Combination Of Caspofungin Research Articles

In vitro evaluation of antifungal combinations against neurotropic dematiaceous fungi associated with primary cerebral phaeohyphomycosis.

Primary cerebral phaeohyphomycosis is a life-threatening disease caused by neurotropic dematiaceous fungi. At present, there are no consensus guidelines regarding optimal antifungal therapy in such cases. Generally, a combination of antifungal agents is recommended for treatment. However, the activities of antifungal combinations against these fungi have not been investigated. In this study, we evaluated the in vitro activities of 13 double and five triple antifungal combinations against clinical isolates of Cladophialophora bantiana (n = 7), Fonsecaea monophora (n = 2), and Cladosporium cladosporioides (n = 1), using a simplified checkerboard procedure. The minimum inhibitory concentrations (MICs) of nine antifungal drugs were determined by the broth microdilution method, and the interaction between antifungal agents in each combination was assessed by the fractional inhibitory concentration index. Excellent activity was observed for posaconazole and itraconazole. Flucytosine had potent activity against C. bantiana but was ineffective against F. monophora, and C. cladosporioides. The echinocandins demonstrated high MICs for all the isolates. Synergistic interactions were observed for all the double combinations, except when itraconazole was combined with either amphotericin B or flucytosine. The combination of amphotericin B with caspofungin showed synergistic interactions against 40% of the isolates. Antagonism was observed with isavuconazole-flucytosine combination against two C. bantiana isolates. The triple combinations of caspofungin and flucytosine with amphotericin B or posaconazole were synergistic against one isolate of F. monophora. For C. cladosporioides, synergy was observed for the triple combination of amphotericin B with caspofungin and flucytosine. Our results indicate that combination of caspofungin with amphotericin B or a triazole, with or without 5-flucytosine has great potential against neurotropic dematiaceous fungi.IMPORTANCEThis research uses a modified version of the checkerboard assay to standardize the in vitro testing of double and triple combinations of antifungal agents against neurotropic dematiaceous fungi. Antifungal combination therapy is associated with improved outcomes in cerebral phaeohyphomycosis. In this study, we demonstrate that posaconazole is the single most active antifungal drug against this group of fungi. The double combination of amphotericin B with caspofungin or a trizole, and the triple combinations of caspofungin and flucytosine with amphotericin B or posaconazole might hold promise in the treatment of cerebral phaeohyphomycosis. Our findings will guide in developing optimal therapeutic strategies for these refractory infections.

Efficacy of initial caspofungin plus trimethoprim/sulfamethoxazole for severe PCP in patients without human immunodeficiency virus infection

BackgroundThe number of pneumocystis pneumonia (PCP) cases is increasing in immunocompromised patients without human immunodeficiency virus infection (HIV), causing serious morbidity with high mortality. Trimethoprim/sulfamethoxazole (TMP/SMZ) monotherapy has limited effectiveness in the treatment of PCP. Clinical data on whether initial caspofungin plus TMP/SMZ for this disease is superior to monotherapy in non-HIV-infected patients are limited. We aimed to compare the clinical effectiveness of these regimens for severe PCP in non-HIV patients.MethodsA retrospective study reviewed 104 non-HIV-infected patients with confirmed PCP in the intensive care unit between January 2016 and December 2021. Eleven patients were excluded from the study because TMP/SMZ could not be used due to severe hematologic disorders or clinical data were missing. All enrolled patients were divided into three groups according to different treatment strategies: Group 1 received TMP/SMZ monotherapy, Group 2 received caspofungin combined with TMP/SMZ as first-line therapy, and Group 3 initially received TMP/SMZ monotherapy and later received caspofungin as salvage therapy. The clinical characteristics and outcomes were compared among the groups.ResultsA total of 93 patients met the criteria. The overall positive response rate of anti-PCP treatment was 58.06%, and the overall 90-day all-cause mortality rate was 49.46%. The median APACHE II score was 21.44. The concurrent infection rate was 74.19%, among whom 15.05% (n = 14) of those patients had pulmonary aspergillosis, 21.05% (n = 20) had bacteremia, and 23.65% (n = 22) had CMV infections. The patients who received initial caspofungin combination with TMP/SMZ had the best positive response rate (76.74%) compared to others (p = 0.001). Furthermore, the group that received initial caspofungin combined with TMP/SMZ had a 90-day all-cause mortality rate (39.53%) that was significantly different from that of the shift group (65.51%, p = 0.024), but this rate showed no statistically significant difference compared with that in the monotherapy group (48.62%, p = 0.322). None of the patients had serious adverse events from caspofungin therapy.ConclusionsFor non-HIV-infected patients with severe PCP, initial combination therapy with caspofungin and TMP/SMZ is a promising first-line treatment option compared with TMP/SMZ monotherapy and combination therapy as salvage therapy.

