Combination Of Caspofungin Research Articles

Therapeutic Potential of Caspofungin Combined with Trimethoprim-Sulfamethoxazole for Pneumocystis Pneumonia: A Pilot Study in Mice

Pneumocystis pneumonia (PcP) is a major cause of mortality and morbidity in immunocompromised patients. There are limited alternative therapeutic choices to trimethoprim-sulfamethoxazole (TMP-SMX) which is the standard first line therapy/prophylaxis for PcP. The efficacy of low doses of caspofungin and caspofungin in association with TMP-SMX standard-prophylactic dose was evaluated in an experimental model of Pneumocystis. Susceptibility of Pneumocystis spp. to low doses of caspofungin and caspofungin/TMP-SMX was evaluated in Balb/c immunosuppressed mice, infected intranasally with P. murina. Caspofungin was administered once daily at 0.1 mg/kg, 0.05 mg/kg, and 0.001 mg/kg and TMP-SMX was administered by oral gavage (12.25 mg/62.5 mg/day), for 21 days. Efficacy was calculated based on the reduction in organism burden determined through quantitative fluorescent-based real-time PCR (qPCR). Serum β-1,3-D-glucan was measured as an additional marker of infection. The present data showed that caspofungin demonstrated anti-Pneumomocystis effect. However, the doses administrated were too low to achieve Pneumocystis eradication, which suggests that echinocandin treatment should not be administrated as mono-therapy. After 21 days of treatment, P. murina was not detected in the lungs of mice with either TMP-SMX or caspofungin/TMP-SMX. The results showed that, even at the lowest concentrations tested, the efficacy of caspofungin in association with TMP-SMX was higher than the efficacy of either drug used alone. The administration of caspofungin/TMP-SMX was at least 1.4 times more effective against P. murina infection than TMP-SMX used alone. The most promising result was achieved with the combination of caspofungin 0.05 mg/kg/day with TMP-SMX 12.5 mg–62.5 mg/day, which reduced the parasite burden to undetectable levels immediately at the 14th day of treatment, showing a highly marked anti-Pneumomocystis effect. These data suggest that the administration of low doses of caspofungin in combination with low doses of TMP-SMX may provide an improved treatment protocol for Pneumocystis infection clearance.

A mucormycosis case treated with a combination of caspofungin and amphotericin B

Mucormycosis is a rare, invasive and fatal disease that occurs mainly in diabetes mellitus patients with uncontrolled blood glucose levels or in immunocompromised patients. The mortality rate of this disease is as high as 25 to 80%, despite aggressive surgical treatment and antifungal therapy. This high mortality requires alternative treatment approaches. The accepted treatment modality of invasive mucormycosis are amphotericin B lipid formulations. Although echinocandins generally show no activity against Mucorales, it was shown that Rhizopus oryzae expressed the target enzyme for echinocandins, 1,3-beta-glucan synthase. Additionally, there are some experimental studies in a diabetic mouse model and case reports regarding the effects of caspofungin. In this report, we present a rhinocerebral mucormycosis case treated with liposomal amphotericin B and caspofungin. There was regression of the patient's clinical and radiological condition with the addition of caspofungin, but she died due to discontinuation of her treatment and reasons other than mucormycosis.

Drug Combinations against Mucor irregularis In Vitro

Combinations of terbinafine or caspofungin with amphotericin B, posaconazole, or itraconazole were studied as potential treatments against 18 isolates of Mucor irregularis in vitro. Synergism of the combinations of terbinafine with amphotericin B, posaconazole, and itraconazole against 38.9, 33.3, and 44.4% of the strains studied was observed. In contrast, synergism of the combinations of caspofungin with amphotericin B, posaconazole, and itraconazole against 99.4, 66.7, and 99.4% of the strains studied was observed. Furthermore, no antagonism was observed.

