恶性血液病伴发侵袭性肺曲霉病3例诊治分析

侵袭性肺曲霉病诊断图难，病情凶险，死亡率高。本对合并有侵袭性肺曲霉病的3例恶性血液病(2例急性白血病和l例MDS-RA)患的诊治过程进行了回顾性分析。3例患均有免疫力低下的病史，虽经过预防性抗真菌治疗，仍发生了肺曲霉菌感染，经过痰培养确诊后采用脂质体两性霉素B，伊曲康唑和氟胞嘧啶联合治疗。结果表明，联合治疗7—14天后，3例中2例痊愈，l例显效。结论：对侵袭性肺曲霉病的早期诊治很关键，脂质体两性霉素B，伊曲康硅和氟胞嘧啶联合治疗起效快，效果好。     

Liposomal amphotericin B in critically ill paediatric patients

What is known and Objective: Literature provides much evidence regarding liposomal amphotericin B treatment for fungal infections in neonates and infants. Relevant data regarding critically ill paediatric patients of older age are scarce. We aimed to present our experience regarding liposomal amphotericin B use in critically ill paediatric patients from a tertiary‐care paediatric hospital in Athens, Greece. Methods: We prospectively identified all paediatric patients who received treatment with liposomal amphotericin B in the intensive care unit of a tertiary‐care paediatric hospital during a 3‐year period (2005–2008). Data were retrieved from the evaluation of the available medical records. Results and Discussion: Twenty‐three (nine females, mean age: 26·4 months, range: 5–39 months) critically ill paediatric patients were included; 12 had malignancy. In 16 of the 23 included children, liposomal amphotericin B was administered for the treatment of confirmed fungal infections (all but one were invasive), whereas in seven patients, it was used as pre‐emptive treatment. One patient received voriconazole concomitantly. Eleven of the 16 children with documented infections were cured; five improved. Six of the seven children who received pre‐emptive treatment also showed clinical improvement. Nine deaths were noted, all attributed to underlying diseases. Two cases of hepatotoxicity and one case of nephrotoxicity (all leading to drug‐discontinuation) occurred. Seven and five cases of mild reversible hypokalaemia and hyponatraemia, respectively, were also noted. What is new and Conclusion: According to the findings of our small case series, liposomal amphotericin B may provide a useful treatment option for fungal infections of vulnerable critically ill paediatric patients with considerable comorbidity.     

Invasive aspergillosis in AIDS

Invasive pulmonary aspergillosis was diagnosed in two patients with HIV infection, one with prolonged neutropenia and another receiving corticosteroid therapy. We found 17 additional cases in the literature. A known predisposing risk factor for invasive aspergillosis, eg, neutropenia, corticosteroid use, or intravenous drug abuse, was present in 79% of the cases. That the known immunologic defect of AIDS is not a major host defense against Aspergillus is supported by the empiric observation of the relative rarity of aspergillosis in patients with AIDS. The lung was the most common site of Aspergillus infection (75%), and transbronchial biopsy is diagnostically useful. Central nervous system involvement was seen in 55% and appears to be more frequent in HIV-infected patients than in other immunosuppressed patients with invasive aspergillosis. Prognosis is grim. Despite early institution of amphotericin B therapy in a few cases, the disease was uniformly fatal. Efficacy of therapy with amphotericin B plus rifampin or itraconazole remains to be evaluated. We conclude that aspergillosis is not an AIDS-related opportunistic infection.     

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.     

Systematic review on the first line treatment of amphotericin B in critically ill adults with candidemia or invasive candidiasis

ABSTRACT

Introduction: Invasive candidiasis is the most common fungal infection affecting critically ill adults. International guidelines provide differing recommendations for first-line antifungal therapy, with echinocandins considered first-line in the majority. Amphotericin B has broad activity and low minimum inhibitory concentration resistance patterns across most Candida species and guidance away from its use should be supported by the available evidence.

Areas Covered: A systematic literature review was conducted from August to September 2017 to determine whether treatment with echinocandins or other available drugs, namely voriconazole, confers a therapeutic or survival benefit over amphotericin B in critically ill adults with invasive candidiasis. Inclusion criteria were: (1) studies describing critically ill adults with invasive candidiasis, (2) studies describing therapeutic benefit or survival as an outcome, and (3) studies comparing amphotericin B, deoxycholate or lipid preparations, with any newer antifungal agent. Eight studies were included in the final review, incorporating 2352 unique patients. No difference in treatment efficacy or mortality outcomes in critically ill patients with invasive candidiasis receiving an amphotericin B formulation compared with those receiving an echinocandin or voriconazole was shown.

