Randomized, double-blind, multicenter study of caspofungin versus amphotericin B for treatment of oropharyngeal and esophageal candidiases.

Caspofungin is an antifungal agent of the novel echinocandin class. We investigated its efficacy, safety, and tolerability as therapy for oropharyngeal and/or esophageal candidiasis in a phase II dose-ranging study. Patients were randomized in a double-blind manner to receive either caspofungin acetate (35, 50, or 70 mg) or amphotericin B (0.5 mg/kg of body weight) intravenously once daily for 7 to 14 days. A favorable response required both complete resolution of symptoms and quantifiable improvement of mucosal lesions 3 to 4 days after discontinuation of study drug. Efficacy was assessed using a modified intent-to-treat analysis. No hypothesis testing of efficacy was planned or performed. Of 140 enrolled patients, 63% had esophageal involvement and 98% were infected with the human immunodeficiency virus (HIV) (median CD4 count, 30/mm(3)). A modestly higher proportion of patients in each of the caspofungin groups (74 to 91%) achieved favorable responses compared to amphotericin B recipients (63%), but there was considerable overlap in the 95% confidence intervals surrounding these point estimates. Similar trends were found in the subgroups with esophageal involvement, a history of fluconazole failure, and CD4 counts of < or =50/mm(3). A smaller proportion of patients receiving any dose of caspofungin experienced drug-related adverse events compared to patients given standard doses of conventional amphotericin B (P < 0.01). Caspofungin provided a generally well-tolerated parenteral therapeutic option for HIV-infected patients with oropharyngeal and/or esophageal candidiasis in this study.     

Caspofungin: the first representative of a new antifungal class

Caspofungin (MK-0991; L-743,872) belongs to the echinocandin family, a new class of antifungal agents that act on the fungal cell wall by inhibiting glucan synthesis. Data in vitro, and experimental studies, have demonstrated that caspofungin has antifungal activity against yeasts of the genus Candida (including isolates resistant to azoles and amphotericin B), several species of filamentous fungi, including Aspergillus, and certain dimorphic fungi, such as Histoplasma, Blastomyces and Coccidioides. In vitro and in animals, caspofungin shows additive or synergic antifungal activity with amphotericin B and triazoles. It also possesses activity against Pneumocystis carinii. Clinical trials have shown caspofungin to be well tolerated and effective in invasive aspergillosis in patients refractory or intolerant to standard treatment (45% favourable responses), in oropharyngeal and oesophageal candidiasis (67-93% favourable responses with an efficacy similar to those of amphotericin B and fluconazole), and in invasive candidiasis with efficacy equivalent to that of amphotericin B, and better tolerability. The results of these first clinical trials were promising, and led to the approval of caspofungin for invasive aspergillosis after failure of, or intolerance to, standard therapy. Further studies are required to define the exact role of caspofungin in the antifungal armamentarium.     

Caspofungin for the treatment of less common forms of invasive candidiasis

OBJECTIVES: Caspofungin has demonstrated efficacy in invasive candidiasis. However, in a comparative study, most patients (>83%) had candidaemia. Therefore, we performed a study in patients with non-fungaemic invasive candidiasis. PATIENTS AND METHODS: Adults with proven non-fungaemic invasive candidiasis or probable chronic disseminated candidiasis (CDC) received caspofungin primary or salvage monotherapy. Most patients received 50 mg daily following a 70 mg loading dose. Patients with endocarditis, osteomyelitis or septic arthritis received caspofungin at 100 mg daily and were allowed dose escalation up to 150 mg. Primary efficacy endpoint was the overall response at end of caspofungin therapy. A favourable overall response required complete resolution of symptoms and either eradication of Candida or radiographic resolution. RESULTS: All 48 patients enrolled had confirmed infection and received>or=1 dose of caspofungin. At study entry, 8% were neutropenic. The mean APACHE II score was 14.3. Most infections were due to Candida albicans (60%) or Candida glabrata (14%). The overall success at end of caspofungin therapy was 81%. Success by site of infection was as follows: peritonitis 77% (10/13), abdominal abscess 89% (8/9), CDC 88% (7/8), osteomyelitis/septic arthritis 100% (4/4), endocarditis 33% (1/3) and multiple sites 75% (6/8). Outcomes were similar across Candida spp. None of the patients had a serious drug-related adverse event or discontinued caspofungin due to toxicity. Overall mortality until 12 week follow-up was 23%. CONCLUSIONS: In deep-seated invasive candidiasis, including peritonitis, abdominal abscesses, CDC and arthritis, caspofungin was effective and safe at regular doses and up to 100 mg daily.     

