnosed with IPA due to A. lentulus successfully treated with voriconazole, and we also report the findings of a literature review on IPA caused by A. lentulus.     

Concentration-dependent synergy and antagonism within a triple antifungal drug combination against Aspergillus species: analysis by a new response surface model

Triple antifungal combinations are used against refractory invasive aspergillosis without an adequate understanding of their pharmacodynamic interactions. We initially studied the in vitro triple combination of voriconazole, amphotericin B, and caspofungin against Aspergillus fumigatus, A. flavus, and A. terreus by a spectrophotometric microdilution broth method after 48 h of incubation. We then analyzed these results with a recently described nonlinear mixture response surface E(max)-based model modified to assess pharmacodynamic interactions at various growth levels. The new model allows flexibility in all four parameters of the E(max) model and is able to describe complex pharmacodynamic interactions. Concentration-dependent pharmacodynamic interactions were found within the triple antifungal combination. At the 50% growth level, synergy (median interaction indices of 0.43 to 0.82) was observed at low concentrations of voriconazole (<0.03 mg/liter) and amphotericin B (相似文献   

Characterization of Aspergillus spp. isolated from patients with coronavirus disease 2019

IntroductionInvasive pulmonary aspergillosis (IPA) is an important complication of coronavirus disease 2019 (COVID-19), and while there are case reports and epidemiological studies, few studies have isolated Aspergillus strains from patients. Therefore, we analyzed the strains, sensitivities, and genetic homology of Aspergillus spp. Isolated from patients with COVID-19.MethodsWe investigated the Aspergillus strains detected from patients with COVID-19 hospitalized in Osaka Metropolitan University Hospital from December 2020 to June 2021. A molecular epidemiological analysis of Aspergillus spp. was performed using drug susceptibility tests and TRESPERG typing, and data on patient characteristics were collected from electronic medical records.ResultsTwelve strains of Aspergillus were detected in 11 of the 122 patients (9%) with COVID-19. A. fumigatus was the most common species detected, followed by one strain each of Aspergillus aureolus, Aspergillus nidulans, Aspergillus niger, and Aspergillus terreus. A. aureolus was resistant to voriconazole, and no resistance was found in other strains. All A. fumigatus strains were genetically distinct strains. Six of the 11 patients that harbored Aspergillus received antifungal drug treatment and tested positive for β-D-glucan and/or Aspergillus galactomannan antigen. The results indicated that Aspergillus infections were acquired from outside the hospital and not from nosocomial infections.ConclusionStrict surveillance of Aspergillus spp. is beneficial in patients at high-risk for IPA. When Aspergillus is detected, it is important to monitor the onset of IPA carefully and identify the strain, perform drug sensitivity tests, and facilitate early administration of therapeutic agents to patients with IPA.     

Treatment of severe neutropenic sepsis with granulocyte transfusion in the current era – experience from an adult haematology unit in Singapore

Objectives: Granulocyte transfusion's (GT) efficacy among adult severe neutropenic sepsis (SNS) patients remains uncertain. We assessed GT's efficacy and its determinants among SNS patients in an adult haematology unit. The feasibility and safety of granulocyte donation (GD) and determinants of granulocyte yield were also evaluated. Methods: Retrospective analysis of granulocyte donors and recipients from March 2008 to October 2009. Results: Donors: Sixty GDs with a median WBC yield (WBCY) of 65·49 (31·30–131·72) × 10⁹ were collected from 48 donors (9 repeat donors) using hydroxyethyl starch and intermittent flow centrifugation aphaeresis after receiving 8 mg dexamethasone and 300 mcg granulocyte colony‐stimulating factor, with no serious adverse reactions (SAR). Six donations were urgently collected <3 h after pre‐medication, the median WBCY of which was not significantly different from donations collected >12 h after pre‐medication [59·18 (45·68–62·90) × 10⁹ vs 67·45 (31·30–131·72) × 10⁹, P = 0·140]. Only pre‐GD absolute neutrophil count (ANC) correlated with WBCY. Patients: Fifteen patients (12 acute leukaemias, 1 severe AA, 1 myelodysplastic syndrome and 1 lymphoma) received median 3 (2–9) ABO/RhD‐matched GTs over 2–24 (median 7) days at 3–61 (median 28) days from severe neutropenia (SN) onset without SAR. They received intensive chemotherapies (N = 9), allogeneic transplant (N = 3), autologous stem cell rescue (N = 1) or immunosuppressants (N = 2). Fourteen had bacterial (N = 1) infections, fungal (N = 3) infections or both (N = 10) and one had severe viral pneumonitis; 63·6 and 30·8% of bacterial and fungal infections responded, respectively. Median ANC increase (ANC_increase) was 1·26 (0–9·25) × 10⁹ at 5–20 (median 11) h post‐GT. On multivariate analysis, each patient's median ANC_increase only significantly correlated positively with median WBC dose/kg (P = 0·013). Five (33·3%) patients survived to discharge; the rest had infection‐related mortality (IRM). IRM was significantly associated with inotropic requirement (P = 0·004), ventilatory requirement (P = 0·017) and persistent SN (P = 0·007). Conclusion: GD is safe and feasible with good WBCY obtainable using our protocol. The effect of shortening pre‐medication interval on WBCY which may prevent delay in initiating GT is worth evaluating. GT most likely benefits SNS patients with prospects of neutrophil recovery before haemodynamic deterioration. Large randomised trials investigating the role and timing of GT among such patients are required.     