Expert Commentary: We conclude that in the existing literature, there is no evidence that choice between echinocandins, voriconazole, or amphotericin B formulations as first-line therapy for critically ill adults with invasive candidiasis is associated with a therapeutic or survival benefit. Clinicians must therefore consider other factors in the selection of first-line therapy     

Assessment of Efficacy of Antifungals against Aspergillus fumigatus: Value of Real-Time Bioluminescence Imaging

Aspergillus fumigatus causes life-threatening infections, especially in immunocompromised patients. Common drugs for therapy of aspergillosis are polyenes, azoles, and echinocandins. However, despite in vitro efficacy of these antifungals, treatment failure is frequently observed. In this study, we established bioluminescence imaging to monitor drug efficacy under in vitro and in vivo conditions. In vitro assays confirmed the effectiveness of liposomal amphotericin B, voriconazole, and anidulafungin. Liposomal amphotericin B and voriconazole were fungicidal, whereas anidulafungin allowed initial germination of conidia that stopped elongation but allowed the conidia to remain viable. In vivo studies were performed with a leukopenic murine model. Mice were challenged by intranasal instillation with a bioluminescent reporter strain (5 × 10⁵ and 2.5 × 10⁵ conidia), and therapy efficacies of liposomal amphotericin B, voriconazole, and anidulafungin were monitored. For monotherapy, the highest treatment efficacy was observed with liposomal amphotericin B, whereas the efficacies of voriconazole and anidulafungin were strongly dependent on the infectious dose. When therapy efficacy was studied with different drug combinations, all combinations improved the rate of treatment success compared to that with monotherapy. One hundred percent survival was obtained for treatment with a combination of liposomal amphotericin B and anidulafungin, which prevented not only pulmonary infections but also infections of the sinus. In conclusion, combination therapy increases treatment success, at least in the murine infection model. In addition, our novel approach based on real-time imaging enables in vivo monitoring of drug efficacy in different organs during therapy of invasive aspergillosis.     

Efficacy of voriconazole against invasive pulmonary aspergillosis in a guinea-pig model

We compared the efficacies of amphotericin B and voriconazole against invasive pulmonary aspergillosis in a guinea-pig model. A susceptible isolate of Aspergillus fumigatus was used to produce the infection. Voriconazole-treated animals had significantly better survival and decreased fungal burden in the lungs as compared with controls. Although no statistical difference was seen between the efficacies of voriconazole and amphotericin B, a trend favouring voriconazole was noted. Thus, voriconazole, with its cidal activity, may be an attractive alternative to potentially toxic amphotericin B in the treatment of invasive pulmonary aspergillosis.     

Disseminated fusariosis with cerebral involvement in a patient with acute myeloid leukemia: Successful outcome with intrathecal –and systemic antifungal treatment

The outcome of invasive fusariosis in hematological patients is usually dismal, particularly in patients with persistent neutropenia. We report a patient with acute myeloid leukemia (AML) with Fusarium dimerum sinusitis with hematogenic dissemination to the brain. Despite surgical debridements of the sinuses and liposomal amphotericin B, voriconazole and terbinafine, there was progression with cerebral involvement after recovery of neutropenia and with detection of F. dimerum in the cerebrospinal fluid. Topical antifungal treatment with amphotericin B deoxycholate (deoxy-AMB) intrathecally was initiated with administration three times a week. After 99 treatments of intrathecal deoxy-AMB, she had regression of the fusarium CNS lesions and is currently in complete remission from AML. This report supports the use of intrathecal amphotericin B for treatment of CNS fusariosis.     

