Recommendations for the treatment of fungal pneumonias

Incidences of fungal pneumonias have increased in immunocompromised patients with HIV infection or receiving bone marrow replacement or solid organ transplantation. Fungal pneumonias including aspergillosis, cryptococcosis, candidiasis, coccidioidomycosis, histoplasmosis and blastomycosis are one of the major causes of morbidity and mortality among the immunosuppressed hosts. Therefore, clinicians should consider the most appropriate and aggressive treatment of fungal pneumonias in this population. This report outlines the state of the art in the treatment of fungal pneumonias and discusses recent advances in antifungal therapy. Practice guidelines for the treatment with commonly used antifungal agents including amphotericin B, fluconazole, itraconazole, ketoconazole and flucytosine, are very useful for clinicians to manage the diseases appropriately. Echinocandins and second-generation triazoles will hopefully help clinicians to overcome the limitations of the current therapy.     

Minimal inhibitory concentration (MIC) of caspofungin and itraconazole inhibiting growth of Candida strains calculated from the linear regression equation

PurposeThe aim of the study was to compare the susceptibility of Candida species to caspofungin and itraconazole.Material and methods118 strains of Candida species were used in the study: 8 pattern strains and 110 strains isolated from different ontocenoses. The susceptibility of fungi strains to drugs was determined by diffusion in agar gel. The minimal inhibitory concentration (MIC) was calculated from the linear regression equation with the use of the method by Kad?ubowski.ResultsThe MIC value for caspofungin for the pattern strains ranged from 0.321 mg/L to 0.552 mg/L and for itraconazole from 0.019 mg/L to 0.11 mg/L. All the analyzed strains isolated from patients exhibited susceptibility to caspofungin; 5 strains of Candida albicans (8.06%) proved to be resistant to itraconazole. The MIC values for caspofungin ranged from 0.114 mg/L to 1.26 mg/L and for itraconazole from 0.012 mg/L to 16.1 mg/L.Conclusions1. All the studied pattern strains are susceptible to the examined drugs; all those isolated from patients show susceptibility to caspofungin; some Candida albicans strains (8.06%) are resistant to itraconazole. 2. The mean MIC values calculated from the activity curves are 0.426 mg/L for caspofungin and 1.0245 mg/L for itraconazole. 3. The mean MIC values calculated for caspofungin are lower than for itraconazole in the case of Candida albicans, C. glabrata and C. tropicalis. Having compared the influence of the drugs on C. famata, C. lusitaniae, C. parapsilosis and C. ciferri we proved there are statistically significant differences (0.0046>p<0.044).     

Pharmacology and metabolism of anidulafungin,caspofungin and micafungin in the treatment of invasive candidosis - review of the literature

Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clinical use in various indications. They act as inhibitors of β-(1,3)-glucan synthesis in the fungal cell wall and have a favorable pharmacological profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been observed against C. parapsilosis and C. guilliermondii. Data from clinical trials for invasive Candida infections / candidaemia suggest that the clinical outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clinical settings such as invasive Candida infections, Candida oesophagitis and candidaemia. Differences between the three echinocandins with regard to the route of metabolism, requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for intravenous use. All three agents have an excellent safety profile.     

Clinical hepatotoxicity associated with antifungal agents

Introduction: Invasive fungal diseases (IFDs) are a leading cause of morbidity and mortality among immunocompromised patients with bone marrow failure syndromes, hematological malignancies, hematopoietic stem cell transplantation (HSCT), those admitted in intensive care units (ICUs) and those with prolonged febrile neutropenia. IFDs occur in a setting of multiple morbidities and are associated with case fatality rates between 30 and 70%. Along with the development of classes and compounds, the last two decades have seen substantial improvements in the prevention and management of these infections and an overall increased use of antifungal agents.

Areas covered: All antifungal agents, including amphotericin B formulations, echinocandins and the triazoles, may cause hepatic toxicity that ranges from mild and asymptomatic abnormalities in liver function tests to substantial liver injury and fulminant hepatic failure.

Expert opinion: The present article reviews incidence and severity of hepatotoxicity associated with different classes and agents to provide a better understanding of this specific end organ toxicity and safer use of antifungal agents A thorough understanding of the distribution, metabolism, elimination and drug-drug interactions of antifungal agents used for management of IFDs in combination with safety data from clinical trials, pharmacokinetic and pharmacodynamic studies may guide the use of antifungal treatment in patients at high risk for the development of hepatic dysfunction and in those with underlying liver damage due to cytotoxic therapy.     

