Caspofungin Use in Daily Clinical Practice for Treatment of Invasive Aspergillosis: Results of a Prospective Observational Registry

<p>Abstract</p> <p>Background</p> <p>A prospective observational registry assessed real world experience with caspofungin monotherapy or combination therapy for the initial or salvage treatment of proven or probable invasive aspergillosis (IA).</p> <p>Methods</p> <p>Data were collected from April 2006 to September 2007 for patients treated with caspofungin for a single episode of IA. Clinical effectiveness was categorized as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT).</p> <p>Results</p> <p>Consecutive patients (n = 103) with proven or probable IA (per EORTC/MSG criteria) were identified from 11 countries. Malignancy (76.7%), neutropenia (64.1%), allogeneic hematopoietic stem cell transplantation (HSCT, 22.3%), solid organ transplantation (8.7%), autologous HSCT (4.9%), and HIV/AIDS (2.9%) were the most common underlying conditions. Most patients (84.5%) had pulmonary IA. <it>Aspergillus fumigatus </it>was the most frequently isolated species. The majority of patients received caspofungin monotherapy (82.5%) primarily as salvage therapy (82.4%). The main reason for switching to salvage therapy was clinical failure of the first-line therapy (69%). A favorable response at EOCT was seen in 56.4% (57/101) of patients overall, including 56.5% (48/85) and 56.3% (9/16) of patients receiving caspofungin monotherapy and combination therapy, respectively. Favorable response rates in clinically relevant subgroups were: malignancy, 51.9% (41/79); allogeneic HSCT, 56.5% (13/23); and neutropenia at time of hospitalization, 53.0% (35/66). There was a 72.3% (73/101) survival at 7 days after EOCT. Serious adverse events related to caspofungin were reported in 4 cases (3.9%); 3 patients (2.9%) discontinued treatment due to an adverse event related to caspofungin.</p> <p>Conclusions</p> <p>Caspofungin was both effective and well tolerated among high-risk patient groups such as those with neutropenia and active malignancies.</p

Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy

Background. Invasive aspergillosis (IA) is an important cause of morbidity and mortality among immuno-compromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo activity against Aspergillus species. Methods. We investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin. Results. Efficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received greater than or equal to1 dose of study drug. Common underlying conditions included hematologic malignancy ( 48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently. Conclusion. Caspofungin demonstrated usefulness in the salvage treatment of IA

A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients.

We evaluated the safety, tolerability, and efficacy of caspofungin in pediatric patients with invasive aspergillosis, invasive candidiasis, or esophageal candidiasis. METHODS: This was a multicenter, prospective, open-label study in children 3 months to 17 years of age with proven or probable invasive aspergillosis, proven invasive candidiasis, or proven esophageal candidiasis. All of the patients received caspofungin 70 mg/m(2) on day 1, followed by 50 mg/m(2) per day (maximum: 70 mg/day), as primary or salvage monotherapy. Favorable response was defined as complete resolution of clinical findings and microbiologic (or radiographic/endoscopic) eradication (complete response) or significant improvement in these parameters (partial response). Efficacy was assessed at the end of caspofungin therapy in patients with a confirmed diagnosis who received >/=1 dose of caspofungin. The primary safety evaluation was the proportion of patients with clinical or laboratory drug-related adverse events. RESULTS: Of the 49 patients enrolled, 3 were <2 years of age, 30 were 2 to 11 years of age, and 16 were 12 to 17 years of age. Forty-eight patients had confirmed disease: invasive aspergillosis (10), invasive candidiasis (37), and esophageal candidiasis (1). Eight of 10 patients with invasive aspergillosis had pulmonary involvement; 34 of 37 patients with invasive candidiasis had candidemia. Caspofungin was given for 2 to 87 days. Success at end of therapy was achieved in 5 of 10 patients with invasive aspergillosis, 30 of 37 with invasive candidiasis, and 1 of 1 with esophageal candidiasis. One patient (invasive candidiasis) relapsed during the 28-day follow-up period. Drug-related clinical or laboratory adverse events occurred in 27% and 35% of patients, respectively. There were no serious drug-related adverse events or discontinuations of caspofungin because of toxicity. CONCLUSIONS: Caspofungin was generally well tolerated in pediatric patients aged 6 months through 17 years. Efficacy outcomes in patients with invasive aspergillosis or invasive candidiasis were consistent with previous adult studies in these indications

Pharmacokinetics and Pharmacodynamics of Antifungals in Children and their Clinical Implications

Invasive fungal infections are a significant cause of morbidity and mortality in children. Successful management of these systemic infections requires identification of the causative pathogen, appropriate antifungal selection, and optimisation of its pharmacokinetic and pharmacodynamic properties to maximise its antifungal activity and minimise toxicity and the emergence of resistance. This review highlights salient scientific advancements in paediatric antifungal pharmacotherapies and focuses on pharmacokinetic and pharmacodynamic studies that underpin current clinical decision making. Four classes of drugs are widely used in the treatment of invasive fungal infections in children, including the polyenes, triazoles, pyrimidine analogues and echinocandins. Several lipidic formulations of the polyene amphotericin B have substantially reduced the toxicity associated with the traditional amphotericin B formulation. Monotherapy with the pyrimidine analogue flucytosine rapidly promotes the emergence of resistance and cannot be recommended. However, when used in combination with other antifungal agents, therapeutic drug monitoring of flucytosine has been shown to reduce high peak flucytosine concentrations, which are strongly associated with toxicity. The triazoles feature large inter-individual pharmacokinetic variability, although this pattern is less pronounced with fluconazole. In clinical trials, posaconazole was associated with fewer adverse effects than other members of the triazole family, though both posaconazole and itraconazole display erratic absorption that is influenced by gastric pH and the gastric emptying rate. Limited data suggest that the clinical response to therapy may be improved with higher plasma posaconazole and itraconazole concentrations. For voriconazole, pharmacokinetic studies among children have revealed that children require twice the recommended adult dose to achieve comparable blood concentrations. Voriconazole clearance is also affected by the cytochrome P450 (CYP) 2C19 genotype and hepatic impairment. Therapeutic drug monitoring is recommended as voriconazole pharmacokinetics are highly variable and small dose increases can result in marked changes in plasma concentrations. For the echinocandins, the primary source of pharmacokinetic variability stems from an age-dependent decrease in clearance with increasing age. Consequently, young children require larger doses per kilogram of body weight than older children and adults. Routine therapeutic drug monitoring for the echinocandins is not recommended. The effectiveness of many systemic antifungal agents has been correlated with pharmacodynamic targets in in vitro and in murine models of invasive candidiasis and aspergillosis. Further study is needed to translate these findings into optimal dosing regimens for children and to understand how these agents interact when multiple antifungal agents are used in combination