Amphotericin B--not so terrible

OBJECTIVE: To describe a patient who developed adverse reactions to two different lipid formulations of amphotericin B: liposomal amphotericin B (AmBisome) and amphotericin B colloidal dispersion (ABCD, Amphocil), yet tolerated amphotericin B deoxycholate (Fungizone) despite renal toxicity. CASE SUMMARY: A 72-year-old woman with acute myelomonocytic leukemia was treated with amphotericin B deoxycholate for suspected pulmonary aspergillosis; the drug was well tolerated but resulted in renal failure. Antifungal therapy was then changed to liposomal amphotericin B. Within 10 minutes of liposomal amphotericin B infusion, the patient developed severe dyspnea, chest pain, and a feeling of imminent death. On the following day, liposomal amphotericin B was switched to amphotericin B colloidal dispersion. Again, within 10 minutes of this infusion, the patient developed fever, chills, hypotension, severe chest pain, dsypnea, and a feeling of imminent death. The patient refused any further treatment with these drugs and insisted on switching back to amphotericin B deoxycholate, which was then administered for 10 days and was well tolerated. DISCUSSION: Severe adverse reactions, such as anaphylaxis, cardiac toxicity, and respiratory failure, following administration of all three lipid formulations of amphotericin B have been reported. In most reported cases, switching to a different lipid formulation of amphotericin B was well tolerated. This is in contrast to our case, where a severe reaction was repeated when another lipid preparation was given, necessitating switching back to amphotericin B deoxycholate despite its nephrotoxicity. CONCLUSIONS: In some patients, paradoxically, lipid formulations of amphotericin B may be less tolerable than conventional amphotericin B.     

Efficacy of aerosolized amphotericin B desoxycholate and liposomal amphotericin B in the treatment of invasive pulmonary aspergillosis in severely immunocompromised rats.

The effects of treatment with aerosolized amphotericin B desoxycholate and aerosolized liposomal amphotericin B were evaluated in severely immunosuppressed rats with invasive pulmonary aspergillosis. Aerosol treatment with amphotericin B desoxycholate consisted of a single dose (60 min) with amphotericin B concentrations in the nebulizer reservoir of 1, 2 and 4 mg/mL, respectively. For liposomal amphotericin B, aerosol treatment consisted of single, double or quadruple doses with a nebulizer reservoir concentration of 4 mg/mL of amphotericin B. Treatment, started at 30 h after inoculation, with aerosolized amphotericin B desoxycholate (nebulizer reservoir concentration 2 mg/mL) significantly prolonged survival of rats as compared with placebo-treated rats, whereas treatment with aerosolized amphotericin B desoxycholate with nebulizer reservoir concentration of 1 or 4 mg/mL did not have a significant effect on survival. Treatment with aerosolized liposomal amphotericin B significantly prolonged survival with all treatment regimens when compared with placebo-treated animals. Aerosol treatment did not prevent dissemination of the infection. The effects of amphotericin B desoxycholate and liposomal amphotericin B on pulmonary surfactant function were also evaluated in vitro. Amphotericin B desoxycholate inhibited surfactant function in a dose-dependent fashion. Liposomal amphotericin B had no detrimental effect on surface activity of surfactant. These results indicate that aerosol administration of amphotericin B, especially the liposomal formulation, could be an additional approach to optimizing treatment of invasive pulmonary aspergillosis.     

Fungal infection and liposomal amphotericin B (AmBisome) therapy in liver transplantation: a 2 year review.

We reviewed the use of liposomal amphotericin B in 30 patients receiving therapy following liver transplantation over a 2 year period. Five of these patients were treated for presumed invasive aspergillosis: four of them died despite therapy, each having combined renal and respiratory failure at the time of diagnosis of presumed aspergillosis. Post-mortem examination of three of these patients confirmed the diagnosis of aspergillosis. Twenty-five patients were treated empirically; 11 died and supportive evidence for invasive fungal infection following commencement of therapy was found in only one case. Following liver transplantation, the use of liposomal amphotericin B following confirmation of aspergillus infection or for empirical therapy is of uncertain value, and strategies based on selective prophylaxis for high-risk cases may be preferable.     

Systematic review and mixed treatment comparison of randomized evidence for empirical, pre-emptive and directed treatment strategies for invasive mould disease

