Caspofungin treatment in two infants with persistent fungaemia due to Candida lipolytica

Candida lipolytica has infrequently been identified as a cause of infection and is associated mostly with vascular catheter-related fungaemia. Patients reported in the literature have been successfully treated with catheter removal or amphotericin B treatment. We report 2 infants with C. lipolytica fungaemia unresponsive to catheter removal and amphotericin B therapy and treated successfully with the addition of caspofungin to amphotericin B.     

Beta -1,3 glucan as a test for central venous catheter biofilm infection

Biofilms are microbial communities that are associated with solid surfaces such as intravascular catheters. Candida species are a major cause of medical device-associated infections. Twenty percent to 70% of all candidemias are associated with this biofilm process. Diagnosis and effective treatment of Candida device-associated infections requires removal of the involved device. The ability to identify a biofilm device infection before catheter removal may obviate removal of a substantial number of devices. Prior studies in our laboratory identified cell wall changes (specifically, increased beta -1,3 glucan) associated with biofilm, compared with planktonic C. albicans. Both in vitro and in vivo (catheter) biofilm models were used to determine whether biofilm cells secreted more beta -1,3 glucan and whether these differences could be used to discern the presence of a Candida biofilm infection with 3 species (C. albicans, C. glabrata, and C. parapsilosis). A limulus lysate assay was used to quantify beta -1,3 glucan in supernatants from planktonic or biofilm cultures and in the serum of rats with an intravascular catheter biofilm infection or disseminated candidiasis. beta -1,3 glucan was detected from both in vitro and in vivo models from each condition. However, the concentrations of beta -1,3 glucan from the biofilm conditions were 4-10-fold greater in vitro (P<.001) and were 10-fold greater in vivo (P<.001), despite equal or fewer numbers of cells in the biofilm conditions. These results suggest the secreted polysaccharide beta -1,3 glucan may serve as a useful tool for the diagnosis of Candida biofilm and device-associated infections.     

Treatment options of invasive fungal infections in adults

A panel of infectious disease specialists, clinical microbiologists and hospital epidemiologists of the five Swiss university hospitals reviewed the current literature on the treatment of invasive fungal infections in adults and formulated guidelines for the management of patients in Switzerland. For empirical therapy of Candida bloodstream infection, fluconazole is the drug of choice in non-neutropenic patients with no severe sepsis or septic shock or recent exposure to azoles. Amphotericin B deoxycholate or caspofungin would be the treatment option for patients with previous azole exposure. In neutropenic patients, empirical therapy with amphotericin B deoxycholate is considered first choice. In patients with severe sepsis and septic shock, caspofungin is the drug of first choice. For therapy of microbiologically-documented Candida infection, fluconazole is the drug of choice for infections due to C. albicans, C. tropicalis or C. parapsilosis. When infections are caused by C. glabrata or by C. krusei, caspofungin or amphotericin B deoxycholate are first line therapies. Treatment guidelines for invasive aspergillosis (IA) were stratified into primary therapy, salvage therapy and combination therapy in critically ill patients. Voriconazole is recommended for primary (ie upfront) therapy. Caspofungin, voriconazole (if not used for primary therapy) or liposomal amphotericin B are recommended for salvage therapy for refractory disease. Combination therapy with caspofungin plus voriconazole or liposomal amphotericin B should be considered in critically ill patients. Amphotericin B deoxycholate is recommended as initial therapy for the empirical therapy in patients with neutropenia and persistent fever with close monitoring of adverse events.     

Invasive candidiasis in cancer patients: observations from a randomized clinical trial

