Efficacy of caspofungin in prophylaxis and treatment of an adult leukemic patient with invasive pulmonary aspergillosis in allogeneic stem cell transplantation

Summary Invasive aspergillosis is a major problem in the management of immunocompromised patients, its prevalence is rising and it is still a major cause of death in this group. The clinical success rate with classical drugs is far away from expectations. New drugs are needed in the treatment of this complication. Belonging to the new class of echinocandins, caspofungin is a newly introduced and promising drug in this fatal situation. We report a patient with acute myeloid leukemia who had invasive pulmonary aspergillosis during induction therapy being treated with amphotericin B in first step and afterwards with caspofungin. The patient received consolidation therapy and allogeneic stem cell transplantation while using caspofungin, and did not experience any adverse effect related to drug. Many side effects, e.g. derangements in liver and kidney functions, hypokalemia, infusion-related side effects and especially thrombocytopenia, which are common with amphotericin B treatment are no longer problem with caspofungin. The efficacy of caspofungin in terms of regression of pulmonary lesions and control of fever is quite successful. The optimal therapies for opportunistic fungal infections are still debated, and further evaluation is needed.     

Pharmacological properties and clinical efficacy of a recently licensed systemic antifungal, caspofungin

Caspofungin, a semisynthetic derivative of the pneumocandin B(0), is the first licensed compound of a new class of antifungal agents, the echinocandins. It attacks the fungal cell by selective inhibition of the beta-(1,3)-d-glucan synthase, which is not present in mammalian cells. In vitro studies have indicated a potent fungicidal effect on Candida species, and in vivo studies in immunocompromised animals with invasive candidiasis demonstrated a favourable outcome. In randomized clinical trials in patients with oropharyngeal/oesophageal and invasive candidiasis, caspofungin was at least as effective as amphotericin B deoxycholate, yet showed a significantly superior safety profile. Of patients with invasive aspergillosis refractory to or intolerant of other antifungal agents, 45% showed a partial or complete response to caspofungin given as a salvage treatment. Also, it demonstrated comparable clinical efficacy but superior tolerability in the empirical antifungal therapy in neutropenic patients compared with liposomal amphothericin B. Caspofungin has an excellent tolerability and a low potential for drug interactions. Thus, caspofungin represents an interesting and clinically valuable new antifungal drug that broadens the available therapeutic armamentarium for the treatment of invasive fungal infections.     

Infectious disease update: new anti-microbials

Effective antimicrobials are critical in controlling one of the most common conditions encountered in medicine, namely, skin and skin structure infections. Unfortunately, the identification of appropriate and novel antimicrobials is continually challenged by the emergence of antimicrobial resistance among bacteria, fungi, and parasites. This work will focus on describing novel antibacterials and antifungals approved by the United States Food and Drug Administration in the past 4 years.     

Impact of special patient populations on the pharmacokinetics of echinocandins

Echinocandins belong to the class of antifungal agents. Currently, three echinocandin drugs are licensed for intravenous treatment of invasive fungal infections: anidulafungin, caspofungin and micafungin. While their antifungal activity overlaps, there are substantial differences in pharmacokinetics (PK). Numerous factors may account for variability in PK of echinocandins including age (pediatrics vs adults), body surface area and body composition (normal weight vs obesity), disease status (e.g., critically ill and burn patients) and organ dysfunction (kidney and liver impairment). Subsequent effects of altered exposure might impact efficacy and safety. Knowledge of PK behavior is crucial in optimal clinical utilization of echinocandin in a specific patient or patient population. This review provides up-to-date information on PK data of anidulafungin, caspofungin and micafungin in special patient populations. Patient populations addressed are neonates, children and adolescents, obese patients, patients with hepatic or renal impairment, critically ill patients (including burn patients) and patients with hematological diseases.     

Echinocandins - an update

Echinocandins and echinocandin-like compounds are non-competitive inhibitors of the synthesis of 1,3-β-D-glucan, a major and essential component in the wall of many important fungal pathogens. Since this polysaccharide is not present in mammalian cells the glucan synthase became an attractive target for the development of new antifungal agents. In the last 25 years, several research institutes claimed new synthetic derivatives of echinocandin B and related natural cyclic hexapeptides with antifungal activity. The main goal is to find glucan synthesis inhibitors with a broad spectrum of fungicidal activity and useful oral bioavailability. In the last 3 years several patents have been filed and papers published, most of them claim novel echinocandin-like compounds, a few present processes for preparing oral echinocandin formulations and others include combinations of echinocandins with other antifungal agents, calcineurin inhibitors or human effector cells.     

Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study

M. Winkler, J. Pratschke, U. Schulz, S. Zheng, M. Zhang, W. Li, M. Lu, D. Sgarabotto, G. Sganga, P. Kaskel, S. Chandwani, L. Ma, J. Petrovic, M. Shivaprakash. Caspofungin for post solid organ transplant invasive fungal disease: results of a retrospective observational study.
Transpl Infect Dis 2010: 12: 230–237. All rights reserved Objective. This study was designed to determine clinical outcomes with caspofungin in patients with proven or probable invasive fungal infection (IFI) after a solid organ transplant (SOT) procedure. Methods. In this retrospective observational study, data were collected for a single episode of IFI in patients with an SOT between January 2004 and June 2007. Response was determined by the investigator as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT). The primary effectiveness population was the proportion of patients who received ≥5 doses of caspofungin (modified all‐patients‐treated population). Safety was assessed for patients who received ≥1 dose of caspofungin. Results. A total 81 of patients from 13 sites in China, Germany, Italy, and the United Kingdom were enrolled, including 49 (60%) liver, 22 (27%) heart, 5 (6%) lung, 2 (2%) kidney, 2 (2%) liver and kidney, and 1 (1%) pancreas and kidney recipients. Candidiasis was diagnosed in 64/81 patients (79%) and aspergillosis in 22/81 patients (27%). Most patients received caspofungin monotherapy (75%). Caspofungin was given as first‐line therapy to 59 (73%) patients. The overall favorable response at EOCT was 87% (58/67; 95% confidence interval [CI]: 76%, 94%), with favorable responses in 88% (43/49; 95% CI: 75%, 95%) of patients receiving caspofungin monotherapy and 83% (15/18; 95% CI: 59%, 96%) of patients receiving combination therapy with caspofungin (modified all‐patients‐treated population). Response by type of SOT was as follows: liver 87% (39/45), heart 93% (14/15), kidney 100% (5/5), and lung 50% (2/4). An overall survival rate (all‐patients‐treated) of 69% (56/81; 95% CI: 59%, 79%) was observed at 7 days post EOCT. No serious drug‐related adverse events were reported. Conclusion. In this study, caspofungin was effective and well tolerated in the treatment of IFIs involving SOT recipients.     

Evaluation of synergistic anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans

This study aimed to investigate the synergy between anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans and Candida glabrata, with the help of a quantitative checkerboard microdilution assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as a viability dye. Apoptotic effects of caspofungin and ferulic acid concentrations (alone and combined) were analyzed for C. albicans and C. glabrata based on annexin V–propidium iodide binding capacities using flow cytometric analysis. C. albicans showed a synergistic effect, represented by a fractional inhibitory concentration index of < 0.5, but C. glabrata showed no synergistic effect (fractional inhibitory concentration index > 0.5). Early and late apoptotic effects of caspofungin and ferulic acid concentrations (1 μg/mL and 1000 μg/mL) were calculated as 55.7% and 18.3%, respectively, while their necrotic effects were determined as 5.8% and 51.6%, respectively, using flow cytometric analyses. The apoptotic effects of the combination of caspofungin and ferulic acid at concentrations of 1 μg/mL and 1000 μg/mL on C. albicans and C. glabrata were 73.0% and 48.7%, respectively. Ferulic acid also demonstrated a synergistic effect in combination with caspofungin against C. albicans. Another possibility is to combine the existing anticandidal drug with phytochemicals to enhance the efficacy of anticandidal drug.     

Pharmacokinetic Characteristics of Caspofungin in Two Pediatric Liver Transplant Patients

Background: The pharmacokinetic characteristics of the antifungal drug caspofungin have not been reported in children.Objective: The aim of this study was to report limited caspofungin pharmacokinetic data for pediatric liver transplant patients.Methods: Two pediatric liver transplant patients, aged 5 years (not dialyzed) and 9 months (dialyzed), were assessed. Using a novel, validated, liquid-phase extraction with high-performance liquid chromatography, we measured plasma caspofungin concentrations from blood samples obtained within a 24-hour period after the patients were given 1 mg/kg IV of caspofungin.Results: Noncompartmental analysis for the nondialyzed patient showed an elimination half-life of 10.7 hours, a volume of distribution of 0.11 L/kg, and a systemic clearance of 0.12 mL/min/kg. Liver enzyme activities increased briefly; the increase may have been due to concomitant graft rejection. For the dialyzed patient, the half-life was 11.7 hours, with an adjusted volume of distribution of 0.18 L/kg and a systemic clearance of 0.24 mL/min/kg. No clinically relevant treatment-related adverse events were noted.Conclusions: Pharmacokinetic data found in the 2 patients in this study are similar to those reported in adults. Until more thorough data are published, caspofungin 1 mg/kg may be considered a reasonable, tolerable dose for children.     

Triacetylfusarinine C: A urine biomarker for diagnosis of invasive aspergillosis

1. Download high-res image (76KB)
2. Download full-size image