Combination Of Caspofungin Research Articles

Antifungal Activity of Caspofungin in Combination with Amphotericin B against Candida glabrata : Comparison of Disk Diffusion, Etest, and Time-Kill Methods

The in vitro activities of caspofungin plus amphotericin B against 50 Candida glabrata isolates were evaluated by the time-kill, disk diffusion, and Etest methods. In vitro experiments showed a positive interaction. Even though each of these methods uses different conditions and endpoints, the results of the different methods frequently agreed.

Caspofungin-mediated beta-glucan unmasking and enhancement of human polymorphonuclear neutrophil activity against Aspergillus and non-Aspergillus hyphae.

We investigated whether caspofungin and other echinocandins have immune-enhancing properties that influence human polymorphonuclear neutrophil (PMN)-mediated mold hyphal damage. Using aniline blue staining, we compared patterns of beta-glucan exposure in Aspergillus fumigatus, Aspergillus terreus, Rhizopus oryzae, Fusarium solani, Fusarium oxysporum, Scedosporium prolificans, and Scedosporium apiospermum hyphae after caspofungin exposure. We also determined PMN-mediated hyphal damage occurring with or without preexposure to caspofungin or with preexposure to the combination of caspofungin and anti-beta-glucan monoclonal antibody, using 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-sH-tetrazolium hydroxide (XTT) assay. Preincubation with caspofungin (32 microg/mL for R. oryzae; 0.0625 microg/mL for other isolates) increased exposure to beta-glucan. PMN-induced damage increased after caspofungin exposure and was further augmented by the addition of anti-beta-glucan antibody. Preincubation with micafungin or anidulafungin had similar effects on PMN-induced damage of A. fumigatus hyphae. Finally, preexposure of A. fumigatus, but not S. prolificans, to caspofungin induced expression of Dectin-1 by PMN. The results of the present study suggest inducement of beta-glucan unmasking by echinocandins and enhancement of PMN activity against mold hyphae, thereby supporting the immunopharmacologic mode of action of echinocandins.

Successful treatment of disseminated Geotrichum capitatum infection with a combination of caspofungin and voriconazole in an immunocompromised patient

Disseminated Geotrichum capitatum infection is uncommon, and has been reported exclusively in immunocompromised patients. The prognosis is poor with a mortality rate of approximately 50-75%. We report a case of disseminated G. capitatum infection in a severely neutropenic patient who was receiving chemotherapy for acute myeloblastic leukaemia. G. capitatum was isolated from blood cultures, skin lesions, bronchoalveolar lavage fluid, throat swabs and stools. The infection was successfully cured with a combination of voriconazole and caspofungin.

Successful Treatment of Invasive Aspergillus Sinusitis with Caspofungin and Voriconazole

Chronic invasive Aspergillus sinusitis is a rare and potentially devastating infection. Management typically requires extensive surgical debridement followed by long-term antifungal therapy, primarily with intravenous amphotericin B. We describe the case of an elderly woman who had been diagnosed with extensive Aspergillus sinusitis that had invaded critical structures. The extensiveness of the infection and the patients frailty and unwillingness to undergo a disfiguring procedure precluded surgery, and her medical condition was too fragile to withstandamphotericin B therapy Therefore, we decided to treat her with a combination ofcaspofungin and voriconazole, two relatively nontoxic antifungal agents that have different mechanisms of action. After administration of this novel regimen, the infection resolved rapidly.

Therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate for coccidioidomycosis in a mouse model

The therapeutic efficacy of caspofungin alone and in combination with amphotericin B deoxycholate was evaluated in treatment of murine coccidioidomycosis. Survival and tissue burdens of the spleens and livers were used as antifungal response markers. In a monotherapy study, caspofungin was injected intraperitoneally at 0.1, 0.2, 0.5, 1 and 5 mg/kg per day on days 2 through 15. Amphotericin B deoxycholate was given at 0.1, 0.2 and 0.5 mg/kg intravenously and 1 and 5 mg/kg intraperitoneally three times per week for 2 weeks. In a combination therapy study, amphotericin B deoxycholate at 0.1 mg/kg was administered intravenously three times per week for 2 weeks, respectively, with and without caspofungin intraperitoneally given at 0.1, 0.5 and 5 mg/kg daily on days 2 through 15 post-infection. The study shows that caspofungin and amphotericin B deoxycholate at > or =0.5 and > or =0.1 mg/kg, respectively, were significant in both prolongation of survival and reduction of the tissue fungal burdens of mice compared with controls. No sterilization of either organ was observed with caspofungin doses. In combination therapy, any combination of caspofungin (0.1, 0.5 and 5 mg/kg) with amphotericin B deoxycholate (0.1 mg/kg) improved the period of survival and significantly reduced spleen and liver counts compared with controls. This study indicates that caspofungin has efficacy against systemic coccidioidomycosis in a murine model given in combination with amphotericin B deoxycholate.