In vitro and in vivo evaluation of antifungal combinations against azole-resistant Aspergillus fumigatus isolates.

Azole resistance in Aspergillus fumigatus (Af) has become a widespread threat and a major concern for optimal management of patients with invasive aspergillosis (IA). Combination of echinocandins with azoles is an attractive alternative option for the treatment of IA due to azole-resistant Af strains. The aim of this study was to evaluate the in vitro and in vivo combination of caspofungin (CAS) with either voriconazole (VRZ) or posaconazole (PSZ). In vitro interactions were assessed by two methods, and an animal model of IA in Galleria mellonella was used for in vivo evaluation. Assessment of efficacy was based on larvae mortality. Groups of 10 larvae were infected by 3 clinical strains of Af (azole susceptible, AfS; PSZ resistant, AfR1; VRZ and PSZ resistant strain, AfR2). In vitro, combination of CAS and azoles was indifferent against AfS, and AfR2, and a synergy was found for AfR1. When compared to VRZ monotherapy, the combination of VRZ at 4 µg/larva with CAS at 4 µg/larva improved survival of AfR2-infected larvae (p=0.0066). Combination of PSZ at 4µg/larva with CAS at 4 µg/larva improved survival of AfR1-infected larvae compared to CAS (p=0.0002) and PSZ (0.0024) monotherapy. Antagonism was never observed. In conclusion, the combination of caspofungin with azoles is a promising alternative for the treatment of azole resistant strains of Af.

Antifungal activity and potential mechanism of action of caspofungin in combination with ribavirin against Candida albicans

The number of invasive fungal infections has increased dramatically, resulting in high morbidity and mortality among immunocompromised patients. With increasing use of caspofungin (CAS), resistant strains have emerged frequently and led to limitations in the treatment of patients with severe invasive Candida albicans infections. Combination therapy is an important method to deal with this issue. As such, this study investigated the activity of CAS in combination with ribavirin (RBV) against C. albicans. The results of this in-vitro study showed that the minimum inhibitory concentrations (MICs) of CAS and RBV when they were used as monotherapy were 0.5-1 μg/mL and 2-8 μg/mL, respectively, while the MIC of CAS decreased from 0.5-1 μg/mL to 0.0625-0.25 μg/mL when used in combination with RBV, with a fractional inhibitory concentration index (FICI) ≤0.5. In addition, the RBV+CAS combination group displayed synergistic effects against C. albicans biofilm over 4 h; the sessile MIC (sMIC) of CAS decreased from 0.5-1 µg/mL to 0.0625-0.25µg/mL and the sMIC of RBV decreased from 4-16 µg/mL to 1-2 µg/mL, with FICI <0.5. The survival of C. albicans-infected Galleria mellonella was prolonged, the fungal burden was decreased, and the area of tissue damage was reduced after combination therapy. Further study showed that the mechanisms of action of the synergistic effect were related to the inhibition of biofilm formation, the inhibition of hyphal growth, and the activation of metacaspases, but were not related to the accumulation of reactive oxygen species. It is hoped that these findings will contribute to the understanding of drug resistance in C. albicans, and provide new insights for the application of RBV.