BACKGROUND: Invasive candidiasis is a common and serious complication of cancer and its therapy. METHODS: We retrospectively identified patients with malignancies enrolled in a double-blind randomized trial of caspofungin (50 mg/day after a 70 mg loading dose) vs. conventional amphotericin B (0.6-1.0 mg/kg/day) as treatment of documented invasive candidiasis. A favorable response required complete resolution of signs and symptoms plus eradication of the Candida pathogen(s). The primary efficacy analysis used a modified intention-to-treat (MITT) approach that included all patients with a confirmed diagnosis of invasive candidiasis who received > or =1 dose of study medication. RESULTS: 74/224 (33%) patients in the MITT population had active malignancies. 25/30 (83%) hematological malignancies were acute or chronic leukaemias. 22/44 (50%) solid tumors were related to the gastrointestinal tract. Patients with hematological malignancies tended to be younger (median [range] age: 49 [19-74] vs. 59 [19-81] years) and have higher baseline acute physiology and chronic health evaluation (APACHE) II scores (mean [range]: 17 [0-28] vs. 15 [5-35]) than patients with solid tumors. Neutropenia [< or =500/microl] was present on entry in 23 (77%) patients with hematological malignancies and in one (3%) patient with a solid tumor. Candidemia was demonstrated in 56 (88%) cancer patients. C. albicans was the single most frequent isolate in cancer patients, although the majority of cases were caused by non-albicans species. Cancer patients in the caspofungin arm had more hematological malignancies (55 vs. 29%), higher baseline APACHE II scores (>20 in 36 vs. 15%), more frequent neutropenia (42 vs. 24%), and less C. albicans infections (27 vs. 49%) than the amphotericin B-treated cancer patients. Favorable response rates were 11/18 (61%) and 6/12 (50%) for patients with hematological malignancies treated with caspofungin or amphotericin B, respectively; the corresponding outcomes in patients with solid tumors were 12/15 (80%) and 17/29 (59%) for the 2 treatment arms. 7/14 (50%) caspofungin- and 4/10 (40%) amphotericin B-treated patients who were neutropenic on entry responded favorably. All-cause mortality rates during the study for caspofungin recipients were 11/18 (61%) with hematological malignancies and 6/15 (40%) with solid tumors, and for amphotericin recipients were 4/12 (33%) with hematological malignancies and 6/29 (21%) with solid tumors. CONCLUSIONS: Underlying cancers, most commonly leukaemias and gastrointestinal tumors, were present in one-third of patients enrolled in this study of invasive candidiasis. Overall, 70% of caspofungin-treated and 56% of amphotericin B-treated cancer patients responded favorably. Response rates were lower for neutropenic leukaemic patients than for non-neutropenic patients with solid tumors in both treatment groups.     

A cost-effectiveness analysis of caspofungin vs. liposomal amphotericin B for treatment of suspected fungal infections in the UK

OBJECTIVE: To evaluate the cost-effectiveness of caspofungin vs. liposomal amphotericin B in the treatment of suspected fungal infections in the UK. METHODS: The cost-effectiveness of caspofungin vs. liposomal amphotericin B was evaluated using a decision-tree model. The decision tree was populated using both data and clinical definitions from published clinical studies. Model outcomes included success in terms of resolution of fever, baseline infection, absence of breakthrough infection, survival and quality adjusted life years (QALYs) saved. Discontinuation due to nephrotoxicity or other adverse events were included in the model. Efficacy and safety data were based on additional analyses of a randomised, double blind, multinational trial of caspofungin compared with liposomal amphotericin B. Information on life expectancy, quality of life, medical resource consumption and costs were obtained from peer-reviewed published data. RESULTS: The caspofungin mean total treatment cost was 9762 pounds (95% uncertainty interval 6955-12,577), which was 2033 pounds (-2489; 6779) less than liposomal amphotericin B. Treatment with caspofungin resulted in 0.40 (-0.12; 0.94) additional QALYs saved in comparison with liposomal amphotericin B. Probabilistic sensitivity analysis found a 95% probability of the incremental cost per QALY saved being within the generally accepted threshold for cost-effectiveness (30,000 pounds). Additional analyses with varying dose of caspofungin and liposomal amphotericin B confirmed these findings. CONCLUSION: Given the underlying assumptions, caspofungin is cost-effective compared with liposomal amphotericin B in the treatment of suspected fungal infections in the UK.     

Development of Candidemia on Caspofungin Therapy: a Case Report

Abstract Caspofungin, an echinocandin, is approved for use in invasive candidiasis. Few cases of break-through candidal infections during caspofungin therapy have been reported and none have involved Candida parapsilosis. Here, we report a patient who developed multiple post-operative complications after pancreaticoduodenectomy for a pancreatic mass, including fungemia due to C. parapsilosis, while on caspofungin for treatment of Candida glabrata peritonitis. The fungemia resolved after a central venous catheter was removed and therapy was switched from caspofungin to amphotericin B lipid complex. Studies of C. parapsilosis susceptibility and the pharmacodynamics and drug interactions of caspofungin that may contribute to breakthrough fungemia are discussed.     

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 immunocompromised 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 >or=1 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.     

Severe Candida albicans panophthalmitis treated with all available and potentially effective antifungal drugs: fluconazole, liposomal amphotericin B, caspofungin, and voriconazole

A severe case of Candida albicans panophthalmitis, probably prompted by an underlying diabetes mellitus, is reported. The course was prolonged (more than 16 weeks), although favourable after treatment with several antifungal agents, all with a predictable activity in this ocular complication and with proven susceptibility in the present case: fluconazole, liposomal amphotericin B, caspofungin, and voriconazole.     

