Immunomodulatory Effect of the Antifungal Itraconazole (original) (raw)
Fibrogenesis & Tissue Repair
Background: Pentoxifylline (PTX) is a methylxanthine compound with immunomodulatory and antifibrotic properties. The simultaneous use of PTX and antifungal therapy (itraconazole) has previously been evaluated in an experimental model of pulmonary paracoccidioidomycosis (PCM), a systemic fungal disease caused by the fungus Paracoccidioides brasiliensis (Pb) and characterized by chronic inflammation and lung fibrosis that appears even after a successful course of antifungal therapy. The results revealed prompt and statistically significant reductions in inflammation and fibrosis when compared to itraconazole alone. However, the effect of monotherapy with PTX on the host response to PCM has not been well-documented. Our aim was to determine the effect of PTX on the course of pulmonary lesions and on the local immune response. Results: At the middle and end of treatment, the Pb-infected-PTX-treated mice exhibited significant reductions in lung density compared to the Pb-infected-non-treated mice as assessed by the quantification of Hounsfield units on high-resolution computed tomography (HRCT) (p <0.05 by Kruskal-Wallis test); additionally, at the end of therapy, the lung areas involved in the inflammatory reactions were only 3 vs. 22 %, respectively, by histomorphometry (p <0.05 by Mann-Whitney test), and this reduction was associated with a lower fungal burden and limited collagen increment in the pulmonary lesions. PTX treatment restored the levels of IFN-γ, MIP-1β, and IL-3 that had been down-regulated by Pb infection. Additionally, IL-12p70, IL-10, IL-13, and eotaxin were significantly increased, whereas Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) levels were decreased in the lungs of the Pb-infected-PTX-treated mice compared to the non-treated group. Conclusions/significance: This study showed that PTX therapy administered at an "early" stage of granulomatous inflammation controlled the progress of the PCM by diminishing the pulmonary inflammation and the fungal burden and avoiding the appearance of collagen deposits in the pulmonary lesions.
Antimicrobial Agents and Chemotherapy, 2010
We have evaluated the in vitro activity of posaconazole (PSC) against 50 clinical strains of Rhizopus oryzae using a broth microdilution method, the Neo-Sensitabs tablet diffusion method, and minimal fungicidal concentration (MFC) determination. In general, PSC showed low MICs against this fungus, and the MICs correlated with the inhibition zone diameters. Most of the MFCs, however, were from 1 to 4 dilutions higher than their corresponding MICs. We then investigated the efficacies of several different doses of PSC in a murine model. All treatments began 24 h after challenge and lasted for 7 days. The drug was administered twice a day to mice infected with three strains that showed intermediate PSC susceptibility (MIC ؍ 2 g/ml) and three PSC-susceptible strains (MIC ؍ 0.25 g/ml). A dose of 10 mg/kg of body weight was ineffective, while doses of 20 and 30 mg/kg prolonged the survival of the mice. The 50 strains tested were segregated into two groups on the basis of the in vitro data. For the group with the most strains (85%), the strains had low PSC MICs, mice infected with the strains showed higher rates of survival (30 to 40%), and PSC was able to reduce the fungal load in the kidney and less regularly in the brain. For the second group (15% of the strains), the strains had intermediate PSC MICs, mice infected with the strains had lower survival rates (10 to 20%), and PSC treatment resulted in variable and no reductions in the fungal loads in the kidneys and brains, respectively.
Microbes and Infection, 2010
A comparative study, based on histopathologic findings (inflammation, cellularity, and fibrosis) and immunologic parameters (proinflammatory and anti-inflammatory cytokines), was carried out in order to evaluate the effects of itraconazole (ITC) treatment and its starting time in a BALB/c murine model of chronic pulmonary paracoccidioidomycosis (PCM), induced by intranasal inoculation of Paracoccidioides brasiliensis (Pb) conidia. Two different groups of mice were exposed to ITC therapy beginning at the 4th or 8th week after Pb infection, respectively. ITC was administered daily, via gavage, for a period of sixty days. At weeks 0, 4, 8, 12 and 16 the animals were sacrificed and their lungs removed for histology staining with hematoxylin and eosin (H&E), Masson's trichromic and GomorieGrocott; pulmonary levels of IL-1b, TNF-a, IFN-g, IL-13 and TGF-b were also measured by ELISA. The development or absence of the principal pulmonary PCM sequela, lung fibrosis, was directly related to the therapy's starting time. This and other histopathologic findings were related to the behavior of cytokine levels.