Bronchopulmonary Disposition of Intravenous Voriconazole and Anidulafungin Given in Combination to Healthy Adults

Voriconazole and anidulafungin in combination are being investigated for use for the treatment of pulmonary aspergillosis. We determined the pulmonary disposition of these agents. Twenty healthy participants received intravenous voriconazole (at 6 mg/kg of body weight every 12 h [q12h] on day 1 and then at 4 mg/kg q12h) and anidulafungin (200 mg on day 1 and then 100 mg every 24 h) for 3 days. Five participants each were randomized for collection of bronchoalveolar lavage samples at times of 4, 8, 12, and 24 h. Drug penetration was determined by the ratio of the total drug area under the concentration-time curve during the dosing interval (AUC_0-τ) for epithelial lining fluid (ELF) and alveolar macrophages (AM) to the total drug AUC_0-τ in plasma. The mean (standard deviation) half-life and AUC_0-τ were 6.9 (2.1) h and 39.5 (19.8) μg·h/ml, respectively, for voriconazole and 20.8 (3.1) h and 101 (21.8) μg·h/ml, respectively, for anidulafungin. The AUC_0-τ values for ELF and AM were 282 and 178 μg·h/ml, respectively, for voriconazole, and 21.9 and 1,430 μg·h/ml, respectively, for anidulafungin. This resulted in penetration ratios into ELF and AM of 7.1 and 4.5, respectively, for voriconazole and 0.22 and 14.2, respectively, for anidulafungin. The mean total concentrations of both drugs in ELF and AM at 4, 8, 12, and 24 h remained above the MIC₉₀/90% minimum effective concentration for most Aspergillus species. In healthy adult volunteers, voriconazole achieved high levels of exposure in both ELF and AM, while anidulafungin predominantly concentrated in AM.Over the last few decades, the incidence of infections caused by Aspergillus spp. has steadily increased (17, 27). This increase parallels the rise in the numbers of immunocompromised patients who have been seen. Given the vulnerability of this patient population, Aspergillus infections cause a considerable number of deaths. The reported mortality rate for pulmonary aspergillosis, the most common presentation, ranges from 60 to 86% (9, 17).Recent clinical practice guidelines recommend the use of voriconazole as the first-line therapy for patients with pulmonary aspergillosis (29). This recommendation stems from the predictable in vitro activity of voriconazole, coupled with its proven clinical efficacy in a randomized control trial (12, 18). The same guidelines note the potential utility of monotherapy or combination therapy with antifungal agents of different classes in patients whose infections are refractory to primary treatment. Secondary to their potent in vitro activity, unique mechanism of action, and favorable side effect profile, the echinocandin class of antifungals has become a popular option for combination therapy with voriconazole or polyenes. While at present caspofungin is the only echinocandin approved for use for the treatment of invasive aspergillosis (29), clinical trials with anidulafungin plus voriconazole are currently under way (see http://clinicaltrials.gov/).Given that pulmonary aspergillosis is the most common presentation of invasive Aspergillus infections, it is important to understand the bronchopulmonary disposition of these agents. While a previously conducted pilot study shed at least some light on the penetration of voriconazole (5), no data exist for anidulafungin or a combination of anidulafungin and voriconazole. The purpose of this study was to characterize the pulmonary disposition of intravenous (i.v.) voriconazole and anidulafungin when they were given in combination to healthy adult volunteers.     

造血干细胞移植后侵袭性肺曲霉病患者12例的肺功能改变

目的观察12例造血干细胞移植(HSCT)后并发侵袭性肺曲霉病(IPA)对患者肺功能参数及动脉血气的影响。方法 2007年2月~2009年10月本院接受HSCT后并发IPA患者12例,男8例,女4例,中位年龄34岁(26~67岁)。移植前后均行肺功能测试、动脉血气分析以及影像学检查。结果中位随访时间为132 d(97~432 d),无1例发生Ⅲ、Ⅳ度急性移植物抗宿主病(GVHD)。2例在移植1年后发生慢性GVHD。12例均为病理确诊或临床诊断IPA者,移植前肺功能测定仅有弥散功能轻度减退。抗真菌治疗8周后肺功能测试发现所有患者均存在不同程度的阻塞性通气障碍,其中8例患者呈小气道病变[FEF50和FEF75分别为(55.9±3.4)%和(41.9±4.1)%],4例患者则出现混合性通气障碍,总弥散量(DLCO)也显著降低[(47.4±2.9)%预计值],动脉血氧分压(PaO2)仅为(68.7±4.1)mmHg,但弥散常数(DLCO/VA)尚正常,与移植前无显著差异(P0.05)。结论 HSCT后并发IPA可对患者的肺功能造成不同程度的损害,肺内多部位感染或反复发生IPA的患者可出现较严重的混合性通气障碍,弥散也显著减退。     