Enhanced efficacy of synergistic combinations of antimicrobial peptides with caspofungin versus Candida albicans in insect and murine models of systemic infection

The objective of this study was to determine whether combinations of antimicrobial peptides (AMPs) with caspofungin display enhanced antifungal activity versus Candida albicans in vitro and in vivo. Three conventional AMPs that satisfied criteria favouring their potential development as novel antifungals were selected for investigation. Colistin sulphate was also included as a cyclic peptide antibiotic used in the clinic. Minimum inhibitory concentrations (MICs) were determined for each antifungal agent and checkerboard assays were used to determine fractional inhibitory concentration index (FICI) values for dual combinations of AMPs or colistin with caspofungin. Viability assays were performed for the same combinations in order to investigate fungicidal interactions. Synergistic antifungal combinations were then tested for efficacy in vivo and compared to monotherapies in wax moth larva and murine models of systemic C. albicans infection. In combination with caspofungin, each of the AMPs [hMUC7-12, DsS3(1-16), hLF(1-11)] and colistin were synergistic and candidacidal in vitro. The treatment of infected wax moth larvae with combinations of caspofungin with hMUC7-12, DsS3(1-16) or colistin resulted in significant enhancements in survival compared to treatment with monotherapies. Notably, the treatment of C. albicans-infected mice with a combination of caspofungin and DsS3(1-16) resulted in the enhancement of survival compared to groups treated with just the individual agents. This study demonstrates that combination therapies containing caspofungin and AMPs or colistin merit further development as potential novel treatments for C. albicans infections.

Candida Bloodstream Infection in Left Ventricular Assist Device Recipients

Purpose Left ventricular assist devices (LVADs) are being increasingly used as bridge-to-transplant and destination therapy for end-stage heart failure that is refractory to medical management. Fungal infections, especially due to Candida species, are uncommon in LVAD recipients but require special consideration in regards to management interventions. There is limited data on clinical presentation and outcome of infections due to Candida species in LVAD recipients. Methods and Materials We retrospectively reviewed hospital records of 247 patients who underwent LVAD implantation at Mayo Clinic campuses in Minnesota, Arizona and Florida, from January 2005 to December 2011. Demographic and clinical data of patients that developed infection due to Candida species were extracted. Results Of the 247 patients with LVADs, 7 (2.83%) developed infection with Candida species. The median age of seven patients was 68 years (range, 53-75 years). All patients presented with Candida blood stream infection (BSI). The causative Candida species included C. albicans (5) and C. glabrata (2). One patient underwent LVAD exchange and two patients underwent heart transplantation. Five of the seven BSI were non-LVAD-related, one was LVAD-related, and one was associated with LVAD pump/cannula infection. Patients received intravenous fluconazole (1), caspofungin (2), amphotericin (1), anidulafungin (1) and a combination of caspofungin and fluconazole (2). The average duration of anti-fungal therapy was 4.16 weeks (range, 1wk to 8.5 wks.). Two patients received lifelong antifungal suppression with oral fluconazole. Only two of the patients were alive (both had undergone orthotopic heart transplant). Average survival in this cohort of LVAD recipients with Candida BSI was 6 months (0.3 –10.5 months) from the time of candidemia. Conclusions Despite non-LVAD source of BSI in majority of cases, candidemia in LVAD recipients portends poor long-term survival. Only patients who had undergone heart transplantation survived beyond 6 months.

Interaction of the Echinocandin Caspofungin with Amphotericin B or Voriconazole against Aspergillus Biofilms In Vitro

Aspergillus biofilms were prepared from 22 strains of Aspergillus spp. via a 96-well plate-based method. Using a broth microdilution checkerboard technique with the XTT [2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide] colorimetric assay, we demonstrated a synergistic antifungal activity against 18 of 22 Aspergillus biofilm strains with a combination of caspofungin and amphotericin B and against 13 of 22 strains with a combination of caspofungin and voriconazole. We did not observe antagonism.

