Caspofungin: an overview

The echinocandins are a novel class of antifungal agents that have come into use over the past 10 years. The mechanism of action of these lipopeptide agents is via noncompetitive inhibition of the synthesis of 1,3-β-glucans, which are fungal cell wall constituents. All agents of this class are only available in an intravenous formulation. The first approved agent of this class was caspofungin (Cancidas^®). Caspofungin is a therapeutic option for patients with candidal esophagitis and deep-seated candidal infections, and is an alternative therapy for Aspergillus infections, especially in the salvage setting. In addition, it is a therapeutic option for the empiric therapy of febrile neutropenia. The usefulness of this agent in treating less common fungal infections has been cited in anecdotal reports. One major limitation of this drug is the lack of an oral formulation. Caspofungin may be considered as a component of combination antifungal regimens. Caspofungin represents a significant advance in the care of patients with serious fungal infections.     

Endogenous Candida endophthalmitis

Intraocular Candida infections, although uncommon, represent an important clinical problem owing to the potential for visual loss, which can be bilateral. Candida chorioretinitis and endophthalmitis are complications of systemic candidiasis with extension of the fungal pathogens to the uvea and retina. Early diagnosis and prompt management significantly affect the visual prognosis for these patients. This review evaluates the current literature on Candida endophthalmitis and includes discussion on presentation, diagnosis and management strategies. New systemic and intravitreal antifungal agents are also reviewed in the context of the management of intraocular fungal infection.     

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.     

卡泊芬净、伏立康唑序贯疗法与伊曲康唑完整疗程治疗52例恶性血液病患者继发侵袭性真菌感染的疗效比较

 目的 评价卡泊芬净（caspofungin）静脉注射后口服伏立康唑(voriconazole)序贯治疗与伊曲康唑（itraconazole）完整疗程两种不同经验性抗真菌治疗方法在恶性血液病患者中的疗效及安全性。方法 回顾性分析无锡市人民医院2005年1月至2008年4月间52例恶性血液病患者继发侵袭性真菌感染患者根据不同抗真菌治疗方法分成两组,A组（22例）,采用卡泊芬净静注后伏立康唑口服序贯疗法;B组（30例）,采用伊曲康唑完整疗程治疗。观察两组患者的疗效和不良反应。结果 A组的总有效率为81.8%（18/22）,药物相关的不良反应发生率9.1％（2/22）。B组的总有效率63.3％（19/30）,不良反应发生率16.7％（5/30）。两组总有效率均较高,但有显著性差异（P <0.05）,A组不良反应率显著低于B组。结论 二种方案对恶性血液病继发侵袭性真菌感染的患者均有效。卡泊芬净联合伏立康唑疗法比伊曲康唑完整疗程疗法更具有疗效优势,且安全性好,不良事件发生率低。     

A multicentre study of antifungal strategies and outcome of Candida spp. peritonitis in intensive-care units

Information on the species causing Candida peritonitis, their in vitro susceptibility, antifungal strategies in this setting and patient outcome is still scarce. AmarCand was a prospective, non-interventional study in 271 adult intensive-care unit (ICU) patients with proven invasive Candida infection who received systemic antifungal therapy (France, 2005–2006). Of these ICU patients, 93 (median age 65 years, simplified acute physiology score II 52) had Candida peritonitis, including 73 nosocomial peritonitis, 53 concomitant bacterial peritoneal infections and 26 candidaemias. Candida species were C. albicans (n = 63/108 isolates, 58%), C. glabrata (n = 22, 20%), C. krusei (n = 9), C. kefyr (n = 5), C. parapsilosis (n = 3), C. tropicalis (n = 3), C. ciferii (n = 2) and C. lusitaniae (n = 1). Of tested isolates, 28% were fluconazole-resistant or susceptible dose-dependent (C. albicans 3/32, C. glabrata 9/14, C. krusei 4/4). Empiric antifungal treatment was started 1 day (median) after peritonitis diagnosis, with fluconazole (n = 72 patients), caspofungin (n = 12), voriconazole (n = 3), amphotericin B (n = 2), or a combination (n = 4). Following susceptibility testing, empiric antifungal treatment was judged inadequate in 9/45 (20%) patients and modified in 30 patients (fluconazole was replaced by caspofungin (n = 14) or voriconazole (n = 4)). Mortality in ICU was 38% (35/93) and was not influenced by type of Candida species, fluconazole susceptibility, time to treatment, candidaemia, nosocomial acquisition, or concomitant bacterial infection. No specific factors for death were identified. In summary, a high proportion of fluconazole-resistant or susceptible dose-dependent strains was cultured. These results confirm the high mortality rates of Candida peritonitis and plead for additional investigation in this population. Antifungal treatment for severe cases of Candida peritonitis in ICU patients remains the standard care.     