Evaluation of single-drug and combination antifungal therapy in an experimental model of candidiasis in rabbits with prolonged neutropenia

We developed an experimental model of candidiasis in rabbits with prolonged neutropenia. Rabbits were made neutropenic with cytosine arabinoside (Ara-C) administered through an indwelling silastic catheter that had been surgically implanted in the external jugular vein. Neutropenia was sustained with intravenous Ara-C, and bacterial complications were prevented with parenteral ceftazidime plus ampicillin. Candidiasis was established by intravenously administering Candida albicans or Candida tropicalis (1-2 x 10(5) colony-forming units) and resulted in hepatic and splenic lesions that mimicked those associated with hepatosplenic candidiasis in humans. The kidney proved to be the site most refractory to eradication of Candida spp. and offered a target organ for assessing antifungal therapy. We evaluated amphotericin B, 5-flucytosine, ketoconazole, and rifampin, alone and in combination. Although each agent reduced the colony counts of Candida in the liver, spleen, and lung, the combination of amphotericin B and 5-flucytosine was the only regimen effective in eradicating renal candidiasis.     

Effects of sublethal concentrations of amphotericin B on Candida albicans

Because sublethal concentrations of antibodies can have important effects on bacteria and may aid host defenses, even in the absence of direct microbial killing, the effect of brief sublethal exposures to amphotericin B on Candida albicans blastoconidia was evaluated. Amphotericin B (0.01-1.0 micrograms/ml for 60 min) inhibited germ tube formation and yeast adherence to both serum-coated plastic surfaces and fibrin matrices. These effects were not reversed by cation (K+ or Mg++) supplementation. Amphotericin B pretreatment accelerated clearance of C. albicans from the peritoneal surfaces of mice and reduced the inflammatory stimulus associated with this clearance, at least as measured by neutrophil influx. However, pretreatment did not facilitate killing of C. albicans by either neutrophils or monocytes in vitro. Thus sublethal concentrations of amphotericin B inhibit two activities of C. albicans that probably contribute to surface colonization and tissue invasion. These results provide one explanation for the clinical benefits observed with short courses of amphotericin B therapy for surface-limited candidal infections (e.g., esophagitis).     

Safety and efficacy of caspofungin and liposomal amphotericin B, followed by voriconazole in young patients affected by refractory invasive mycosis

OBJECTIVE: Data on the use of combination of liposomal amphotericin B and caspofungin followed by voriconazole, as maintenance or further rescue treatment, in 10 patients with invasive mycosis are reported. MATERIAL AND METHODS: The diagnoses were acute leukemia (7), myelodysplastic syndrome (1) and Hodgkin's lymphoma (1). All patients developed an invasive mycosis (proven, 3; probable, 6; and possible, 1) refractory to first-line antifungal treatment (liposomal amphotericin B in all patients except one who received fluconazole). RESULTS: Rescue therapy with a combination of caspofungin and liposomal amphotericin B was well tolerated, hypokalemia, and thrombophlebitis being the most common side-effects. Combination therapy was administered for a median of 17 d, range 6-40. Among the nine patients with proven or probable mycosis, one was not evaluated because of early death caused by massive hemoptysis whilst in the remaining eight patients, the response was classified as complete, stable and failure in four, three, and one patients, respectively. Complete response was also observed in patient with possible mycosis. Eight of nine patients received voriconazole for a median of 75 d, range 42-194. Voriconazole was well tolerated although some drug interactions were observed during treatment with methotrexate and digoxin. After a median follow-up of 125 d, nine of 10 patients are alive. Overall, a favorable response to antifungal treatment (including the case of possible mycosis) was obtained in eight of 10 patients. CONCLUSION: These data suggest that medical antifungal treatment may be intensified in severely ill patients without significantly compromising patient safety. The combination of synergistic antifungal drugs as well as their sequential use warrants further investigation by a larger randomized controlled study.     

Breakthrough fungemia caused by fluconazole-resistant Candida albicans with decreased susceptibility to voriconazole in patients with hematologic malignancies

A 7-year retrospective analysis of candidemia in patients with hematologic malignancies demonstrated that ten patients, who received itraconazole and fluconazole during neutropenia, developed breakthrough fungemia caused by fluconazole-resistant Candida albicans (C. albicans) with decreased susceptibility to voriconazole. Eight of these ten patients died of candidemia despite amphotericin B administration. Karyotype analysis of C. albicans isolates revealed that all isolates were genetically unrelated? Our findings suggest that blood isolates of C. albicans in neutropenic patients receiving azoles could be azole cross-resistant, and that the patients should be treated by other antifungals such as echinocandins.     

Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis.