Fatal bronchial invasion of Scopulariopsis brevicaulis in an acute monocytic leukemia patient

A case of fatal invasion of Scopulariopsis brevicaulis to the bronchus in an acute monocytic leukemia (M5) patient is described. This infection leads to mediastinal emphysema, bronchial bleeding, and bronchial obstruction before finally spreading to the entire lung. The patient was initially diagnosed with pulmonary aspergillosis based on clinical signs and morphological examination. However, S. brevicaulis was finally identified by 18S rDNA sequencing. The patient failed lipid amphotericin B therapy and voriconazole plus caspofungin combination therapy. To the best of our knowledge, this is the first report on S. brevicaulis affecting the bronchus and resulting in a fatal prognosis in an M5 patient.

Lack of Response in Severe Pneumocystis Pneumonia to Combined Caspofungin and Clindamycin Treatment: a Case Report

Pneumocystis pneumonia (PCP) is among the most common opportunistic infections in patients with acquired immune deficiency syndrome (AIDS). Although trimethoprim-sulfamethoxazole (TMP-SMX) is the first line therapy for that condition given its efficacy, approximately one third of patients experienced dose-limiting toxicity. For cases of severe to moderate PCP, if TMP-SMX treatment fails or is contraindicated, primaquine combined with clindamycin or intravenous pentamidine is recommended as second line therapy. However, both primaquine and pentamidine are associated with severe adverse reactions and often unavailable at hospitals in China.As a result, other treatment options have been explored. Caspofungin, an echinocandin, has broad antifungal activity against a wide range of fungi including Candida and Aspergillus species. Cases of PCP patients treated with caspofungin have been reported, although conflicting conclusions have been arrived at. In addition, the use of caspofungin and clindamycin as the first line therapy for severe PCP in AIDS patients has not been reported yet. This article described an AIDS case with severe PCP, treated with the combination of caspofungin and clindamycin.

In vitro interaction of caspofungin and immunosuppressives against agents of mucormycosis

Mucormycosis is a rare but refractory mycosis with high mortality. Few therapeutic options are available and novel strategies are needed. Calcineurin inhibitors are known to have antifungal activity, including synergy with various antifungals. We examined the interaction of caspofungin with calcineurin inhibitors and sirolimus against Glomeromycetes. Twenty-six strains of Glomeromycetes representing seven species (Rhizopus arrhizus, Rhizopus microsporus, Mucor sp., Rhizomucor pusillus, Cunninghamella berthollettiae, Mycocladus corymbifera and Apophysomyces elegans) were studied. Antifungal susceptibility testing was performed according to CLSI M38-A2, modified for chequerboard dilution testing using the minimum effective concentration (MEC) endpoint for caspofungin and calcineurin inhibitors/sirolimus. Synergy was defined as a fractional inhibitory concentration index ≤0.5, indifference >0.5 to ≤4.0 and antagonism >4.0. Caspofungin had no intrinsic activity against Glomeromycetes (MEC >8 mg/L). The combination of caspofungin with calcineurin inhibitors and sirolimus showed synergy in seven isolates. In the presence of calcineurin inhibitors and sirolimus, the MEC of caspofungin was significantly lowered (>4-fold) in 24 and 7 isolates, respectively. All species showed lower MECs of caspofungin with calcineurin inhibitors and only R. arrhizus, Mucor sp. and R. pusillus showed lower MECs with sirolimus. No antagonism was observed. Calcineurin inhibitors and sirolimus significantly lowered MECs of caspofungin for Glomeromycetes, with occasional synergy observed. The clinical significance of this should be further investigated.