P012 Antibiofilm activity of staphylococcal peptide derivative(s) against Candida auris biofilms in vitro and in an animal model of catheter-associated infection

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMObjectives Candida auris has emerged as a major multidrug-resistant nosocomial pathogen worldwide. The organism exhibits a persistent, colonizing phenotype, usually associated with biofilm formation on hospital surfaces, medical equipment, and indwelling medical devices. Biofilm formation by C. auris can further aggravate the infection acquisition and outcome, owing to the intrinsic resistance of biofilms to disinfectants, antiseptics, and antifungal drugs. The present study aimed to evaluate the preventive and therapeutic efficacy of select peptide derivative(s) from staphylococci against C. auris biofilms in vitro and in a mouse model of C. auris catheter-associated infection.MethodsThree potentially antimicrobial, staphylococcal alpha-helical amphipathic peptides (19-23 amino acids) were evaluated for antifungal and antibiofilm activity against clinical isolates of C. auris. The antifungal activity against C. auris planktonic cells was tested by broth microdilution assay according to the method of the Clinical and Laboratory Standards Institute. Biofilm assays were performed in 96 well, flat-bottomed microtiter plates in RPMI-1640, and the effect of the test agents on biofilm formation (MBPC, minimum biofilm preventive concentration) as well as pre-formed biofilms (MBIC, minimum biofilm inhibitory concentration) was determined by subjecting to a two-fold dilution range of the test agents (0.03-64 μm) for 24 h at 37°C, followed by XTT dye reduction test. Field-Emission Scanning Electron Microscopy was performed to observe the effect of peptides on biofilm morphology. The cytotoxicity of these compounds was elucidated on HeLa, HEK-293, and Raw 264.7 murine macrophages by MTT reduction test. The synergistic effect of the selected peptide with representative antifungal drugs belonging to three different classes (amphotericin B, caspofungin, and voriconazole) was tested by fractional inhibitory concentration assays. In vivo activity of the selected peptide was determined in a murine model of subcutaneous C. auris catheter-associated infection, alone and in combination with amphotericin B and caspofungin.ResultsBased on the antimicrobial activity, antibiofilm activity, and cytotoxicity data, the 19 amino acid, alpha helical staphylococcal peptide derivative (charge, +3; hydrophobicity, 0.634, and hydrophobic moment, 0.623) exhibited promising activity against C. auris biofilms. The peptide was particularly effective in preventing C. auris biofilm formation, with a median MBPC50 of 1 μm. It demonstrated synergistic activity with amphotericin B (FIC index, 0.3) as well as caspofungin (FIC index, 0.18), and an additive effect with voriconazole (FIC index, 0.71). When combined with 0.125 μm of the peptide derivative, nearly 4-to-8-fold lower amount of the drug was required to achieve results comparable to the drug-only controls. Furthermore, nearly 99% reduction in biofilm formation was noted at clinically-achievable trough levels of amphotericin B or caspofungin in combination with this peptide derivative. Similar results were noted in vivo, with nearly 99% reduction in biofilm formation of C. auris in catheter lumen using combination therapy with 0.125 μm of the peptide.ConclusionThe present study demonstrates that a 19 amino acid, alpha helical staphylococcal peptide derivative exhibits promising antibiofilm activity against C. auris, particularly in preventing biofilm formation, in vitro and in a murine model of subcutaneous catheter-associated infection.

Clinical Characteristic, Diagnosis and Treatment of Acute Lymphoblastic Leukemia Combined with Pneumocystis Carinii Pneumonia in Children