Disseminated Invasive Aspergillosis with Cerebral Involvement Successfully Treated with Caspofungin and Voriconazole

We describe a case of cerebral aspergillosis which was successfully treated with a combination of caspofungin and voriconazole. The patient remains in remission 18 months after stopping antifungal treatment. We discuss primary and salvage therapy of invasive aspergillosis with focus on cerebral involvement. Since historical data showed a fatal outcome in most cases, amphotericin B does not cross the blood brain barrier while voriconazole does, we chose a combination of voriconazole plus caspofungin as primary therapy.

Treatment of Candida albicans pericarditis in a heart transplant patient

Pericarditis due to Candida species is a rare clinical entity, associated with thoracic surgery and immunosuppression. We report here the second case of pericarditis due to Candida albicans in a heart transplant patient, which presented as tamponade approximately 3 weeks post transplant, in the absence of evidence of sternal osteomyelitis. The patient was treated with pericardiocentesis and a combination of caspofungin and fluconazole, but the patient ultimately required the explantation of retained epicardial leads and the creation of a pericardial window. This case illustrates that Candida species must be considered in the differential diagnosis in post-transplant pericarditis, and that foreign body removal is, as always, key in helping to resolve such infections. This case also demonstrates the first use of caspofungin with fluconazole to treat Candida pericarditis. We discuss the conflicting data regarding the use of caspofungin, alone or in combination therapy, in treating infections involving biofilms, such as the infected pericardium.

High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation

Pneumocandins have concentration-dependent antifungal activity and higher dose of caspofungin (HD-CAP) in combination with other licensed antifungal therapy (OLAT) may improve response. Thirty-four patients who received HD-CAP were compared with 63 patients who received standard dose (SD)-CAP. There were no differences between the groups in either patient or disease characteristics. Significantly more patients in the HD-CAP arm had extrapulmonary infections (29 vs 8% in SD group; P=0.0053), and non-Aspergillus species infection (21 vs 6%; P=0.05) and had received prior antifungal therapy (71 vs 33%; P=0.0004). No serious adverse reactions were noted in patients receiving HD- or SD-CAP therapy. Twelve weeks after treatment commenced 44% had a complete or partial response compared with 29% in SD-CAP group (P=0.1). Logistic regression analysis showed a significant probability of a favorable outcome at 12 weeks in patients who received HD-CAP (OR 3.066, 95% CI, 1.092-8.61; P=0.033). This may in part reflect higher number of patients in HD group had received granulocyte-macrophage colony-stimulating factor (41 vs 14% in SD group; P=0.04) and/or interferon gamma (26 vs 5% in SD group; P=0.003) immune enhancement. Further studies are needed to evaluate efficacy of HD-CAP in severely immunosuppressed cancer patients with invasive fungal infections.

Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvage therapy in adults with invasive aspergillosis

Caspofungin inhibits synthesis of beta-1,3-glucan, an essential component of the Aspergillus cell wall. This echinocandin has demonstrated efficacy (45% success) as salvage monotherapy of invasive aspergillosis (IA). Interest remains as to whether caspofungin, in combination with other antifungal classes, can improve the efficacy against IA. The study involved 53 adults with documented IA who were refractory to or intolerant of standard antifungal therapy and received caspofungin and 1 other mold-active antifungal agent (at the investigator's discretion). Efficacy was assessed by signs, symptoms, and radiographs at the end of combination therapy and Day 84 after combination therapy initiation. Favorable (complete or partial) responses required significant clinical and radiographic improvement. Diagnoses and outcomes were assessed by an independent expert. Among the 53 patients enrolled the most common underlying diseases were acute leukemia (53%), lymphoma (11%), and chronic leukemia (6%). Pulmonary aspergillosis (81%) was the most common site, and most patients (87%) were refractory to prior therapy. Success at the end of combination therapy and Day 84 was 55% (29/53) and 49% (25/51), respectively. Fifty-seven percent of patients with neutropenia and 54% who received an allogeneic hematopoietic stem cell transplant responded favorably. Survival at Day 84 was 55%. Combination therapy, dosed on average for 31.3 days, was well tolerated. Two (4%) serious drug-related adverse events, both attributed to voriconazole, occurred. None of the patients discontinued caspofungin due to toxicity. Caspofungin in combination with a triazole or polyene was an effective alternative as salvage therapy for patients with recalcitrant Aspergillus infections.