Treatment of Alternaria Keratitis with Intrastromal and Topical Caspofungin in Combination with Intrastromal, Topical, and Oral Voriconazole

To report a case of refractory atypical Alternaria keratitis that was treated with intrastromal and topical caspofungin 0.5% in combination with topical, oral, and intrastromal voriconazole. A 67-year-old female with a history of bilateral intraocular lens exchange and left pseudophakic bullous keratopathy was referred to the emergency department of the Royal Victorian Eye and Ear Hospital, Melbourne, Australia. Visual acuity of her left eye was limited to counting fingers. A fine branching pattern was noted throughout the anterior stroma of her left corneal graft. The anterior chamber was deep and quiet. Hourly topical voriconazole 1% was initiated, with limited response. One week later, Alternaria spp. was cultured from the corneal scraping. Subsequently, topical caspofungin 0.5% was added, with concomitant use of topical, oral, and intrastromal voriconazole. Despite gradual symptomatic improvement, topical voriconazole was increased to 2% and intrastromal caspofungin was added. The patient was discharged after almost 5 weeks of treatment. Topical voriconazole 2% and topical caspofungin 0.5% were continued for an additional 3 weeks and 1 week, respectively, in the outpatient setting. The patient underwent left penetrating keratoplasty 3 weeks postdischarge. Visual acuity was stable at 20/150, with no reported adverse event 15 months postoperative. Treatment for Alternaria keratitis remains challenging, as it is refractory to existing antifungal agents. To our knowledge, this is the first reported instance of the use of intrastromal caspofungin to treat Alternaria keratitis in a case in which clinical resolution was not fully achieved despite the use of topical caspofungin in addition to extensive use of topical, intrastromal, and oral voriconazole. This case highlights the importance of intensive pharmacologic management and therapeutic penetrating keratoplasty in preventing evisceration of the patient's eye, especially when Alternaria keratitis is involved. Intrastromal and topical caspofungin were employed in combination with voriconazole for the management of refractory Alternaria keratitis, with no observed adverse effects.

A rescue therapy with a combination of caspofungin and liposomal amphotericin B or voriconazole in children with haematological malignancy and refractory invasive fungal infections

Combination treatment of paediatric invasive fungal infections (IFIs) has rarely been reported. A total of 17 children with 19 IFI episodes were enrolled in the study. The median age of the patients was 5.3 (range 0.5-17) years. IFI was classified as proven in 4, probable in 12 and possible in 3 episodes. These patients received empiric antifungal treatment, which consisted of liposomal amphotericin B (LAmB) monotherapy for a median duration of 12 days (range 3-69 days). All patients were refractory to LAmB; therefore, caspofungin was added to the therapy in 11 patients. In the remaining six patients, LAmB was ceased and a combination of caspofungin and voriconazole was started. Among the patients who received caspofungin + LAmB, four did not show favourable response and the combination was switched to caspofungin + voriconazole. The median (range) and total duration of the therapy were 7 (3-14) days and 91 patient days for LAmB + caspofungin combination and 49 (7-126) days and 516 patient days for caspofungin + voriconazole combination. We found a favourable response rate of 68.4% in 16 proven or probable IFI episodes. Twelve-week survival rate of these patients was 75%. No serious side effect was observed among the patients. Our data suggest that combination antifungal therapy is safe and effective in children with haematological malignancies.

Emergence of Disseminated Infections Due to Geosmithia argillacea in Patients with Chronic Granulomatous Disease Receiving Long-Term Azole Antifungal Prophylaxis

We report two cases of invasive infections due to Geosmithia argillacea, an emerging mold, in patients with chronic granulomatous disease receiving prolonged azole antifungal prophylaxis. One patient died despite receiving a combination of four antifungals, and the other developed cerebral and medullary lesions under a combination of caspofungin, posaconazole, terbinafine, and gamma interferon.

Caspofungin plus posaconazole as salvage therapy of invasive fungal infections in immunocompromised patients

