Invasive fungal infections during the neonatal period: diagnosis,treatment and prophylaxis

Introduction: The incidence of preterm births seems to be increased in many countries around the world, in parallel to the advances in neonatal medicine. However, this has resulted in longer hospital stays and more exposure to invasive interventions, both of which can lead to an increase in late-onset nosocomial infections in the newborn period. In addition to bacteria, fungi are thought to be an important cause of hospital infections.

Areas covered: The present article reviews the diagnosis, treatment and prophylaxis of invasive fungal infections (IFIs) during the neonatal period. IFIs are associated with high morbidity and mortality in preterm neonates. The main risk factors are multiple antibiotics, central venous catheters, parenteral nutrition, immunodepression, very low birth weight, and fungal colonization. Successful management of IFIs relies on early recognition and rapid initiation of effective treatment.

Expert opinion: Invasive-fungal-infection-related morbidity and mortality is a major concern for most neonatal intensive care units worldwide. Incidence rates are increasing for preterm neonates. Preterm infants display clinical characteristics that make them prone to fungal infections, and there is a high frequency of neurodevelopmental sequelae in those who survive after neonatal fungal infections. Specific prevention – rather than treatment – should be the optimal strategy. Both ?uconazole and nystatin prophylaxis reduce the incidence of IFI and fungal colonization in very preterm infants.     

Mucosal and systemic fungal infections in patients with AIDS: prophylaxis and treatment

In countries where highly active antiretroviral therapy (HAART) is widely available, a decrease in the incidence of fungal infections has been observed in the last 5 years compared with countries that cannot afford this treatment. Even refractory fungal infections may be controlled when HAART is given to patients, and end-stage AIDS infections, such as aspergillosis, are now only infrequently seen. In contrast, fungal infections in certain regions, such as penicilliosis in Southeast Asia or cryptococcosis in Sub-Saharan Africa, are a growing problem. Antifungal therapy for documented infections has not changed very much during recent years; however, new drugs such as caspofungin and voriconazole may be more effective in the treatment of opportunistic fungal infections, in particular, those involving resistant organisms. Secondary antifungal prophylaxis for many opportunistic pathogens can now be temporarily or even permanently discontinued in many HIV-positive patients who have a marked improvement in immune function parameters, such as CD4(+) cell counts, after initiation of HAART. The link between effective virustatic control of HIV infection and a decreasing incidence of fungal infections has been recognised; and so, despite the availability of very effective new antifungal drugs, the cornerstone of treatment and prevention of opportunistic fungal infections in patients with HIV infection is effective antiretroviral therapy including protease inhibitors.     

Catheter-associated urinary tract infections: diagnosis and prophylaxis

Catheter-associated urinary tract infections (CAUTI) are the commonest nosocomial infections worldwide. While they are often asymptomatic and frequently cost less than nosocomial surgical site infections or nosocomial pneumonia, they are major reservoirs of antimicrobial resistant pathogens. Numerous strategies have been devised in an attempt to reduce the incidence of CAUTI but few have proven effective. Novel technologies such as the potential use of antiseptic or antimicrobial coatings on catheters hold promise for possibly reducing these infections in the fight against antimicrobial resistance.     

Cost effectiveness of itraconazole in the prophylaxis of invasive fungal infections

BACKGROUND: 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. OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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%. CONCLUSIONS: 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.     

Posaconazole : a review of its use in the prophylaxis of invasive fungal infections

Posaconazole is a second-generation triazole antifungal agent with a broad spectrum of activity that includes Aspergillus spp., Candida spp. and the Zygomycetes. In the US, posaconazole oral suspension administered three times daily is indicated for prophylaxis against invasive Aspergillus and Candida infections in patients aged > or =13 years who are at high risk of developing these infections because of immunosuppression, such as haematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or those with haematological malignancies with prolonged neutropenia as a result of chemotherapy. EU-approved prophylactic indications for posaconazole are similar to those in the US.Posaconazole provided effective prophylaxis against invasive fungal infections and was generally well tolerated in two large, well designed trials in HSCT recipients with GVHD, or patients receiving induction-remission chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) that was expected to result in prolonged neutropenia. It offers coverage of clinically relevant pathogens and is potentially associated with fewer drug-drug interactions than other licensed triazole antifungal agents. Its usefulness in some patients may be limited by the lack of an intravenous formulation, although one is currently being developed. As with other antifungal agents, concerns remain regarding the potential emergence of resistance to broad-spectrum antifungal prophylaxis with posaconazole. Despite this, posaconazole is a valuable emerging option for use as prophylaxis against invasive fungal infections in immunocompromized patients who are at high risk of developing these infections.     