Efficacies of caspofungin and a combination of caspofungin and meropenem in the treatment of murine disseminated candidiasis

Disseminated candidiasis is relatively common in immunocompromised patients. The treatment protocol of these patients usually includes broad-spectrum antibiotics and also emprical antifungals initiated due to unresponsiveness to antibiotics. In this study the efficacies of caspofungin and meropenem - separately and together - in mice with disseminated candidiasis were studied. Immunocompetent mice were infected intravenously with 2x10(6) CFU of Candida albicans. At 24 h postinfection, intraperitoneal therapy was initiated and was continued for 7 days. Therapy groups included those given caspofungin (0.5, 1.25, 5 mg/kg/day), meropenem (20 mg/kg/day), and a combination of the two drugs. The outcome of therapy was evaluated by kidney tissue burden studies and histologic examination. In vitro, drug susceptibilities were tested by checkerboard analysis. Kidney CFU counts showed that mice that had received both drugs had lower residual burdens. Caspofungin was effective at doses of 0.5, 1.25, 5 mg/kg compared to infected untreated controls. In vitro, MICs of caspofungin and meropenem were <0.075 micro g/ml and >64 micro g/ml, respectively. Synergism was observed with the combination. Histopathology showed that the degree of inflammation was 25% less and tubular necrosis was more restricted in combined therapy than monotherapy. The results indicate that concurrent caspofungin and meropenem therapy may be beneficial.

Successful treatment of Candida parapsilosis mural endocarditis with combined caspofungin and voriconazole

BackgroundFungal mural endocarditis is a rare entity in which the antemortem diagnosis is seldom made. Seven cases of mural endocarditis caused by Candida spp. have been collected from literature and six of these patients died after treatment with amphotericin B.Case presentationWe report a case of mural endocarditis diagnosed by transesophageal echocardiogram and positive blood cultures to Candida parapsilosis. Because blood cultures continued to yield C. parapsilosis despite caspofungin monotherapy, treatment with voriconazole was added.ConclusionThis is the first description of successful treatment of C. parapsilosis mural endocarditis with caspofungin and voriconazole.

Caspofungin: antifungal activity in vitro, pharmacokinetics, and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis

Evaluation of the potential of caspofungin, in relation to pharmacokinetics, in order to optimize its use in the treatment of filamentous fungal infections. The in vitro antifungal activity, pharmacokinetics and therapeutic efficacy of caspofungin versus amphotericin B was investigated in vitro as well as in a model of aerogenic Aspergillus fumigatus infection in neutropenic rats, using rat survival and decrease in fungal burden as parameters for therapeutic efficacy. In contrast to amphotericin B, caspofungin shows a concentration-dependent gradual decrease in fungal growth in vitro, which makes it difficult to perform visual readings of antifungal activity (CLSI guidelines). The quantitative XTT [2,3-bis(2-methoxy-4-nitro-5-[(sulphenylamino) carbonyl]-2H-tetrazolium-hydroxide] assay measuring a decrease in fungal metabolic activity seems more appropriate for caspofungin susceptibility testing. Using this assay, in vitro caspofungin was 4-fold less active than amphotericin B. In the infection model, therapy was started 16 h after fungal inoculation, and continued once daily for 10 days. Caspofungin was administered intraperitoneally at 1, 2, 3 or 4 mg/kg/day (CAS 1, 2, 3 or 4), amphotericin B at 1 mg/kg/day (AMB 1). Treatment with CAS 1 or AMB 1 provided modest prolongation of animal survival. The combination of caspofungin and amphotericin B did not show additive effects. Increasing the dosage of caspofungin to 2, 3 or 4 mg/kg/day resulted in a dose-dependent significant increase in efficacy. There was 100% survival among rats in the CAS 4 group, which was correlated with a significant decrease in fungal burden, based on the concentration of A. fumigatus galactomannan in serum and lung tissue and quantification of A. fumigatus DNA in lung tissue. Pharmacokinetic analysis suggested that the CAS 4 dose in rats produced drug exposure comparable to the human situation, visualized by similar 24 h AUC and trough concentrations. The therapeutic efficacy of caspofungin is superior to amphotericin B, which seemed to be discrepant with their in vitro antifungal activity.