卡泊芬净治疗中国成年人侵袭性念珠菌病和食管念珠菌病的安全性、耐受性及疗效的非对照、多中心、开放性研究

目的评价卡泊芬净注射剂治疗中国成年人侵袭性念珠菌病和食管念珠菌病的疗效及安全性。方法本研究为非对照、多中心、开放性临床研究,入选对象为年龄≥18岁,确诊为侵袭性念珠菌病或食管念珠菌病需要进行抗真菌治疗的中国成人患者。采用卡泊芬净静脉给药,每日50 mg,首日采用70 mg负荷剂量。在最后一次血液或其他正常无菌部位培养阳性后继续治疗至少14 d。食管念珠菌病患者每日50 mg,疗程至少7 d,症状缓解后继续治疗72 h。结果共入选63例患者,包括侵袭性念珠菌病60例,食管念珠菌病3例,其中安全性分析集（SS）63例,全分析集（FAS）63例,符合方案集（PPS）50例。SS 63例患者中,14例发生19例次严重不良事件,均与研究药物无关;发生与药物有关的非严重不良事件31例73例次,其中4例同时发生临床不良事件和实验室指标异常;8例发生12例次临床不良事件,主要为皮疹等,其中91.7%（11/12）属轻、中度。27例发生实验室指标异常,主要为ALT等肝酶升高、血钾降低等。与研究药物相关的不良事件总发生率为49.2%（31/63）,其中临床不良事件发生率为12.7%（8/63）,实验室指标异常发生率为42.9%（27/63）。1例因不良事件终止治疗,占1.6%（1/63）。FAS和PPS中的总有效率分别为58.1%（36/62）和70.0%（35/50）。FAS中,侵袭性念珠菌病的有效率为57.6%（34/59）,食管念珠菌病为2/3。PPS中,侵袭性念珠菌病的有效率为68.8%（33/48）,食管念珠菌病为3/3。结论卡泊芬净治疗中国成年人侵袭性念珠菌病和食管念珠菌病临床不良反应大多为轻、中度,患者可耐受。卡泊芬净可有效治疗中国成年人侵袭性念珠菌病和食管念珠菌病。     

Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey

OBJECTIVES: Although a paediatric dosage has not been established, caspofungin is occasionally used in paediatric patients. We conducted a multicentre retrospective survey to obtain data on immunocompromised paediatric patients considered to require caspofungin therapy. METHODS: The survey identified 64 patients (median age: 11.5 years; 25 females, 39 males) with haematological malignancies (48), marrow failure (9), solid tumours (3), haematological disorders (2) and congenital immunodeficiency (2) who received caspofungin for proven (17), probable (14) and possible (17) invasive fungal infections or empirically (16). Caspofungin was administered until intolerance or maximum efficacy at dosages individually determined by the responsible physician for refractory infection (38), intolerance of other agents (10) or as best therapeutic option (16). RESULTS: The 64 patients received caspofungin for a median of 37 days (range 3-218) as single agent (20) or in combination (44). The median daily maintenance dosage was 1.07 mg/kg (95% CI 1.09-1.35; range 0.40-2.92) or 34.3 mg/m2 (95% CI 32.3-37.3; range 16.3-57.5). In none of the patients was therapy discontinued due to adverse events (AEs). Clinical AEs were mild to moderate and observed in 34 patients (53.1%). While mean glutamate pyruvate transaminase and glutamate oxalate transaminase values were slightly (P < 0.005) higher at the end of treatment (EOT), serum bilirubin, alkaline phosphatase and creatinine values were not different from baseline. Complete responses, partial responses or stabilization were observed in 5/7/3 of 17 patients with proven, in 3/4/3 of 14 patients with probable and in 7/6/1 of 15 evaluable patients with possible invasive infections. Thirteen of 16 patients on empirical therapy completed without breakthrough infection. Overall survival was 75% at the EOT and 70% at 3 months post-EOT, respectively. CONCLUSIONS: Caspofungin displayed favourable safety and tolerance and may have useful antifungal efficacy in severely immunocompromised paediatric patients.     