Laboratory diagnosis and therapy of invasive fungal infections

Diagnosing fungal infections remains a problem, particularly in the immunocompromised patient. Symptoms are mostly non-specific and colonization is difficult to distinguish from invasive disease. Existing diagnostic tools often lack sensitivity. Thus, the combination of various diagnostic tools is mandatory to allow earlier diagnosis of systemic fungal infections. Microscopy, culture based methods, antigen detection, and PCR may help to facilitate and accelerate the diagnosis. Galactomannan and glucan are two promising antigens that may be useful for early detection of the infection, but also for therapeutic monitoring. Sensitive and specific PCR assays to detect fungal DNA are an important part of the diagnostic approach. But extensive validation and standardization is strongly needed, before PCR assays can be used in a routine laboratory. The tremendous increase in invasive fungal infections has led to an increased interest in new antifungal agents and the field of antifungal chemotherapy evolved even more rapidly than diagnostic assays. The development of less toxic formulations of amphotericin B, the introduction of improved azoles and the availability of the echinocandins are opening new opportunities for the treatment of fungal infections. However, continuing efforts in the laboratory and well-designed clinical trials are still needed.     

Invasive fungal infections in patients with cancer in the Intensive Care Unit

Invasive fungal infections (IFIs) have emerged as a major cause of morbidity and mortality amongst critically ill patients. Cancer patients admitted to the Intensive Care Unit (ICU) have multiple risk factors for IFIs. The vast majority of IFIs in the ICU are due to Candida spp. The incidence of invasive candidiasis (IC) has increased over recent decades, especially in the ICU. A shift in the distribution of Candida spp. from Candida albicans to non-albicans Candida spp. has been observed both in ICUs and oncology units in the last two decades. Timely diagnosis of IC remains a challenge despite the introduction of new microbiology techniques. Delayed initiation of antifungal therapy is associated with increased mortality. Therefore, prediction rules have been developed and validated prospectively in order to identify those ICU patients at high risk for IC and likely to benefit from early treatment. These rules, however, have not been validated in cancer patients. Similarly, major clinical studies on the efficacy of newer antifungals typically do not include cancer patients. Despite the introduction of more potent and less toxic antifungals, mortality from IFIs amongst cancer patients remains high. In recent years, aspergillosis and mucormycosis have also emerged as significant causes of morbidity and mortality amongst ICU patients with haematological cancer.     

伏立康唑的临床合理应用

新型高效低毒抗真菌药物的出现和应用,优化了临床抗真菌治疗方案,提高了抗真菌治疗的疗效.伏立康唑作为新一代三唑类抗真菌药物,具有抗菌谱广、安全且组织分布广等特点,在临床抗真菌治疗中发挥重要作用,但其也存在明显的不良反应,并与较多的药物具有相瓦作用.临床应根据真菌感染类型、感染部位、机体免疫状况、真菌药敏以及药物间相互作用等合理选用伏立康唑.伏立康唑在真菌感染防治中的疗效和安全性需通过大规模前瞻性随机对照临床研究进一步观察和研究.     

Current issues on the prophylaxis and the management of fungal infections in leukemic patients

During the last few years, recent developments of the antifungal armamentarium have led to large studies on chemoprophylaxis as well as on new therapeutic regimen using new antifungal agents such as triazoles but also new modalities to administer amphotericin B. This progress, combined with increased awareness of clinicians about the high morbidity and mortality related to invasive fungal infection, suggests that there will be significant improvement of the prognosis for immunocompromised patients at risk of invasive fungal infections.     

肺部真菌感染诊断研究进展

<正>近20年来,随着器官移植免疫抑制剂的使用,癌症放疗化疗的增多,广谱抗菌药物的滥用和艾滋病的流行,免疫功能低下者不断增多。深部真菌感染作为一种并发病,感染率大幅上升,其中肺部真菌感染占深部真菌感染的首位,约50%～60%侵犯支气管、肺,以念珠菌和曲霉菌最常见,其次为新型隐球菌和毛霉菌[1,2]。肺部真菌感染临床表现无特异性,早期诊断困难,病情常被原发病掩盖,易被     

深部真菌感染的诊断和治疗

深部真菌感染指致病性真菌侵犯皮下组织、黏膜和内脏,感染器官所引起的真菌感染性疾病。常见深部真菌病主要包括念珠菌病,隐球菌病、曲霉病、毛霉病、孢子丝菌病、马内菲青霉病、组织胞2007第5卷第1期Clinical Medication Journal合理用药临临临临床床床床药药药药物物物物治治治治疗疗疗杂杂志浆菌病、副球孢子菌病和皮炎芽生菌病等。近年来,危重病人深部真菌感染呈逐年上升趋势,除临床医生对此病认识提高和诊断技术的改进外,还与下列因素有关:人口老龄化、广谱强效抗生素的大量应用;恶性肿瘤的放、化疗;导管插管,器官移植,皮质类固醇激…     

Recent advances in the treatment of life-threatening,invasive fungal infections

Introduction: Invasive fungal infections (IFIs) pose significant morbidity and are often life-threatening to many high-risk patients. Timely diagnosis and treatment of these infections with optimal therapy is imperative.