Update on antifungal agents for paediatric patients

Paediatric age groups display important differences in host biology, predisposing conditions, epidemiology and presentation of fungal infections relative to the adult population. During the past decade, several new antifungal agents have been developed. Although not all of these agents are yet approved for children, the paediatric development of antifungal agents has moved forwards in an exemplary manner. Invasive fungal infections will remain important causes of morbidity and mortality in immunocompromised paediatric patients. Whereas the availability of new therapeutic options is an important advance, antifungal therapy has become increasingly complex, and a thorough understanding of the available antifungal armamentarium is essential for the successful management of the individual patient. This article provides an update on the pharmacokinetics, safety and dosing of antifungal agents in paediatric patients, and their clinical indications.     

Caspofungin for the treatment of candidaemia in patients with haematological malignancies

This study was prospectively conducted in 11 haematology divisions over a 2-year period to evaluate the efficacy of caspofungin in 24 neutropenic patients with haematological malignancies (HM) and candidaemia. These patients had received chemotherapy for HM and were neutropenic (PNN < 0.5 × 10⁹/L) for a median of 12 days (2–41) before candidaemia. The patients received caspofungin for a median duration of 12 days (range 6–26), obtaining a favourable overall response of 58%. At 30 days, 11 patients had died (46%); candidaemia was responsible for mortality in six patients (25%). These results suggest that treatment of candidaemia with caspofungin in neutropenic HM was efficacious, as it is in non-haematological subgroups.     

Successful management of postpneumonectomy Aspergillus pleural empyema by combined surgical and anti‐fungal treatment with voriconazole and caspofungin

Aspergillus pleural empyema is a rare but often fatal infection complicating thoracic surgery. Three men and one woman aged 23–47 years were diagnosed with Aspergillus pleural empyema after lung resection. Underlying diseases were lung cancer (n = 2), Hodgkin’s disease (n = 1) and thoracic trauma (n = 1). The treatment protocol consisted of systemic anti‐fungal treatment with caspofungin and voriconazole, intrapleural application of amphotericin B and surgical debridement with secondary closure of the leaking bronchial stump. Two patients with chronic Aspergillus pleural empyema had been pretreated with itraconazole and/or amphotericin B. Two patients were treated with a thoracostoma. Two patients had undergone pneumonectomy for previously diagnosed pulmonary aspergillosis. Caspofungin was given for 13–60 days, Voriconazole for up to 100 days. Surgical debridement was performed in all cases and in two cases the created thoracostoma was closed during a second surgical procedure. Aspergillus PCR using blood samples, bronchoalveolar lavage or aspiration fluid was used for monitoring. All four patients had complete clinical and microbiological remission. Our case series shows promising results and underscores the importance of a combined therapeutic approach for Aspergillus pleural empyema consisting of anti‐fungal treatment and surgery. Voriconazole and caspofungin seem to be a suitable combination for this infection.     

Caspofungin versus liposomal amphotericin B for treatment of invasive fungal infections or febrile neutropenia

Background Nowadays,there are published trials in regards to the comparison of caspofungin with liposomal amphotericin B （L-AmB）.However,these studies have a modest sample size and convey inconclusive results.The aim of this study was to review the efficacy and safety of caspofungin for the treatment of invasive fungal infections （IFIs）,compared with L-AmB.Methods Electronic databases （up to July 31,2013） PubMed and Embase databases,the Cochrane Library,and Google Scholar were searched to identify relevant trials of caspofungin and L-AmB.Analyses of efficacy and adverse outcomes were performed by relative risks （RRs） and 95% confidence intervals （C/s）.Heterogeneity was assessed by x2-test and the/2-statistic.Results Three trials were included in this meta-analysis with 1249 modified intention-to-treat （MITT） patients.The results showed that caspofungin produced equal efficacy in favorable overall response （RR=1.02,95% Cl 0.88-1.18; P=0.81） and mortality rate （RR=1.53,95% Cl 0.38-6.27,P=0.55）,safer in clinical adverse events （RR=0.20,95% Cl 0.08-0.54; P=0.001）,laboratory adverse events （RR=0.69,95% Cl 0.57-0.84; P=0.0002）,and discontinuation rate （RR=0.26,95% Cl 0.08-0.83,P=0.02）,compared with L-AmB in the treatment of patients with IFls.Conclusion Based on the results of this meta-analysis,it would appear that caspofungin was measured to have equal efficacy in clinical outcomes and safer in terms of adverse events.