The records of 239 immunosuppressed patients receiving amphotericin B for suspected or proven aspergillosis were reviewed to determine rates of nephrotoxicity, dialysis, and fatality. The mean and median durations of treatment were 20.4 and 15.0 days, respectively. The creatinine level doubled in 53% of patients and exceeded 2.5 mg/dL in 29%; 14.5% underwent dialysis; and 60% died. A multivariate Cox proportional hazards analysis showed that patients whose creatinine level exceeded 2.5 mg/dL (hazard ratio [HR], 42.02; P<.001), allogeneic bone marrow transplantation (BMT) patients (HR, 6.34; P<. 001), and autologous BMT patients (HR, 5.06; P=.024) were at greatest risk for requiring hemodialysis. Use of hemodialysis (HR, 3. 089; P<.001), duration of amphotericin B use (HR, 1.03 per day; P=. 015), and use of nephrotoxic agents (HR, 1.96; P=.017) were associated with greater risk of death, whereas patients undergoing solid organ transplantation were at lowest risk (HR, 0.46; P=.002). These data indicate that elevated creatinine levels during amphotericin B treatment are associated with a substantial risk for hemodialysis and a higher mortality rate, but the risks vary in different patient groups.     

Salvage therapy with caspofungin for invasive aspergillosis: results from the caspofungin compassionate use study

OBJECTIVES: The objective was to prospectively assess the efficacy and safety of caspofungin as salvage therapy for invasive aspergillosis in patients enrolled in the caspofungin compassionate-use study. METHODS: Forty-eight patients with invasive Aspergillus infections (36 with pulmonary infection, 12 with extrapulmonary or disseminated infection) were enrolled in this study. All patients were refractory to or intolerant of intravenous amphotericin B or a lipid amphotericin formulation(s). Efficacy was assessed at end of intravenous caspofungin therapy based on the clinical (symptom/sign and radiographic) response. RESULTS: Underlying diseases included hematological malignancy (69%), organ transplant (8%), and AIDS (6%). Forty-three (90%) patients were refractory to prior antifungal treatment, including 25 patients refractory to multiple agents. Sixteen (33%) were neutropenic at study entry. Following caspofungin therapy, a favorable response was noted in 44% (20/45) of the patients, including nine (20%) and 11 (24%) patients with complete and partial responses, respectively. Caspofungin was generally well tolerated one serious drug-related adverse event was reported. CONCLUSIONS: In this study, caspofungin was an effective alternative for patients with refractory Aspergillus infections.     

A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis.

Caspofungin is a new broad-spectrum antifungal drug. A multicenter, double-blind, randomized trial was conducted to assess the efficacy, safety, and tolerability of caspofungin relative to amphotericin B in adults with endoscopically documented symptomatic Candida esophagitis. By use of a modified intent-to-treat analysis, endoscopically verified clinical success was achieved in 74% (95% confidence interval [CI], 59%-86%) and 89% (95% CI, 72%-98%) of patients receiving caspofungin at 50 and 70 mg/day, respectively, and in 63% (95% CI, 49%-76%) of patients given amphotericin B at 0.5 mg/kg/day. Therapy was stopped because of drug-related adverse events in 24% of patients in the amphotericin B group and 4% and 7%, respectively, for the caspofungin groups. This report provides the first demonstration of clinical utility for an echinocandin compound. Caspofungin appeared in this study to be as effective as and better tolerated than amphotericin B for the treatment of esophageal candidiasis.     

Amphotericin B tolerance: a characteristic of Candida parapsilosis not shared by other Candida species

Thirty yeast isolates from clinical specimens were tested for their susceptibility to amphotericin B at 30 C, 37 C, and 39 C. Of the six Candida albicans, five Candida tropicalis, one Candida guilliermondii, one Candida krusei, one Candida pseudotropicalis, two Torulopsis glabrata, and four Cryptococcus neoformans isolates tested, all were inhibited at amphotericin B concentrations of less than or equal to 0.4 micrograms/ml and killed by concentrations of amphotericin B that were less than or equal to 16-fold higher than the minimal inhibitory concentration (MIC). Although growth of Candida parapsilosis was also inhibited by concentrations of amphotericin B of less than or equal to 0.4 micrograms/ml, minimal fungicidal concentrations of amphotericin B were greater than or equal to 32-fold higher than MICs for each of the 10 isolates examined. This unique susceptibility pattern of C. parapsilosis resembles the antibiotic tolerance observed with Staphylococcus aureus. Variations in temperature within the experimental range did not affect the amphotericin B susceptibility for any of the yeasts examined.     