Acremonium sclerotigenum-Acremonium egyptiacum: a multi-resistant fungal pathogen complicating the course of aplastic anaemia

A patient with aplastic anaemia, successively treated with caspofungin then liposomal amphotericin, developed a disseminated infection due to Acremonium, further confirmed as resistant in vitro to these drugs. Successful treatment was achieved with voriconazole. Multiple antifungal treatments may expose to the risk of breakthrough of multi-resistant pathogens in haematology patients.     

Disseminated aspergillosis in an adolescent with acute lymphoblastic leukemia

Disseminated aspergillosis in immunocompromised patients has a mortality rate of almost 100%. Despite the development of new antifungal agents, the outcome of disseminated aspergillosis has only improved slightly, particular in patients with central nervous system (CNS) involvement. The use of combination antifungal therapy might improve the dismal outcome of disseminated aspergillosis. We describe a critically ill adolescent with acute lymphoblastic leukemia who was successfully treated with voriconazole and caspofungin for disseminated aspergillosis with involvement of the lung, brain and thyroid gland.     

Caspofungin is less nephrotoxic than amphotericin B in vitro and predominantly damages distal renal tubular cells.

BACKGROUND: Caspofungin (CAS) has recently been approved for treatment of invasive aspergillosis. In clinical trials, CAS-induced nephrotoxicity was markedly less pronounced compared to amphotericin B (AmB). Nevertheless, in a recent trial, nephrotoxicity in CAS-treated patients was considerably more pronounced than in preceding studies. Therefore, the aim of this study was to assess toxic effects of CAS on human renal proximal and distal tubular epithelial cells (PTC and DTC) in vitro, and to compare them to those of AmB. METHODS: Cells were isolated from human kidney tissue, and exposed to clinically relevant concentrations of CAS and AmB for 24 h. Total DNA content and cell viability were determined by DAPI staining and a modified MTT assay. For testing of cytotoxicity, LDH activity was measured in cell culture supernatants. To assess apoptotic effects, AnnexinV-binding assay and DAPI staining for detection of fragmented DNA were performed. RESULTS: DTC were more vulnerable towards the antifungal agents than PTC. In contrast to AmB, cell-damaging effects of CAS were less severe. DAPI staining revealed slight and dose-dependent antiproliferative effects of CAS at concentrations reflecting relevant plasma levels. At these concentrations, cell viability, determined by MTT assay, was not decreased in PTC and DTC. LDH release was marginally increased in a dose-dependent manner; apoptosis was not detected. Nevertheless, at CAS concentrations reflecting potential tissue concentrations, cell damaging effects were considerably more pronounced. CONCLUSION: Our results suggest that CAS is less nephrotoxic than AmB in vitro. The antiproliferative and cytotoxic effects of CAS predominantly affect DTC, which seem to be more susceptible to CAS-induced damage.     

Uncommon Candida Species Fungemia among Cancer Patients,Houston, Texas,USA

Many uncommon Candida species that cause bloodstream infections (BSIs) are not well-characterized. We investigated the epidemiology, antifungal use, susceptibility patterns, and factors associated with all-cause death among cancer patients in whom uncommon Candida spp. BSIs were diagnosed at a cancer treatment center during January 1998–September 2013. Of 1,395 Candida bloodstream isolates, 79 from 68 patients were uncommon Candida spp. The incidence density of uncommon Candida spp. BSIs and their proportion to all candidemia episodes substantively increased during the study period, and the rise was associated with increasing use of echinocandin antifungal drugs. Thirty-seven patients had breakthrough infections during therapy or prophylaxis with various systemic antifungal drugs for >7 consecutive days; 21 were receiving an echinocandin. C. kefyr (82%), and C. lusitaniae (21%) isolates frequently showed caspofungin MICs above the epidemiologic cutoff values. These findings support the need for institutional surveillance for uncommon Candida spp. among cancer patients.