To investigate the clinical characteristics and treatment of pneumocystis carinii pneumonia (PCP) in children with acute lymphoblastic leukemia (ALL), in order to improve the early diagnosis and effective treatment. Clinical data of five children with ALL developing PCP in the post-chemotherapy granulocyte deficiency phase were analyzed retrospectively. The clinical manifestations, laboratory tests, imaging findings, treatment methods and effect were summarized. The male-to-female ratio of the five children was 1∶4, and the median age was 5.5 (2.9-8) years old. All patients developed PCP during granulocyte deficiency phase after induction remission chemotherapy. The clinical manifestations were generally non-specific, including high fever, tachypnea, dyspnea, non-severe cough, and rare rales in two lungs (wet rales in two patients). Laboratory tests showed elevated C-reactive protein (CRP), serum procalcitonin (PCT), (1,3)-β-D-glucan (BDG), lactate dehydrogenase (LDH) and inflammatory factors including IL-2R, IL-6 and IL-8. Chest CT showed diffuse bilateral infiltrates with patchy hyperdense shadows. Pneumocystis carinii(PC) was detected in bronchoalveolar lavage fluid (BALF) or induced sputum by high-throughput sequencing in all patients. When PCP was suspected, chemotherapy was discontinued immediately, treatment of trimethoprim-sulfame thoxazole (TMP-SMX) combined with caspofungin against PC was started, and adjunctive methylprednisolone was used. Meanwhile, granulocyte-stimulating factor and gammaglobulin were given as the supportive treatment. All patients were transferred to PICU receiving mechanical ventilation due to respiratory distress during treatment. Four children were cured and one died. PCP should be highly suspected in ALL children with high fever, dyspnea, increased LDH and BDG, and diffuse patchy hyperdense shadow or solid changes in lung CT. The pathogen detection of respiratory specimens should be improved as soon as possible. TMP/SMZ is the first-line drug against PCP, and the combination of Caspofungin and TMP/SMZ treatment for NH-PCP may have a better efficacy. Patients with moderate and severe NH-PCP may benefit from glucocorticoid.

In vitro synergistic antifungal activities of caspofungin in combination with fluconazole or voriconazole against Candida species determined by the Etest method

ObjectivesIncreased resistance of Candida species, especially Candida. glabrata is problematic. Combination antifungal therapies were studied to solve the problem. MethodsIn this study, combinations of caspofungin with fluconazole and voriconazole were evaluated in 28 Candida species (including 15 C. glabrata and 12 with FKS mutation) at 24 and 48 hours using two Etest methods (direct cover method and MIC/MIC method). ResultsFor Candida isolates, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) isolates at 48 hours. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/28 (39%) and 12/28 (43%) isolates at 24 hours, and against 16/28 (57%) and 17/28 (61%) isolates at 48 hours, respectively. For C. glabrata, direct cover method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against 11/15 (73%) and 10/15 (67%) isolates at 24 hours, and 11/15 (73%) and 13/15 (87%) isolates at 48 hours, respectively. The MIC/MIC method showed synergy of caspofungin-fluconazole and caspofungin-voriconazole against both 11/15 (73%) isolates at 24 hours, and 10/15 (67%) and 14/15 (93%) isolates at 48 hours, respectively. ConclusionA combination of caspofungin and fluconazole or voriconazole might be effective against infections caused by Candida species, especially C. glabrata with FKS mutation.

In Vitro Characterization of Twenty-One Antifungal Combinations against Echinocandin-Resistant and -Susceptible Candida glabrata.

This study was designed to analyze the interaction of 21 antifungal combinations consisting of seven major antifungal agents against 11 echinocandin- susceptible and six-resistant C. glabrata isolates. The combinations were divided into five major groups and were evaluated by checkerboard, disc diffusion, and time-killing assays. Synergy based on the fractional inhibitory concentration index of ≤0.50 was observed in 17.65–29.41% of the cases for caspofungin combinations with azoles or amphotericin B. Amphotericin B combination with azoles induced synergistic interaction in a range of 11.76–29.41%. Azole combinations and 5-flucytosine combinations with azoles or amphotericin B did not show synergistic interactions. None of the 21 combinations showed antagonistic interactions. Interestingly, 90% of the detected synergism was among the echinocandin-resistant isolates. Disk diffusion assays showed that the inhibition zones produced by antifungal combinations were equal to or greater than those produced by single drugs. The time-killing assay showed the synergistic action of caspofungin combination with fluconazole, voriconazole, and posaconazole, and the amphotericin B-5-flucytosine combination. Furthermore, for the first time, this assay confirmed the fungicidal activity of caspofungin-voriconazole and amphotericin B-5-flucytosine combinations. The combination interactions ranged from synergism to indifference and, most importantly, no antagonism was reported and most of the synergistic action was among echinocandin-resistant isolates.