Comparison between E-test and CLSI broth microdilution method for antifungal susceptibility testing of Candida albicans oral isolates

Thirty Candida albicans isolated from oral candidosis patients and 30 C. albicans isolated from control individuals were studied. In vitro susceptibility tests were performed for amphotericin B, fluconazole, 5-flucytosine and itraconazole through the Clinical and Laboratorial Standards Institute (CLSI) reference method and E test system. The results obtained were analyzed and compared. MIC values were similar for the strains isolated from oral candidosis patients and control individuals. The agreement rate for the two methods was 66.67% for amphotericin B, 53.33% for fluconazole, 65% for flucytosine and 45% for itraconazole. According to our data, E test method could be an alternative to trial routine susceptibility testing due to its simplicity. However, it can not be considered a substitute for the CLSI reference method.     

In vitro activities of voriconazole as a triazole derivative and caspofungin as an echinocandin were compared with those of some antifungal agents against Candida species isolated from clinical specimens

We evaluated the in vitro activity of ketoconazole (KET), fluconazole (FLU), amphotericin B (AmpB), and flucytosine (FCU) in comparison to voriconazole (VOR) as a triazole derivative and caspofungin (CAS) as an echinocandin against 114 Candida spp. isolated from different cultures (blood, urine, sputum). The most common species of identified Candida were C. albicans (88), followed by C. parapsilosis (8), C. glabrata (7), C. tropicalis (6), C. famata (2), C. kefyr (2), and C. sake (1). The Clinical and Laboratory Standards Institute M 27-A method was used to evaluate the activity of antifungal agents. The minimal inhibitory concentrations of the strains were evaluated by RPMI 1640 medium using a microdilution method. Of 114 isolates, 100% were sensitive to AmpB, VOR, and CAS, 1.75% showed intermediate resistant to FCU also 0.87% showed intermediate resistant to FLU, and 2.63% were fully resistant to FLU and FCU. These results suggest that KET, AmpB, CAS, and VOR demonstrated excellent activity against all Candida spp. Taken together; these antifungal agents should be effective in the treatment of a broad range of Candida infections.     

Successful treatment of subcutaneously disseminated aspergillosis with caspofungin acetate in an allogeneic peripheral blood stem cell transplantation patient

We present a patient with acute myeloid leukaemia who developed subcutaneously disseminated aspergillosis after allogeneic peripheral stem cell transplantation (PSCT). Disseminated aspergillosis after stem cell transplantation has a high mortality despite treatment with amphotericin B or one of the azoles. Aspergillosis in our patient was refractory to amphotericin B and itraconazole but was successfully treated with caspofungin acetate.     

Fusarium infection in lung transplant patients: report of 6 cases and review of the literature

Fusarium is a fungal pathogen of immunosuppressed lung transplant patients associated with a high mortality in those with severe and persistent neutropenia. The principle portal of entry for Fusarium species is the airways, and lung involvement almost always occurs among lung transplant patients with disseminated infection. In these patients, the immunoprotective mechanisms of the transplanted lungs are impaired, and they are, therefore, more vulnerable to Fusarium infection. As a result, fusariosis occurs in up to 32% of lung transplant patients. We studied fusariosis in 6 patients following lung transplantation who were treated at Massachusetts General Hospital during an 8-year period and reviewed 3 published cases in the literature. Cases were identified by the microbiology laboratory and through discharge summaries. Patients presented with dyspnea, fever, nonproductive cough, hemoptysis, and headache. Blood tests showed elevated white blood cell counts with granulocytosis and elevated inflammatory markers. Cultures of Fusarium were isolated from bronchoalveolar lavage, blood, and sputum specimens.Treatments included amphotericin B, liposomal amphotericin B, caspofungin, voriconazole, and posaconazole, either alone or in combination. Lung involvement occurred in all patients with disseminated disease and it was associated with a poor outcome. The mortality rate in this group of patients was high (67%), and of those who survived, 1 patient was treated with a combination of amphotericin B and voriconazole, 1 patient with amphotericin B, and 1 patient with posaconazole. Recommended empirical treatment includes voriconazole, amphotericin B or liposomal amphotericin B first-line, and posaconazole for refractory disease. High-dose amphotericin B is recommended for treatment of most cases of fusariosis. The echinocandins (for example, caspofungin, micafungin, anidulafungin) are generally avoided because Fusarium species have intrinsic resistance to them. Treatment should ideally be based on the Fusarium isolate, susceptibility testing, and host-specific factors. Prognosis of fusariosis in the immunocompromised is directly related to a patient's immune status. Prevention of Fusarium infection is recommended with aerosolized amphotericin B deoxycholate, which also has activity against other important fungi.