Caspofungin treatment in severely ill, immunocompromised patients: a case-documentation study of 118 patients

BACKGROUND: Caspofungin has shown efficacy in empirical antifungal therapy in neutropenic patients, refractory invasive Aspergillus infections and invasive candidiasis. Here we report the currently largest series of patients treated with caspofungin outside clinical trials. METHODS: Centres in Germany that were known to treat patients with invasive fungal infections were asked to fill out detailed questionnaires for all patients treated with caspofungin. No effort was made to influence the decision to use caspofungin. RESULTS: A total of 118 patients were evaluable (median age 48 years, interquartile range 38-58), out of which 41 (35%) suffered from acute leukaemia, 31 (26%) had allogeneic stem cell transplants, 16 (14%) lymphoma or myeloma, 8 (7%) autologous stem cell transplants and 22 (19%) other causes for immunosuppression. One hundred and six patients were evaluable for efficacy out of which 68 (64%) patients achieved a complete or partial remission. A total of 81 out of 115 (70%) patients were alive 30 days after the end of caspofungin therapy. Response rates were similar in proven (20/32, 63%) and probable (27/46, 59%) infections, in neutropenic patients (41/55, 75%) and in patients who were (44/70, 63%) or were not (24/36, 67%) refractory to antifungal pre-treatment. The response rate in mechanically ventilated patients was 29% (7/24). Caspofungin was well tolerated, even in 14 patients, who were concomitantly treated with ciclosporin A, no drug-related elevations of bilirubin, alanine aminotransferase or creatinine were found. CONCLUSIONS: This open case study of severely ill patients with invasive fungal infections demonstrates both excellent efficacy and very low toxicity of caspofungin.     

Invasive candidiasis treated in the intensive care unit: observations from a randomized clinical trial

OBJECTIVES: The objectives of this study were to contrast risk factors, microbiology, and outcomes in patients with invasive candidiasis treated in an intensive care unit (ICU) with those in patients with invasive candidiasis treated outside an ICU and to describe therapeutic results with caspofungin in ICU patients. MATERIALS AND METHODS: We retrospectively identified patients with documented invasive candidiasis who received their first dose of the study drug in the ICU as part of a double-blind randomized trial. Participants were not stratified at entry by their ICU status. Patients received caspofungin (50 mg/d after a 70-mg loading dose) or conventional amphotericin B (0.6-1.0 mg/kg per day) for 10 to 14 days. A favorable response required resolution of signs and symptoms as well as eradication of Candida pathogens. RESULTS: Of the 224 patients, 97 (43%) received their first dose of the study drug in the ICU. Most patients had well-recognized risk factors for invasive candidiasis, including broad-spectrum antibiotics, central venous catheters, and hyperalimentation. Recent surgery was more common whereas malignancy, neutropenia, and immunosuppression were less common among ICU patients than among non-ICU patients. Candidemia was demonstrated in 81% of ICU patients and in 84% of non-ICU patients. Favorable response rates in the ICU patients vs the non-ICU patients were 68% (95% confidence interval [CI] = 53%, 82%) vs 77% (95% CI = 67%, 87%) for caspofungin and 56% (95% CI = 43%, 69%) vs 67% (95% CI = 55%, 79%) for amphotericin B. After accounting for differences in APACHE (Acute Physiology and Chronic Health Evaluation) II score, neutropenia status, and geographic region, we found that patients initiating the study therapy in an ICU were still more likely to die than patients initiating study therapy outside an ICU. For ICU patients, all-cause mortality rates were 45% (95% CI = 30%, 60%) for caspofungin recipients and 40% (95% CI = 28%, 53%) for amphotericin B recipients, whereas candidiasis-attributable mortality rates were 5% (95% CI = 0%, 12%) for caspofungin recipients and 11% (95% CI = 3%, 19%) for amphotericin B recipients. Overall, drug-related adverse events were reported less often among the ICU patients than among the non-ICU patients. CONCLUSIONS: In ICU patients treated with antifungal therapy, invasive candidiasis is associated with substantial mortality, but most deaths cannot be directly attributed to this infection.     