Effects of caspofungin, tolcapone and other FDA-approved medications on MRSA susceptibility to vancomycin

ObjectivesVancomycin is a first-line antibiotic for the treatment of invasive infections in humans caused by methicillin-resistant Staphylococcus aureus (MRSA). Based on the premise that antibiotic combinations can exhibit synergistic and antagonistic interactions, medications used for the treatment of infection and other medical conditions were evaluated for their ability to alter MRSA susceptibility to vancomycin. MethodsA chemical library comprised of 1237 pharmacological agents was evaluated in a 96-well plate format for its ability to inhibit MRSA growth in combination with half the minimum inhibitory concentration (MIC) of vancomycin. Caspofungin and tolcapone were further assessed for synergistic potential by isobologram (checkerboard) and flow cytometric analysis. In addition, the antibacterial activity spectrum and effects of growth conditions of the two drugs were delineated by MIC determination. ResultsThe study identified 17 nonantibiotic library members with synergistic or additive potential, including caspofungin and tolcapone. Further analyses revealed that the respective medications for invasive candidiasis and Parkinson disease were bactericidal and bacteriostatic inhibitors of S. aureus growth. Flow cytometric analysis of viability further demonstrated that caspofungin in combination with vancomycin increased MRSA cell death in an additive manner, whereas tolcapone appeared to suppress the bactericidal action of vancomycin. ConclusionOverall, this proof of concept study concluded that nonantibiotic drugs can alter the pharmacodynamic properties of vancomycin, with potential clinical implications in patients with a MRSA infection receiving medications for other medical conditions.

A retrospective study of patients with systemic lupus erythematosus combined with Pneumocystis jiroveci pneumonia treated with caspofungin and trimethoprim/sulfamethoxazole.

Systemic lupus erythematosus (SLE) complicated with Pneumocystis jiroveci pneumonia (PCP) is a clinical complex with unsatisfying treatment efficacy and poor prognosis which is difficult to be diagnosed at early stage. The present study aimed to investigate the clinical features of SLE with PCP, recognize the early onset indicating factors, and evaluate the treatment efficacy of combined caspofungin and trimethoprim/sulfamethoxazole (coSMZ).We reviewed data of 9 patients admitted with SLE-PCP and treated with caspofungin combined with coSMZ at Tangshan Gongren Hospital from January 2013 to December 2017. Patients’ clinical manifestation and laboratory data [leucocyte, lymphocyte, cluster of differentiation 4 (CD4)+T cell, lactate dehydrogenase (LDH), blood gas, etc] were compared before and after treatments. And the early onset factors of SLE-PCP, treatment efficacy of combined caspofungin and CoSMZ were analyzed.Among these 9 patients, 8 patients suffered renal impairment, and all of them had been taking prednisone in the past 3 months at an average dose of 29.4 ± 13.6 mg/day. In addition, they had taken at least one kind of immunosuppressants. Laboratory data (leucocyte, lymphocyte, CD4+T cell, PaO2, LDH) were remarkably abnormal at hospital admission, but they were improved significantly after 2 weeks of treatment, which is also statistically significant (P < .05), except that leukocyte had no significance change to the value at admission (P = .973). In addition, none of the studied patients died.The results of the study indicated that long-term use of glucocorticoids and immunosuppressants, low CD4+T cell count, and renal impairment are the early-onset factors for SLE-PCP, caspofungin, when combined with CoSMZ, it could be a promising and effective strategy to treat SLE with PCP.

Combination antifungal treatment for invasive fungal disease after hematopoietic stem cell transplantation in children with hematological disorders.