Areas covered: Advances have been made in diagnostic biomarkers such as peptide nucleic acid fluorescent in situ hybridization, β-D-glucan and galactomannan, although more research is needed in this area to assist with both diagnosis and monitoring for improvement of IFI management. Novel antifungal agents (azole antifungals and echinocandins) are being investigated that have activity against Candida spp. and Aspergillus spp. Optimizing the pharmacodynamics (PD) of our current antifungal therapies through such strategies as continuous infusion of amphotericin B and dose escalation of echinocandins and liposomal formulations of amphotericin B have also been investigated with mixed results. Therapeutic drug monitoring (TDM) shows promise as evident from data with such agents as flucytosine, itraconazole, voriconazole and posaconazole.

Expert opinion: The goal for the future of biomarkers in IFIs will be to have excellent sensitivity and specificity to ideally identify a particular fungus causing the infection or eliminate its existence to prevent unnecessary costs, resistance and antifungal usage. In addition, further developments of new antifungals are needed and judicious use of the current regimens needs to be optimized through antifungal PD properties and TDM.     

Pramiconazole, a triazole compound for the treatment of fungal infections

Pramiconazole from Barrier Therapeutics Inc is a new addition to the family of triazole antifungal agents that act by inhibiting fungal cell membrane ergosterol synthesis, thereby leading to increased cell permeability and destruction. Barrier Therapeutics was developing an oral formulation of pramiconazole for the potential treatment of seborrheic dermatitis (erythematosquamous skin disease), onychomycosis and dermatomycosis (including tinea versicolor, tinea pedis and tinea cruris/corporis). In preclinical studies, pramiconazole exhibited similar or superior antifungal activity to ketoconazole and itraconazole, and selectively inhibited ergosterol synthesis with a broad spectrum activity. Pramiconazole was absorbed rapidly and had a long half-life, allowing for once-daily dosing. In phase I and II clinical trials, pramiconazole reduced the growth of Candida albicans, Malassezia globosa, Microsporum canis, Trichophyton mentagrophytes and Trichophyton rubrum, and was generally well tolerated. At the time of publication, Barrier Therapeutics had suspended the development of pramiconazole as part of a series of cost-cutting initiatives; the company had also been acquired by Stiefel Laboratories Inc. No formal announcement had been made regarding the further development of pramiconazole. The results of studies performed to date suggest that pramiconazole may be useful in the treatment of dermatomycoses when oral treatment is mandated. Promising preclinical and early phase II clinical data warrant the further development of the drug in larger clinical trials.     

Therapeutic strategies for invasive fungal infections in neonatal and pediatric patients

Invasive Candida and Aspergillus infections are the most commonly encountered fungal infections. They appear to be life threatening in the setting of profound immunosuppression, whereas cases that are resistant to antifungal therapy are occasionally encountered. Novel antifungal triazole and echinocandin agents appear to exhibit good activity as first-line or salvage therapy, whereas the use of amphotericin B formulations is particularly valuable in neonates. Significant differences in toxicity have been demonstrated among various antifungal agents with in vitro activity from available comparative data on fungal infections in children: however, no clear difference in treatment efficacy has been demonstrated. However, very little data are available about neonates. Host factors and responsible fungal species most frequently guide the choice of therapy.     

Invasive fungal infections in oncology and haematology unit care: review of literature and costs analysis

Invasive fungal infections are an important cause of mortality in oncology and haematology unit care. Immunosuppression allows the occurrence of Candida or Aspergillus infectious disease. Treatment is based on antifungal agents (liposomal amphotericin B, azoles and caspofungin) administrated alone. The lack of study does not yet validate the combination of two drugs which are not recommended in medical practice. The aim of this pharmacoeconomics study is to assess different therapeutic strategies compared to standard treatment. Health care system point of view is used. Results show that liposomal amphotericin B is the reference standard drug during no documented infection in term of cost. But, voriconazole does not have significative cost variation for Aspergillus disease. Same conclusion can be showed, in case of candidosis for caspofungin. The sensitivity analysis shows that daily cost treatment and body weight are variables with important impact on results. This preliminary analysis must be continued by a clinical study in order to assess different antifungal treatments.