Antimicrobial Agents and Chemotherapy, 2001
The antifungal efficacy, safety, and pharmacokinetics of posaconazole (SCH 56592) (POC) were investigated in treatment and prophylaxis of primary pulmonary aspergillosis due to Aspergillus fumigatus in persistently neutropenic rabbits. Antifungal therapy consisted of POC at 2, 6, and 20 mg/kg of body weight per os; itraconazole (ITC) at 2, 6, and 20 mg/kg per os; or amphotericin B (AMB) at 1 mg/kg intravenously. Rabbits treated with POC showed a significant improvement in survival and significant reductions in pulmonary infarct scores, total lung weights, numbers of pulmonary CFU per gram, numbers of computerized-tomography-monitored pulmonary lesions, and levels of galactomannan antigenemia. AMB and POC had comparable therapeutic efficacies by all parameters. By comparison, animals treated with ITC had no significant changes in outcome variables in comparison to those of untreated controls (UC). Rabbits receiving prophylactic POC at all dosages showed a significant reduction in infarct scores, total lung weights, and organism clearance from lung tissue in comparison to results for UC (P < 0.01). There was dosage-dependent microbiological clearance of A. fumigatus from lung tissue in response to POC. Serum creatinine levels were greater (P < 0.01) in AMB-treated animals than in UC and POC-or ITC-treated rabbits. There was no elevation of serum hepatic transaminase levels in POC-or ITC-treated rabbits. The pharmacokinetics of POC and ITC in plasma demonstrated dose dependency after multiple dosing. The 2-, 6-, and 20-mg/kg dosages of POC maintained plasma drug levels above the MICs for the entire 24-h dosing interval. In summary, POC at >6 mg/kg/day per os generated sustained concentrations in plasma of >1 g/ml that were as effective in the treatment and prevention of invasive pulmonary aspergillosis as AMB at 1 mg/kg/day and more effective than cyclodextrin ITC at >6 mg/kg/day per os in persistently neutropenic rabbits.
Antimicrobial Agents and Chemotherapy, 2017
PC945 is a novel triazole optimized for lung delivery, and the objective of this study is to determine the effects of intranasally dosed PC945 on Aspergillus fumigatus infection and associated biomarkers in immunocompromised mice. PC945, posaconazole, or voriconazole was administered intranasally once daily on days 0 to 3 (early intervention) or days 1 to 3 (late intervention) postinfection in temporarily neutropenic A/J mice infected intranasally with A. fumigatus , and bronchoalveolar lavage fluid (BALF) and serum were collected on day 3. The effects of extended prophylaxis treatment (daily from days −7 to +3 or days −7 to 0) were also compared with those of the shorter treatment regimens (days −1 to +3 or days −1 and 0). Early and late interventions with PC945 (2.8 to 350 μg/mouse; approximately 0.11 to ∼14 mg/kg of body weight) were found to inhibit lung fungal loads and to decrease the concentrations of galactomannan (GM) in both BALF and serum as well as several biomarkers in ...
Antimicrobial Agents and Chemotherapy, 2000
An intravenous (i.v.) formulation of itraconazole was evaluated in disseminated fungal infection models in guinea pigs. In acute disseminated Candida albicans and Aspergillus fumigatus infections, treatment at 5 mg/kg of body weight twice a day (b.i.d.) significantly prolonged survival. In these models and in animals with chronic disseminated cryptococcosis, itraconazole given i.v. at 2.5 and 5 mg/kg b.i.d. greatly reduced the proportions of organs with culture-detectable fungal burdens. The efficacy of i.v. itraconazole in these animal models justifies its further investigation for the treatment of life-threatening mycoses in humans.
Immunomodulating effects of antifungal therapy
Current Fungal Infection Reports, 2009
The action of modern antifungal drugs may not be restricted to their direct fungicidal or fungistatic activity. Recent evidence suggests that antifungals may stimulate or alter the host immune response by mechanisms that may result in enhanced fungal clearance, but with possible increased collateral damage to the host. Dissecting the net impact of antifungal therapy-mediated immunomodulation is diffi cult because the type and magnitude of these immunostimulatory properties are infl uenced by the class and type of the drug, the immunologic status of the host, and the specifi c fungal pathogen. Ultimately, immunopharmacologic considerations may become important in selecting and dosing antifungal therapy for opportunistic mycoses.