Invasive fungal disease (IFD) has a poor prognosis in children with hematological disorders after hematopoietic stem cell transplantation (HSCT). We assessed if drug combinations with different targets may improve the outcome. Retrospective study to assess the outcome of combination antifungal therapy (CAT) for proven-probable IFD (PP-IFD) in children with hematological disorders after HSCT from January 2008 to June 2018. Over the 10-year period, 95 PP-IFD were diagnosed in pediatric recipients, median age of 5.6years. Twenty-seven patients received combinations of caspofungin and voriconazole, 28 patients received combinations of caspofungin and amphotericin B, and 40 patients received combinations of voriconazole and amphotericin B. The overall response rate of PP-IFD was 77.9%, while the 100-day overall survival rates were 66.8%. Univariate analysis showed that factors that significantly affected the response to combination treatments were type of combination (P=0.02), the stem cell source (P=0.04), the donor type (P=0.03), HLA-match (P=0.03), aGVHD (P=0.02), period of treatment (P=0.044), use of corticosteroids (0.036), CD4:CD8 ratio (P=0.014), and CMV viremia (P=0.033). In addition, multivariate analysis demonstrated that only the type of combination remained a significant factor (odds ratio=0.335, 95% confidence interval: 0.071-0.812, P=0.042). Forty-three children suffered from mild and reversible adverse reactions, no serious side effects during treatment. A variety of factors can affect the outcome of CAT. Combination of caspofungin with voriconazole is a safe and helpful treatment option for HSCT recipients with IFD.

Efficacy of caspofungin combined with trimethoprim/sulfamethoxazole as first-line therapy to treat non-HIV patients with severe pneumocystis pneumonia.

Combined treatment with caspofungin and trimethoprim/sulfamethoxazole (TMP/SMZ) as salvage therapy in non-HIV positive patients with severe pneumocystis pneumonia (PCP) yields poor outcomes. It remains unknown whether the use of this combination strategy as a first-line therapy would improve patient outcomes. The present study aimed to assess the efficacy of caspofungin combined with TMP/SMZ as a first-line therapy in non-HIV positive patients with severe PCP. A retrospective cohort study was conducted between March 2016 and February 2017. Patient clinical characteristics and outcomes were compared between two groups receiving first-line and second-line therapy respectively. In addition, similar cases from previous studies were assessed. A total of 14 patients were included in the present study (mean age, 58.79±14.41 years); including 9 patients receiving caspofungin and TMP/SMZ as a first-line therapy and 5 that received it as a second-line therapy. The overall positive response rate was 71.43% (10/14), with 88.89 (8/9) and 40.00% (2/5) in the first-line and second-line therapy groups, respectively (P=0.095). The positive response rates of patients requiring invasive mechanical ventilation differed significantly between the first-line (5/6, 83.33%) and the second-line (0/3, 0%) therapy groups (P=0.048). All-cause hospital mortality was 42.86% (6/14), with mortality rates of 33.33 (3/9) and 60.00% (3/5) in the first-line and second-line therapy groups, respectively (P=0.580). Combined with previously reported cases (n=27), the positive response rate was significantly greater in the first-line therapy group (11/12, 91.67%) than in the second-line therapy group (8/15, 53.33%, P=0.043). No significant differences were in all-cause mortality rates between the two groups (25.00 vs. 46.67%, P=0.424) were identified, despite the fact that all-course mortality in the first-line therapy group was ~50% that of the second-line therapy group. Therefore, the results of the present study indicate that combined caspofungin and TMP/SMZ as first-line therapy may be a promising and effective strategy to treat non-HIV positive patients with severe PCP, particularly for those requiring invasive mechanical ventilation.

In Vitro Interactions of Echinocandins with Triazoles against Multidrug-Resistant Candida auris.

We determined the in vitro interactions between echinocandins and azoles against 10 multidrug-resistant Candida auris strains by use of a microdilution checkerboard technique. Our results suggest synergistic interactions between micafungin and voriconazole with fractional inhibitory concentration index (FICI) values of 0.15 to 0.5, and we observed indifferent interactions when micafungin was combined with fluconazole (FICI, 0.62 to 1.5). Combinations of caspofungin with fluconazole or voriconazole exhibited indifferent interactions. No antagonism was observed for any combination.