Invasive fungal infections: epidemiology and analysis of antifungal prescriptions in onco-haematology

What is known and Objective: Invasive fungal infections (IFI) are associated with high rates of morbidity and mortality, particularly in onco‐haematology patients. We aimed to study the epidemiology of IFI in neutropenic patients and estimate the economic impact of treatment of those infections. Methods: All patients hospitalized in onco‐haematology, and treated with antifungal agents, in 2005 were investigated. Four features were studied: the diagnosis for each patient, the antifungal drugs used, the thoracic densitometry reports and the sero‐mycological data. Infectious episodes were stratified according to the EORTC 2008 classification criteria (10). Results and Discussion: Of the 1130 patients surveyed, 192 patients received systemic antifungal agents. Of these 46% had acute leukaemia, 29% bone‐marrow allografts, 7% lymphoma and 18% other malignant haemopathies. Using the EORTC 2008 criteria (10), there were 8 proved IFI (3 aspergillosis, 3 candidosis and 2 other IFI), 17 probable IFI (11 aspergillosis, 6 candidosis) and 16 possible aspergillosis. The incidence of IFI was 2·1%. Eighty patients (41·7%) had received prophylaxis: 56 with fluconazole and 24 with voriconazole. Treatment was most often empirical (n = 127, 66·1%). Combination of two antifungals was used in 17 cases. The mean duration of prophylactic, empirical, proved/probable aspergillosis‐directed, candidaemia‐directed and combination treatment was 19, 19, 46, 32 and 27 days, respectively. The cost of antifungal treatment in 2005 reached almost 2 000 000€, including 427 000€ for documented infections (proved and probable), 1 246 000€ for empirical treatment and 58 300€ for prophylaxis. What is new and Conclusion: The incidence of IFI is low but the pharmacoeconomic impact is extremely high. Improved strategies are required to reduce the frequency and duration of empirical treatment without compromising beneficial outcome.     

Chronic pulmonary aspergillosis

Aspergillus species causes a variety of pulmonary diseases, invasive pulmonary aspergillosis in severely immunocompromised patietnts, chronic pulmonary aspergillosis (CPA) in patients with chronic lung diseases and allergic bronchopulmonary aspergillosis in patients with hypersensitivity to Aspergillus antigens. There are many species of Aspergillus, however Aspergillus fumigatus is the most commonly encountered species. CPA is usually seen in patients with documented or suspected underlying lung diseases like cystic fibrosis, bronchiectasis, inactive tuberculosis, pulmonary fibrosis, sarcoidosis, previous lung section, of these, previous pulmonary tubercurosis is the most associated condition. Development of new antifungal agents, such as micafungin and voriconazole significantly affect the management and outcome of patients with CPA. This article reviews the clinical features, diagnosis, and treatment of CPA, and that provides recent advances in the CPA-related pathogenic factor.     

Increased circulating levels of plasma ATP in cystic fibrosis patients

Recent studies have shown that the cystic fibrosis transmembrane conductance regulator (CFTR), an ATP‐binding cassette (ABC) transporter whose mutations are responsible for cystic fibrosis (CF), permeates ATP. However, little information is available concerning extracellular ATP concentrations in CF patients. Thus, the goal of this preliminary study was to determine the circulating levels of plasma ATP in CF patients. Circulating levels of plasma ATP were determined by the luciferin‐luciferase assay in both CF patients and healthy volunteer control subjects. The two groups were compared using an analysis of variance. CF genotype and age, which ranged from 7 to 56 years, were also used to compare data by single‐blind analysis. With comparable sample numbers, CF patients had statistically higher levels of circulating ATP (34%, P<0·01) when compared by analysis of covariance with the age of the subjects as the cofactor. The CF patients bearing the ΔF508 genotype had a 54% (n=33, P<0·01) higher plasma ATP concentration compared to controls, while patients bearing other CF genotypes were similar to controls (n=10, P<0·4). We conclude that CF patients have higher circulating levels of ATP when compared to controls. Increased levels of plasma ATP, which is an important autocrine/paracrine hormone in many cell types, may be associated with chronic manifestations of the disease.     

Incidence of invasive aspergillosis among allogeneic hematopoietic stem cell transplant patients receiving voriconazole prophylaxis

We performed a retrospective observational study to examine the incidence of invasive aspergillosis (IA) among allogeneic hematopoietic stem cell transplant (HSCT) recipients, according to whether patients received at least 1 week of voriconazole prophylaxis. We report no cases of IA among 92 HSCT recipients who received voriconazole prophylaxis compared with a 10% (23/223) incidence among those receiving other systemic antifungals for prophylaxis (P < .0005).