Antimicrobial agents and chemotherapy, 2017
Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in immunocompromised patients. We hypothesized that simultaneous inhibition of biosynthesis of ergosterol in the fungal cell membrane and (1→3)-β-D-glucan in the cell wall, respectively, by the antifungal triazole isavuconazole and the echinocandin micafungin, may result in improved outcome in experimental IPA in persistently neutropenic rabbits. Treatment groups included isavuconazole (ISA) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day, micafungin at 2 mg/kg/day (MFG2), or combinations of (ISA20+MFG2), (ISA40+MFG2), (ISA60+MFG2), and untreated rabbits (UC). Galactomannan index (GMI) and (1→3)-β-D-glucan levels were measured in serum. Residual fungal burden (CFU/g) was significantly reduced in ISA20-, ISA40-, ISA60-, ISA20+MFG2-, ISA40+MFG2-, and ISA60+MFG2-treated rabbits vs that of MFG2-treated or UC (p<0.01). Measures of organism-mediated pulmonary injury, lung weights and pulmonary i...
Fungal infections in the immunocompromised host
Diagnostic Microbiology and Infectious Disease, 1989
With the increased number of immunocompromised patients there has been a concomitant increase in patient morbidity and mortality due to fungi. The etiologic microorganisms vary depending upon the type of immune dysfunction. Patients with malignancies and chemotherapy-induced neutropenia commonly are infected with Candida and Aspergillus. Other ubiquitous fungi such as Rhizopus, Fusarium, and Trichosporon are more frequently implicated as agents of disease in these patients. Patients with cell-mediated immune dysfunction such as acquired immune deficiency syndrome (AIDS) are susceptible to mucocutaneous candidiasis and pulmonary and disseminated cryptococcosis. Histoplasmosis and coccidioidomycosis have been particularly lethal infections in AIDS patients. Contributing factors such as broad-spectrum antibiotic use, intravenous catheterization, malnutrition, hy-peralimentation, multiple surgical procedures and/or trauma, and steroids used either singly or in combination may also predispose patients to invasive fungal disease. Definitive diagnosis is often difficult to establish and usually requires invasive biopsy. Delay of culture results due to the time required to process specimens and to allow the fungus to grow also contributes to the poor results of therapy. Biopsy of skin lesions represents a useful technique for making a diagnosis. Recent advances in antifungal therapeutics promise to change the current approach to treatment for several of the mycoses. The availability of new oral azoles with spectra of activity that include aspergillosis and cryptococcosis, which currently require treatment with parenteral amphotericin B, may prove practical for prolonged oral therapy of otherwise lethal mycoses.
Diagnostic microbiology and infectious disease, 2018
Posaconazole (PSC) in combination with anidulafungin (AFG) was evaluated in a murine model of pulmonary aspergillosis. Immunosuppressed animals were infected via the nasal cavity with 2 different A. fumigatus strains. The animals received PSC (oral, 20mg/kg per day) and/or AFG (i.p., 10mg/kg per day) for 7days. On Day 8, the mice were euthanized and fungal burdens were determined from the lungs. Survival curves were constructed for mortality analysis. Compared to untreated groups, groups singly treated with PSC or AFG showed a reduced fungal burden in the lungs (P=0.0001-0.006) and prevention of mortality (66.66-83.33% of survival). Combination treatment with PSC and AFG significantly reduced the fungal burden (or sterilized the lungs) compared to the findings in the untreated and monotherapy groups and improved the survival rate to 100%. The PSC and AFG combination therapy was highly effective and should be evaluated in larger-scale experiments.
Journal of Infectious Diseases, 2016
Background. Impaired delivery of antifungals to hyphae within necrotic lesions is thought to contribute to therapeutic failure in invasive pulmonary aspergillosis (IPA). We hypothesized that transfusion of leukocytes loaded ex vivo with the lipophilic antifungal posaconazole could improve delivery of antifungals to the sites of established infection and improve outcome in experimental IPA. Methods. The HL-60 leukemia cell line was differentiated to a neutrophil-like phenotype (differentiated HL-60 [dHL-60] cells) and then exposed to a range of posaconazole concentrations. The functional capacity and antifungal activity of these cells were assessed in vitro and in a mouse model of IPA. Results. Posaconazole levels in dHL-60 cells were 265-fold greater than the exposure concentration. Posaconazole-loaded cells were viable and maintained their capacity to undergo active chemotaxis. Contact-dependent transfer of posaconazole from dHL-60 cells to hyphae was observed in vitro, resulting in decreased fungal viability. In a neutropenic mouse model of IPA, treatment with posaconazole-loaded dHL-60 cells resulted in significantly reduced fungal burden in comparison to treatment with dHL-60 cells alone. Conclusions. Posaconazole accumulates at high concentrations in dHL-60 cells and increases their antifungal activity in vitro and in vivo. These findings suggest that posaconazole-loading of leukocytes may hold promise for the therapy of IPA.