Activity of Combined Antifungal Agents Against Multidrug-Resistant Candida glabrata Strains.

In this study, we evaluated the in vitro activity of echinocandins, azoles, and amphotericin B alone and in combination against echinocandin/azole-sensitive and echinocandin/azole-resistant Candida glabrata isolates. Susceptibility tests were performed using the broth microdilution method in accordance with the Clinical and Laboratory Standards Institute document M27-A3. The checkerboard method was used to evaluate the fractional inhibitory concentration index of the interactions. Cross-resistance was observed among echinocandins; 15% of the isolates resistant to caspofungin were also resistant to anidulafungin and micafungin. Synergistic activity was observed in 70% of resistant C. glabrata when anidulafungin was combined with voriconazole or posaconazole. Higher (85%) synergism was found in the combination of caspofungin and voriconazole. The combinations of caspofungin with fluconazole, posaconazole and amphotericin B, micafungin with fluconazole, posaconazole and voriconazole, and anidulafungin with amphotericin B showed indifferent activities for the majority of the isolates. Anidulafungin combined with fluconazole showed the same percentage of synergism and indifference (45%). Antagonism was detected in 50% of isolates when micafungin was combined with amphotericin B. Combinations of echinocandins and antifungal azoles have great potential for in vivo assays which are required to evaluate the efficacy of these combinations against multidrug-resistant C. glabrata strains.

Evaluation of synergistic anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans

This study aimed to investigate the synergy between anticandidal and apoptotic effects of ferulic acid and caspofungin against Candida albicans and Candida glabrata, with the help of a quantitative checkerboard microdilution assay using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as a viability dye. Apoptotic effects of caspofungin and ferulic acid concentrations (alone and combined) were analyzed for C. albicans and C. glabrata based on annexin V–propidium iodide binding capacities using flow cytometric analysis. C. albicans showed a synergistic effect, represented by a fractional inhibitory concentration index of < 0.5, but C. glabrata showed no synergistic effect (fractional inhibitory concentration index > 0.5). Early and late apoptotic effects of caspofungin and ferulic acid concentrations (1 μg/mL and 1000 μg/mL) were calculated as 55.7% and 18.3%, respectively, while their necrotic effects were determined as 5.8% and 51.6%, respectively, using flow cytometric analyses. The apoptotic effects of the combination of caspofungin and ferulic acid at concentrations of 1 μg/mL and 1000 μg/mL on C. albicans and C. glabrata were 73.0% and 48.7%, respectively. Ferulic acid also demonstrated a synergistic effect in combination with caspofungin against C. albicans. Another possibility is to combine the existing anticandidal drug with phytochemicals to enhance the efficacy of anticandidal drug.

Voriconazole plus caspofungin for treatment of invasive fungal infection in children with acute leukemia.

BackgroundInvasive fungal infections (IFIs) are a life-threatening problem in immunocompromised patients. Despite timely diagnosis and appropriate antifungal therapy, clinical outcomes of IFIs remain unsatisfactory, necessitating treatment with a combination of antifungal agents. Therefore, childhood leukemic patients treated with voriconazole plus caspofungin were evaluated for the safety and efficacy of the combination antifungal therapy to treat IFIs.MethodsIn this retrospective study, medical records were retrieved for patients admitted to the Pediatric Department of Yeungnam University Hospital, Daegu, South Korea, between April 2009 and May 2013. Medical records of 22 patients were analyzed.ResultsOf the 22 patients studied, nine (41%) had been diagnosed with probable IFI, and 13 (59%) with possible IFI. All patients, except one, were already receiving antifungal monotherapy for the treatment of neutropenic fever. After a diagnosis of IFI was confirmed, antifungal monotherapy was replaced with combination therapy. The study's overall response rate was 90.9%, with complete responses in 86.3% of the patients. Two patients experienced a side effect of a small increase in liver enzyme levels.ConclusionVoriconazole plus caspofungin combination therapy is an effective and safe treatment for serious IFI in pediatric patients with acute leukemia.