Randomized controlled trials (RCTs) provide the most reliable estimates of the effects of treatments. However, not all treatments are compared in available RCTs, making comparison of treatments problematic. Mixed treatment comparisons (MTCs) can provide estimates of the comparative effects of treatments across a range of available therapeutic options. MTCs use networks of available direct comparisons to estimate differences in treatments that have not been estimated in trials via a common comparator. We conducted a systematic review and MTCs of comparative RCTs in haematological patients of anti-mould active agents used for the empirical treatment of febrile neutropenia (Analysis 1), and pre-emptive therapy (Analysis 2) of invasive mould diseases. In addition, we summarized the evidence available associated with the use of directed treatment strategies (Analysis 3). For empirical therapy, caspofungin proved superior to amphotericin B, liposomal amphotericin B, amphotericin B lipid complex and voriconazole in the outcome of survival, but no agents showed superiority for treatment response. There was no evidence of a difference between pre-emptive and empirical strategies on mortality outcomes. For directed therapy, voriconazole was superior to amphotericin B for overall survival, and both voriconazole and liposomal amphotericin B were superior to amphotericin B and amphotericin B colloidal dispersion on the outcome of response. While limited to some degree by the availability of RCTs, the MTCs reported here provide the best available evidence of relative therapeutic success for different available treatment strategies.     

Treatment of zygomycosis: current and new options

Zygomycosis is a frequently lethal invasive infection in high-risk patients such as the immunocompromised [especially haematopoietic stem cell transplant (HSCT) recipients] and patients with type 2 diabetes mellitus. However, zygomycosis has also been reported in individuals without known risk factors. The causative fungi are members of the order Mucorales and individual species within this group require a high level of laboratory skill for their identification. These organisms are resistant to voriconazole and also to the echinocandins, and although zygomycosis is less commonly documented than invasive aspergillosis in leukaemic and HSCT patients, there are recent reports suggesting that it has increased in incidence since the introduction of voriconazole. Zygomycosis can present clinically as rhinocerebral, pulmonary or disseminated disease which progresses rapidly. The management of cases is based on early diagnosis, surgical debridement when possible and aggressive antifungal therapy. Based on clinical experience, but without the benefit of comparative studies, liposomal amphotericin B has become the therapeutic agent of choice. Posaconazole is a new orally administered triazole antifungal and the first member of this class to have comparable in vitro activity to amphotericin B against most zygomycetes. Studies of salvage therapy of zygomycosis with posaconazole have yielded promising results and there are additional case reports of successful outcomes using these and other antifungal drugs as combination therapy. Adjunctive approaches that are showing promise but with limited clinical experience are iron chelation and immunotherapy.     

Liposomal nystatin in patients with invasive aspergillosis refractory to or intolerant of amphotericin B

We assessed the activity and safety of liposomal nystatin, a broad-spectrum antifungal agent, for invasive aspergillosis in patients refractory to or intolerant of amphotericin B. Thirty-three patients were enrolled, received at least one dose of the study drug, and were evaluable for safety. Twenty-six patients had confirmed probable or definite aspergillosis and were fully eligible. Most patients had a hematological malignancy (53.8%) or hematopoietic stem cell transplantation (23.0%), were neutropenic (61.5%), and were refractory to previous amphotericin B (92.3%). The median duration of previous amphotericin B treatment was 16.5 days (range, 5 to 64 days). Aspergillosis was definite in 3 cases and probable in 23 cases. Liposomal nystatin was initiated at a dose of 4 mg/kg of body weight/day. Twenty-five patients were evaluable for response: a complete response was achieved for one patient, and a partial response was achieved for six. Thus, the overall response rate is 7 of 25 (28%; 95% confidence interval, 12 to 49%). Seventeen (68.0%) of the 25 evaluable patients died during therapy or within 1 month after the end of therapy. The primary cause of death was invasive aspergillosis for nine patients and underlying malignancy for eight patients. The most frequent side effects included chills, shivering, and fever, leading to discontinuation of therapy for two patients. Grade 1 decline in renal function was seen for 10 (30.3%) patients, and hypokalemia was seen for 13 (39.4%). We conclude that liposomal nystatin can be effective for salvage therapy of invasive aspergillosis. Infusion-related adverse events have been observed frequently.     

Chronic necrotizing pulmonary aspergillosis treated by endobronchial amphotericin B

Chronic necrotizing pulmonary aspergillosis is an indolent, locally invasive form of Aspergillus infection. Treatment options are limited and controversial. Resection is often curative if the patient has sufficient ventilatory reserve. Even though intravenous amphotericin B is effective in a few patients, toxicity limits its use. Aerosolized amphotericin B has proven ineffective. Anecdotal reports of intracavitary and endobronchial antifungal therapy show limited success. Our patient had unresectable chronic necrotizing pulmonary aspergillosis treated successfully with intracavitary instillation of amphotericin B, delivered via the flexible fiberoptic bronchoscope.     