Pulmonary Pharmacology & Therapeutics, 2011
Fibrosis is a severe and progressive sequel of many pulmonary diseases, has no effective therapy at present and, consequently, represents a serious health problem. In Latin America, chronic pulmonary paracoccidioidomycosis (PCM) is one of the most important, prevalent and systemic fungal diseases that allows the development of lung fibrosis, with the additional disadvantage that this sequel may appear even after an apparently successful course of antifungal therapy. In this study, was propose the pentoxifylline as complementary treatment in the pulmonary PCM due to its immunomodulatory and anti-fibrotic properties demonstrated in vitro and in vivo in liver, skin and lung. Our objective was to investigate the possible beneficial effects that a combined antifungal (Itraconazole) and immunomodulatory (Pentoxifylline) therapy would have in the development of fibrosis in a model of experimental chronic pulmonary PCM in an attempt to simulate the naturally occurring events in human patients. Two different times post-infection (PI) were chosen for starting therapy, an "early time" (4 weeks PI) when fibrosis was still absent and a "late time" (8 weeks PI) when the fibrotic process had started. Infected mice received the treatments via gavage and were sacrificed during or upon termination of treatment; their lungs were then removed and processed for immunological and histopathologic studies in order to assess severity of fibrosis.
Experience with itraconazole in cryptococcosis and aspergillosis
Journal of Infection, 1989
Cryptococcosis and aspergillosis in immunocompromised patients are extremely difficult clinical conditions to manage and treatment with available antifungal drugs often fails. Itraconazole, R-512II, Janssen Pharmaceutica, a new orally absorbed triazole, is a possible alternative drug which is potentially effective and nontoxic. Preliminary experience with 28 patients, eight with cryptococcosis and 20 with aspergillosis, is reported. Of these patients, 16 were immunocompromised (seven with the acquired immune-deficiency syndrome (AID S), five heart transplant recipients and four with leukaemia or lymphoma). Overall, results of treatment were good (I8 in remission, four markedly improved, four moderately improved and two failed). Prevention of relapses of cryptococcosis was obtained in all patients with AIDS on long-term itraconazole monotherapy (3 mg/kg). Treatment of invasive aspergillosis required a higher dosage (about 5 mg/kg) and prolonged administration. Besides its efficacy this antifungal agent allowed outpatient management. orally administered triazole, is active against Aspergillus fumigatus and Cryptococcus neoformans in vitro as well as in experimental infections in
Antimicrobial Agents and Chemotherapy, 2021
Aspergillus galactomannan antigenemia is an accepted tool for the diagnosis of invasive pulmonary aspergillosis (IPA) in neutropenic patients. Little is known, however, about the utility of this biomarker to assess the efficacy of antifungal therapies. The pharmacokinetics (PK) and pharmacodynamics (PD) of posaconazole in treatment and prophylaxis were investigated in the persistently neutropenic rabbit model of Aspergillus fumigatus IPA at doses between 2 and 20 mg/kg per day. Sparse plasma sampling was used to obtain PK data at steady state, and the serum galactomannan index (GMI), as a dynamic endpoint of antifungal response, was obtained every other day, in addition to conventional outcome parameters including survival and fungal tissue burden. Nonparametric PK/PD model building was performed using the Pmetrics package in R. A one-compartment model with linear elimination best described the PK of posaconazole. The PD effect of posaconazole exposure in plasma on the GMI in serum was best described by dynamic Hill functions reflecting growth and killing of the fungus. Through calculations of the area under the concentration-time curve from 0 to 24 h (AUC 0-24) at steady state, the exposure-response relationship between posaconazole and the GMI for treatment followed a sigmoidal function with an asymptote forming above an AUC 0-24 of 30 mg • h/liter. All prophylactic doses were able to control the fungal burden. A nonparametric population PK/PD model adequately described the effect of posaconazole in prophylaxis and treatment of experimental IPA. An AUC 0-24 greater than 30 mg • h/liter was associated with adequate resolution of the GMI, which well supports previously suggested exposure-response relationships in humans.