Invasive aspergillosis (IA) is a major cause of mortality in immunocompromised patients. Substantial improvements of treatment have been achieved by the introduction of new antifungal agents including azoles (e.g. posaconazole) and echinocandins (e.g. caspofungin). However, mortality associated with treatment-refractory aspergillosis remains high. Preliminary data suggest that the combination of azoles and echinocandins may increase activity against refractory IA. The objective of the present study was to evaluate efficiency and safety of caspofungin plus posaconazole for salvage therapy in immunocompromised patients. In this monocentric, retrospective study, 31 hospitalised haematopoietic stem cell transplant recipients with IA refractory to primary treatment were treated with a combination therapy of caspofungin 50 mg a day and posaconazole 200 mg four times per day. Efficacy was assessed by signs, symptoms and the degree of pulmonary infiltrate regression. A favourable response was seen in the majority of patients (77%). In two patients (6%), clinical improvement, but no decline in pulmonary infiltrates, was observed. Five patients (16%) did not respond to combination therapy with a fatal outcome in four of them. Combination therapy was well tolerated. No patient discontinued treatment due to toxicity. This study indicates that the combination of caspofungin and posaconazole may provide an effective and tolerable therapy of IA in immunocompromised patients refractory to primary treatment.

Antifungal Activity of Antifungal Drugs, as Well as Drug Combinations Against Exophiala dermatitidis

To evaluate the invitro efficacy of common antifungal drugs, as well as the interactions of caspofungin with voriconazole, amphotericin B, or itraconazole against the pathogenic black yeast Exophiala dermatitidis from China, the minimal inhibitory concentrations (MICs) of terbinafine, voriconazole, itraconazole, amphotericin B, fluconazole, and caspofungin against 16 strains of E. dermatitidis were determined by using CLSI broth microdilution method (M38-A2). The minimal fungicidal concentrations (MFCs) were also determined. Additionally, the interactions of caspofungin with voriconazole, amphotericin B, itraconazole or fluconazole, that of terbinafine with itraconazole, or that of fluconazole with amphotericin B were assessed by using the checkerboard technique. The fractional inhibitory concentration index (FICI) was used to categorize drug interactions as following, synergy, FICI≤0.5; indifference, FICI>0.5 and ≤4.0; or antagonism, FICI>4.0. The MIC ranges of terbinafine, voriconazole, itraconazole, amphotericin B, fluconazole, and caspofungin against E. dermatitidis were 0.06-0.125mg/l, 0.25-1.0mg/l, 1.0-2.0mg/l, 1.0-2.0mg/l, 16-64mg/l, and 32-64mg/l, respectively. The invitro interactions of caspofungin with voriconazole, amphotericin B, and itraconazole showed synergic effect against 10/16(62.5%), 15/16(93.75%), and 16/16(100%) isolates, while that of caspofungin with fluconazole showed indifference. Besides, the interaction of terbinafine with itraconazole as well as that of fluconazole with amphotericin B showed indifference. Terbinafine, voriconazole, itraconazole, and amphotericin B have good activity against E. dermatitidis. The combinations of caspofungin with voriconazole, amphotericin B or itraconazole present synergic activity against E. dermatitidis. These results provide the basis for novel options in treating various E. dermatitidis infections.

Vertebral osteomyelitis due toAspergillus fumigatusin a patient with chronic granulomatous disease successfully treated with antifungal agents and interferon-gamma

We report a case of invasive aspergillosis due to Aspergillus fumigatus involving the cervical and thoracic vertebrae and upper mediastinum of a 17 year-old Saudi male with chronic granulomatous disease (CGD). The patient did not respond to a long course of liposomal amphotericin B but did to surgical drainage and a combination of caspofungin and itraconazole with subsequent suppression with oral voriconazole. Fourteen months after the start of therapy, the patient had anterior dislocation of T2 thoracic vertebra with cord transection and quadriplegia. He was then treated intravenously with liquid itraconazole and interferon-gamma. The patient made a remarkable recovery over a 2-year period and was eventually able to walk independently. Thus, a combination of antifungals and interferon-gamma may have resulted in the positive outcome in this case.