Anidulafungin: a new echinocandin with a novel profile

BACKGROUND: Until recently, available treatment for serious fungal infections comprised amphotericin B and azoles, which have limitations. Renal toxicity is a major concern with amphotericin B, while drug-drug interactions, hepatotoxicity, and skin rashes are the primary concerns with the azole medications. The development of the echinocandins, including caspofungin, has helped to fill the need for more efficacious antifungals that are useful across different patient populations and have a good safety profile. Anidulafungin is an echinocandin being developed to treat mucosal and invasive fungal infections. OBJECTIVE: The aim of this report was to describe the pharmacodynamic and pharmacokinetic (PK) properties of anidulafungin. METHODS: Data were identified using MEDLINE and National Library of Medicine Gateway searches for English-language literature (key words: anidulafungin, esophageal candidiasis, echinocandin, caspofungin, ravuconazole, voriconazole, posaconazole, micafungin, and fluconazole; years: 1996-2004), and from meeting abstracts of the American Society for Blood and Marrow Transplantation (Arlington Heights, Illinois), European Congress of Clinical Microbiology and Infectious Diseases (Basel, Switzerland), International Conference on Antimicrobial Agents and Chemotherapy (Washington, DC), and Infectious Diseases Society of America (Arlington, Virginia). RESULTS: Anidulafungin has potent in vitro activity against Aspergillus and Candida spp, including those resistant to either fluconazole or amphotericin B. Results of several clinical trials imply that anidulafungin is effective in treating esophageal candidiasis (EC), candidemia, and invasive candidiasis (IC). In a Phase III, randomized, blinded clinical trial evaluating anidulafungin (50 mg/d) versus fluconazole (100 mg/d) for the treatment of EC, 97.2% and 98.9% of patients who received anidulafungin and fluconazole, respectively, showed evidence of cure or improvement (treatment difference, -1.6%; 95% CI, -4.1 to 0.8). In a Phase II study of candidasis and candidemia, anidulafungin showed success rates of 72%, 85%, and 83% in patients receiving the drug at dosages of 50, 75, or 100 mg/d, respectively. Studies evaluating the concomitant use of anidulafungin and either amphotericin, voriconazole, or cyclosporine did not show clinically significant drug-drug interactions or altered adverse-event (AE) profiles (P < 0.05). A population PK analysis showed no significant effect of age, race, concomitant medications, or renal or hepatic insufficiency on the PK properties of anidulafungin (P < 0.05). CONCLUSIONS: Anidulafungin may offer a new option to treat serious fungal infections, such as EC, azole-refractory EC, candidemia, and IC. In addition, anidulafungin has been associated with no clinically significant drug-drug interactions and few treatment-related AEs. Anidulafungin may offer a new option in the management of serious and difficult-to-treat invasive fungal infections.     

Efficacy of caspofungin in a juvenile mouse model of central nervous system candidiasis

Neonatal candidiasis is an increasingly common occurrence causing significant morbidity and mortality and a higher risk of dissemination to the central nervous system (CNS) than that seen with older patients. The current understanding of optimal antifungal therapy in this setting is limited. We have developed a model of disseminated candidiasis with CNS involvement in juvenile mice to assess the efficacy of the echinocandin caspofungin relative to amphotericin B (AmB). Juvenile mice were inoculated intravenously with 5.64 × 10(4) CFU of Candida albicans MY1055. Treatment with caspofungin at 1, 2, 4, and 8 mg/kg of body weight/day, AmB at 1 mg/kg/day, or a vehicle control (VC) was initiated 30 h after infection and continued for 7 days. Pharmacokinetic parameters for caspofungin were also determined. Culture and histology showed evidence of disseminated candidiasis with multifocal encephalitis at the start of antifungal therapy. Survival was 100% in all treated groups, while mortality was 100% in the VC by day 11 after infection. By day 5, all mice in the caspofungin treatment (four doses) groups showed reductions in kidney and brain burden relative to the VC, while AmB treatment reduced kidney burden but gave no reduction of brain fungal burden. Systemic levels of caspofungin were similar in infected and uninfected mice, while brain levels were higher in infected animals. In this juvenile mouse model, caspofungin demonstrated dose-dependent activity, equivalent to or better than that of AmB at 1 mg/kg, against disseminated candidiasis with CNS involvement.     

Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients

We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m2 daily after 70 mg/m2 on day 1). The area under the concentration-time curve from time zero to 24 h (AUC0-24), the concentration at the end of infusion (1 h after the start of infusion; C1), and the trough concentration (24 h after the start of infusion; C24) were obtained for 32 pediatric patients with invasive candidiasis, 10 with invasive aspergillosis, and 82 in the setting of empirical therapy with fever and neutropenia. Exposures were modestly higher (93 to 134% for C1, 45 to 78% for C24, ～40% for AUC0-24) in pediatric patients than in adults receiving the standard 50-mg daily dose. The potential for covariates (age, gender, weight, race, renal status, serum albumin level, and disease state) to alter PKs was evaluated with a multiple-linear-regression model. Weight and disease state had statistically significant (P<0.05) yet small effects on caspofungin PKs in pediatric patients. Concomitant use of dexamethasone (a cytochrome p450 inducer) was associated with a statistically significant reduction (44%) in C24 in a limited number of patients (n=4). Odds ratios were estimated for the association between log-transformed PKs and treatment outcome or adverse events. No PK parameter or hybrid parameter (AUC/MIC, C1/MIC, and C24/MIC) was significantly correlated with treatment outcome or adverse events in the setting of similar response levels as adults, which suggests that the concentrations examined fall within the therapeutic window for caspofungin in pediatric patients. These results support a 50-mg/m2 daily dosing regimen (after a 70-mg/m2 loading dose) in children ages 3 months to 17 years.     

Caspofungin susceptibility testing of isolates from patients with esophageal candidiasis or invasive candidiasis: relationship of MIC to treatment outcome

The caspofungin clinical trial database offers an opportunity to assess susceptibility results for Candida pathogens obtained from patients with candidiasis and allows for correlations between efficacy outcomes and MICs. Candida isolates have been identified from patients enrolled in four studies of esophageal candidiasis and two studies of invasive candidiasis. The MICs of caspofungin for all baseline isolates were measured at a central laboratory using NCCLS criteria (document M-27A); MICs for caspofungin were defined as the lowest concentration inhibiting prominent growth at 24 h. MICs were then compared to clinical and microbiological outcomes across the two diseases. Susceptibility testing for caspofungin was performed on 515 unique baseline isolates of Candida spp. obtained from patients with esophageal candidiasis. MICs for caspofungin ranged from 0.008 to 4 microg/ml; the MIC50 and MIC90 were 0.5 and 1.0 microg/ml, respectively. Susceptibility testing was also performed on 231 unique baseline isolates of Candida spp. from patients with invasive candidiasis. The majority (approximately 96%) of MICs were between 0.125 and 2 microg/ml, with MIC50 and MIC90 for caspofungin being 0.5 and 2.0 microg/ml, respectively. Overall, caspofungin demonstrated potent in vitro activity against clinical isolates of Candida species. A relationship between MIC for caspofungin and treatment outcome was not seen for patients with either esophageal candidiasis or invasive candidiasis. Patients with isolates for which the MICs were highest (>2 microg/ml) had better outcomes than patients with isolates for which the MICs were lower (<1 microg/ml). Additionally, no correlation between MIC and outcome was identified for specific Candida species.     

Caspofungin: an echinocandin antifungal agent

BACKGROUND: The mainstays of treatment for nosocomial fungal infections have been amphotericin B and azole derivatives. Caspofungin acetate is a new echinocandin antifungal agent with a mechanism of action that targets a structural component of the fungal cell wall. OBJECTIVE: This article describes the pharmacologic properties and potential clinical usefulness of caspofungin. METHODS: Relevant information was identified through searches of MEDLINE (1966-September 2001). Iowa Drug Information Service (1966-September 2001), and International Pharmaceutical Abstracts (1970-September 2001), as well as meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996-2001), using the terms caspofungin, MK-0991, pneumocandin, echinocandin, candin, and beta-(1,3)-glucan inhibitor. RESULTS: In vitro, caspofungin exhibits antifungal activity against an array of clinically important yeasts and molds, including Candida and Aspergillus spp. The proposed susceptibility breakpoint for caspofungin against Candida spp, the most common cause of nosocomial fungal infections, is a minimum inhibitory concentration of < or =1 microg/mL. In humans, caspofungin has a volume of distribution of 9.67 L, is extensively bound to albumin (97%), has a plasma elimination half-life of 9 to 11 hours, and is metabolized to inactive metabolites in the liver. Dose adjustment based on age, sex, race, or renal function does not appear to be necessary, although patients with moderate hepatic insufficiency (Child-Pugh score 7-9) should receive a lower maintenance dose. The results of clinical trials, although somewhat preliminary, suggest that caspofungin is effective in the treatment of esophageal and oropharyngeal candidiasis and invasive aspergillosis. When combined with other antifungal agents, caspofungin produces a synergistic or additive effect against a variety of clinically important fungi. The most commonly reported adverse events with caspofungin have included fever, infusion-related reactions, headache, nausea, elevations in liver transaminase levels, and histamine-type reactions. The recommended dosage in adults is 70 mg IV on day 1 followed by 50 mg/d, with the duration of treatment depending on the severity of the patient's underlying condition and the clinical response. CONCLUSION: Although additional studies are needed, caspofungin appears to be a promising agent for the treatment of patients with difficult-to-treat or life-threatening fungal infections.     