Efficacy of amphotericin B or amphotericin B–intralipid in combination with caspofungin against experimental aspergillosis

Infections caused by Aspergillus species are increasing in importance, especially among immunocompromised hosts. The objective of this study was to evaluate the efficacy of combination treatment consisting of the polyene amphotericin B (AMB) or amphotericin B-intralipid admixture (AMB-IL) and the echinocandin caspofungin (CAS) in experimental murine systemic aspergillosis. Inhibition of synthesis of a major component of the fungal cell wall and an effect on the cell membrane, by combining echinocandin and a polyene, may result in a synergistic interaction in vitro and in vivo against Aspergillus fumigatus. ICR mice were immunosuppressed by intraperitoneal (ip) administration of cyclophosphamide (CY). Three days post-CY administration the mice were inoculated intravenously (iv) with A. fumigatus conidia. Infection and treatment were evaluated during an observation period of 30 days in terms of mortality (survival rate and mean survival time) and morbidity (quantitative determination of fungal burden, histopathology, and detection of serum galactomannan). The data showed that combined CAS and AMB or AMB-IL treatment increased the survival of the mice (up to 69.2%) as compared to those treated with each agent alone (44.4, 40.7 and 50%, respectively), and prolonged their mean survival time to 22.5 days. These combinations also resulted in reduction of fungal burden in organs, and decrease in serum galactomannan. The successful results obtained in the experimental animal model of this study may possibly open the way to more effective management of aspergillosis in humans.

Safety of Caspofungin for Treating Invasive Nasal Sinus Aspergillosis in a Kidney Transplant Recipient

Introduction Invasive fungal sinusitis is a rare but often fatal infection in immunocompromised patients. Aggressive antifungal treatment is mandatory, but is not without risk. Caspofungin, an antifungal agent that is a member of the echinocandin family, an inhibitor of glucan synthesis in the fungal wall, is active against Aspergillus and Candidae infections. Although it works on the fungal wall, it does not affect mammalian cells; hence, its toxicity is minimal. Case Summary This report describes a case of invasive Aspergillus sinusitis in a kidney transplant recipient with diabetes mellitus. The infection involved the apex of the right orbit causing optic nerve compression. The patient was treated with transnasal endoscopic decompression of the optic nerve and intravenous AmBisome (liposomal amphotericin B) for 2 weeks without clinical improvement. The combination of caspofungin and AmBisome administered for another 2 weeks yielded partial improvement. The AmBisome had to be discontinued due to deterioration of renal and hepatic function, but the patient completed a further 7-week course of caspofungin alone. Retro-orbital biopsy confirmed a complete response to treatment; the patient’s renal and hepatic function returned to normal. Conclusion This case indicates that caspofungin is effective to treat invasive Aspergillus sinusitis in kidney transplant recipients. This agent is well tolerated and safe with respect to renal and hepatic function.

Experimental systemic murine aspergillosis: treatment with polyene and caspofungin combination and G-CSF

In view of the poor therapy outcomes of invasive aspergillosis, the objective of this study was to evaluate the efficacy of combination treatment consisting of the polyene amphotericin-B-intralipid, the echinocandin caspofungin and granulocyte-colony stimulating factor (G-CSF) in experimental murine systemic aspergillosis. With inhibition of synthesis of 1,3-beta-d-glucan in the fungal cell wall by caspofungin and an effect on the cell membrane by amphotericin-B-intralipid, this treatment may result in a synergic effect against Aspergillus fumigatus. Addition of G-CSF may further contribute to therapy of aspergillosis. ICR mice were immunosuppressed by intraperitoneal administration of cyclophosphamide. Three days later, the mice were inoculated intravenously (iv) with A. fumigatus conidia. Infection and treatment were evaluated during an observation period of 30 days in terms of mortality (survival rate and mean survival time) and morbidity (quantitative determination of fungal burden, histopathology, and detection of serum galactomannan). Combination of caspofungin + G-CSF or addition of G-CSF to the combination of caspofungin + amphotericin-B-intralipid increased the survival rate of infected mice up to 78.9% and prolonged their mean survival time to 25 days. These combinations also resulted in a reduction in fungal burden in organs, and a decrease in serum galactomannan. The successful results obtained in the experimental model may possibly open the way to more effective management of aspergillosis in humans.