Sequential or combination antifungal therapy with voriconazole and liposomal amphotericin B in a Guinea pig model of invasive aspergillosis

We evaluated combinations of voriconazole (VRC) and liposomal amphotericin B (L-AMB) in a guinea pig invasive aspergillosis model. Simultaneous VRC and L-AMB was most effective, although VRC monotherapy was also effective. These regimens as well as sequential L-AMB followed by VRC were more effective than L-AMB alone or VRC followed by L-AMB.     

Ph阳性急性淋巴细胞白血病合并肺、脑曲霉菌病

为了探讨Ph染色体阳性急性淋巴细胞白血病合并侵袭性曲霉菌病的临床特点和治疗措施,对1例Ph＋ALL患者进行了血常规、骨髓像、胸片、头颅CT扫描和细胞遗传学等检查,并先后给予DVCP、善唯达及格列卫联合诱导化疗.患者在骨髓抑制期发生侵袭性肺、脑曲霉菌感染,给予伊曲康唑、两性霉素等抗真菌治疗,进行了开颅病灶引流术.经过上述综合治疗,患者获得缓解,肺、脑曲霉菌感染临床治愈.结论：Ph＋ALL是一种常规方案化疗效果差的特殊亚型,格列卫联合化疗是其较好的治疗方案.由于临床真菌检出率低,早期经验性选用抗真菌药物如伊曲康唑,并结合手术切除病灶是治疗肺、脑曲霉菌的较好方法.     

Fatal bronchial invasion of Scopulariopsis brevicaulis in an acute monocytic leukemia patient

A case of fatal invasion of Scopulariopsis brevicaulis to the bronchus in an acute monocytic leukemia (M(5)) patient is described. This infection leads to mediastinal emphysema, bronchial bleeding, and bronchial obstruction before finally spreading to the entire lung. The patient was initially diagnosed with pulmonary aspergillosis based on clinical signs and morphological examination. However, S. brevicaulis was finally identified by 18S rDNA sequencing. The patient failed lipid amphotericin B therapy and voriconazole plus caspofungin combination therapy. To the best of our knowledge, this is the first report on S. brevicaulis affecting the bronchus and resulting in a fatal prognosis in an M(5) patient.     

Invasive pulmonary aspergillosis in critically ill immunocompetent patients

Invasive pulmonary aspergillosis (IPA) is a severe and well recognized infection in patients with hematological malignancies. However, increasing number of studies has reported the emergence of IPA in critically ill immunocompetent patients, mainly represented by chronic obstructive pulmonary disease (COPD) patients, with an estimated incidence of 2%. These patients are characterized by multifactorial impairments in their local defense. The major risk factors are systemic steroid use and administration of broad-spectrum antibiotics. IPA is responsible for high mortality, and its usual clinical, radiological, and biological specificities are generally absent in the immunocompetent patient. Rapid diagnosis requires histological evidence. Sensitivity of lower respiratory tract cultures and serology remains poor. The detection of galactomannan fungal antigen in the bronchoalveolar lavage may offer an interesting alternative diagnostic tool. The first-line recommended antifungal treatment is voriconazole, but other therapies exist like amphotericin, which was largely used in the past. We conducted a literature review focusing at IPA in the critically ill immunocompetent patients, in order to analyze its epidemiology, physiopathology, prognosis, diagnostic methods, and treatment.     

Nonfatal pulmonary Trichoderma viride infection in an adult patient with acute myeloid leukemia: report of one case and review of the literature

Trichoderma species have been recognized to be pathogenic in immunosuppressed hosts with increasing frequency. Trichoderma species are responsible for continuous ambulatory peritoneal dialysis associated peritonitis and infections in immunocompromised patients with a hematologic malignancy or solid organ transplantation. Trichoderma longibrachiatum is the most common species involved in these infections. We report the first case of nonfatal pulmonary infection caused by Trichoderma viride in leukemia patient. It had a successful answer to new antifungal agents as voriconazole and caspofungin. Trichoderma viride was isolated from pulmonary aspirate culture from a 54-year-old female who had received chemotherapy for acute myeloid leukemia. The minimal inhibitory concentrations for the organism were the following: amphotericin B (0.25 microg/mL) and voriconazole (2 microg/mL). Initially, she was treated unsuccessful with liposomal amphotericin B and voriconazole and caspofungin were added later. The patient is alive. We report one case along review of the literature.