Combination of caspofungin or anidulafungin with antimicrobial peptides results in potent synergistic killing of Candida albicans and Candida glabrata in vitro

Administering synergistic combinations of antifungals could be a route to overcome problems with toxicity and the development of resistance. Combination of the echinocandins caspofungin or anidulafungin with a range of structurally diverse antimicrobial peptides resulted in potent synergistic killing of Candida spp. in vitro. Fungicidal synergy was measured by calculating fractional inhibitory concentration indices from checkerboard assays as well as loss of viability. Inhibitory combinations of the antifungals did not induce cytotoxicity in vitro. However, in a murine model of systemic candidiasis, co-administration of caspofungin with one example of the cationic peptides tested, ranalexin, did not show enhanced efficacy compared with the single treatments alone. Further study using alternative peptides will identify whether this combination approach could represent a novel treatment for fungal pathogens.

Assessment of the In Vitro Kinetic Activity of Caspofungin against Candida glabrata

Echinocandins have become the drug of choice in infections caused by Candida glabrata. The objective of this study was to evaluate the in vitro activity of caspofungin alone and in combination against C. glabrata. In vitro assays demonstrated that caspofungin alone showed excellent fungicidal activity against C. glabrata, including fluconazole-resistant strains. The combination of caspofungin and azole antifungals showed potential synergy against C. glabrata. Overall, caspofungin demonstrated excellent in vitro activity, alone and in combination, against strains of C. glabrata.

Clinical outcomes of lung-transplant recipients treated by voriconazole and caspofungin combination in aspergillosis

Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune-compromised patients such as organ-transplant recipients. Recently, voriconazole has been approved for first-line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung-transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter's tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without. Lung-transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student's t-test. Statistical significance was defined by P-value <0.05. Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12.3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14.9 days vs. 8.3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole. This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung-transplant recipients a median of 12.3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.

Comparative pharmacodynamic interaction analysis of triple combinations of caspofungin and voriconazole or ravuconazole with subinhibitory concentrations of amphotericin B againstAspergillusspp.

Triple combination therapy with an antifungal triazole, echinocandin and amphotericin B (AmB) is used in some centres to treat refractory aspergillosis. The objective of this study was to investigate the effect of subinhibitory concentrations of AmB on the double combinations of caspofungin (CAS) + voriconazole (VOR) or ravuconazole (RAV) against Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus. Isolates were studied in triplicate against CAS/VOR and CAS/RAV combinations by chequerboard broth microdilution. AmB was added to each double combination at concentrations of 0, 0.1 and 0.2 microg ml(-1). The fractional inhibitory concentration (FIC) index was calculated for the double and triple combinations. Comparative analysis was performed by repeated measures analysis followed by Dunnett's post-test. The double combinations of CAS/RAV and CAS/VOR were synergistic or additive in most conditions. Addition of AmB to the double combinations resulted in increased FIC indices for A. fumigatus and A. flavus. By contrast, AmB increased the synergism of the double combinations decreasing FIC indices for A. terreus (P < 0.05). RAV and VOR displayed similar synergistic activity with CAS. The addition of sub-inhibitory amphotericin B concentrations reduced but did not eliminate the synergistic interaction between the echinocandin and triazole against A. fumigatus and A. flavus, while it increased the synergy against A. terreus.

In vitrosynergy of caspofungin with licensed and novel antifungal drugs against clinical isolates ofFusariumspp.

Combinations of caspofungin (CAS) with amphotericin-B (AMB), voriconazole (VRC), terbinafine (TRB) and tacrolimus (FK-506) were tested in vitro with 10 Fusarium isolates. MIC and minimal effective concentrations (MEC) were investigated in accord with the CLSI methodology. Drug interactions were assessed by the fractional inhibitory concentration index (FICI). Synergy occurred in 10/10, 9/10, 7/10 and 4/10 isolates with CAS/FK-506, CAS/TRB, CAS/AMB and CAS/VRC, respectively. Caspofungin MECs reached clinically attainable concentrations with FK-506 and TRB. Hyphal length and DiBAC staining demonstrated enhanced inhibition and killing with CAS/FK-506 and CAS/TRB. The combination of CAS/TRB and CAS/FK-506 is strongly synergistic in vitro against Fusarium spp. Our finding should be further studied in animal models of invasive infections caused by this fungus.