Combination of caspofungin and an azole or an amphotericin B formulation in invasive fungal infections

Combination of caspofungin and another anti-fungal agent raise expectation of improved efficacy in severe fungal infections including failures to first line therapy. We assessed the efficacy and safety of a combination therapy including caspofungin in 17 immunosuppressed or postoperative patients progressive despite standard anti-fungal therapy. The infections included aspergillosis (6), invasive candidiasis (9), mucormycosis (1) and Scedosporium pneumonia (1). Infections had failed one to four prior lines of treatment. The anti-fungal agent combined to caspofungin was either an amphotericin B formulation or an azole. There were 12 favourable responses (71%) and five failures. The survival rate at 3 months was 47%. Eleven patients died within 2-533 days. The causes of death included the initial fungal infection (4), relapse of the infection after switching to oral monotherapy (2), breakthrough aspergillosis (1), and the underlying condition (4). Clinical and renal tolerance were good. Significant hepatic abnormalities were recorded in eight (50%) of the 16 patients evaluable for biological tolerance. Caspofungin combined with an azole or with amphotericin B may be of interest in the treatment of serious fungal infections after failure of conventional therapy. Close monitoring of hepatic function is required. These approach should be evaluated in prospective trials.

Effects of several antifungal drug combinations against clinical and environmental isolates of Cryptococcus neoformans from China.

The in vitro interactions of caspofungin (CSP) with terbinafine (TRB) and ravuconazole (RVC) with 5-fluorocytosine (5-FC) were tested against 82 clinical and environmental isolates of Cryptococcus neoformans from China. The interaction of CSP with TRB proved synergistic against those isolates with a CSP MIC < or =2 microg ml-1 (5% of the isolates), additive against 42% of the isolates and indifferent against 53%. The effects of RVC with 5-FC were synergistic, additive or indifferent against 8%, 26% and 67% of the isolates, respectively. No antagonistic effects were found among any of the drugs. The combinations of CSP with TRB and RVC with 5-FC may display beneficial effects in a strain-dependent manner, while in no case showed antagonistic effects. These data might be of use to design safer and more efficient treatments for patients with cryptococcosis and warrant further evaluation.

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

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. 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). 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. 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.

Differential effects of the combination of caspofungin and terbinafine against Candida albicans, Candida dubliniensis and Candida kefyr

The activity of caspofungin (CSP) combined with terbinafine (TRB) against Candida dubliniensis, Candida kefyr and azole-resistant Candida albicans was evaluated in vitro by checkerboard analysis. The combination of CSP with TRB resulted in positive interactive effects in vitro against C. albicans and C. kefyr but not against C. dubliniensis. Moreover, true synergism was observed only against TRB resistant strains which became susceptible to this drug in the presence of CSP. In contrast, indifference was observed against strains that were already sensitive to TRB indicating that CSP may inhibit resistance to TRB.

In vitro evaluation of double and triple combinations of antifungal drugs against Aspergillus fumigatus and Aspergillus terreus.

Microdilution broth checkerboard techniques based on the National Committee for Clinical Laboratory Standards methodology were used to study double and triple antifungal combinations against clinical isolates of Aspergillus fumigatus and A. terreus. The influences of the end-point definition (partial or complete inhibition) and the mode of reading (visually or spectrophotometrically) were determined. Interactions between antifungal drugs were also evaluated by agar diffusion tests. Combinations of caspofungin with either amphotericin B or voriconazole were additive for all the isolates, and antagonism was not observed. The interaction between caspofungin and flucytosine was synergistic for 62% of the isolates. In contrast, the interaction between voriconazole and flucytosine was never synergistic and antagonism was noted for 93% of the isolates. The triple combination of caspofungin with flucytosine and amphotericin B was synergistic for all the isolates tested. The triple combination of caspofungin with flucytosine and voriconazole was also mostly synergistic; but complex interactions were obtained for some isolates, with synergy or antagonism depending on the concentrations of caspofungin and voriconazole. Analysis of the influence of the reading technique on the results showed that spectrophotometric reading was a good alternative to the recommended visual reading. The results of these in vitro tests suggest that the activity of flucytosine as part of a double combination with caspofungin and as part of a triple combination with caspofungin and amphotericin B against Aspergillus spp. warrants further investigations. Animal studies are needed to evaluate the in vivo efficacies of these combinations.