Antimicrobial agents and chemotherapy, 2018
The antifungal effects of the novel triazole PC1244, designed for topical or inhaled administration, against were tested in a range of and studies. PC1244 demonstrated potent antifungal activities against clinical isolates ( = 96) with a MIC range of 0.016 to 0.25 μg/ml, whereas the MIC range for voriconazole was 0.25 to 0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinant CYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis in with a 50% inhibitory concentration of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC range, <0.0078 to 2 μg/ml), especially , , , , , , , and PC1244 also proved to be quickly absorbed into both hyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (minimum fungicidal concentration, 2 μg/ml) which indicated that it was 8-fold more potent than voriconazole. , once-daily intranasal administration of...
Antimicrobial agents and chemotherapy, 2016
We studied the pharmacokinetics and efficacy of the third-generation broad-spectrum triazole isavuconazole for the treatment of experimental invasive pulmonary aspergillosis (IPA) in persistently neutropenic rabbits. Treatment started 24 h after endotracheal administration of A. fumigatus inoculum, and included rabbits receiving orally administered prodrug isavuconazonium sulfate (BAL8557) equivalent to active moiety isavuconazole (BAL4815, ISA) at 20 (ISA20), 40 (ISA40), and 60 (ISA60) mg/kg/day with an initial loading dose of 90 mg/kg (ISA90), or untreated rabbits (UC). There was a significant concentration-dependent reduction of residual fungal burden (log CFU/g) and of organism-mediated pulmonary injury, lung weights and pulmonary infarct score in ISA40- and ISA60-treated rabbits in comparison to those of UC (p<0.001). ISA20- (p<0.05), SA40-, and ISA60- (p<0.001) treated rabbits demonstrated significantly prolonged survival in comparison to that of UC. ISA40- and ISA60-...
Use of prophylactic antifungals in the immunocompromised host
Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology, 2007
Oral candidiasis is a significant infection in patients being treated with chemotherapy and radiotherapy for cancer, and in patients who are immunocompromised because of HIV infection and AIDS. Candida albicans is the most common fungal pathogen and has developed an extensive array of putative virulent mechanisms that allows successful colonization and infection of the host under suitable predisposing conditions. The purpose of this review of the literature was to assess the effectiveness of interventions for the prevention of oral candidiasis in immunocompromised patients and in patients treated for cancer with radiotherapy and/or chemotherapy. These patient categories were selected because they have been the topic of published randomized controlled clinical trials. The studies reviewed provide strong evidence that oral candidiasis is associated with greater morbidity and mortality in these populations, which substantiates the aggressive treatment and prophylaxis of this infection. The literature supports the recommendation that systemically applied antifungal drugs have the greatest efficacy for the treatment of oral candidiasis in cancer and immunocompromised patients; however, these therapies must be prescribed with a thorough assessment for the risk for developing drug-induced toxicities. Guidelines on the prevention of drug-resistant oral candidiasis in these patients are not available and require elucidation. Further studies are required to expand the knowledge base of evidence-based antifungal therapies in a wider variety of immunocompromised patients and conditions, such as Sjögren's syndrome, diabetes, and denture wearers. Additional exploration is needed to determine which antifungal drug formulation, dose, and method of delivery is preferable for the type of fungal infection and the underlying etiology. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103(suppl 1):S6.e1-S6.e14)
Efficacy of PTX3 and Posaconazole Combination in a Rat Model of Invasive Pulmonary Aspergillosis
Antimicrobial Agents and Chemotherapy, 2014
ABSTRACTPosaconazole is currently used for the prophylaxis of invasive pulmonary aspergillosis (IPA). Limitations to posaconazole usage are drug-drug interactions and side effects. PTX3 is an innate immunity glycoprotein with opsonic activity, proven to be protective in IPA animal models. This study investigated the combination of posaconazole with PTX3. The results indicate synergy between PTX3 and posaconazole against aspergillosis, suggesting that a combination of reduced doses of posaconazole with the immune response enhancer PTX3 might represent a treatment option with a higher therapeutic index than posaconazole.
International journal of immunopharmacology, 1990
Itraconazole and fluconazole are triazole compounds recently licensed for the therapy of systemic fungal infections. At 10 micrograms/ml concentrations, itraconazole was found to suppress neutrophil chemotaxis, random movement, deoxyglucose uptake and hexose-monophosphate shunt activity to the same extent as ketoconazole, an older generation azole antifungal. Itraconazole was also found to suppress mitogen-induced lymphocyte transformation to the same extent as ketoconazole at concentrations as low as 1 microgram/ml. By contrast, significant inhibition of both neutrophil and lymphocyte functions was not observed with fluconazole at concentrations as high as 50 micrograms/ml. These results suggest that fluconazole may be less immunotoxic than itraconazole, and may be more suitable for use in immunocompromised patients.