In Vitro Antifungal-Antibacterial Combinations are Effective Against MRSA in Candida albicans-Staphylococcus aureus Polymicrobial Biofilms

A significant proportion of human infections involve biofilms, which are more resistant to antimicrobial agents than their planktonic counterparts. It is well established that C. albicans readily forms polymicrobial biofilms with S. aureus. We hypothesized that the addition of an antifungal to an antibacterial, or combination therapy would be more effective in reducing the microbial load, most notably in polymicrobial biofilms, and possibly impact overall management of infection. In vitro results demonstrate that clinical strains of both methicillin-susceptible and methicillin-resistant S. aureus are less susceptible to vancomycin in polymicrobial biofilms with C. albicans when compared to S. aureus monomicrobial biofilms. Treatment of biofilms with either amphotericin B or caspofungin in combination with vancomycin resulted in greater inhibition and even elimination of methicillin-susceptible and methicillin-resistant S. aureus in C. albicans polymicrobial biofilms. The results of this study indicate that combination therapy should be a consideration in the management of polymicrobial biofilms, specifically C. albicans-S. aureus biofilm infections.

In Vitro Triple Combination of Antifungal Drugs against Clinical Scopulariopsis and Microascus Species.

Broth microdilution checkerboard techniques based on the methodology of the Clinical and Laboratory Standards Institute (CLSI) were employed to study the triple antifungal combination of caspofungin, posaconazole, and terbinafine against 27 clinical isolates of Scopulariopsis and Microascus species. Synergy was observed for 26 isolates, whereas antagonism was observed for Scopulariopsis candida in this study.

The Evaluation of the Combination of Caspofungin with Voriconazole and Amphotericin B against Clinical Candida krusei Isolates by Etest and Disk Diffusion Methods

Background: C. krusei is an opportunistic fungal pathogen that known of its intrinsic fluconazole resistance and its frequency is increasing especially among hematology patients. The increase in the frequency of high mortality fungal infections have accelerated the efforts of new drug development with broad spectrum, low toxicity and the studies including their combination. However, there is no standardized method to evaluate the activity of drug combinations. Aims: To evaluate the activity of caspofungin (CAS) with voriconazole (VOR) and amphotericin B (AMB) alone and in combination and the utility of Etest and disk diffusion methods for antifungal combinations. Methodology: The minimum inhibitory concentrations of VOR, CAS and AMB against 30 clinical C. krusei isolates were determined by using Etest, disk diffusion and reference broth microdilution methods. Combinations of CAS with VOR and CAS with AMB were evaluated using disk diffusion (three different ways) and Etest (two different ways) methods. Original Research Article British Microbiology Research Journal, 4(5): 497-508, 2014 498 Results: All isolates tested were susceptible to VOR and CAS in vitro by all three methods. Categorical agreements of Etest and disk diffusion methods with reference microdilutiontest were 100% for CAS and VOR (for each method), 86.7% and 50% for AMB, respectively. In the all ways of both combination methods, we did not observe distinctly antagonistic or synergic interaction. Conclusion: Etest and disk diffusion could be easy, convenient, and nontime-consuming alternative methods to evaluate the antifungal combinations. The combinations of CAS with VOR and AMB exhibited promising results because of an apparent antagonistic interaction was not detected in this study.

Combination of caspofungin and low‐dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients

Pneumocystis jirovecii pneumonia (PJP) is a severe and life-threatening complication in immunocompromised patients. Trimethoprim/sulfamethoxazole (TMP-SMZ) is well known for its effectiveness as prophylaxis of PJP. However, the use of TMP-SMZ is associated with various adverse effects that may not be tolerated by critically ill patients. Caspofungin is recommended for invasive fungal infections, but the treatment of PJP after solid organ transplantation (SOT) is an off-label use of this drug. In this study, three cases of severe PJP in renal transplant recipients treated with a combination of caspofungin and low-dose TMP-SMZ were presented. Initial findings indicated that the combined treatment may be beneficial for the treatment of PJP and decrease the incidence of TMP-SMZ-related adverse effects.