Phase II dose escalation study of caspofungin for invasive Aspergillosis

Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.     

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.     

抗真菌新药卡泊芬净在血液病患者经验性抗真菌治疗中的疗效观察

目的 探讨卡泊芬净在血液病患者经验性抗真菌治疗中的疗效.方法 将2008年10月至2010年10月收治的40例抗生素治疗无效且怀疑真菌感染的血液病患者随机分为两组,各20例,A组给予卡泊芬净治疗,第1天70 mg静脉滴注,第2天起50 mg静脉滴注;B组患者给予脂质体两性霉素B治疗,3 mg/(kg·d)静脉滴注.两组均治疗10 d,观察两组患者的疗效和不良反应.结果两组总有效率比较(66.7% vs.61.1%),差异无统计学意义(χ2=1.17,P>0.05),但A组肾毒性、输液反应发生率明显低于B组(χ2=4.37,4.37,P<0.05).结论 卡泊芬净用于血液病患者经验性抗真菌治疗,效果较好,患者耐受性较好,是侵袭性真菌感染的一个较好选择.     

Treatment of Candida glabrata infection in immunosuppressed mice by using a combination of liposomal amphotericin B with caspofungin or micafungin

While Candida albicans remains the most common Candida isolate, Candida glabrata accounts for approximately 15 to 20% of all Candida infections in the United States. In this study we used immunosuppressed mice infected with C. glabrata to investigate the efficacy of liposomal amphotericin B alone or in combination with the echinocandin caspofungin or micafungin. For monotherapy, mice were given six daily doses of liposomal amphotericin B (3 to 20 mg/kg of body weight), caspofungin (1 to 5 mg/kg), or micafungin (2.5 to 10 mg/kg). With concomitant therapy, mice received liposomal amphotericin B (7.5 mg/kg) in addition to caspofungin (2.5 mg/kg) or micafungin (2.5 mg/kg) for 6 days. For sequential therapy, liposomal amphotericin B was administered on days 1 to 3 and caspofungin or micafungin was given on days 4 to 6; conversely, caspofungin or micafungin was administered on days 1 to 3 and liposomal amphotericin B was given on days 4 to 6. Efficacy was based on the number of CFU per gram of kidney 21 days postchallenge. Monotherapy with liposomal amphotericin B (7.5 to 20 mg/kg) was significantly more effective than no drug treatment (control group) (P < 0.05) and demonstrated a dose-dependent response, with 20 mg/kg lowering the CFU/g from 6.3 to 4.2 (significantly different from the value for the control group [P < 0.001]). Monotherapy with all echinocandin doses lowered the CFU/g from 6.0 to 6.4 to 2.7 to 3.3 (significantly different from the value for the control group [P < 0.001]) with no dose-dependent response. Complete clearance of infection could be achieved only when liposomal amphotericin B was given either concomitantly with caspofungin or micafungin or if liposomal amphotericin B was given sequentially with caspofungin. In conclusion, the combination of liposomal amphotericin B with an echinocandin markedly improved the therapeutic outcome in murine C. glabrata systemic infection.     

Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents

Caspofungin is a parenteral antifungal that inhibits beta-1,3-D-glucan synthesis. Although licensed for adult use, the appropriate caspofungin dosing regimen in pediatric patients is not yet known. We therefore investigated the pharmacokinetics and safety of caspofungin in pediatric patients. Thirty-nine children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) with neutropenia were administered caspofungin using either a weight-based regimen (1 mg/kg of body weight/day) or a body surface area regimen (50 mg/m2/day or 70 mg/m2/day). Plasma samples for caspofungin profiles were collected on days 1 and 4. These results were compared to those from adults treated with either 50 or 70 mg/day for mucosal candidiasis. In children receiving 1 mg/kg/day (maximum, 50 mg/day), the area under the concentration-time curve over 24 h (AUC(0-24)) was significantly smaller (46% after multiple doses) than that observed in adults receiving 50 mg/day (P < 0.001). In children and adolescents receiving 50 mg/m2/day (maximum, 70 mg/day), the AUC(0-24) following multiple doses was similar to that for the exposure in adults receiving 50 mg/day. The AUC(0-24) and concentration trough (at 24 h) in pediatric patients receiving the 50-mg/m2 daily regimen were consistent across the range of ages. Caspofungin was generally well tolerated in this study. None of the patients developed a serious drug-related adverse event or were discontinued for toxicity. These results demonstrate that caspofungin at 1 mg/kg/day in pediatric patients is suboptimal. Caspofungin administration at 50 mg/m2/day provides a comparable exposure to that of adult patients treated with 50 mg/day.     

卡泊芬净与米卡芬净治疗重症侵袭性真菌感染的临床疗效与药物利用评价

目的探讨卡泊芬净和米卡芬净治疗重症侵袭性真菌感染（invasive fungal infections,IFI）患者的临床疗效,评价药物利用。方法随机抽取四川省人民医院2009年1月至2011年12月分别经卡泊芬净和米卡芬净治疗的IFI病例各40例,分析评价卡泊芬净和米卡芬净治疗IFI的疗效、不良反应及药物利用情况。结果治疗总有效率卡泊芬净组为57.5%,米卡芬净组为55.0%,差异无统计学意义（P〉0.05）;两组首选治疗有效率均远高于三唑类（如氟康唑、伊曲康唑）、多烯类（如两性霉素B及其脂质体）治疗无效或不能耐受而进行的挽救治疗有效率,差异有统计学意义（P〈0.05）;不良反应发生率卡泊芬净组高于米卡芬净组,但差异无统计学意义（P〉0.05）;药物利用指数（DUI）卡泊芬净为0.985,米卡芬净为1.000,使用基本合理;日用药金额卡泊芬净为1942.04元/天,米卡芬净为1260.00元/天。结论卡泊芬净和米卡芬净治疗重症IFI的疗效相当,首选二者治疗的有效率均高于挽救治疗;二者不良反应发生率相近;DUI≤1.0,为合理用药。二者在疗效和不良反应相当的情况下,从经济学角度考虑米卡芬净更具优势。     

Efficacy of oral E1210, a new broad-spectrum antifungal with a novel mechanism of action, in murine models of candidiasis, aspergillosis, and fusariosis

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action-inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by Candida species, Aspergillus spp., and Fusarium solani. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (P < 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant Candida albicans or Candida tropicalis. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the Aspergillus flavus pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (P < 0.05). E1210 was also effective in the treatment of Aspergillus fumigatus pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by F. solani. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.     

Antifungal interactions within the triple combination of amphotericin B, caspofungin and voriconazole against Aspergillus species

OBJECTIVES: The in vitro effects of caspofungin combined with voriconazole and amphotericin B were tested in triplicate experiments against nine clinical isolates of Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus. METHODS: The isolates were tested against a range of concentrations of voriconazole (0.015-1.0 mg/L), caspofungin (0.125-256 mg/L) and five concentrations of amphotericin B (0.1-0.5 mg/L) with a microdilution chequerboard method based on the CLSI M38-A reference method and the results were analysed with the fractional inhibitory concentration (FIC) index. The effect of individual drugs on the FIC index of each of the double combinations was also evaluated. RESULTS: The triple combination of voriconazole, caspofungin and amphotericin B against all Aspergillus spp. was synergistic (FIC index 0.49-0.57) at low median concentrations of amphotericin B (0.10-0.22 mg/L) and voriconazole (0.07-0.15 mg/L) over a wide range of caspofungin concentrations (4.32-17.28 mg/L). Antagonistic interactions (FIC index 1.65-2.15) were found at higher median concentrations of amphotericin B (0.3-0.5 mg/L) and voriconazole (0.23-0.68 mg/L) over a similarly wide range of caspofungin concentrations (1.47-32 mg/L). CONCLUSIONS: These concentration-dependent interactions may have important clinical implications, which require further evaluation in animal models of invasive aspergillosis.